Antibiotics

TABLE OF CONTENTS Use the page numbers and your mouse to navigate the file!

PREFACE ..................................................................................................................IV ANTIMICROBIAL COST AWARENESS ....................................................................VI

PROCEDURES TO FOLLOW AFTER NOTIFICATION OF A POSITIVE BLOOD CULTURE....................................................................................................................... 1

Interpretation of Laboratory Reports........................................................................ 1 Management Of Patients With Positive Blood Cultures .......................................... 3 Management Of Confirmed S. Aureus Bacteraemia ............................................... 5

EVALUATION AND MANAGEMENT OF THE FEBRILE PATIENT ............................. 7 Procalcitonin Testing ............................................................................................... 7 Septicaemia............................................................................................................. 8 Neutropenic Fever In Adult Patients...................................................................... 11 Neutropenic Fever In Paediatric Patients .............................................................. 13

TREATMENT GUIDELINES FOR COMMON CONDITIONS IN ADULT PATIENTS .. 15 CARDIOVASCULAR SYSTEM INFECTIONS .......................................................... 15

Bacterial Endocarditis............................................................................................ 15 CENTRAL NERVOUS SYSTEM INFECTIONS ...................................................... 19

Community-Acquired Meningitis In Adults............................................................. 19 Herpes Simplex Encephalitis................................................................................. 21

EAR, NOSE AND THROAT INFECTIONS ............................................................... 22 Acute Otitis Media ................................................................................................. 22 Acute Sinusitis ....................................................................................................... 23 Chronic Sinusitis.................................................................................................... 24 Pharyngitis............................................................................................................. 25

RESPIRATORY TRACT INFECTIONS..................................................................... 26 Exacerbations Of COPD And Chronic Bronchitis .................................................. 26 Pneumonia ............................................................................................................ 27 Tuberculosis .......................................................................................................... 30 Influenza................................................................................................................ 31

GASTROINTESTINAL TRACT AND INTRA-ABDOMINAL INFECTIONS............... 32 Dental And Gingival Infections .............................................................................. 32 Acute Peritonitis..................................................................................................... 33 Cholecystitis / Cholangitis...................................................................................... 34 Acute Pancreatitis/Severe Necrotising Pancreatitis .............................................. 35 Infectious Diarrhoea .............................................................................................. 36 Antibiotic-Associated Diarrhoea ............................................................................ 37 Typhoid / Paratyphoid Fever ................................................................................. 38 Helicobacter Pylori Infection .................................................................................. 39

URINARY TRACT INFECTIONS .............................................................................. 40 Uncomplicated Acute Urinary Tract Infections ...................................................... 40 Acute Pyelonephritis Or Complicated UTI ............................................................. 41

GENITAL TRACT INFECTIONS............................................................................... 42 Pelvic Inflammatory Disease ................................................................................. 43 Bacterial Vaginosis ................................................................................................ 44 Candidosis / Vulvo-Vaginitis .................................................................................. 45 Chlamydial Cervicitis / Urethritis............................................................................ 46 Genital Herpes Simplex......................................................................................... 47 Gonorrhoea ........................................................................................................... 48 Non-Gonococcal Urethritis .................................................................................... 49 Trichomoniasis ...................................................................................................... 50 Syphilis .................................................................................................................. 50

SKIN, MUSCLE AND BONE INFECTIONS .............................................................. 51 Osteomyelitis - Acute............................................................................................. 51

ii

Septic Arthritis - Non Prosthetic Joint .................................................................... 52 Septic Arthritis - Prosthetic Joint............................................................................ 52 Bites And Clenched Fist Injuries............................................................................ 53 Cellulitis - Simple ................................................................................................... 54 Cellulitis - Complicating Ulcer................................................................................ 56 Necrotising Fasciitis Or Synergistic Gangrene ...................................................... 57 Mastitis / Breast Abscess ...................................................................................... 58 Wound Infections................................................................................................... 59

EYE INFECTIONS .................................................................................................... 60 Blepharitis.............................................................................................................. 60 Conjunctivitis ......................................................................................................... 61

TRAVELLERS’ INFECTIONS ................................................................................... 62 Malaria................................................................................................................... 62

TREATMENT GUIDELINES FOR COMMON CONDITIONS IN PAEDIATRIC PATIENTS.................................................................................................................... 64

Cellulitis ................................................................................................................. 64 Conjunctivitis Neonatorum..................................................................................... 65 Epiglottitis .............................................................................................................. 65 Meningitis .............................................................................................................. 66 Osteomyelitis - Acute............................................................................................. 68 Otitis Media – Acute .............................................................................................. 69 Periorbital / Orbital Cellulitis .................................................................................. 70 Pharyngitis............................................................................................................. 71 Pneumonia ............................................................................................................ 72 Pyelonephritis ........................................................................................................ 73 Urinary Tract Infections ......................................................................................... 74 Aminoglycoside Dosing In Children....................................................................... 75

GUIDELINES FOR EFFECTIVE USE OF ANTIMICROBIAL DRUGS ........................ 78 INFORMATION ON SELECTED ANTIMICROBIAL DRUGS.................................... 78

Antibacterial Drugs ................................................................................................ 79 Antiviral Drugs ....................................................................................................... 88 Antifungal Agents .................................................................................................. 88

DOSING, PHARMACOKINETICS AND PHARMOCODYNAMICS........................... 91 IMPORTANT PHARMACODYNAMIC PRINCIPLES............................................. 91 AMINOGLYCOSIDES: PRINCIPLES OF USAGE AND DOSING......................... 93 Vancomycin Dosing............................................................................................... 98 Metronidazole Dosing............................................................................................ 99 Beta-Lactam Dosing ............................................................................................ 100

IMPAIRED RENAL FUNCTION .............................................................................. 101 HEPATIC INSUFFICIENCY.................................................................................... 105 OBESE PATIENTS ................................................................................................. 106 PREGNANCY AND LACTATION............................................................................ 107

Drugs In Pregnancy............................................................................................. 107 Drugs In Lactation ............................................................................................... 108

ORAL ANTIMICROBIAL THERAPY ....................................................................... 111 Switch Therapy.................................................................................................... 111 Selecting An Appropriate Oral Antimicrobial Drug............................................... 112

PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS ............................................. 114 SURGICAL PROPHYLAXIS ................................................................................... 114 ENDOCARDITIS PROPHYLAXIS........................................................................... 119

Antibiotic Regimens............................................................................................. 120 SPLENECTOMY..................................................................................................... 121

Prevention of Severe Infections........................................................................... 121 Treatment Of Post-Splenectomy Sepsis ............................................................. 121

APPENDICES ............................................................................................................ 122 Outpatient Intravenous Therapy.............................................................................. 122

iii

Long Term IV Antibiotics ..................................................................................... 122 Short Term IV Therapy ........................................................................................ 122 Chronic/Speciality Patients Requiring IV Therapy............................................... 122 Emergency Department Cellulitis Protocol .......................................................... 122

LOCAL RESISTANCE PATTERNS TO ANTIMICROBIAL DRUGS ....................... 123 Susceptibility of Common Organisms in Blood Culture ....................................... 123

CUMULATIVE SENSITIVITY STATISTICS WAIKATO HOSPITAL 1 JAN - 31 DEC 2006 ........................................................................................................................ 125 ANTIMICROBIAL RESISTANCE IN ORGANISMS OF SPECIAL INTEREST........ 128 MRSA MANAGEMENT........................................................................................... 131 BLOOD AND BODY FLUID EXPOSURES ............................................................. 133 NOTIFIABLE DISEASES IN NEW ZEALAND......................................................... 135

How To Notify A Notifiable Disease..................................................................... 136

iv

PREFACE Role of This Guide This booklet is intended as a guide for the initial treatment of common conditions. Always remember that an alternative therapy is available if needed and is only a phone-call or a good textbook away. In most cases, antimicrobial treatment is initiated before the causative organism is known. A major role of microbiological laboratory testing is to enable the spectrum of the antibiotic used to be narrowed with confidence. Remember that restraint in the use of all antimicrobials is the best way to ensure their continuing efficacy. This document has been developed by Waikato District Health Board (Waikato DHB) specifically for its own use. Use of this document and any reliance on the information contained therein by any third party is at their own risk. Recommendations are based on current (July 2008) international clinical practice and may sometimes differ from product registration information. This handbook has been developed in association with the Waikato Hospital clinical services and is approved for use within Waikato District Health Board. Intranet Version The Antimicrobial Handbook is also available from the Waikato DHB Intranet under Clinical Guidelines. Acknowledgements The following documents have been helpful in the production of this handbook and are gratefully acknowledged: New Zealand Pharmaceutical Schedule, Pharmac, April 2008. Principles and Practice of Infectious Diseases, Mandell, Douglas, Bennett, 6th Edition, 2004. Guide to Pathogens and Antibiotic Treatment 7th Edition, Selwyn Lang, 2004. The Sandford Guide to Antimicrobial Therapy; 37th Edition, 2007. Antibiotic Guidelines, Victorian Medical Postgraduate Foundation Inc, 13th Edition, 2006. Antimicrobial Therapy and Vaccines; Yu, Merigan, Barriere, 1st Edition, 1999. A Practical Approach to Infectious Diseases, Reese & Betts, 4th Edition, 1996.

v

PRINCIPLES OF ANTIMICROBIAL PRESCRIBING The principles of prescribing remain straightforward, but the ever-increasing number of alternatives has made the task complex. The following concepts underpin prescribing: Efficacy: Therapy has to be effective for the suspected condition in the

majority of circumstances. Although efficacy is an over-riding concern, the problem that we encounter is not so much a lack of choice, but too many regimens that are equally effective.

Tolerability: The choice has to have an acceptable side effect profile and

ease of administration. Some of the most difficult antibiotic selection problems arise, not from resistant organisms, but when a patient has contraindications to several classes of drugs. It is important to document the nature of any adverse reaction so that a patient is not inadvertently re-exposed, nor unnecessarily disadvantaged in future by a label of “drug allergy”.

Economically Sound: Given the wide choice and the constraints on health spending,

cost has to be considered if two products are similar. With the movement to generic antibiotics, many antibiotics have become considerably cheaper in recent years. Remember that an effective oral regimen is always superior to an intravenous regimen.

Ecological Impact: An awareness is needed of the impact of antibiotic selection

pressure on the hospital environment and beyond. Ignoring this will lead to ever increasing resistance problems.

The choices that have been made in this handbook reflect these concepts. The aim is to provide effective first-line therapy realising that the majority of our patients will improve without needing second-line therapy. ADMINISTRATIVE ROLE OF THIS GUIDE Pharmacy staff will be taking on the task of encouraging use of these guidelines. The 2000 Infection Control NZ Standard includes a requirement to promote the prudent prescribing of antibiotics. For WDHB to comply with this standard, ongoing auditing of the use of antibiotics will be required. This handbook will form the antibiotic standard that our practice will be audited against. In some cases, the best treatment for an individual patient will differ from these guidelines. The reason(s) for the need to vary should be documented within the clinical record. We trust that you will find these guidelines helpful. Graham Mills Chris Mansell Infectious Diseases Physician Clinical Microbiologist

vi

ANTIMICROBIAL COST AWARENESS Cost awareness is an important factor that needs to be considered in choosing antibiotics. Agents of similar efficacy can vary in cost by greater than a 1000% - yet often because of pharmaceutical company marketing efforts, the more expensive agent is chosen. Remember that a non-marketed antibiotic does not mean an ineffective antibiotic. Often it is simply that the patent has run out! The dosage regimen used for cost comparison is an indication only and should not be used as a dosing guideline for all infections. The stated costs in this table are based on hospital acquisition costs as at January 2006 and should be seen as approximate only. Prices are subject to change over time. Drug Route Av. Adult Dose* Hospital Cost Cost/Unit

($) Cost/Day

($) ANTIBACTERIALS Cephalosporins Cephalexin 500mg PO 250mg q6h 0.54 1.08 Cefaclor 250mg PO 250mg q8h 0.29 0.87 Cephazolin 500mg IV/IM 1g q6h 1.69 13.52 Cefotaxime 1g IV/IM 1g q8h 5.99 17.97 Cefoxitin 1g IV/IM 1g q6h 9.25 37.00 Cefuroxime axetil 500mg PO 500mg q12h 0.71 2.84 Cefuroxime 750mg IV/IM 750mg q8h 3.06 9.18 Ceftriaxone 1g IV/IM 1g q24h 9.00 9.00 Ceftazidime 1g IV/IM 1g q8h 17.10 51.30 Cefepime 1g IV/IM 1g q12h 23.00 46.00

Penicillins Amoxycillin 500mg PO 500mg q8h 0.06 0.18 Amoxycillin 1g IV/IM 1g q8h 2.20 6.60 Amoxycillin/ 500mg clavulanate

PO 500mg q8h 0.32 0.96

Amoxycillin/ 1.2g clavulanate

IV 1.2g q8h 2.39 7.17

Penicillin V 500mg PO 500mg q6h 0.16 0.64 Benzylpenicillin 600mg IV/IM 600mg q6h 0.70 2.80 Flucloxacillin 500mg PO 500mg q6h 0.14 0.56 Flucloxacillin 1g IV 1g q6h 1.51 6.04 Piperacillin/ 4.5g tazobactam

IV/IM 4.5g q8h 37.50 112.50

Ticarcillin/ 3.1g clavulanate

IV/IM 3.1g q6h 18.00 72.00

Carbapenems Meropenem 1g IV/IM 1g q8h 59.50 178.50

* Calculations based on body weight of 70kg

vii

Drug Route Av. Adult Dose* Hospital Cost Cost/Unit

($) Cost/Day

($) ANTIBACTERIALS Aminoglycosides Gentamicin 80mg IV/IM 400mg q24h 0.46 2.30 Tobramycin 80mg IV/IM 400mg q24h 4.95 19.80 Amikacin 500mg IV/IM 1g q24h 15.00 30.00

Glycopeptides Vancomycin 500mg IV 1g q12h 6.40 25.60 Teicoplanin 400mg IV/IM 400mg q24h 107.99 107.99

Macrolides Erythromycin 400mg ethylsuccinate

PO 400mg q6h 0.15 0.60

Erythromycin 1g lactobionate

IV 1g q6h 6.50 26.00

Roxithromycin 300mg PO 300mg q24h 0.60 0.60 Clarithromycin 250mg PO 500mg q12h 0.77 3.08 Azithromycin 500mg PO 1g stat 7.77 15.54

Fluoroquinolones Norfloxacin 400mg PO 400mg q12h 0.92 1.84 Ciprofloxacin 500mg PO 500mg q12h 0.30 0.60 Ciprofloxacin 200mg IV 200mg q12h 9.75 19.50 Gatifloxacin 400mg PO 400mg q24h 2.52 2.52 Moxifloxacin 400mg PO 400mg q24h 13.00 13.00

Nitroimidazoles Metronidazole 500mg IV 500mg q12h 3.99 7.98 Metronidazole 500mg PR 500mg q12h 2.23 4.46 Metronidazole 400mg PO 400mg q12h 0.18 0.36

Tetracyclines Doxycycline 100mg PO 100mg q24h 0.03 0.03

Miscellaneous Clindamycin 150mg PO 300mg q6h 0.71 5.68 Clindamycin 600mg IV/IM 600mg q8h 19.45 58.35 Cotrimoxazole 480mg PO 960mg q12h 0.03 0.12 Cotrimoxazole 480mg IV 960mg q12h 6.70 26.80 Fusidic acid 250mg PO 500mg q8h 2.88 17.28 Fusidic acid 500mg IV 500mg q8h 16.95 50.85 Linezolid 600mg PO 600mg q24h 110.00 110.00 Nitrofurantoin 50mg PO 50mg q8h 0.17 0.51 Trimethoprim 300mg PO 300mg q24h 0.16 0.16


viii

Drug Route Av. Adult Dose* Hospital Cost Cost/Unit

($) Cost/Day

($) ANTIBACTERIALS Antituberculins Isoniazid 100mg PO 300mg q24h 0.21 0.63 Pyrazinamide 500mg PO 2000mg q24h 0.59 2.36 Rifampicin 600mg PO 600mg q24h 3.81 3.81

ANTIFUNGALS Amphotericin 50mg IV 50mg q24h 27.41 27.41 Amphotericin 50mg liposomal

IV 200mg q24h 345.00 1380.00

Caspofungin 50mg IV 50mg q24h 577.27 577.27 Fluconazole 200mg PO 200mg q24h 22.41 22.41 Fluconazole 100mg IV 200mg q24h 31.37 62.74 Itraconazole 100mg PO 100mg q24h 2.47 2.47 Ketoconazole 200mg PO 200mg q24h 1.21 1.21 Terbinafine 250mg PO 250mg q24h 1.79 1.79 Voriconazole 200mg PO 200mg q12h 51.78 103.56 Voriconazole 200mg IV 200mg q12h 207.00 414.00

ANTIVIRALS Acyclovir 200mg PO 200mg 5 times

daily 0.10 0.50

Acyclovir 400mg PO 400mg 5 times daily

0.15 0.75

Acyclovir 800mg PO 800mg 5 times daily

0.27 1.35

Acyclovir 250mg IV Indication dependent

5.74

Valganciclovir 450mg PO Indication dependent

50.00

Ganciclovir 500mg IV Indication dependent

76.00

Foscarnet 6000mg IV Indication dependent

105.00


1

PROCEDURES TO FOLLOW AFTER NOTIFICATION OF A POSITIVE BLOOD

CULTURE

Interpretation of Laboratory Reports

Positive blood cultures are phoned through when the organism has grown in the blood culture bottle and has been gram-stained. The following table gives some guidance to interpreting the gram-stain description of the organism. Initially this is all the information that will be available, as the organism then needs to grow on agar plates overnight before it can be identified further. Antimicrobial susceptibility and identification to species level take a further 12-48 hrs. A rapid coagulase test will often give an indication that a gram-positive coccus is Staph. aureus 2- 4 hrs after the initial gram stain result is available. All positive blood culture results should be followed up urgently. If a doctor receives a report for a patient that is not directly under his/her care, it is the responsibility of the doctor to check that suitable treatment is under way.

2

Interpretation of Blood Culture Gram Stain Reports

Description of Gram Stain

Most Serious Possible Cause of Infection

Most Likely Cause of Infection

Other Possible Causes of Infection

GRAM-POSITIVE COCCI

- Clusters Staph. aureus Coagulase-negative Staph (usually contaminant)

Micrococcus Aerococcus Anaerobic gram- positive Coccus

- Pairs (diplococci)

Strep. pneumoniae Strep. pneumoniae

- Chains Group A Strep Group B Strep

Viridans strep group Group C or G Strep Strep milleri or Strep anginosus Anaerobic gram-positive coccus

GRAM-POSITIVE BACILLI

Listeria monocytogenes Bacillus anthracis

Diphtheroids (Corynebacteria or Propionibacterium acnes - both are usually contaminants).

Erysipelothrix Bacillus sp (Aerobic spore-forming gram- positive bacillus) Clostridium (Anaerobic spore-forming gram-positive bacillus)

GRAM-NEGATIVE COCCI

Neisseria meningitidis


Commensal Neisseria Strep pneumoniae Anaerobic gram-negative cocci Gram-negative coccobacilli e.g. Kingella, Acinetobacter sp

- Pairs (diplococci)



Neisseria gonorrhoeae

GRAM-NEGATIVE BACILLI

E. coli-like organisms (Coliform) e.g. Klebsiella, Enterobacter, Proteus,

Serratia, Yersinia

Coliform e.g. E. coli Klebsiella, Enterobacter, Proteus, Serratia, Yersinia

Pseudomonas-like organisms Stenotrophomonas maltophilia Anaerobic gram- negative bacilli e.g. Bacteroides sp Aeromonas Haemophilus

- Curved Campylobacter fetus

Campylobacter jejuni

YEAST Candida albicans Candida albicans Other Candida sp e.g. C. krusei, C. glabrata

3

Management Of Patients With Positive Blood Cultures

1. Possible Staph Aureus Infection (Staph with suggestive clinical context) • Visit within 2 hr unless diagnosis has been made and antibiotic already given. • Repeat blood cultures (all lumens of IV lines plus peripheral). • Sample obvious sites of infection. • Check notes for MRSA alert and susceptibility of previous isolates. • Antibiotic of choice is IV flucloxacillin 1-2g every 6 hours. • Discuss with any other medical teams involved and notify patient’s own team

next day. • Staph aureus infection can lead to significant complications from inadequate

therapy. For this reason, Waikato Hospital has specific guidelines on how to manage this condition (see below).

2. Possible Meningococcus Infection (Any Gram-Negative Cocci)

• Urgently phone ward to check whether IV ceftriaxone 1g every 12 hours or any other antibiotic is being given.

• If diagnosis has not already been made, then visit patient urgently (<1hr).

3. Possible Gram-Negative Sepsis (Any Gram-Negative Bacilli)

• Urgently phone ward to check whether any IV antibiotic is being given. • If patient is stable and has already been treated, visit within 4 hr to document in

notes. • Briefly check the patient. • Check that specimens have been sent: urine for culture + dipstick, swab any

wounds, sputum if available, diarrhoea if present, ideally more than one set of blood cultures before antibiotics, gentamicin levels.

• Notify patients’ own team first thing next working day. • If diagnosis has not already been made or if antibiotics have not yet been

given, visit urgently (<1hr). • Assess urinary tract, genital tract, abdomen, respiratory tract, recent surgical

sites, recent antibiotic history and gentamicin level results if available. • If UTI give gentamicin 5mg/kg IV once daily. • If abdominal infection, give gentamicin 5mg/kg IV daily + amoxycillin 1g IV

every 6 hours + metronidazole 500 mg IV every 12 hours. • If PID, take cervical bacterial and chlamydial swabs and urine for chlamydia,

give Augmentin and doxycycline and refer to O&G.

4

4. Possible Pneumococcus Infection (Gram-Positive Diplococci)

• Urgently phone ward to check whether any antibiotic is being given. • If diagnosis has not already been made or if antibiotics have not yet been

given, visit urgently (<1hr). • Check that the following tests have been done and whether any results are

available: • ABG, FBC, CXR, sputum, ± repeat blood cultures, check ears and sinuses,

possibility of meningitis. • If patient is stable and has already been started on treatment, visit within 4

hours to record details of test results in notes. Briefly check patient. Appropriate antibiotics include any penicillin or cephalosporin. Ciprofloxacin or macrolides such as erythromycin alone are not adequate.

• Consult General Medical or Respiratory team if patient is under the care of another team.

5. Suspected Endocarditis Or Subacute PUO Associated With Any Murmur Or Embolic Symptom (Streptococci or Staph. aureus, for patient with any abnormal valve). • Visit patient within 4 hours. • Check the following tests have been done: • 3 sets of blood cultures, preferably from different sites. • Perform a clinical review for changing murmur, decompensated heart failure,

sepsis syndrome and emboli, particularly cerebral. • Discuss with General Medicine of Cardiology before giving further antibiotics or

arranging TTE or TOE.

6. Apparent Contaminant (Coagulase Negative Staph or Gram-Positive Bacilli from patient who is well) • Check history to rule out possible Staph. aureus disease or Listeria. • Arrange repeat blood cultures to confirm.

5

Management of Confirmed S. Aureus Bacteraemia

BACKGROUND Staphylococcus aureus bacteraemia (SAB) is a common problem in Health Waikato patients with about a hundred positive cultures every year. Local experience has suggested there have been issues in management of SAB over the years. A small audit identified several problems in the management of SAB with a poor appreciation of the significance of SAB, under investigation, particularly in the use of echocardiography and repeated cultures, and inadequate IV antibiotic treatment.

Approach to Management There are no local or national guidelines but there are U.S. guidelines from the Duke Medical Centre and published Australian experience of using these U.S. guidelines. There has been agreement within the Medical Unit on local guidelines for: • Categorisation into treatment groups. • Use of repeated blood cultures. • Use of echocardiography: TTE and TOE. • Antibiotic treatment and duration. • A system of notification for positive SAB cultures.

Investigation • Investigation needs to be individualised. • Cultures are to be repeated after 2-4 days treatment. • Trans-thoracic echocardiogram (TTE) to be performed if:

- Unresponsive fever. - No apparent focus of infection. - IV device and abnormal heart examination.

• Trans-oesophageal echocardiogram (TOE) to be performed if: - High index suspicion of endocarditis. - Abnormal TTE with findings such that endocarditis cannot be excluded. - Continuing lack of response with a normal TTE.

Categorisation Cases are categorised into 4 groups based on: • Clinical features. • Response after 72 hours treatment. • Results of repeated cultures at 2-4 days. • Echocardiographic findings. • The presence of a removable focus or prosthesis.

6

(1) Uncomplicated IV cannulae associated bacteraemia All of the following:

- Removable IV cannulae associated focus of infection. - Clinical resolution within 72 hours. - Negative follow up blood cultures after 2-4 days treatment. - Normal cardiovascular examination or no significant findings on echocardiogram. - No indwelling prosthetic devices.

Treatment duration: 1 week for uncomplicated IV cannulae associated bacteraemia. Always remove the IV cannulae insitu and replace with a new one when Staph aureus has been identified in blood cultures.

(2) Bacteraemia with risk factors for complications (but without any evidence of endocarditis or deep tissue infection) One or more of: - A superficial non-removable focus of infection. - A removable IV cannula associated focus of infection with persistent signs of

infection after 72 hours or positive blood cultures after 2-4 days of antibiotic treatment.

- Valve abnormalities but no vegetations on echocardiography. - An indwelling prosthetic device.

If one or more of these condition apply, associated infection must be excluded. If there is no apparent focus of infection, the patient should have an echocardiography and a bone scan to exclude endocarditis and osteomyelitis. Treatment duration: If associated infections have been excluded 2 weeks of IV therapy for complicated bacteraemia is acceptable.

(3) Endocarditis Diagnosis to be based on the Duke criteria. Treatment should be 4-8 weeks for

endocarditis. Mono-therapy with Flucloxacillin IV is usually acceptable if MRSA has been excluded.

(4) Deep tissue infection Deep tissue infection without endocarditis. Treatment duration is 4-8 weeks for deep tissue infections.

Treatment • Rembember that treatment always needs to be individualised. • Single agent therapy with Flucloxacillin is acceptable if a sensitive organism

(MSSA) is identified. MRSA infection requires specialist input

Microbiology Input The requesting doctor will be notified as soon as the blood culture becomes positive and the patient’s consultant is to be notified after confirmation of SAB with a standard letter.

7

EVALUATION AND MANAGEMENT OF THE FEBRILE PATIENT

Procalcitonin Testing Procalcitonin (PCT) testing was introduced into the WDHB in 2003 for those adults (<40 yrs) and paediatric patients with undiffentiated fever to help assess the likelihood of bacterial sepsis. With the decline in meningococcal disease cases as a result of the Menz B vaccination programme, changes are currently being considered (August 2008) regarding the merits of continuing with our previous protocol. Procalcitonin testing is relatively expensive (>$20 per test) and is not automated within the laboratory The current protocol states that those under the age of 40 years should be screened for a fever on presentation and procalcitonin (PCT) requested if a specific focus of infection can not be found. If the procalcitonin result is positive in a person with a non-specific febrile presentation (≥0.5 ng/ml in adults and ≥2.0 ng/ml in children) we strongly recommended that a dose of intravenous ceftriaxone be given before being discharged home or admitted. If the procalcitonin result is negative, then many of these individuals would be considered suitable for discharge without the need for antibiotics. Those with a negative PCT test fall into three distinct groupings:

i. Patients presenting very early after the onset of symptoms (i.e. within the first six hours);

ii. Meningitis without systemic infection (easily diagnosed by a lumbar puncture); and

iii. Bacteraemia at very low levels that either self clears or is relatively benign as the bacteria do not exponentially proliferate.

Meningococcal disease at an early stage can look like a viral illness which is why this protocol was initially introduced.

8

Septicaemia

Principles of Therapy Therapy must be initiated urgently as soon as blood and site cultures are taken and before septic shock and/or toxic effects become irreversible. Initial therapy should be based on the predicted source of infection and the usual susceptibility of the common pathogens until results of microbiological specimens are known. Procalcitonin testing has been introduced into Waikato Hospital to assist in the evaluation of possible sepsis.

No Obvious Source Of Infection In Normal Host

Pathogens: Gram-negative organisms, including meningococcus, Staphyloccus aureus. DRUG DOSE Empiric Ceftriaxone 100mg / kg iv up to 2g 24 hourly ± Flucloxacillin1 2g iv 6 hourly 1If Staph infection likely. Meningococcus has to be covered in the setting of septicaemia without obvious cause for those under the age of 40 years. Treatment Duration: Dependent on specific aetiology

Urinary Tract – Presumed Origin

Pathogens: Enterobacteriaceae, Enterococcus, Staphylococcus aureus, Pseudomonas aeruginosa. DRUG DOSE Empiric Gentamicin 5mg / kg iv1 and Amoxycillin 1g iv 6 hourly 1Adjust gentamicin dosing interval for renal function.

9

Skin Cellulitis – Presumed Origin

Pathogens: Staphylococcus aureus, Group A Streptococci. DRUG DOSE Flucloxacillin 1,2 1g iv 4 hourly 1 There is no need to combine flucloxacillin and benzylpenicillin in this setting, as

flucloxacillin has excellent activity against Group A Streptococci. 2 For patients hypersensitive to penicillin, use cephazolin 1g 8 hourly, or clindamycin

600mg 8 hourly.

Biliary/Gastrointestinal Tract– Presumed Origin

Pathogens: Enterobacteriaceae, Anaerobes, Enterococcus. DRUG DOSE Gentamicin1, 5mg / kg iv2 and Amoxycillin1 1g iv 6 hourly and Metronidazole 500mg iv 12 hourly 1 If patient has significant renal impairment, i.e. creatinine clearance <0.33ml/sec, or

mild penicillin allergy, use ceftriaxone 1g iv 24 hourly (instead of gentamicin and amoxycillin) together with metronidazole 500mg iv inf 12 hourly.

2 Adjust gentamicin dosing interval for renal function.

Female Genital Tract– Presumed Origin

Pathogens: Enterobacteriaceae, Anaerobes, Streptococci. DRUG DOSE Gentamicin1 5mg / kg iv2 and Amoxycillin3 1g iv 6 hourly and Metronidazole 500mg iv inf 12 hourly 1 If gentamicin is contraindicated, use ceftriaxone 1 g iv 24 hourly and metronidazole

500mg iv inf 12 hourly. 2 Adjust gentamicin dosing interval for renal function. 3 If patient has mild penicillin allergy, substitute amoxycillin with cephazolin 1g iv 8

hourly.

10

Decubitus Or Ischaemic Ulcers, Diabetic Foot Infections – Presumed Origin

Pathogens: Staphylococcus aureus, Enterobacteriaceae, Anaerobes. DRUG DOSE Gentamicin1 5mg / kg iv2 and Flucloxacillin1 1g iv 4 hourly and Metronidazole 500mg iv inf 12 hourly 1 If patient has significant renal impairment or mild penicillin allergy, use ceftriaxone 1g

iv 24 hourly (instead of gentamicin and flucloxacillin) together with metronidazole 500mg iv 12 hourly.

2 Adjust gentamicin dosing interval for renal function.

Intravascular Cannulae, Including Central Lines – Presumed Origin Pathogens: Coagulase-negative staphylococci, Staphylococcus aureus, Gram-negative rods, Candida sp. DRUG DOSE Flucloxacillin 2g iv 6 hourly and Gentamicin 5mg / kg iv1 1 Adjust gentamicin dosing interval for renal function. Note: Once the infected catheter is removed, sepsis may readily resolve if caused by organisms of relatively low virulence and may not always require antimicrobial therapy, e.g. coagulase-negative Staphylococci. Patients with bacteraemia or fungaemia caused by more virulent organisms, e.g. Staphylococcus aureus or Candida sp. must be subjected to more prolonged therapy because of the possibility of subsequent development of deep-seated infections, such as endocarditis, osteomyelitis and endophthalmitis (see specific Staphylococcus aureus guidelines).

11

Neutropenic Fever in Adult Patients

Definition Neutropenic fever is a body temperature ≥38.3oC or ≥38.0oC on two occasions over at least one hour in a patient who is severely neutropenic (i.e. neutrophil count < 0.5 x 109 /L).

Principles Of Therapy • All patients who become febrile whilst severely neutropenic must be assessed by

medical staff within 20 minutes of the fever (as defined above) developing. • Treatment is empiric. • Antibiotic therapy is commenced without an isolated organism or even possible site

of infection. • Antibiotic choice must be broad spectrum, particularly covering gram-negative

organisms, which carry a high morbidity and mortality. • Currently, all antibiotics are given intravenously with a high degree of urgency. The

first dose of intravenous antibiotics should be given within 30 minutes. • Patients on Ward 25 at Waikato Hospital will be routinely reviewed by their

consultant each day. • For patients in other locations (especially at T Hospitals), the relevant

haematologist or oncologist should be contacted within 24 hours of admission or commencing treatment for neutropenic fever to discuss ongoing management. After hours, or at weekends, this should be discussed with the on-call consultant.

First Line Therapy

Summary Providing there is no known allergy, severe renal impairment (estimated creatinine clearance less than 0.3ml/sec) or previous use of cisplatin, the recommended combination treatment is tobramycin and piperacillin/tazobactam (Tazocin). Alternative regimens, as described below, must be used for patients in whom the usual first line therapy is likely to cause severe toxicity. If there is any uncertainty, the haematologist or oncologist on- call should be contacted for discussion.

1. Usual First Line Therapy (Tazocin® and Tobramycin)

TazocinR (Piperacillin + Tazobactam) The conventional starting dose in adults is 4.5g 8 hourly IV. Adjustments of

dosage are made for severe renal impairment i.e. if creatinine clearance less than 0.3ml/sec, use 4.5g 12 hourly.

12

Tobramycin In adults this should be commenced with a single dose of 5 mg/kg IV, regardless of gender or age. Doses should be calculated using ideal body weight (IBW), or actual weight, if this is less than IBW. If actual weight is >20% above IBW, dosing should be based on the Obese Dosing Weight (ODW). The dosing interval should be in accordance with estimated creatinine clearance as per the modified Cockcroft and Gault formula, based on an extended interval regimen (see section on aminoglycoside dosing). Beware of continuing aminoglycosides for prolonged periods of time given the complication of renal toxicity and ototoxicity which are more likely to occur with treatment durations of more than seven days.

2. Patients with Penicillin Allergy but without Anaphylaxis (Cefepime and Tobramycin)

Cefepime is a fourth generation cephalosporin with slightly broader spectrum activity than ceftazidime. The usual dose is 2 g 12 hourly IV. Cross allergy with penicillins is estimated to be less than five percent. Usually, the benefits of highly potent gram-positive cover will outweigh the possible risk of allergic reactions.

Tobramycin should be commenced with a single dose of 5 mg/kg IV, regardless of gender or age. Doses should be calculated using ideal body weight (IBW), or actual weight, if this is less than IBW. If actual weight is >20% above IBW, dosing should be based on the Obese Dosing Weight (ODW). The dosing interval should be in accordance with estimated creatinine clearance as per the Cockcroft formula, based on an extended interval regimen (see guidelines on Aminoglycoside dosing).

3. Patients Receiving Nephrotoxic Drugs or Previously Treated with Cisplatin

Monotherapy with IV cefepime 2g 12 hourly is recommended.

4. Patients with Severe Renal Impairment (Calculated creatinine clearance <0.3ml/sec)

Monotherapy with IV cefepime 1g 12 hourly is recommended for treatment of patients with severe renal failure. Aminoglycosides and intravenous vancomycin are not usually recommended for treatment of patients with severe renal failure. However, they may be used in life-threatening situations after consultation with the specialist on call.

Subsequent Changes in Antimicrobial Therapy Changes from first line therapy will be made by the Haematology or Oncology team, with the guidance of a departmental protocol. Antibacterial spectrum may be widened, antifungal or antiviral therapy may be added or treatment may be narrowed or discontinued in light of laboratory results or changes in the patient’s clinical condition. If a change in antimicrobial therapy appears indicated out of hours, please discuss with the haematologist or oncologist on call.

13

Neutropenic Fever in Paediatric Patients Protocol adapted from Auckland Starship Hospital Protocol for Treatment of Febrile Neutropenia in Children for use at Waikato Hospital (May 2005).

Definitions • Fever: Temperature > 38.0°C on two consecutive occasions within 2 hours, or

>38.5°C on one occasion. • Neutropenia: A neutrophil count of <0.5 x 109/L

Evaluation Of Patient • Examine patient. • Obtain CBC. • Culture blood from all lumens for bacteria and fungi and indicate which culture bottle

contains blood from which lumen. • Peripheral culture should be taken if possible. • Culture other sites as clinically indicated. • Order CXR/urine specimens, as clinically indicated.

Risk Groups RISK FACTORS LOW RISK HIGH RISK Absolute neutrophil count 0.1 – 0.5 x 109/L <0.1 x 109/L Duration of neutropenia <7 days >7-10 days Comorbidity Nil Toxic/clinical focus/

High-dose Ara-C

Treatment

i) Low Risk • First line therapy is cefepime 50 mg/kg/dose 8-12 hourly (max 4g/day) • Evaluate after 48 hours.

- If afebrile with negative cultures and still neutropenic, discharge home on once daily IV ceftriaxone 80 mg/kg/day (max 2g/day). This can be given by District Nurse until neutrophil and platelet counts start to increase or until absolute neutrophil count >0.5 x 109/L.

- If still febrile with negative cultures, reassess and re-culture. Add tobramycin 5mg/kg/dose 24 hourly.

Note: Tobramycin/Ceftriaxone is inadequate for Pseudomonas. • If still febrile at 96 hours, consider consulting ID team (Auckland Starship Hospital)

for reassessment and individualised therapy.

14

ii) High Risk • First line therapy is tobramycin 5mg/kg/dose 24 hourly and Timentin

(ticarcillin/clavulanate) 75mg/kg/dose (ticarcillin) 6 hourly (max 12g/day). • Evaluate after 48 hours.

- If afebrile with negative culture and still neutropenic, consider discharge home to return to ward or outreach for once daily iv ceftriaxone 80mg/kg/day (max 2g/day) and tobramycin (5 mg/kg/dose).

- District nurse not to give. - Such patients will need a daily medical review, temperature and CBC. - Antibiotics should continue until absolute neutrophil count >0.5 x 109/L. - If still febrile with negative cultures, reassess and reculture. - Add IV vancomycin 20-30 mg/kg/dose 8 or 12 hourly (max 2g/day).

• If still febrile at 96 hours, consult ID team (Auckland Starship Hospital) for reassessment. - Consider meropenem (20-40 mg/kg/dose) 8 hourly (max 3g/day).

• If still febrile at 5-7 days, consider amphotericin 0.5mg/kg/day, increasing to 1.5mg/kg/day, or fluconazole, if there is renal impairment.

Monitoring Levels • Vancomycin Troughs only prior to the 4th dose. • Tobramycin (8 hourly dosing) Peak after 3rd dose and trough prior to

the 4th dose. • Tobramycin (daily dosing) Trough prior to 2nd dose – refer to

Aminoglycoside nomogram

15

TREATMENT GUIDELINES FOR COMMON

CONDITIONS IN ADULT PATIENTS

CARDIOVASCULAR SYSTEM INFECTIONS

Bacterial Endocarditis Blood cultures (3 venepunctures) must be taken before antibiotics are given. Take 6 sets if antibiotics have been given within the last 2 weeks. Patients with suspected endocarditis do not have an urgency to commence antibiotics unless evidence of complications or extremely unwell. An etiological agent should always be established first, if possible. A delay of 24 hours is unlikely to cause harm in most patients. (See also section on prophylactic use of antimicrobials for prevention of endocarditis).

Pathogens: (a) Native Valves Common: Viridans Streptococcus, Staphylococcus aureus, Enterococci. Other: Gram-negative bacilli, Haemophilus, Actinobacillus, Cardiobacterium,

Eikenella, and Kingella. (b) Prosthetic Valves As above, plus coagulase-negative Staphylococci. Drug Treatment:

DRUG DOSE Empiric1 (a) Native Valve

Benzylpenicillin 1.8g iv 4 hourly and Gentamicin

5 mg /kg iv 2.3

and Flucloxacillin

2g iv 4 hourly

16

(b) Prosthetic Valve Vancomycin 30mg/kg/day (Up to 1g iv inf 12 hourly) and Gentamicin 5 mg /kg iv 2.3

1 Consult Cardiology Specialist, Infectious Disease or Microbiology regarding treatment. Once the organism in known, move to specific therapy recommendation.

2 Extended interval dosing of aminoglycosides is usually recommended in endocarditis. The exceptions are proven enterococcal infection.

3 Adjust dosing interval according to renal function. Patients should be clinically monitored for vestibular and auditory ototoxicity particularly when aminoglycoside usage extends beyond 14 days. Vestibular toxicity may be irreversible; it can occur even when drug levels are within the normal therapeutic range. Pateints should be informed and regularly asked about ataxia, dysequibibrium and loss of balance or loss of visual acuity during head movement.

4 Staphylococcus aureus is likely if aggressive disease or patient is a drug addict. 5 Modify regimens as soon as the organism and its susceptibility pattern are known. Treatment Duration: Native Valve: 4 – 6 weeks Short course , i.e. 2 weeks appropriate in some cases Prosthetic Valve: 4 - 6 weeks Note: Prophylactic treatment is recommended for patients with pre-existing valvular abnormalities when procedures may cause bacteraemia (See section on Surgical Prophylaxis).

Specific Therapy of Viridans Streptococci Viridans Streptococci remain the most common cause of endocarditis. The following table (adapted from Elliot et al) is the most up to date and comprehensive guide. Notation: PxGy denotes x weeks of penicillin IV 1.2 - 2.4g q4h or by continuous infusion and y weeks of gentamicin 5mg/kg daily, each adjusted for renal function. Ceftriaxone may be substituted for penicillin for convience reasons and if patients are hypersensitive to penicillin but without a previous anaphylactic reaction to penicillin. V4-6 denotes 4-6 weeks of vancomycin 1g IV q12h. Pen MIC (μg/mL)

Native Valve Endocarditis Prosthetic Valve Endocarditis

≤ 0.12 P2G2 or P4

P6G2

>0.12 - ≤ 0.5 P4G2 or P4 if aminoglycosides are contraindicated.

P6G4

>0.5 - < 16 P4-6, G4-6 P6G6 Monitor blood culture and inflammatory markers during treatment.

≥16 V4-6, G4-6

Reference: Elliot, T.S.J. et al. Guidelines for the antibiotic treatment of endocarditis in

17

adults: report of the working party of the British Society for Antimicrobial Chemotherapy JAC 2004, 54:971-981. Contact the Clinical Microbiologist or Infectious Diseases Physician for specific advice.

Infective Endocarditis Modified Duke Criteria (Clinical Infectious Diseases 30: 633-8, 2000) The following criteria should help in the decision making around Infective Endocarditis. The Duke criteria are meant to be only a clinical guide for diagnosing IE and, certainly, must not replace clinical judgement.

Major Criteria

1. Blood culture positive for infective endocarditis • Typical micro-organisms consistent with IE from 2 separate blood cultures:

Viridans streptococci, Strep bovis, HACEK group, Staph aureus or community-acquired enterococci in the absence of a primary focus; or

• Micro-organisms consistent with IE from persistently positive blood cultures, defined as follows: - At least 2 positive cultures of blood samples drawn >12 h apart; or - All of 3 or - A majority of ≥4 separate cultures of blood (with first and last sample drawn

at least 1 hour apart). • or Single positive blood culture for Coxiella burnetti.

2. Evidence of endocardial involvement

3. Echocardiogram positive for IE • TOE recommended in patients with:

- prosthetic valves, rated at least “possible IE” by clinical criteria, or - complicated IE (paravalvular abscess);

• TTE as first test in other patients, defined as follows:

- Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or

- Abscess; or - New partial dehiscence of prosthetic valve.

4. New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient)

Minor Criteria

1. Predisposition • Predisposing heart condition or intravenous drug use.

2. Fever • Temperature >38oC

18

3. Vascular phenomena • Major arterial emboli • Septic pulmonary infarcts • Mycotic aneurysm • Intracranial haemorrhage • Conjunctival haemorrhages • Janeway's lesions.

4. Immunologic phenomena • Glomerulonephritis • Osler’s nodes • Roth’s spots • Rheumatoid Factor

5. Microbiological evidence • Positive blood culture but does not meet a major criterion as noted above, or • Serological evidence of active infection with organism consistent with IE.

Diagnoses Of Infective Endocarditis

1. Definite Infective Endocarditis

Pathologic criteria • Micro-organisms demonstrated by culture or histologic examination of a

vegetation, or a vegetation that has embolized or an intracardiac abscess specimen; or

• Pathologic lesions, vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis.

Clinical criteria • 2 major criteria; or • 1 major criterion and 3 minor criteria; or • 5 minor criteria

2. Possible Infective Endocarditis • 1 major criterion and 1 minor criterion; or • 3 minor criteria.

3. Rejected Diagnosis • Firm alternate diagnosis explaining evidence of infective endocarditis syndrome

or • Resolution of infective endocarditis syndrome with antibiotic therapy for ≤4

days; or • No pathologic evidence of infective endocarditis at surgery or autopsy, with

antibiotic therapy for ≤4 days; or • Does not meet criteria for possible infective endocarditis, as above.

19

CENTRAL NERVOUS SYSTEM INFECTIONS

Community-Acquired Meningitis in Adults • Physical findings exclude diagnosis in low risk adults. • Please remember that meningococcal septicaemia can occur in the absence of

meningeal features. • Meningitis is unlikely if there is no fever, neck stiffness or altered mental status. • LP first line investigation. • CT prior to LP if:

- Impaired level of consciousness or lateralising neurological signs - Features of raised intracranial pressure - Seizures - Very ill - Sinus or ear infections.

• If LP cannot be performed immediately, start antibiotics. Pathogens: Common: Viruses, Streptococcus pneumoniae, Neisseria meningitidis. Other: Haemophilus influenzae, Staphylococcus aureus, Listeria monocytogenes. Drug Treatment: DRUG DOSE Empiric 1 Ceftriaxone

2g iv 12 hourly for first 24 hours, then reduce to 1g iv 12 hourly (unless penicillin resistance identified)

± Amoxycillin 2 2g iv 4 hourly Pathogens Known Streptococcus pneumoniae5 Ceftriaxone 1g q12h iv for 7-10 days or Benzylpenicillin 40mg/kg/dose iv 4 hourly (up to 12g daily) Neisseria meningitidis Ceftriaxone 1g q12h iv for 3 days For clearance of nasopharyngeal Neisseria meningitidis 3 Rifampicin 600mg po 12 hourly for 2 days or Ceftriaxone 250mg im single dose Listeria monocytogenes Amoxycillin and 2g iv 4 hourly Gentamicin 5 mg / kg iv 4

20

1 Hospital acquired meningitis is commonly due to Escherichia coli or Staphylococcus aureus. An Infectious Disease consultation is recommended.

2 Add amoxycillin if at risk for infection with Listeria, which occurs mainly in pregnancy, immunosuppression, cirrhosis and those older than 60. Third generation cephalosporins are inactive in meningitis caused by L. monocytogenes and the addition of amoxycillin is required for empiric therapy.

3 Rifampicin is not required for nasal clearance if the patient has already received ceftriaxone.

4 Adjust gentamicin dosing interval according to renal function 5 Due to increasing resistance, Health Waikato policy determines that a positive CSF

gram-stain suggestive of Streptococcus pneumoniae now requires treatment with both ceftriaxone and vancomycin, until sensitivity results become available. Use both agents until sensitivity results, available then reduce to benzylpenicillin or ceftriaxone alone.

6 Recent evidence suggests that early treatment with dexamethasone (starting before or with the first dose of antibiotic) may improve outcomes in some adults and children with acute bacterial meningitis. Recommendations on the initiation of steroids have yet to be developed within Waikato DHB (Aug 2008). Uncertainty still exists as to the role of dexamethasone in meningococcal meningitis.

Treatment Duration: Meningococcal disease Minimum of 3 days.Streptococcus pneumoniae 10 days. Staphylococcus or Listeria 14 days.

Prophylaxis for Hospital Staff It would be extremely unlikely that hospital staff will require prophylaxis as contacts of meningococcal disease. The “Red Book” states that “Prophylaxis is not recommended routinely for medical personal except those who have had intimate exposure such as occurs with unprotected mouth to mouth resuscitation, intubation or suctioning before antibiotic therapy was begun”.

21

Herpes Simplex Encephalitis • Consider if altered consciousness, seizures, or focal neurology. • Fever and personality changes are uniformly present in Herpes simplex

encephalitis. • LP usually abnormal with the presence of mononuclear cells. • EEG may be characteristic. • PCR testing is very sensitive and specific but should not be ordered prior to

knowledge of LP findings. Pathogen: Herpes simplex. Drug Treatment: DRUG DOSE Empiric Aciclovir

10 mg/kg iv 8 hourly

Treatment Duration: 10 –21 days Notes: • Most patients with biopsy-proven HSV encephalitis present with a focal

encephalopathic process characterised by altered mentation and decreasing levels of consciousness with focal neurologic findings, including dysphasia, weakness and paresthesias. Fever and personality changes are uniformly present.

• Approximately two-thirds of patients with biopsy-proven disease develop either focal or generalised seizures.

• Herpes simplex PCR on CSF is a very sensitive and specific diagnostic test. It will usually only be performed with the presence of mononuclear cells in CSF.

• Intravenous aciclovir is very expensive. It is therefore important to make all efforts to confirm the diagnosis.

• All suspected cases of Herpes simplex encephalitis should be reviewed by the Infectious Diseases Physician or Virologist so that PCR testing can be performed in a timely manner

22

EAR, NOSE AND THROAT INFECTIONS

Acute Otitis Media • True acute otitis media may be either viral or bacterial, but in either case is usually

a self-limiting disease (60% of placebo-treated children become pain-free in 24 hours and 80% of cases resolve without antibiotics).

• Provision of adequate analgesia is necessary. • Treatment with antibiotics should be considered only after a 24 hour trial of

analgesia.

Pathogens: Common: Viral, Streptococcus pneumoniae, Haemophilus influenzae. Other: Streptococcus pyogenes, Moraxella catarrhalis, Staphylococcus aureus.

Drug Treatment: DRUG DOSE Empiric1 Amoxycillin 500mg po 8 hourly Patients with penicillin allergy Cotrimoxazole2 960mg po 12 hourly Beta-lactamase producing organisms (known or suspected) Amoxycillin/clavulanate 500/125mg po 8 hourly 1 Cefaclor is no longer recommended due to the lack of efficacy for penicillin-resistant

pneumococcus. Amoxycillin achieves levels in the middle ear fluid adequate to treat most infections due to S. pneumoniae with reduced susceptibility to penicillin.

2 Avoid cotrimoxazole in pregnancy. Beware with use of cotrimoxazole in the elderly. Treatment Duration: 5 days.

23

Acute Sinusitis • Sinus congestion often occurs with viral infection or allergy, which require no

antibacterial treatment. • Antibiotic therapy should be considered when at least 3 of the following features

are present: - persistent (greater than a week) mucopurulent nasal discharge - facial pain - poor response to decongestants - tenderness over the sinuses, especially unilateral maxillary tenderness - tenderness on percussion of maxillary molar and premolar teeth.

Pathogens: Common: Viral, Streptococcus pneumoniae, Haemophilus influenzae. Other: Moraxella catarrhalis, Staphylococcus aureus, Gram-negative bacilli, anaerobes. Drug Treatment:

DRUG DOSE Empiric1 Amoxycillin 500mg po 8 hourly Patients with penicillin allergy Doxycycline2, or 100mg po 12 hourly Cotrimoxazole3 960mg po 12 hourly Pathogens Known Beta-lactamase producing organisms or anaerobes Amoxycillin/clavulanate 500/125mg po 8 hourly Staphylococcus aureus Flucloxacillin4 500/125mg po 8 hourly 1 Cefaclor is no longer indicated due to its lack of effectiveness in penicillin-resistant

pneumococcus. 2 Avoid doxycycline in both pregnancy and children. 3 Avoid cotrimoxazole in pregnancy and the elderly. 4 For treatment of patients with penicillin allergy - see Empiric treatment. Treatment Duration: At least 10 days.

24

Chronic Sinusitis

Pathogens: Common: Anaerobes, Streptococci, Staphylococcus aureus. Other: Gram-negative bacilli, Pseudomonas aeruginosa.

Drug Treatment: DRUG DOSE Empiric Amoxycillin/clavulanate 500/125mg po 8 hourly Patients with penicillin allergy Doxycycline1, or 100mg po 12 hourly Cotrimoxazole2 960mg po 12 hourly Pathogens Known Pseudomonas aeruginosa Ciprofloxacin1 500mg po 12 hourly Staphylococcus aureus Flucloxacillin3 500mg po 8 hourly 1 Avoid doxycycline and ciprofloxacin in both pregnancy and children. 2 Avoid cotrimoxazole in pregnancy and the elderly. 3 For treatment of patients with penicillin allergy - see Empiric treatment. Treatment Duration: At least 14 days.

Note: Consider referral to the ENT Service as structural abnormalities may be present.

25

Pharyngitis • Most cases of pharyngitis are caused by viral infection and therefore do not require

antibiotic therapy. • A bacterial cause of acute sore throat is more common in children aged 3 to 13

years (30-40%), than in children aged less then 3 years (5-10%) or adults (5-15%). • The four diagnostic features suggestive of Streptococcus pyogenes infection are:

- fever >38 C - tender cervical lymphadenopathy - tonsillar exudate - no cough

Pathogens: Common: Viral, Streptococcus pyogenes. Other: Corynebacterium diphtheriae, Chlamydia pneumoniae, Neisseria gonorrhoea, Mycoplasma pneumoniae.

Drug Treatment: DRUG DOSE Empiric Phenoxymethylpenicillin 500mg po 12 hourly Patients with penicillin allergy Roxithromycin 300mg po daily Pathogens Known Streptococcus pyogenes Phenoxymethylpenicillin 500mg po 12 hourly Other organisms, or penicillin allergy Roxithromycin 300mg po daily Treatment Duration: 10 days.

Note: Diphtheria infections require urgent referral to a Specialist.

26

RESPIRATORY TRACT INFECTIONS

Exacerbations of COPD And Chronic Bronchitis

Pathogens: Common: Viruses, Streptococcus pneumoniae, Haemophilus influenzae. Other: Moraxella catarrhalis.

Drug Treatment: DRUG DOSE Empiric1 Smokers Amoxycillin/clavulanate 500/125mg po 8 hourly Non Smokers Amoxycillin 500mg po 8 hourly Patients with penicillin allergy Doxycycline2 100mg po 24 hourly Pathogens Known Streptococcus pneumoniae Amoxycillin 500mg po 8 hourly Penicillinase- producing Haemophilus influenzae or Moraxella catarrhalis Amoxycillin/clavulanate 500/125mg po 8 hourly 1 Empiric treatment is often used in moderate to severe exacerbations. 2 Avoid doxycycline in pregnancy and children. Treatment Duration: Variable depending on clinical response.

Notes: • Antibiotics have only been shown to be effective when all 3 cardinal symptoms of

acute bacterial exacerbations are present: increased dyspnoea, increased sputum volume and sputum purulence.

• There is no indication for IV therapy in the treatment of chronic bronchitis. • If pneumonia is diagnosed, refer to pneumonia protocol.

27

Pneumonia

Pathogens: Common: Streptococcus pneumoniae. Other: Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, Staphylococcus aureus, Moraxella catarrhalis, Klebsiella pneumoniae, Chlamydia pneumoniae. Community Acquired - Mild / Moderate Disease

Drug Treatment: DRUG DOSE Empiric Amoxycillin 1g po 8 hourly 1 g iv 8 hourly1 Patients with COPD or smokers Amoxycillin/Clavulanate 1g/200mg iv 8 hourly1 500/125mg po 8 hourly Patients with penicillin allergy Roxithromycin 300mg po daily 1 IV therapy is usually only necessary when concerns are held regarding

absorption of oral antibiotics. Treatment with “atypical agents” is not usually recommended in mild/moderate pneumonia

Treatment Duration: Usually 5 - 7 days depending on severity. Aspiration pneumonia 10 days Atypical pneumonia 14 days

28

Community Acquired - Severe Disease

Definition: Community acquired pneumonia with at least two of the following CURB-65 risk factors:

- Confusion - Urea >7mmol/l - Respiratory rate > 30/min - Diastolic BP < 60mmHg - Age >65years

Drug Treatment: DRUG DOSE Erythromycin 1g iv inf 6 hourly and Amoxycillin/clavulanate 1g/200mg iv 8 hourly Treatment Duration: 7-10 days, although most patients will change to oral therapy within 24 hours. Notes: • Most patients admitted to hospital will not have severe disease by the above

definition. • Most patients will be able to change to oral therapy within 24 hours.

If no pathogen is identified and the patient is improving, change iv amoxycillin/ clavulanate to oral amoxycillin 1g 8hrly and change IV erythromycin to oral macrolide e.g. roxithromicin 300 mg daily.

• CXR changes will persist despite appropriate therapy for up to eight weeks (dependent on age of patient and underlying lung condition).

• With increasing pneumococcal resistance, cefuroxime is no longer recommended for community acquired pneumonia. Its use may still be appropriate in patients with penicillin allergy.

• The new fluoroquinolone agents are not recommended for pneumonia at Waikato Hospital.

Hospital Acquired - Severe Or Proven Gram-Negative Infection

Drug Treatment: DRUG DOSE Gentamicin 5mg/kg iv1 and Amoxycillin/Clavulanate 1g/200mg iv 8 hourly and Erythromycin 1g iv inf 6 hourly

1 Adjust gentamicin dosing interval for renal function. Treatment Duration: 10 days

29

Aspiration Pneumonia Drug Treatment: DRUG DOSE Amoxycillin/Clavulanate 1g/200mg iv 8 hourly or Clindamycin 600mg iv inf 8 hourly Treatment Duration: 10 days.

Community / Hospital Acquired Infection-Pathogens Known Drug Treatment:

DRUG DOSE Streptococcus pneumoniae 1g po 8 hourly Amoxycillin 1 g iv 8 hourly Staphylococcus aureus Flucloxacillin 1g iv 6 hourly or Vancomycin 1 1g iv inf 12 hourly2 Klebsiella pneumoniae Cefuroxime

750mg iv 8 hourly

Legionella pneumophila, Mycoplasma pneumoniae Erythromycin

500mg – 1g iv inf 6 hourly

1 If methicillin-resistant, or patient has severe penicillin allergy 2.Adjust vancomycin dosing for renal function. Treatment Duration: Variable dependent on patient characteristics.

Notes: • Streptococcus pneumoniae still remains the most common cause of pneumonia

and must be adequately covered by any regime chosen. • If Legionella pneumophila is suspected, use high dose macrolide therapy. The

addition of either ciprofloxacin or rifampicin may be used. Please seek Infectious Diseases advice. Legionella PCR can be undertaken on serum, sputum or BAL at Waikato Hospital.

• Although pneumococcal resistance is increasing, clinical trials suggest that amoxycillin still remains adequate treatment for pneumonia, as drug levels still exceed the MIC levels of the resistant organism (less than 5% of pneumococci show high level resistance – August 2008).

30

Tuberculosis • Tuberculosis is a notifiable disease- notify to Medical Officer of Health ext 2065 • Treatment of tuberculosis is a specialised area and should involve respiratory

physician and public health input to ensure adequate treatment and contact tracing occurs.

• Liver function, serum creatinine, electrolytes, are essential blood tests that should be checked before treatment.

• Liver function should be monitored routinely. Pathogen: Mycobacterium tuberculosis. Drug Treatment: • Multiple antitubercular drug therapy is initiated primarily to guard against the

existence and/or emergence of resistant organisms. • The current recommendations are for a short course, i.e six months of therapy in

pulmonary tuberculosis. Extra-pulmonary Tb often requires longer courses. • This consists of an initial two months of therapy using 3 or 4 drugs, the aim of which

is to obtain a rapid decrease in the number of viable organisms, followed by a further four months of therapy with 2 drugs, rifampicin and isoniazid, to eradicate any remaining organisms.

• The initial regimen must contain pyrazinamide for the short course to be effective.

DRUG DOSE Rifampicin1 Wt <50kg, 450mg po mane for 6 months Wt ≥50kg, 600mg po mane for 6 months and Isoniazid 1,2,3 300mg po mane for 6 months and Pyrazinamide1 Wt <50kg, 1.5g po mane for 2 months Wt ≥50kg, 2g po mane for 2 months ± Ethambutol 1,4,5,6 15mg/kg po mane for 2 months, or until

sensitivity results return 1 Four drugs are given daily in those with previous TB therapy, those from high

incidence countries and those with extensive disease. i.e. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol.

2 Combination tablets of Isoniazid and Rifampicin exist in NZ – Rifinah 150 (Rifampicin 150mg/Isoniazid 100mg) and Rifinah 300 (Rifampicin 300mg/Isoniazid 150mg)

3 Pyridoxine 25mg po is usually given daily while on isoniazid to prevent neurotoxicity. 4 Ethambutol (the 4th drug) can be omitted from NZ born patients without prior

treatment. 5Ethambutol is not recommended for children under 6 years. 6 Visual acuity with a Snellen chart and red-green vision should be checked prior to

commencement of ethambutol and regularly throughout treatment Treatment Duration: At least 6 months Notes: • Intermittent supervised therapy is often given in twice or three times week regimens

and is preferred for infectious pulmonary tuberculosis. • Always check dosages (Refer to Guidelines for Tuberculosis Control in NZ 1996).

31

Influenza • The typical clinical syndrome caused by Influenza virus infection is an abrupt onset

of fever, myalgia and cough. • Many cases are less typical, however. Most cases of “Influenza – like illness” are

caused by other agents. • Influenza may mimic meningococcal disease – be wary when making a clinical

diagnosis • Influenza usually circulates as a distinct epidemic for 4 to 6 weeks each winter. • Superinfection with bacteria such as Haemophilus influenzae and Staphylococcus

aureus can cause severe pneumonia and these should be covered in empiric treatment.

• Neuraminidase inhibitors such as oseltamivir, if administered early, reduce severity and duration of illness and reduce viral shedding and may be considered in specific circumstances. They are not currently Pharmac funded.

• Outbreaks can occur on hospital wards and in long-term care facilities. • Nasopharyngeal swab for direct immunoflourescence is available within Waikato

Hospital. This is available 6 days a week during influenza season. Sensitivity is 60-80%.

• Acute and convalescent serology is also available to make a retrospective diagnosis of influenza.

32

GASTROINTESTINAL TRACT AND INTRA-ABDOMINAL INFECTIONS

Dental and Gingival Infections • For tooth abscess, inflamed wisdom tooth area or root canal infection, local

treatment includes removal of the dental pulp from the related tooth or extraction of the tooth, as well as drainage of the abscess when fluctuant.

• With mild disease, antibiotics are often not required. Pathogens: Common: Mixed aerobic and anaerobic oral flora. Drug Treatment: DRUG DOSE Empiric Amoxycillin/Clavulanate 500/125mg orally tds or Clindamycin1 300mg orally tds 1 For patients with penicillin allergy. Treatment Duration: 3 - 5 days

33

Acute Peritonitis Pathogens: Common: Enterobacteriaceae, Enterococcus, Anaerobes. Other: Streptococcus milleri (especially in abscesses). Drug Treatment: DRUG DOSE Empiric Amoxycillin 1g iv 6 hourly and Gentamicin 5mg / kg iv1 and Metronidazole 500mg iv inf 12 hourly Patients with mild penicillin allergy or significant renal dysfunction Ceftriaxone 1g iv 24 hourly and Metronidazole 500mg iv inf 12 hourly 1 Adjust gentamicin dosing interval for renal function. Treatment Duration: 5 - 10 days Notes: • Consult Specialist to discuss management of patients with severe penicillin allergy. • Various treatment strategies are suggested in the literature using single, dual and

triple combinations. • All strategies appear equally effective with the proviso that the drug regimen used

has activity against Enterobacteriaceae and Bacteroides fragilis. • Ceftriaxone covers the majority of Enterobacteriaceae involved in acute peritonitis. • Abscesses may require longer therapy and/or drainage.

34

Cholecystitis / Cholangitis Pathogens:

Common: Enterobacteriaceae, Enterococcus. Drug Treatment: DRUG DOSE Empiric Amoxycillin 1g iv 6 hourly and Gentamicin 5mg / kg iv1 and Metronidazole2 500mg iv inf 12 hourly Patients with mild penicillin allergy or significant renal dysfunction Ceftriaxone 1g iv 24 hourly and Metronidazole 500mg iv inf 12 hourly

1 Adjust gentamicin dosing interval for renal function. 2 Patients with simple cholecystitis may not need metronidazole unless obstruction is

present. Treatment Duration: 5 - 10 days Note: Consult Specialist to discuss management of patients with severe penicillin allergy.

35

Acute Pancreatitis/Severe Necrotising Pancreatitis • Antibiotics are not indicated in the initial management of acute pancreatitis. • If a pancreatic abscess develops, the treatment is as for acute peritonitis due to

perforated viscus. • Early surgical drainage is important. • The role of antibiotics in improving the clinical outcome associated with severe

pancreatitis appears to be limited to those patients with necrotising pancreatitis (as assessed by CT imaging).

Pathogens: Common: Enterobacteriaceae, Enterococcus, Anaerobes. Drug Treatment: DRUG DOSE Empiric Meropenem 1g iv 8hourly or

Ceftriaxone 1g iv 24 hourly and Metronidazole 500mg iv inf 12 hourly Treatment Duration: 7 days Note: Empiric antibiotic regimens for severe necrotising pancreatitis should be administered for 7 days, following which a clinical assessment of their risks versus benefit should be undertaken.

36

Infectious Diarrhoea • The first priority in management is to ensure adequate fluid and electrolyte

replacement. • A microbiological diagnosis was only established in 14.6% of 25,539 stools

submitted to an Auckland Lab in 1999 (NZMJ 113; 224, 2000) • Empiric treatment with antibiotics is not generally recommended even if a pathogen

is identified. • The principal aim of treatment is to achieve and maintain adequate hydration Pathogens:

Common: Campylobacter jejuni (73%). Salmonella sp (non typhi) (7%), Shigella sp (1%). Other: (<1%) Yersinia enterocolitica, Vibrio parahaemolyticus, Plesiomonas shigelloides.

Drug Treatment:

DRUG DOSE Pathogens Known Campylobacter jejuni 1

Usually self-limiting If antibiotic required - Erythromycin2

800mg po 8 hourly

or Norfloxacin 400mg po 12 hourly Salmonella species3 Usually self-limiting If antibiotic required - Ciprofloxacin4,5

500mg po 12 hourly

Shigella species6,7 Norfloxacin8 400mg po 12 hourly Giardia9 Metronidazole 2g po daily for 3 days

1 Does not require treatment as usually self-limiting. Consider therapy if high fever or bloody diarrhoea.

2 If illness is of duration >1 week, or very severe. 3 Most do not need treatment. In fact, treatment leads to an increased risk of clinical

relapse. 4 If immuno-compromised, very severe illness or bacteraemia. 5 Avoid ciprofloxacin in pregnancy and childhood. 6 Of all enteric pathogens, Shigella is the one with most evidence for the effectiveness

of therapy. However, mild disease may be self-limiting. 7 Amoxycillin is not recommended in treatment of Shigella infections. 8 For moderate or severe infections. 9 Giardia is a common cause of acute and sometimes persistent diarrhoea, both locally

and in travellers. If treatment fails, a longer course of metronidazole is sometimes required.

Treatment Duration: Variable.

37

Antibiotic-Associated Diarrhoea • Most mild cases are drug-induced and not associated with Clostridium difficile. • The first step is to cease treatment with any antibiotic likely to be causing the

symptoms. • Most mild cases will improve upon discontinuation of antibiotics. • Treat only if diarrhoea persists or antibiotic therapy must continue.

Pathogens: Common: Clostridium difficile. Other: Clostridium perfringens.

Drug Treatment: DRUG DOSE Empiric Metronidazole 400mg po 12 hourly or Vancomycin1 125mg po 6 hourly 1 If metronidazole is inappropriate, or treatment failure occurs. In severe cases IV

metronidazole can be used. IV Vancomycin is ineffective in this condition. Oral vancomycin is administered by dissolving 500mg vancomycin powder in water and measuring the appropriate amount. Flavouring syrups may be added before administration to improve palatability.

Treatment Duration: 7 - 14 days.

Notes: • The recent emergence of resistance in enterococci makes it essential to reserve

vancomycin for severe cases unresponsive to metronidazole. • Relapse rate is 20% with either treatment and does not represent resistance.

Spores persist in the GI tract, therefore re-treat with same agent. • Treatment of asymptomatic colonisation of C. difficile is not warranted. • Children under the age of 2 years are unlikely to have C. difficile-associated

disease. • Hospitalisation is a major risk-factor for C. difficile. This organism is highly

transmissible to other patients. • Fluoroquinolones are increasingly being recognised as a major risk factor for the

development of C. difficile.

38

Typhoid / Paratyphoid Fever Pathogens: Salmonella typhi, Salmonella paratyphi.

Drug Treatment: DRUG DOSE Empiric Ciprofloxacin 1 500mg po 12 hourly or

200mg iv inf 12 hourly2 If reduced susceptibility to ciprofloxacin is suspected due to the country of acquisition or confirmed in laboratory the alternative is:

Ceftriaxone 2g IV daily or Azithromycin 1g po daily 10 days 1 Avoid ciprofloxacin in pregnancy. 2 If unable to tolerate oral ciprofloxacin. Treatment Duration: 5 - 10 days.

Notes: • Salmonella typhi resistance to ciprofloxacin is increasing (particularly from the

Indian subcontinent and Vietnam). Susceptibility testing should be undertaken. If patient is still febrile at 5 days suspect resistance.

• Azithromycin and ceftriazone are alternatives.

39

Helicobacter Pylori Infection Pathogen: Helicobacter pylori.

Drug Treatment: DRUG DOSE Confirmed infection (Losec Hp7 OAC) Fully funded pack Clarithromycin 500mg po 12 hourly and Amoxycillin 1g po 12 hourly and Omeprazole 20mg po 12 hourly Alternative therapy Clarithromycin 500mg po 12 hourly and Metronidazole 400mg po 12 hourly and Omeprazole 20mg po 24 hourly Treatment Duration: 7 days only Notes: • Helicobacter pylori is associated with virtually all duodenal ulcers not attributable to

NSAIDSs and about two-thirds of gastric ulcers. Its eradication greatly reduces the relapse rate of associated peptic ulcers.

• The gold-standard for diagnosis is gastroscopy with multiple biopsies which can be tested for urease production and/or cultured.

• H. pylori eradication therapy is fully funded by Pharmac. Losec Hp7 OAC is a seven-day pack containing omeprazole, amoxycillin and clarithromycin, which has an eradication rate of ~85%.

• Failures are commonly associated with resistance to metronidazole, clarithromycin or both. A negative biopsy, breath test or faecal antigen test, 4 or more weeks after completing the course of treatment, indicates cure rather than temporary suppression.

• The other regimen mentioned above has been shown to be very successful ~ 90% and is of short duration (only seven days) but is more expensive for the patient, who would pay 3 prescriptions fees rather than one.

• If in doubt, seek advice from the Gastroenterology Service.

40

URINARY TRACT INFECTIONS

Uncomplicated Acute Urinary Tract Infections • Cystitis is the syndrome of frequency and dysuria. • It is due to bacterial infection in 70-80% of cases. • Patients with bacterial cystitis usually have pyuria.

Pathogens: Uncomplicated: Escherichia coli, Staphylococcus saprophyticus. Community Acquired: Proteus mirabilis.

Drug Treatment: DRUG DOSE Empiric Trimethoprim1 600mg po stat2, or 300mg po daily If resistant to trimethoprim3 Nitrofurantoin4 200mg po stat3, or 50mg po 8 hourly or Norfloxacin1 800mg po stat3, or 400mg po 12 hourly Pathogens Known Alternatives used according to sensitivities. Enterococci Amoxycillin

500mg po 8 hourly

1 Avoid trimethoprim and norfloxacin during pregnancy. In pregnancy

amoxycillin/clavulanate 500/125mg 12 hourly for 10 days, or cephalexin 500mg 12 hourly for 10 days are suitable.

2 Single dose therapies recommended for women only. 3 Trimethoprim resistance is present in less than 20% of E.coli with 50% of the women

with resistant isolates responding to treatment. 4 Nitrofurantoin 50 mg 8 hourly for 10 days can be used in first or second trimester

only. Treatment Duration: Single dose or 3 days (Therapies are comparable).

41

Acute Pyelonephritis or Complicated UTI • Acute pyelonephritis is a syndrome of fever ± rigors, unilateral or bilateral loin pain

or tenderness with infected urine. Lower urinary tract symptoms may be absent. • 10 – 15% will have bacteraemia. • Acute pyelonephritis may be uncomplicated, with a structurally normal urinary tract,

or complicated, with a structural or functional disorder. • Urgent drainage is required if obstruction or stone is present. • Organ imaging is indicated (usually ultrasound) if acute pyelonephritis follows an

atypical course, UTIs become closely spaced, unusual organisms are identified, UTIs occur prior to commencement of sexual activity, microscopic haematuria persists, or if there is failure of antibiotic treatment.

Pathogens: Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis, Gram-negative aerobes, Pseudomonas aeruginosa.

Drug Treatment: DRUG DOSE Empiric Gentamicin (often single stat dose) 1 5mg / kg iv 2 followed by Ciprofloxacin 3 250mg po 12 hourly or Trimethoprim 3 300mg po daily Pathogens Known Enterococci Amoxycillin 1g iv 8 hourly 500mg po 8 hourly Pseudomonas aeruginosa Tobramycin 5mg / kg iv2 followed by Ciprofloxacin 3 250 - 500mg po 12 hourly 1 Tobramycin is preferred for Pseudomonas aeruginosa infections but if patient is

responding to gentamicin, there is no need to change. 2 Adjust dosing intervals of gentamicin and tobramycin for renal function. 3 Avoid trimethoprim and ciprofloxacin in pregnancy. Treatment Duration: 5 days total therapy. Use IV therapy until satisfactory clinical response, followed by oral therapy, if tolerated.

42

GENITAL TRACT INFECTIONS Genital tract infections usually require more than antibiotic therapy; e.g. full sexual history, partner tracing, appropriate specimen taking and examination, specialist knowledge, support, education and counselling. For these reasons, discussion with or referral to the Sexual Health Service, Health Waikato is recommended. For discussion or urgent referral, phone ext. 8732 or 8753, or fax referrals to ext. 8892. Note that the clinic runs on an appointment basis, rather than a walk-in service. Patients can book their own appointments, on 07 839 8732. The service aims to see all patients within 48 hours.

43

Pelvic Inflammatory Disease

Pathogens: Common: Neisseria gonorrhoea, Chlamydia trachomatis, Enterobacteriaceae, Streptococci sp, Anaerobes. Other: Clostridium perfringens, Group A Streptococci. Drug Treatment: DRUG DOSE Inpatient Regimens 1,2 A. Cefoxitin

and Doxycycline3

2g iv tds 100mg po bd

followed by Doxycycline3

and Metronidazole4

100mg po bd 400mg po bd

B. Clindamycin

and Gentamicin

900mg iv tds 2mg/kg loading dose iv followed by 1.5 mg/kg 8 hourly or 7mg/kg iv daily5

followed by Clindamycin, or Doxycycline3

450mg po qds 100 mg po bd

and Metronidazole4 400mg po bd

Outpatient Regimen

Ceftriaxone, or 500 mg im stat Ciprofloxacin6 500 mg po stat followed by Doxycycline3 100 mg po bd and Metronidazole4 400mg po bd

1 All antibiotic regimens are evidence-based and are of similar efficacy. 2 Patients known to be allergic to one of the suggested regimens should be treated with

an alternative. 3 Avoid doxycycline in pregnancy and children. 4 Metronidazole is included to improve coverage for anaerobic bacteria. Anaerobes are

of relatively greater importance in patients with severe PID and metronidazole may be discontinued in those patients with mild or moderate PID who are unable to tolerate it.

5 Adjust dosing interval of gentamicin for renal function. 6 Avoid ciprofloxacin in pregnancy and children. Treatment Duration: 14 days total therapy. Intravenous therapy should be continued until 24 hours after clinical improvement and then switched to oral.

44

Bacterial Vaginosis

Pathogen: Gardnerella vaginalis. Other: Mixed anaerobes, e.g. Mobiluncus, Bacteroides, Mixed aerobes, e.g. Staphylococcus and Streptococci.

Drug Treatment: DRUG DOSE Empiric Metronidazole 2g po stat or

400mg po 12 hourly for 7 days1

1 If stat treatment is unsuccessful. Treatment Duration: See dosage above.

Notes: • G.vaginalis isolation per se should not be treated. Treatment is indicated only with

Gram-stain confirmation of bacterial vaginosis ± symptoms e.g. malodorous vaginal discharge.

• Screen for all other sexually transmitted diseases. • Empirical partner treatment for Gardnerella has no effect on reducing recurrence

rate in women, but it may be advisable to exclude other infections e.g. non-specific urethritis in sexual partners.

45

Candidosis / Vulvo-Vaginitis

Pathogen: Candida albicans.

Drug Treatment: DRUG DOSE Empiric Clotrimazole 500mg pv stat, or

100mg pv nocte for 6 nights Recurrent infections Consider monthly therapy with: Itraconazole or

200mg po 12 hourly for one day

Fluconazole 150mg po stat

Treatment Duration: See dosage above. Notes: • Make sure diagnosis is correct. • Treating the male partner does not reduce the frequency of recurrences in women;

men should therefore only receive treatment if symptomatic. • Exclude predisposing factors, e.g. urine dip stick for glycosuria. • If frequent recurrences (>4 per year), refer to Sexual Health Clinic or combined

Gynae/Skin Clinic for review.

46

Chlamydial Cervicitis / Urethritis

Pathogen: Chlamydia trachomatis.

Drug Treatment: DRUG DOSE Empiric Azithromycin or

1gm po stat1

Doxycycline2 100mg po bd for 7 days 1 Stat treatment is possible due to the long half-life of azithromycin. 2 Avoid doxycycline in pregnancy and children. Treatment Duration: See dosage above.

Note: Sexual partners (i.e. within the last 3 months) need to be screened for STDs and treated for Chlamydia without delay i.e. without waiting for their test results, to avoid further transmission of infection.

47

Genital Herpes Simplex

Pathogen: Herpes simplex.

Drug Treatment: DRUG DOSE Empiric Acyclovir

200mg po 5 times daily

Treatment of superinfection Cotrimoxazole1

960mg po 12 hourly

1 Avoid cotrimoxazole in pregnancy. Treatment Duration: 5 days.

Notes: • Simple recurrences (secondary attacks) do not always require acyclovir tablets. • Severe HSV infection (e.g. in immunocompromised patients, insulin-dependent

diabetics) may require IV acyclovir. • Suppressive therapy is indicated when confirmed recurrences are frequent (>6-8

per year), severe or associated with significant psychological morbidity – usual dosage is 400mg po bd.

• Consider referral for specialist advice or counselling.

48

Gonorrhoea Pathogen: Neisseria gonorrhoea.

Drug Treatment: DRUG DOSE Empiric Ceftriaxone 500mg im stat and either: Doxycycline 1,2 or

100mg po 12 hourly for 7 days

Azithromycin 2,3 1 g po as a single dose 1 Avoid doxycycline in pregnancy and children. 2 The doxycycline or azithromycin is given to cover Chlamydia, which co-exists with

gonorrhoea in 40-50% cases. This should be given, even if the Chlamydia test is negative, as false-negative Chlamydia tests have been reported in this situation.

Treatment Duration: See dosage above.

Notes: • The incidence of penicillin- resistant Neisseria gonorrhoea means that penicillin or

amoxycillin should be reserved for known penicillin-sensitive strains. Ceftriaxone (500mg stat IM) is now used due to high rates of ciprofloxacin resistance. If sensitivity results are known at time of treatment Ciprofloxacin 500mg stat is an oral alternative.

• Pharyngeal and uncomplicated rectal gonorrhoea can be treated successfully with a single stat dose of ceftriaxone or ciprofloxacin (if the organism is sensitive).

• Sexual partners (i.e. within the last 3 months) need to be screened for STDs and treated for gonorrhoea without delay, i.e. without waiting for their test results, to avoid further transmission of infection.

49

Non-Gonococcal Urethritis (Non-Specific Urethritis, NSU)

Pathogens: Common: Chlamydia trachomatis, Ureaplasma urealyticum. Other: Trichomonas vaginalis, Herpes simplex (less than 5% of cases of NSU) Various skin bacteria.

Drug Treatment: DRUG DOSE Empiric Doxycycline1 100mg po 12 hourly for 7 days or Azithromycin 1 g po stat dose Pathogens Known Trichomonas vaginalis Metronidazole 2g po stat

Herpes simplex Acyclovir 200mg po 5 times daily for 7 days 1 Avoid doxycycline in pregnancy and children. Treatment Duration: See dosage above.

Note: Screen and treat partners as for Chlamydia infection.

50

Trichomoniasis

• Trichomonas vaginalis causes vaginitis and occasionally urethritis in males.

Pathogen: Trichomonas vaginalis.

Drug Treatment: DRUG DOSE Empiric Metronidazole 2g po stat for females or 400mg po bd for 7 days for male contacts Treatment Duration: See dosage above.

Syphilis Pathogen: Treponema pallidum.

Drug Treatment: See note below.

Treatment Duration: Depending on stage of disease.

Note: The management of syphilis usually requires specialist knowledge. Therefore regimens have not been included. Referral to Sexual Health Service, Health Waikato (07) 8398732 is recommended for people with reactive syphilis serology. Dr Jane Morgan, Health Waikato Specialist Sexual Health Physician is available for consultation.

51

SKIN, MUSCLE AND BONE INFECTIONS There is no role for the combined usage of flucloxacillin and penicillin. The belief that flucloxacillin is able to cover Staphylococcus aureus and not Streptococcus pyogenes is incorrect. The MIC90 of flucloxacillin for Streptococcus pyogenes is 0.4µg/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents. If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered.

Osteomyelitis - Acute

Pathogens: Common: Staphylococcus aureus (> 80%), Streptococci species. Other: Enterobacteriaceae, Pseudomonas aeruginosa.

Drug Treatment: DRUG DOSE Empiric Flucloxacillin 2g iv 6 hourly, then 1g po 6 hourly Patients with mild penicillin allergy Cephazolin followed by

1g iv 6 hourly

Cephalexin

1g po 6 hourly

Patients with severe penicillin allergy Clindamycin

450mg iv inf 8 hourly, then 450mg po 8 hourly

Treatment Duration: • Minimum duration of total treatment is 4 weeks in children and 6 weeks in

adults. • IV therapy should be given for at least 14 days in adults. Children with acute

osteomyelitis can be treated with very brief IV courses (suggested by some authorities as a minimum of 3 days).

• Oral therapy may then be started if patient has been afebrile and clinically stable for several days.

Notes: • Chronic osteomyelitis diagnosis and treatment - refer Specialist. • MRSA osteomyelitis - seek Infectious Diseases advice.

52

Septic Arthritis - Non Prosthetic Joint

Pathogens: Common: Staphylococcus aureus, Group A streptococcus. Other: Neisseria gonorrhoea.

Drug Treatment: DRUG DOSE Empiric See empiric therapy for Osteomyelitis Treatment Duration: Duration of total treatment is 4 weeks, including at least 7 days IV therapy.

Notes: • Joint washout usually required - refer Specialist. • Prosthetic joint infections - refer Specialist.

Septic Arthritis - Prosthetic Joint The proportion of prosthetic hips that become infected is 0.5-1%, knees 1-2% and elbows 4-9%. Treatment always involves a combination of surgery and antibiotics; antibiotics are seldom successful when used alone. Eradication of infection is most likely to be achieved if the prosthesis and all associated foreign material are removed, together with devitalised tissue and infected bone.

53

Bites and Clenched Fist Injuries • Bites and clenched fist injuries can often become infected. • In all cases a patient’s tetanus immunisation status must be assessed. • All bites should be cleaned and debrided and irrigated. Elevation and

immobilisation are recommended. • Not all bites require antibiotic therapy. Antibiotics are usually reserved for serious

bites, especially those more than 4 hours old; involving the hand; or associated with deep puncture wounds or crush injury.

Pathogens: Usually multiple, including anaerobes, Staphylococcus aureus, Streptococci species, Pasteurella multocida (cats and dogs) and Eikenella corrodens (humans).

Drug Treatment: DRUG DOSE Empiric Amoxycillin/clavulanate 500/125mg po 8 hourly Patients with severe infection Amoxycillin/clavulanate 1g/200mg iv 8 hourly Patients with penicillin allergy Cotrimoxazole1

and Metronidazole

960mg po 12 hourly 400mg po 12 hourly

or Clindamycin alone 450mg iv inf 8 hourly or

450mg po 8 hourly 1 Avoid cotrimoxazole in pregnancy and the elderly. Treatment Duration: At least 5 days.

Note: • Severe infection or poor response to above regimens may also require surgery.

54

Compound Fractures The patient with a compound frature should have their immune status to tetanus assessed. Prophylaxis or early treatment should be given.

Pathogens: Common: Staphylococcus aureus

Drug Treatment: DRUG DOSE Empiric1 Flucloxacillin

2g iv 6 hourly, then 500mg po 6 hourly

Patients with mild penicillin allergy Cephazolin followed by Cephalexin

1g iv 8 hourly 500mg po 8 hourly

Patients with severe penicillin allergy Clindamycin 450mg iv inf 8 hourly, then

450mg po 8 hourly The duration of antibiotic treatment in compound fractures should be for 1 to 3 days. If presentation is delayed (>8 hours), presumptive early treatment should be given for 5 to 7 days, but continued for longer if bone infection is established. If wound soiling or tissue damage is severe and/or devitalised tissue is present, use amoxicillin/clavulanate 1.2 gm IV 8 hourly instead of flucloxacillin..

55

Cellulitis - Simple Pathogens: Common: Streptococcus pyogenes. Other: Staphylococcus aureus, Enterobacteriaceae, anaerobes.

Drug Treatment: DRUG DOSE Empiric1 Flucloxacillin

1g iv 6 hourly, then 500mg po 6 hourly

Patients with mild penicillin allergy Cephazolin followed by Cephalexin

1g iv 8 hourly 500mg po 8 hourly

Patients with severe penicillin allergy Clindamycin 450mg iv inf 8 hourly, then

450mg po 8 hourly

Pathogens Known Streptococcus pyogenes Benzylpenicillin followed by Penicillin V

1.2g iv 4 hourly 500mg po 6 hourly

Staphylococcus aureus Flucloxacillin alone As for empiric treatment 1 As the distinction between Streptococcal and Staphylococcal cellulitis is often difficult

on clinical grounds, empiric therapy is directed against both organisms. Treatment Duration: • Usual total duration of treatment at least 5 days, depending on response. • Use IV therapy initially for severe infections.

Note: • There is no role for the combined usage of flucloxacillin and penicillin in any

circumstance. The belief that flucloxacillin is able to cover Staphylococcus aureus and not Streptococcus pyogenes is incorrect. The MIC90 of flucloxacillin for Streptococcus pyogenes is 0.4µg/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents.

• If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered.

56

Cellulitis - Complicating Ulcer • Complicating ulcer caused by diabetes, vascular disease. • Usually involves multiple organisms.

Pathogens Common: Streptococcus pyogenes, Staphylococcus aureus, Enterobacteriaceae, Anaerobes.

Drug Treatment: DRUG DOSE Empiric Amoxycillin/clavulanate alone 1g/200mg iv 8 hourly, then 500mg po 8 hourly

Patients with mild penicillin allergy Cefuroxime and Metronidazole

750mg iv 8 hourly 500mg iv inf 8 hourly

followed by Cephalexin and Metronidazole

500mg po 8 hourly 400mg po 12 hourly

Patients with severe penicillin allergy Gentamicin and Clindamycin

5 mg/kg iv1

450mg iv inf 8 hourly 1 Adjust dosing interval of gentamicin for renal function. Treatment Duration: Minimum duration of total treatment is 10 days (longer treatment is often required). Use IV therapy initially for severe infections.

57

Necrotising Fasciitis or Synergistic Gangrene • Necrotizing soft-tissue infections are characterised by rapidly progressing

inflammation and necrosis of skin, subcutaneous fat and fascia, and sometimes muscle.

• The key to successful treatment is early diagnosis and treatment • Clinical clues to early recognition are: oedema beyond the area of erythema, skin

vesicles, crepitus and the absence of lymphangitis and lymphadenitis. • The basis of treatment is surgical removal of devitalised tissue, which reduces

mortality and assists in diagnosis. • Neither antibiotics nor hyperbaric oxygen is a substitute for surgical debridement. • Seek surgical input early if this diagnosis is suspected.

Pathogens: Common: Mixed aerobes and anaerobes, including Escherichia coli, Bacteroides fragilis, Streptococcus pyogenes and Staphylococcus aureus.

Drug Treatment: DRUG DOSE Empiric Benzylpenicillin 2.4g iv q4h and Metronidazole 500mg iv q8h and Gentamicin 1,2 5mg/kg iv3 1 Gentamicin can be discontinued if Streptococcus pyogenes is proven to be causative

agent. 2 Gentamicin can be substituted by cefuroxime if significant renal impairment exists. 3 Adjust dosing interval of gentamicin for renal function. Note: Meropenem monotherapy, or ciprofloxacin plus clindamycin, are also effective. Treatment Duration: Minimum of 10 days. Use IV therapy initially for severe infections.

58

Mastitis / Breast Abscess

Pathogens: Common: Staphylococcus aureus (if lactating), anaerobes (if not lactating). Other: Diphtheroids.

Drug Treatment: DRUG DOSE Empiric Lactating Flucloxacillin 500mg po 8 hourly Non-lactating Amoxycillin/clavulanate Patients with penicillin allergy

500/125mg po 8 hourly

Clindamycin 450mg po 8 hourly

Treatment Duration: 5 days. Note: Failure of symptoms to improve after 2 to 3 days suggests other pathogens or an abscess, requiring review, surgical drainage and bacteriological examination of the pus.

59

Wound Infections

POST-OPERATIVE Local measures such as surgical drainage and irrigation with sodium chloride 0.9% will usually suffice. Topical antibiotics may cause skin hypersensitivity and the emergence of resistant organisms, and are not recommended.

For mild to moderate infection with surrounding cellulitis, use: Flucloxacillin 500mg orally, 6 hourly. Alternatively, if Gram-negative organisms are suspected or known to be involved, use Amoxycillin/Clavulanate 500/125mg 8 hourly.

For more severe infections particularly where systemic symptoms are present, use: Flucloxacillin 2g IV 6 hourly or Cephazolin 1g IV 8 hourly. If Gram-negative organisms are suspected or known to be involved, add Gentamicin 5mg/kg IV daily (adjust dose for renal function).

Episiotomy Infections Infection of the episiotomy site is an uncommon occurrence. Overall, only 0.1% of episiotomies become infected, although this rate increases to 1% to 2% for episiotomies complicated by third- or fourth- degree extensions. Management is as per postoperative wound infections where gram-negative organisms may be involved i.e. Amoxycillin + clavulanate 500/125mg 8 hourly. Very rarely necrotising fasciitis may occur which requires surgery and management as per the necrotising fasciitis protocol.

60

EYE INFECTIONS

Blepharitis • Blepharitis is an inflammation of the lid margins. • Lid hygiene is an important adjunct to antimicrobial therapy. Remove crusts with

warm compresses prior to administration of eye drops or eye ointment. • If in doubt about the need for antibiotics seek advice from Ophthalmology.

Pathogens: Common: Staphylococcus aureus.

Drug Treatment: DRUG DOSE Empiric Chloramphenicol Eye drops 0.5%

1-2 drops in affected eyes(s) 2-3 hourly initially or

Eye ointment 1% Applied to the affected eye(s) 6 hourly

Patients with lid abscesses Add to empiric treatment:

Flucloxacillin 250mg po 6 hourly Treatment Duration: At least 7 days

61

Conjunctivitis

Pathogens: May be mixed, including Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Group A Streptococci, Neisseria gonorrhoea, Chlamydia trachomatis, viruses.

Drug Treatment: DRUG DOSE Empiric: Chloramphenicol Eye drops 0.5%

1-2 drops in both eyes 2-3 hourly initially or

Eye ointment 1% applied to both eyes 6 hourly

Pathogens Known Neisseria gonorrhoea 1

Ceftriaxone 1 g iv stat or 125mg iv stat in neonate

Chlamydia trachomatis 1 Doxycycline 2 100mg po 12 hourly or Azithromycin 1 gm po stat dose 1 Treat sexual partners for N. gonorrhoea and C. trachomatis infections. 2 Avoid doxycycline in pregnancy and children. Treatment Duration: Non-Chlamydia infections 5 days Chlamydia infections 3 weeks

62

TRAVELLERS’ INFECTIONS

Malaria • Malaria must be considered in any patient who has visited a malarious area and

presents with a febrile illness. • Thick and thin blood films together with a blood sample collected into an EDTA tube

should be sent to the laboratory for examination. A single negative blood film does not exclude the diagnosis of malaria, particularly if antimalarials or antibiotics have been taken recently. The Waikato Hospital laboratory also uses a antigen card test which is extremely sensitive for Plasmodium falciparum.

• Therapy depends on the species of Plasmodium and on the clinical severity. • All patients with Plasmodium falciparum should be admitted for the first 24 hours of

treatment due to the rapid deterioration that may occur. • Patients with Plasmodium vivax do not need to be admitted but follow-up is

necessary.

Pathogens: Common: Plasmodium falciparum, Plasmodium vivax. Other: Plasmodium ovale, Plasmodium malariae.

Drug Treatment: DRUG DOSE Empiric1

Pathogens Known Plasmodium falciparum - severe 2,9 Quinine dihydrochloride 20mg/kg iv over 4 hours as loading

dose in 300ml 5% dextrose 3,4 , then 10mg/kg infusion over 2-4 hours every 8 hours. (Maximum 1800mg/day or 600mg/day in renal failure. When clinically improved, complete treatment with an oral regimen (see below).

Plasmodium falciparum – uncomplicated5 Quinine sulphate 600mg (450mg for adults <50kg) po

8 hourly for 7 days and Doxycycline 4

Plasmodium vivax

100mg po 12 hourly for 7 days

Chloroquine sulphate6

or Hydroxychloroquine and

800mg stat po, followed by 400mg po 6 hours later, then 400mg po on days 2 and 3.

Primaquine 7,8 15mg po, daily with food for 2 weeks

63

1 Usually not required as species usually apparent from blood film. 2 Severe: i.e. altered consciousness, jaundice, oliguria, severe anaemia, >2% of RBC

parasitized, vomiting or acidotic. 3 No loading dose is given if the patient has received quinine, quinidine or mefloquine

in the previous 48 hours. 4 Avoid doxycycline in pregnancy and children. 5 Malarone [Atovaquone/proguanil (250mg/100mg)] 4 tablets daily for 3 days in adults

can be used in patients who are mildly unwell (low fever and low parasitaemia) if they did not take this medication as prophylaxis.

6 Chloroquine sulphate 200mg and hydroxychloroquine sulphate 200mg are equivalent to 150mg of chloroquine base.

7 For Plasmodium vivax infection from South-East Asia or the Pacific Islands, increase the dose to primaquine 30mg orally daily.

8 Severe haemolysis may occur with G6PD-deficient patients. 9 Artesunate 2.4 mg/kg IV on admission and repeated at 12 hours and 24 hours, then

once daily until oral therapy is possible, is increasingly being used internationally in the setting of severe plasmodium falciparum infection. This drug is unregistered and is not available on-site at Waikato Hospital. It is available within Auckland hospital pharmacy department and rapid access by courier is possible.

Treatment Duration: Dependent on Plasmodium species (see above).

64

TREATMENT GUIDELINES FOR COMMON CONDITIONS IN

PAEDIATRIC PATIENTS

Doses in this section are given in mg/kg/dose. Please note that dosage for children should never exceed the usual adult dosage.

Cellulitis

Pathogens: Common: Streptococcus pyogenes. Other: Staphylococcus aureus, Enterobacteriaceae, anaerobes.

Drug Treatment: DRUG DOSE Empiric Flucloxacillin 25 mg/kg/dose iv 6 hourly Pathogens Known

Streptococcus pyogenes Benzylpenicillin 30 mg/kg/dose iv 6 hourly followed by Penicillin V 7. 5 - 15 mg/kg/dose po 4 times daily

Treatment Duration: At least 5 days, depending on clinical course.

Notes: • Doses in this section are given in mg/kg/dose. • Dosage for children should never exceed the usual adult dosage.

65

Conjunctivitis Neonatorum

Pathogens: Common: Neisseria gonorrhoea, Chlamydia trachomatis. Other: Staphylococcus aureus, Pseudomonas aeruginosa.

Drug Treatment: DRUG DOSE Empiric Ceftriaxone 30 mg/kg/dose iv 24 hourly Pathogens Known Chlamydia trachomatis Erythromycin succinate 20 mg/kg/dose po 4 times daily for

2 weeks

Treatment Duration: 7 - 14 days


Epiglottitis

Pathogens: Common: Haemophilus influenzae type b.

Drug Treatment: DRUG DOSE Empiric Cefotaxime 50 mg/kg/dose iv 8 hourly

(max 2g per dose) or Ceftriaxone

100 mg/kg/dose iv stat, then 50 mg/kg daily (max 2g daily)

Treatment Duration: 7 – 10 days.


66

Meningitis Consider dexamexethasone 0.15mg/kg/dose 6 hourly for 16 doses, commencing one hour prior to antibiotics, if Streptococcus pneumoniae or Haemophilus influenzae suspected.

Pathogens:

Common: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae. Neonatal: Group B Streptococci, Escherichia coli, Listeria. Other: Staphylococcus aureus. Neonatal: Streptococci, coagulase-negative and positive Staphylococci, Klebsiella, Enterobacter, Pseudomonas.

Drug Treatment:

DRUG DOSE Empiric 0 - 3 Months Amoxycillin

50-100 mg/kg/dose iv

Age 1 week 12 hourly Age 2-4 weeks 8 hourly Age >4 weeks 6 hourly

and Cefotaxime 50 mg/kg/dose iv Age 1 week 12 hourly

Age 2-4 weeks 8 hourly Age >4 weeks 6 hourly

Empiric: >3 Months1 Ceftriaxone

100 mg/kg/dose iv stat, then once daily (max 4g/day, 2g/dose)

Pathogens Known Pseudomonas Ceftazidime 50 mg/kg/dose iv Age 1 week 12 hourly

Age 2-4 weeks 8 hourly Streptococcus pneumoniae 2 Ceftriaxone 100 mg/kg/dose iv stat, then once daily

(max 4g/day, 2g/dose) and Vancomycin 15mg/kg/dose iv

(max 3g/day) 6 hourly

Benzylpenicillin 3

60 mg/kg/dose iv

4 hourly

Neisseria meningitidis Benzylpenicillin 60 mg/kg/dose iv 4 hourly Haemophilus influenzae Ceftriaxone

100 mg/kg/dose iv stat, then 50mg/kg/dose iv once daily

67

1 If organisms are seen on the gram-stain, then therapy may be directed accordingly. 2 Due to increasing resistance, Health Waikato policy determines that a positive gram-

stain suggestive of Streptococcus pneumoniae now requires treatment with both ceftriaxone and vancomycin, until sensitivity results become available. Use both agents until sensitivity results available, then reduce to ceftriaxone or benzylpenicillin alone.

3 For penicillin-sensitive organisms. Treatment Duration: Neonatal: 21 days, or 14 days after CSF sterilisation, whichever is longer Group B Streptococci 14 - 21 days Meningococcal 4 days Pneumococcal 7 - 10 days Haemophilus 7 - 14 days


68

Osteomyelitis - Acute

Pathogens: Common: 0 -2 months: Group B Streptococci, Staphylococcus aureus, E. coli. 2 months-2 years: Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae B, Group B Streptococci. >2 years: Staphylococcus aureus, Streptococci, E coli. Other: Salmonella, anaerobes, fungi.

Drug Treatment: DRUG DOSE Empiric: 0-2 months Flucloxacillin

25-50 mg/kg/dose iv

Age 1 week 12 hourly Age 2-4 weeks 8 hourly Age >4 weeks 4-6 hourly

and Cefotaxime 50 mg/kg/dose iv 8 hourly Empiric: >2 months Flucloxacillin 25-50 mg/kg/dose iv 4-6 hourly and Cefotaxime 50 mg/kg/dose iv 8 hourly Pathogens Known Staphylococcus aureus Flucloxacillin 25-50 mg/kg/dose iv 4-6 hourly E. coli Cefotaxime 50 mg/kg/dose iv 8 hourly H. influenzae Cefotaxime 50 mg/kg/dose iv 8 hourly or Ceftriaxone 100 mg/kg/dose iv 24 hourly

Treatment Duration: 4-6 weeks

Oral antibiotics may be commenced after 7-14 days of iv treatment, depending on clinical course.


69

Otitis Media – Acute Prior to commencing antibiotics consider whether antibiotic treatment is actually needed – in uncomplicated Otitis Media watchful waiting has a high success rate without the side effects of antibiotics.

Pathogens: Common: Streptococcus pneumoniae, Haemophilus influenzae. Other: Streptococcus pyogenes, Moraxella catarrhalis, Staphylococcus aureus.

Drug Treatment: DRUG DOSE Empiric: Amoxycillin 25 mg/kg/dose po/iv 8 hourly or Sulphamethoxazole/ trimethoprim 20/4 mg/kg/dose po 12 hourly or Amoxycillin/clavulanate 10/2.5-20/5 mg/kg/dose po/iv 8 hourly

Treatment Duration: 5 days

Notes: • With increasing pneumococcal resistance, cefaclor is no longer recommended, as it

is active only against fully sensitive strains. • Doses in this section are given in mg/kg/dose. • Dosage for children should never exceed the usual adult dosage.

70

Periorbital / Orbital Cellulitis

Pathogens: Common: Streptococcus pneumoniae, Group A Streptococci, Haemophilus influenzae B, Staphylococcus aureus.

Drug Treatment: DRUG DOSE Empiric Flucloxacillin 25 mg/kg/dose iv 6 hourly and Cefuroxime 50 mg/kg/dose iv 8 hourly followed by Amoxycillin/clavulanate 10/2.5-20/5 mg/kg/dose po 8 hourly

Treatment Duration: IV therapy for a minimum of 48 hrs, then continue with oral therapy. Total duration of therapy at least 7 days.


71

Pharyngitis Most cases of pharyngitis in preschool children are due to viral infection and do not require antibiotic treatment. Before commencing antibiotics obtain a bacterial pharyngeal throat swab. Review bacterial culture 3-4 days before deciding whether to continue antibiotics for a full 10-day course. The four diagnostic features suggestive of Streptococcus pyogenes infection are: • Fever >38oC • Tender cervical lymphadenopathy • Tonsillar exudate • No cough

Pathogens: Common: Viruses, Streptococcus pyogenes. Other: Mycoplasma pneumoniae, Haemophilus influenza B, Corynebacterium diphtheriae.

Drug Treatment: DRUG DOSE Empiric Penicillin V 15 mg/kg/dose po 3 times daily or Erythromycin 10 mg/kg/dose po 6-8 hourly

Treatment Duration: 10 days.


72

Pneumonia Most Lower Respiratory Tract infections in children are viral.

Pathogens: Common: 0-3 months:

Group B Streptococci, Staphylococcus aureus, Listeria, Chlamydia, Gram-negative bacilli.

3 months: Viruses, Streptococcus pneumoniae. Other: Streptococci, Staphylococcus aureus, Haemophilus influenzae, Mycoplasma pneumoniae, Klebsiella, Pseudomonas aeruginosa, Mycobacterium tuberculosis.

Drug Treatment: DRUG DOSE Empiric: 0-3 months Amoxycillin

50 mg/kg/dose iv Age 1 week 12 hourly Age 2-4 weeks 6 hourly Age >4 weeks 3 hourly

and Gentamicin 2-2.5 mg/kg/dose iv 8 hourly Empiric: >3 months

Benzylpenicillin 30 mg/kg/dose iv 4-6 hourly or Penicillin V 15 mg/kg/dose po 6 hourly or Erythromycin succinate

20 mg/kg/dose po 6-8 hourly


Notes: • If suspicious of Staphylococcal infections, use flucloxacillin 25 mg/kg/dose iv

6 hourly. • Use erythromicin only if likely penicillin allergy, or mycoplasma pneumoniae

infection suspected. • If severely unwell, use broad-spectrum antibiotic cover e.g. cefuroxime 50mg/kg iv

8 hourly. • Legionella pneumophila is extremely rare in immunocompetent children. • Doses in this section are given in mg/kg/dose. • Dosage for children should never exceed the usual adult dosage.

73

Pyelonephritis

Pathogens: Common: E. coli, Proteus sp., Klebsiella. Other: Staphylococcus aureus, Pseudomonas, Serratia.

Drug Treatment: DRUG DOSE Empiric: Amoxycillin 50 mg/kg/dose iv 6 hourly and Gentamicin 7 mg/kg/dose iv 24 hourly, or

2 -2.5 mg/kg/dose iv 8 hourly1 1 Appropriate for children under one year of age.

(See section on Aminoglycoside dosing in children).



74

Urinary Tract Infections

Pathogens: Common: E. coli , Proteus sp., Klebsiella. Other: Staphylococcus aureus, Pseudomonas, Serratia.

Drug Treatment: DRUG DOSE Empiric: Sulphamethoxazole/trimethoprim 12.5/2.5-25/5 mg/kg/dose po twice daily or Cefaclor

10-15 mg/kg/dose po 8 hourly

Pathogens Known As per sensitivities

Treatment Duration: 7-10 days, followed by chemoprophylaxis (dependent on organism) while awaiting renal investigations, or if otherwise indicated.


75

Aminoglycoside Dosing In Children The Paediatric Department has moved to use “extended interval dosing” of aminoglycosides in children over one year of age. For children, extended interval usually means once daily dosing. Neonates, children under one year and patients with infective endocarditis have been excluded. Gentamicin is given at a dose of 5 mg/kg/day IV over 10-15 minutes.

Monitoring Of Aminoglycoside Levels

8 Hourly Dosing Regimens When treating patients >3 months of age with normal renal function and who are on concurrent antibiotics (for synergy), peak/trough levels need not be done routinely. Peak concentrations are of no benefit if drug is infused over >1 hour.

• Indications for Peak/Trough Levels: - Age <3 months - Critically ill - Patients receiving concurrent nephrotoxins - Pneumonia, cystic fibrosis - No clinical response after >24 hours of appropriate doses - Burns

• Indications for Trough Levels: - Patients receiving unusually high doses (>3 mg/kg/dose) - Renal failure - After 5th dose, if concerned about potential nephrotoxicity. (Also obtain baseline serum creatinine and repeat on days 5-7 of therapy).

• Indications for Additional Trough Concentrations: - Dose adjusted - Treatment duration >10 days - Additional nephrotoxic drugs being used - Renal insufficiency - High MIC isolate

24 Hourly Dosing Regimens There is no need to measure peak concentrations. Concentrations may be measured at 8 hours (or 10 hours) post dose. If >3.5 µg/ml at 8 hours (or >2 µg/ml at 10 hours), then decrease dose.

76

Dosage Schedules Of Antimicrobial Drugs Used In Paediatric Patients Note that amounts recommended are mg/kg per dose. Do not exceed recommended dose for adults. Drug Route Mild to Moderate Infections Severe Infections Penicillins Penicillin G, crystalline IV/IM 25 mg/kg 6 hourly 50 mg/kg 4-6 hourly (max 12g/day) Penicillin G, procaine IM 25-50 mg/kg 12-24 hourly (max 2.4g/day) Inappropriate Penicillin V PO 5-12.5 mg/kg 6-8 hourly Inappropriate Flucloxacillin PO/IV 12.5-50 mg/kg 6 hourly 50 mg/kg 4-6 hourly Amoxycillin PO 7.5-15 mg/kg 8 hourly Inappropriate Amoxycillin IV Inappropriate 50 mg/kg 4 hourly Amoxycillin/clavulanate PO 7.5-15 mg/kg 8 hourly Inappropriate IV 7.5-15 mg/kg 8 hourly 7.5-15 mg/kg 8 hourly Piperacillin IV Inappropriate 50 mg/kg 6 hourly or 100 mg/kg 8 hourly Piperacillin/tazobactam IV Inappropriate Ticarcillin/clavulanate IV Inappropriate Cephalosporins Cephalothin IV/IM 10-20 mg/kg 6 hourly 40 mg/kg 4 hourly Cephazolin IV/IM 10-15 mg/kg 8 hourly 25 mg/kg 6 hourly Cephalexin PO 6-12.5 mg/kg 6 hourly Inappropriate Cefoxitin IV/IM Inappropriate 25 mg/kg 4-6 hourly Cefaclor PO 10-15 mg/kg 8 hourly Inappropriate Cefuroxime IV/IM Inappropriate 50 mg/kg 6-8 hourly Cefotaxime IV/IM Inappropriate 50 mg/kg 6 hourly Ceftriaxone IV/IM Inappropriate 50-100 mg/kg 12-24 hourly,

(max 2g/dose or 4 g/day) Cefepime IV Inappropriate 50 mg/kg 8 hourly (max 4 g/day) Ceftazidime IV/IM Inappropriate 40-50 mg/kg 8 hourly (max 6 g/day)

77

Dosage Schedules Of Antimicrobial Drugs Used In Paediatric Patients, cont.

Drug Route Mild to Moderate Infections Severe Infections Carbapenems Meropenem IV Inappropriate 20-40 mg/kg every 8 hours Macrolides Erythromycin lactobionate

IV Inappropriate 5 mg/kg 6-8 hourly

Erythromycin base PO 7.5-12.5 mg/kg 6 hourly Inappropriate Erythromycin ethyl succinate PO 7.5-12.5 mg/kg 6 hourly Inappropriate Erythromycin stearate PO 7.5-12.5 mg/kg 6 hourly Inappropriate Erythromycin estolate PO 7.5-12.5 mg/kg 6 hourly Inappropriate Lincosamides Clindamycin IV/IM 5-10 mg/kg 6 hourly 10-20 mg/kg 6 hourly PO 5-10 mg/kg 6 hourly Inappropriate Glycopeptides Vancomycin IV Inappropriate 15 mg/kg 8 hourly (max 500 mg/dose) Aminoglycosides Gentamicin IV/IM Inappropriate 5-7 mg/kg 24 hourly Tobramycin IV/IM Inappropriate 5-7 mg/kg 24 hourly Nitroimidazoles Metronidazole IV 5-10 mg/kg 8 hourly 10 mg/kg 6 hourly PO 5-10 mg/kg 8 hourly 10 mg/kg 6 hourly PR 1-5 years: 250 mg/kg 8 hourly PR 6-12 years: 500 mg/kg 8 hourly

78

GUIDELINES FOR EFFECTIVE USE OF

ANTIMICROBIAL DRUGS

INFORMATION ON SELECTED ANTIMICROBIAL DRUGS

Most conditions requiring antimicrobial treatment can be managed using established drugs. This is reflected in the recommendations made in the body of this booklet. The beta-lactams and aminoglycosides are still important, and new agents in the former group continue to appear. Because of their number and the claims made for them, confusion may occur. Newer examples are usually expensive, but may be valuable in treating some infections. Paradoxically, their use may unfortunately be a factor in the selection of resistant organisms. Brief comments (not intended to be comprehensive) are made on the various classes of antibacterial, antiviral and antifungal agents.

79

Antibacterial Drugs

Beta-Lactams Penicillins, cephalosporins including cephamycins, monobactams and the carbapenems, are structurally related and share bactericidal activity primarily directed at the bacterial cell wall. Most beta-lactams are relatively safe, except in those patients hypersensitive to them.

Penicillins

Narrow Spectrum Penicillins These are mainly active against Gram-positive organisms and anaerobes but are inactivated by beta-lactamases produced by staphylococci and some other organisms. Benzylpenicillin (penicillin G) is administered parenterally. It still remains the treatment of choice for a number of infections. Procaine penicillin is an intramuscular preparation designed to extend the half-life of benzylpenicillin. It provides adequate levels for up to 24 hours but only against highly susceptible organisms. Benzathine penicillin is given intramuscularly and provides low levels of benzylpenicillin for up to 4 weeks. Phenoxymethylpenicillin (penicillin V) is acid-stable and thus may be given orally. It is intrinsically less active than benzylpenicillin.

Antistaphylococcal Penicillins Flucloxacillin is stable to beta-lactamase produced by staphylococci. Anaerobic activity is minimal to none, while these agents do not cover enterococci. Flucloxacillin is reliably absorbed by the oral route, although preferably taken on an empty stomach. It is generally well tolerated but has recently been found to be associated with cholestatic jaundice in some patients. This can manifest up to 6 weeks after treatment and may last for months. It is more commonly seen in elderly patients. This propensity should not prevent use of this excellent anti-staphylococcal drug in patients with serious infections. Dicloxacillin is now available in New Zealand. Dicloxacillin may be less hepatotoxic and therefore may be preferable to flucloxacillin particularly in elderly patients requiring prolonged therapy. It is not fully funded (as at August 2008), on the Pharmaceutical Schedule. Methicillin-resistant Staphylococcus aureus (MRSA) should be regarded as clinically resistant to all beta-lactams, irrespective of laboratory reports of susceptibility. Conversely, the treatment of choice for methicillin-sensitive Staphylococcus aureus (MSSA) is a beta-lactam antibiotic, not a glycopeptide. In New Zealand, many MRSA are not multi-resistant and therapy with macrolides, cotrimoxazole or tetracyclines may be efficacious (see separate section on MRSA management page 152). The practice of combining flucloxacillin with penicillin frequently occurs. There is hardly ever an instance when this is necessary. The belief that you are able to cover Staphylococcus aureus with flucloxacillin and not Streptococcus pyogenes is incorrect. Although it is true that the MIC90 of Streptococcus pyogenes to penicillin is 0.015µg/ml, the MIC90 of Streptococcus pyogenes to flucloxacillin is still excellent at 0.4µg/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents. If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered.

80

Broad-Spectrum Aminopenicillins Amoxycillin has greater activity than benzylpenicillin against some Gram-negative organisms, e.g. Escherichia coli, Haemophilus influenzae but are destroyed by beta-lactamase producing strains. It is the agent of choice against enterococci.

Antipseudomonal Penicillins Piperacillin and Ticarcillin (no longer marketed in NZ) are the only penicillins available that have activity against Pseudomonas aeruginosa. They are more expensive than most other penicillins.

Beta-Lactamase Inhibitors Clavulanic acid, sulbactam and tazobactam inhibit the β-lactamase enzymes produced by Staphylococcus aureus and Bacteroides fragilis; and also the ubiquitous TEM enzyme, found in Escherichia coli, Neisseria gonorrhoea and Haemophilus influenzae. They possess little inherent antibacterial activity, but in combination with penicillins such as amoxycillin, ticarcillin and piperacillin, they significantly extend their spectrum of activity. These combinations should be reserved for the treatment of organisms in which resistance to the beta-lactam antibiotic component is due to enzymes that these agents can inhibit. It should be noted that for Pseudomonas aeruginosa, the addition of a beta-lactamase inhibitor offers no increased activity. The combinations are often more expensive than the beta-lactam antibiotics alone. Amoxycillin/clavulanic acid can cause diarrhoea and cholestasis, which occur more frequently than with amoxycillin alone.

Carbapenems Imipenem/cilastatin, meropenem and ertapenem are now available in New Zealand. Due to inactivation by a renal dipeptidase, imipenem is formulated in combination with the dipeptidase inhibitor, cilastatin. This preparation has wide activity against enteric Gram-negative rods and Pseudomonas aeruginosa, comparable to that of aminoglycosides, and, in addition, has excellent activity against anaerobes including Bacteroides fragilis, and many Gram-positive organisms. However, it is not active against MRSA or some strains of Pseudomonas species. This drug is expensive and should not be regarded as a first-line agent. Meropenem is resistant to renal dipeptidase and can therefore be given alone. It also attains better levels in CSF than imipenem and the risk of seizures is said to be less than with imipenem. At Waikato Hospital, carbapenems are restricted to the Haematology/Oncology ward and Intensive Care. Meropenem is currently the major carbapenem used at Waikato Hospital. Ertapenem has a narrower spectrum of activity; Pseudomonas and Acinetobacter spp. are resistant. Its advantage is that it has a long half-life allowing for once a day administration. Ertapenem is currently on the Waikato Hospital formulary for use with ESBL infections.

Monobactams Aztreonam is a member of this family of beta-lactams. This compound is inactive against Gram-positive organisms and anaerobes but is highly active against the majority of aerobic Gram-negative bacteria, including beta-lactamase producing Haemophilus influenzae, enteric Gram-negative rods and Pseudomonas species, including those resistant to aminoglycosides. It can be given to people with severe penicillin hypersensitivity, as there is little cross sensitisation. It is expensive and has so far found little place in treatment of infections within WDHB.

81

Cephalosporins and Related Drugs For ease of understanding, the cephalosporins have been divided into four classes or "generations" which reflect their spectrum of activity and price. Widespread use of cephalosporins has now been linked with the increasing prevalence of infections due to methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), drug-resistant Streptococcus pneumoniae (DRSP) and multiresistant Gram-negative organisms.

First Generation Cephalosporins Cephalexin / cefaclor / cephradine and cephazolin are “first generation drugs” which have a similar range of antimicrobial activity. They are active against penicillinase-producing staphylococci and their Gram-negative spectrum includes Escherichia coli and Klebsiella species among the enteric Gram-negative rods. They are not active against Enterococcus faecalis or Listeria monocytogenes. Cefaclor has greater activity against Haemophilus influenzae and some authorities class this agent as a second-generation drug. No first generation cephalosporin has useful activity against the Gram-negative anaerobe, Bacteroides fragilis, nor against Gram-negative aerobes such as Serratia, Enterobacter or Pseudomonas. Cefaclor is only active against fully sensitive Streptococcus pneumoniae and not against intermediate or high-level penicillin-resistant strains.

Second Generation Cephalosporins Cephamandole and cefuroxime are "second generation drugs" which are more stable to some Gram-negative beta-lactamases. Cephamandole has activity against Gram-positives similar to that of the first generation cephalosporins. Cefuroxime’s spectrum of activity encompasses methicillin-sensitive staphylococcus and the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. In addition, it exhibits activity against Klebsiella pneumoniae, Proteus mirabilis and Escherichia coli. Enterobacter, Pseudomonas and Acinetobacter species are usually resistant. Cefuroxime is active against fully sensitive Streptococcus pneumoniae and is not as effective as amoxycillin against intermediate or high-level penicillin-resistant strains.

Cephamycins Cefoxitin and cefotetan (no longer marketed in NZ) are cephalosporin-like, but in fact, make up a separate class known as cephamycins. They are resistant to the extended spectrum beta-lactamases of gram-negative organisms. Cefoxitin and cefotetan are less active against gram-positive organisms, particularly against Staphylococcus aureus compared to the second-generation cephalosporins. They however, have greater activity against Bacteroides fragilis (60% to 70% of strains have been reported to be susceptible) than second generation cephalosporins. These drugs have a limited role in therapy and have traditionally been used for prophylaxis, although metronidazole provides superior cover for anaerobes than either cefoxitin or cefotetan.

Third and Fourth Generation Cephalosporins Cefotaxime, ceftriaxone, ceftazidime, cefepime and cefpirome are "third and fourth generation drugs" which have an extended spectrum of activity covering the majority of the enteric Gram-negative rods. Ceftriaxone has a considerably longer half-life than other members of this group. The activity of these drugs against Bacteroides fragilis is considerably less than the cephamycins. Third generation cephalosporins are less active against Gram-positive organisms than are earlier generations. None has clinically useful activity against enterococci or MRSA. However, unlike earlier cephalosporins, which do not enter the cerebrospinal fluid (CSF) in therapeutically

82

useful concentrations, third generation drugs have been effective in meningitis because of better penetration and higher intrinsic activity. Some organisms, e.g. Serratia, Citrobacter and Enterobacter species, have inducible beta-lactamases and resistance can develop during treatment. Combination therapy with an aminoglycoside has been suggested for serious infections with these organisms. Ceftazidime, cefepime and cefpirome have valuable activity against Pseudomonas aeruginosa, with cefepime and cefpirome having improved gram-positive activity compared with ceftazidime. All third and fourth generation cephalosporins are more expensive than gentamicin. Their use should be reserved for meningitis, resistant hospital pathogens and occasions where gentamicin or the other aminoglycoside antibiotics are contraindicated.

Penicillin Hypersensitivity and Cross-Reactivity Between 1% and 10% of penicillin courses result in manifestations interpreted as due to hypersensitivity. Anaphylaxis, angio-oedema and urticaria due to immunoglobulin E (IgE) directed against penicillin-derived antigens occur within 72 hours, often within minutes. Later manifestations (non-IgE) include fever, haemolysis and serum sickness-like reactions, but rashes are by far the most common. Delayed hypersensitivity may present up to 14 days after initiation of the antibiotic with erythema multiforme, toxic erythema or toxic epidermal necrolysis. Unless rashes are urticarial they may not represent acute hypersensitivity reactions and they may not recur. This is particularly so with rashes associated with amoxycillin. Immediate reactions may be serious or fatal, although fatal reactions are usually associated with parenteral rather than oral routes. Thus, a detailed history of penicillin reactions should always be sought before a course of penicillin is commenced. A history of an immediate hypersensitivity reaction (urticaria, angioedema, bronchospasm, or anaphylaxis within one hour of drug administration) contraindicates further exposure to penicillin and other beta-lactam drugs apart from aztreonam. Late manifestations are only a relative contraindication, although rashes, especially if associated with amoxycillin, are much less predictive of future problems. Cross-reaction to cephalosporins occurs in 3-6% of penicillin-allergic individuals. Carbapenem cross-reactivity is considered higher than with cephalosporins, whereas aztreonam cross-reactivity does not occur.

Skin Prick Testing Skin prick testing for penicillin allergy is not undertaken at Waikato Hospital or in the Hamilton region. Auckland Hospital Clinical Immunology service do provide testing, when a good clinical indication is present. Testing is performed with penicillin metabolites against which most specific IgE is directed: penicilloyl (major determinant); and penicilloate and penilloate (minor determinants). Negative skin test results using major and minor determinants reassure patients and carers that the risk of life-threatening penicillin allergy is negligible. There is a <0.1% risk of anaphylaxis after penicillin administration to a patient with a history of penicillin allergy and a negative skin prick test. This is a similar risk to that of patients who do not have a positive history.

Desensitisation It is possible to desensitise individuals. Desensitisation is appropriate for patients who require penicillin treatment who have a history of penicillin allergy with a positive skin prick test or a history of penicillin allergy when skin prick testing is not available.

83

If there has been a history of a life-threatening drug hypersensitivity, desensitisation should be carried out in a hospital setting, with an intravenous line in situ in the patient and resuscitation equipment available, including oxygen and adrenaline. Heart rate and blood pressure should be monitored every 15 minutes with continuous observation of the patient. Intensive Care should be made aware prior to commencing the protocol. Where non-life threatening features (e.g. rash) have occurred, desensitisation may occur on an outpatient basis with regular observation and telephone contact available, and with an action plan for hypersensitivity reactions in place. Protocols are available from the Pharmacy Department who will be involved in making up the solutions. The process involves administration of incremental doses of penicillin – oral followed by IV – given every 15 - 30 minutes. The whole process takes 5 to 6 hours. This process of acute desensitisation is effective and relatively safe. The first therapeutic dose should be given within 4 hours of the end of the desensitisation procedure. The state of desensitisation induced does not last longer than the penicillin course that is administered immediately after the desensitisation process.

Aminoglycosides Gentamicin, tobramycin and amikacin are active against aerobic Gram-negative bacilli including Pseudomonas and are amongst the most rapidly bactericidal drugs available for treatment of aerobic Gram-negative sepsis. Anaerobes are resistant. Alone they are inactive against enterococci, but in combination with penicillin (or amoxycillin) are synergistic. Gentamicin plus penicillin (or amoxycillin) is bactericidal for most enterococci. Although aminoglycosides are active against most staphylococci and may be life-saving in unsuspected staphylococcal sepsis, they should not be used alone to treat staphylococcal infections, because resistance commonly develops. Gentamicin is the aminoglycoside of choice for most cases of hospital-acquired aerobic Gram-negative sepsis. Tobramycin produces greater in vitro activity than gentamicin against Pseudomonas aeruginosa, but not other aerobic Gram-negative bacteria and is nine times more expensive. All aminoglycosides are potentially ototoxic and nephrotoxic, with clinically significant adverse effects more likely with advancing age or pre-existing renal impairment. Yet, despite these limitations, aminoglycosides remain a very valuable group of antibiotics for the treatment of infections within hospitals. During the 1990’s there was a significant change in the way aminoglycosides were prescribed, based on increased understanding of concentration-dependent killing and the post-antibiotic effect.

Pharmacodynamic Properties The aminoglycosides demonstrate a property known as concentration-dependent killing. Clinical studies have demonstrated that achievement of high peak serum concentrations of the aminoglycoside relative to the minimum inhibitory concentration of the micro-organism being treated, is the major determinant of the clinical response to the aminoglycosides. This optimisation of the Peak : MIC ratio, can best be obtained by the “extended interval" administration of aminoglycosides, which result in high peak concentrations of the drug (peak target ~ 20 µg/ml). In addition to this property of the aminoglycosides, these drugs also demonstrate a property known as the post-antibiotic effect, which may be defined as a period of time after complete removal of the antibiotic during which there is no growth of the target organism. Although "extended interval" dosing of aminoglycosides may result in a period of up to 12 hours during which there are no detectable serum concentrations of the drug, this property of the aminoglycosides allows for “extended interval” dosing without compromising therapeutic efficacy. This has now been confirmed by a large

84

number of studies.

Drug Toxicity The major determinant of aminoglycoside-induced renal and ototoxicity is the accumulation of these agents within both the renal cortex and the perilymph of the inner ear, respectively. Uptake and accumulation of aminoglycosides into renal cortical tissue demonstrates saturable kinetics. The saturable feature of these kinetics makes peak aminoglycoside concentrations irrelevant when considering tissue accumulation of the drug. Less frequent dosing of aminoglycosides allows for trough levels of the drug to fall well below the threshold for binding to their tissue receptors. This also allows for the back-diffusion of aminoglycosides from the renal cortex and inner ear that may theoretically limit drug toxicity. In animal models, rats receiving a single daily dose of aminoglycosides have demonstrated less nephrotoxicity and less renal accumulation of the drug than those rats receiving the same total dose by a multiple daily dosing schedule. For recommendations on dosing and monitoring of aminoglycosides, refer to Dosing, Pharmacokinetics and Pharmacodynamics Section (page 92).

Tetracyclines Tetracyclines all have a broad spectrum of activity, which includes Gram-positive and Gram-negative bacteria, Chlamydia, Rickettsia, Mycoplasma, Spirochaetes, some Mycobacteria and some Protozoa. Their main use is in the treatment of pelvic inflammatory disease, acne, periodontal disease, exacerbations of chronic obstructive pulmonary disease, brucellosis, plague, cholera and Lyme disease. Tetracyclines are contraindicated in pregnancy and lactation and in children <8-12 years of age. Minocycline and doxycycline each have a longer half-life and absorption is not significantly affected by the presence of food.

Sulphonamides and Trimethoprim Sulphonamides now have limited use. Sulphamethoxazole in cotrimoxazole, the combined formulation with the dihydrofolate reductase inhibitor trimethoprim, has in the past, found widespread use as a broad-spectrum agent, particularly in respiratory and urinary tract infections. However, the combination is associated with significant serious adverse affects due to the sulphonamide, especially in the elderly. Given that trimethoprim alone is highly effective in the treatment of urinary tract infections, the combination drug should be restricted to the few clinical situations where it is the drug of choice. These include the treatment and prophylaxis of Pneumocystis carinii infection, the treatment of Nocardia infection, the treatment of Listeria monocytogenes infections in patients with penicillin hypersensitivity and treatment of MRSA infections.

Fluoroquinolones This class of antibiotic has a broad spectrum of antimicrobial activity, good bioavailability, excellent penetration into tissues, long serum half-lives, and are generally well tolerated. Their major downfall is the alarming development of resistance with the use of these agents. Norfloxacin is used in the treatment of urinary tract and gastrointestinal infection. Ciprofloxacin has a wider range of therapeutic activity against Gram-negative bacilli including Haemophilus influenzae, enteric Gram-negative rods, Pseudomonas aeruginosa, some Gram-positive cocci, Gram-negative cocci, and various species of

85

Mycobacteria. They generally have poor activity against streptococci and in general should not be considered as the preferred therapy of gram-positive infections. Fluoroquinolone therapy is not advocated as first-line therapy for S. aureus osteomyelitis. These drugs are expensive and adverse effects are relatively common but most are not serious. They should be reserved for treatment of infections resistant to cheaper agents or where an oral agent with this particular antibacterial spectrum is required. Resistance to these fluoroquinolones has commonly occurred, especially where they have been widely used, principally in infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, enteric Gram-negative rods, Campylobacter species and Neisseria gonorrhoeae. Because of excellent bioavailability, oral use is the preferred route in most circumstances and in fact 750mg orally has a preferred pharmacodynamic profile than 400mg iv. Concomitant administration of iron, aluminium, calcium or magnesium-containing medicines can significantly reduce the gastrointestinal absorption of orally administered quinolones. Therefore, a gap of at least two hours should be allowed between these agents. Dairy foods containing large amounts of calcium will also reduce absorption. Quinolones damage the joints of immature animals and therefore should be used with caution in children under 14 years. Considerable experience in cystic fibrosis has shown that they can be used safely in the appropriate clinical situation. Quinolones are inappropriate for first line empiric therapy of common infections such as cellulitis, pharyngitis, otitis media, sinusitis, respiratory tract infections or acute osteomyelitis. Newer fluoroquinolones (moxifloxacin, gatifloxacin) with increased activity against Streptococcus pneumoniae (including drug-resistant strains) are now available in New Zealand (although not Pharmac funded). These drugs have increased activity against Gram-positive bacteria (including streptococci) and wide activity against Gram-negative aerobes (but inferior to ciprofloxacin against pseudomonas). They have good activity against anaerobes and most pathogens causing atypical pneumonia. Resistance is already beginning to be seen with these newer agents, which may limit their future. Currently, the role for these newer fluoroquinolones is extremely limited.

Macrolides The macrolides include erythromycin, roxithromycin, clarithromycin and azithromycin. They have a wide spectrum of activity covering Gram-positive cocci, Legionella, Bordetella, Corynebacteria, Gram-negative cocci, Mycoplasma, Chlamydia and both Gram-positive and Gram-negative anaerobes. They are not active against Gram-negative rods. The newer macrolides have more reliable absorption and longer half-lives, allowing less frequent dosing. They attain high intracellular concentrations that confer theoretical benefits in the treatment of intracellular pathogens. They also cause adverse effects less frequently than erythromycin. Erythromycin in all of its oral formulations has variable absorption and frequent GI side effects. Serious adverse effects are very rare, making it one of the safest antibiotics in clinical use. The only parenteral formulation, erythromycin lactobionate, frequently causes pain and phlebitis. Intravenous doses should be administered slowly to minimise local reactions and also to avoid arrhythmia. Erythromycin should not be given intramuscularly. Several oral preparations are available, including erythromycin base, the stearate, and the estolate forms. Although the blood levels achieved with these forms vary

86

somewhat, when the agents are used against very sensitive organisms, these minor differences are not believed to be clinically significant. Erythromycin ethylsuccinate has different absorption characteristics to other forms of erythromycin and therefore higher oral doses are needed to achieve therapeutic effects. 400mg erythromycin as the ethylsuccinate provides serum concentrations similar to those provided by 250mg erythromycin as the base, stearate or estolate. Unfortunately no one formulation seems to cause substantially less GI upset than others. Erythromycin may produce interactions with other drugs by inhibiting hepatic metabolism vai the cytochrome P450 enzyme system. Waikato District Health Board is now only stocking Erythromycin ethylsuccinate (August 2008) so whenever erythromycin is referred to in this document it is the succinate form. Roxithromycin is an alternative to oral erythromycin. It has good oral bioavailability and may cause less gastrointestinal upset than erythromycin, but is slightly more expensive. It is fully funded on the Pharmaceutical Schedule. Clarithromycin, unlike other macrolides, has a microbiologically active metabolite. It is generally suitable for indications similar to those of erythromycin. It has activity against Mycobacterium avium complex and is used in combination with other agents for the treatment of this infection in patients with AIDS. It is not fully funded (except under special authority for specific indications). Azithromycin has good in vitro activity against a wider range of organisms than erythromycin. It is more active against Haemophilus influenzae. It has good oral bioavailability and in particular rapid and sustained uptake by tissues. Once daily dosage of this drug is generally acceptable. Azithromycin can be used for the usual indications of erythromycin and also for Neisseria gonorrhoea and chlamydial genital tract infections. It is also used for the treatment of cerebral toxoplasmosis in patients with AIDS. Azithromycin has recently been used for uncomplicated typhoid fever (Clin Infect Dis 2004;38:951-957). It is currently fully funded for urethritis and cervicitis due to Chlamydia trachomatis. Glycopeptides Vancomycin and teicoplanin are effective only against gram-positive organisms. They play an important role in the treatment of methicillin-resistant organisms and in treating severe infection with susceptible organisms in patients who are hypersensitive to penicillin. Glycopeptides are not as effective as Beta-lactam antibiotics in the treatment of sensitive Staphylococcus aureus. Vancomycin is given by intravenous infusion over at least 1 hour to avoid producing the "red man syndrome". Teicoplanin can be given by intramuscular injection or by slow intravenous injection or infusion. Teicoplanin is considerably more expensive, no more efficacious, with a similar toxicity profile and should only be considered as a second-line agent. As a result of the emergence of Vancomycin-resistant Enterococcus and the theoretical threat of Vancomycin-resistant Staphylococcus aureus, they need to be used very wisely. The following are the recommended indications for use of parenteral glycopeptides: • Treatment of proven serious methicillin-resistant staphylococcal infections (S.

aureus or coagulase negative staphylococcus); • Initial treatment of serious infections with a high probability of being caused by

coagulase-negative staphylococcus; • Infections related to use of a central line; • Infections involving a prosthesis; • Sternotomy infections; • Treatment of bacterial endocarditis caused by methicillin-resistant S. aureus or

87

coagulase-negative staphylococcus; • Treatment of bacterial meningitis caused by flavobacteria or penicillin-resistant

pneumococcus (+ cefotaxime); • Treatment of central nervous system (CNS) shunt infections caused by methicillin-

resistant staphylococci (+/- removal of infected appliance, +/- use of rifampicin); • Treatment of other infections caused by organisms susceptible only to vancomycin

(e.g. Corynebacterium jeikium); • Enterococcal infections resistant to ampicillin; and • Treatment of serious Gram-positive infections in patients with major penicillin

allergy (i.e. anaphylaxis, exfoliative dermatitis or severe urticaria). Oral Vancomycin should not be used as first line therapy in Clostridium difficile diarrhoea. It should be reserved for severe cases unresponsive to metronidazole.

Lincosamides Clindamycin is active against Gram-positive aerobes and most anaerobes. Although clindamycin has received a great deal of attention as a cause of C. difficile diarrhoea, this condition is now recognised to complicate almost all antibiotic therapy. It should be used as a second choice in those who cannot tolerate conventional therapy. It also has a role to play in the management of Toxoplasma gondii infection. Both oral and intravenous formulations are available. The oral formulation has 90% bioavailability. The intravenous formulation is expensive but is rarely required in someone with a functioning GI tract.

Linezolid Linezolid is the first in a new class of antibiotics called oxazolidinones. It is effective against Gram-positive organisms including MRSA, coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant strains of Streptococcus pneumoniae. Dosing is twice daily. Myelosuppression is common with prolonged administration and haematology should be monitored weekly. Peripheral neuropathy has also been seen with prolonged therapy. The drug is also known to have monoamine oxidase inhibitory activity. It is available in both oral and IV formulations. It is extremely expensive and is not on the WDHB formulary or PHARMAC funded. Its usage within WDHB will only be after discussion with the Infectious Diseases Service. The major value of this new therapy will probably be in the long-term management of chronic infections with multi-resistant Gram-positive organisms. Currently, other options usually exist for this indication. A monitoring programme to avoid adverse reactions has recently been published in Antimicrob Agents Chemother 2006;50:1599-602.

Nitroimidazoles Metronidazole has a spectrum of activity that encompass Gram-negative anaerobes such as Bacteroides fragilis, Gram-positive anaerobes such as Clostridium species and anaerobic protozoa including Trichomonas vaginalis, Giardia lamblia and Entamoeba histolytica. Metronidazole is available as an intravenous preparation; however excellent absorption means that tablets or suppositories can often be used instead. Tinidazole, is no longer funded within New Zealand (Aug 2008). These agents may cause a disulfiram-like reaction with alcohol. Recommended dosage for metronidazole is 400mg orally or 500mg IV with a 12-hourly dosing schedule. This is based on pharmacokinetic data and minimum inhibitory concentrations of the pathogens involved, rather than formal clinical studies.

Rifampicin Apart from its important role as an anti-tuberculous and anti-leprosy agent, rifampicin is

88

used to eradicate nasopharyngeal carriage of N. meningitidis, H. influenzae and S. aureus, and as an adjunct to other antibiotics in serious staphylococcal infection. Rifampicin causes red discoloration of body fluids and occasional influenza-like symptoms and hepatotoxicity. It interferes with oral contraceptive metabolism.

Antiviral Drugs

Purine Nucleoside Analogues Aciclovir is active against Herpes simplex virus and to a lesser extent Varicella-zoster virus. It is the drug of choice for severe infections caused by these viruses. Intravenous doses should be administered slowly. Valacyclovir and famciclovir, which have longer half-lives, are no longer funded in New Zealand. Ganciclovir is used for the treatment of serious cytomegalovirus infections in immuno-compromised patients. Unfortunately, it has dose-dependent bone marrow suppressive effects. The drug also has demonstrated mutagenicity in mammalian cells and carcinogenic potential in animals. Solutions for iv infusion must therefore be prepared in a biohazard cabinet (currently prepared at Waikato Hospital by Baxter).

Neuraminidase Inhibitors Zanamivir and Oseltamivir can shorten the duration of influenza symptoms by about one day if commenced within 48 hours of the onset of symptoms. Both drugs are neuraminidase inhibitors. Zanamivir is produced in a diskhaler format (and should be used with caution in severe asthmatics) while Oseltamivir is an oral medication. The advantages of one over the other are still to be clarified by further trials. These agents are not funded by Pharmac.

Antiretroviral Drugs The last decade has seen an explosion in the number of anti-retroviral therapies specific for HIV infection become available. There were seven nucleoside analogue reverse transcriptase inhibitors (NRTIs), two non-nucleoside reverse transcriptase inhibitors (NNRTIs), six protease inhibitors and an HIV fusion inhibitor currently funded for use within New Zealand as at August 2008. Antiretroviral prescribing can only be undertaken by named specialist. At the time of publication only Dr Jane Morgan and Dr Graham Mills were approved to initiate antiretroviral therapy.

Antifungal Agents The number of systemic antifungal agents has grown considerably during the last decade. The newer agents are usually confined to specific infections in the setting of immunocompromised individuals.

Polyenes Amphotericin Β is a polyene compound that remains the treatment of choice for most serious fungal infections having the broadest spectrum of any antifungal compound currently marketed. The major action of amphotericin B is to damage the membrane of fungal cells. It has significant and serious side effects, predominantly renal toxicity. Consultation with an infectious diseases physician or clinical microbiologist is advised concerning its use. Liposomal amphotericin is less toxic but is extremely expensive (up to $3000 per day dependent on dose used). Evidence of increased efficacy against fungal infection compared with the standard preparation of amphotericin Β is anecdotal only. It is likely to be used only in extremely exceptional circumstances after prior use of standard amphotericin Β when significant toxicity has occurred and alternative

89

antifungal agents are not appropriate. Amphotericin has a long half-life (up to 15 days). It is initially given once daily, although once control of fungal sepsis has been achieved, alternate day dosing can be used. Dosage modifications of amphotericin B are not required in patients with renal insufficiency, in keeping with the low renal excretion of the drug. Hypersensitivity to amphotericin is common and consists of headache, fever, severe rigors, chills, malaise, muscle and joint aches, and hypotension. Symptoms subside within 4 hours after discontinuance. The occurrence of this side effect decreases with continued therapy. Intravenous hydrocortisone (50-100 mg) and promethazine can be given prior to commencing the amphotericin infusion, although the hypersensitivity reactions are, in part, dose-related. The patients should be closely observed during the first dose, but daily incrementation of the dose is not necessary. Regular monitoring of serum electrolytes, renal function and full blood count is essential. Amphotericin is usually infused in 500 ml 5% dextrose, although for volume-restricted patients, amphotericin B can be given in a concentration of 0.5mg/ml of 5% dextrose. It is typically infused via a central line as peripheral venous administration may predispose patients to develop phlebitis because of the irritant effect of amphotericin B. IV administration of 0.5 to 1L sodium chloride 0.9% prior to the amphotericin infusion is strongly recommended. When commencing amphotericin, a slow infusion is recommended over 6 hours. If the patient tolerates this for two successive doses without any evidence of an allergic response occurring, then the infusion can be shortened down to a 2 - hour infusion for subsequent doses. Amphotericin is nephrotoxic, although impaired renal function is generally reversible after discontinuation of therapy. Irreversible renal damage is rare. One must be cautious about using amphotericin in combination with aminoglycosides, vancomycin, cisplatin or cyclosporin.

Imidazoles Clotrimazole, econazole, ketoconazole and miconazole are broad-spectrum antifungal drugs, which are used in mucocutaneous candidiasis, dermatophytosis and tinea versicolor. Clotrimazole has some activity against trichomonas, and ketoconazole shampoo is used in the treatment of seborrhoeic dermatitis and dandruff. Ketoconazole is active against a variety of fungal infections, particularly yeasts. It has acid-dependent oral absorption (similar to itraconazole) and is not significantly excreted in the urine. Hepatotoxicity may occur and liver function tests need to be monitored monthly. It blocks steroid synthesis and may lead to hypoadrenalism and reduction in testosterone levels. Ketoconazole has significant interactions with other drugs that are metabolised in the liver by CYP3A4 isoforms of the cytochrome P450 enzymes.

Triazoles Fluconazole has a narrow spectrum of antifungal activity, and clinical use is usually limited to treatment of Candida species. It has good tissue penetration, including penetration into the central nervous system. It is well absorbed following oral administration. Itraconazole absorption is increased with acidic drinks and food. Itraconazole has a similar spectrum to fluconazole, except for increased activity against filamentous fungi such as Aspergillus species.

90

Itraconazole has significant interactions with other drugs that are metabolised in the liver by the cytochrome P450 enzymes. Fluconazole has a lesser effect on the same pathway. Voriconazole and Posaconazole are newer triazole antifungals structurally related to fluconazole with a spectrum of action similar to itraconazole. They can be used for the treatment of invasive aspergillosis, and serious infection with Candida species, Scedosporium species and Fusarium species. Voriconazole is available both as oral and intravenous preparations, with an oral bioavailability of 96%. As voriconazole is eliminated via a cytochrome P450 pathway, the potential for drug interactions is high. Voriconazole is expensive and should be restricted to patients with proven invasive aspergillosis intolerant or unresponsive to amphotericin Β. Voriconazole is active against Aspergillus species, Scedosporium apiospermum and Fusarium species. Posaconazole (currently only available in an oral formulation) is active against Candida and Aspergillus species. It also has activity against Coccidioides immitis, Fusarium, Histoplasma, Zygomycetes and phaeohyphomycetes.

Caspofungin Caspofungin is the first in a new class of antifungal agents called the echinocandins, which inhibit β-1,3-D-glucan synthesis in the cell wall in a novel way. It is used in the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies, such as amphotericin or voriconazole. It is administered by slow IV infusion. It is not available in oral formulation.

Flucytosine Flucytosine is a fluorinated pyrimidine analogue, with antifungal properties. It is available for oral or parenteral use although it is unregistered in New Zealand and requires a Section 29 application. It is mainly used in a synergistic combination with amphotericin against Cryptococcus neoformans. High serum levels, which often occur with renal impairment, are associated with bone marrow toxicity and monitoring of serum concentrations is therefore advised.

Terbinafine Terbinafine is fungicidal for many dermatophytes. It is well absorbed from the gut and is of value in treating fungal infections of the skin and nail. It should be used with caution in patients with hepatic diseases. It may be used topically.

91

DOSING, PHARMACOKINETICS AND PHARMOCODYNAMICS

The pharmacology of antimicrobial therapy can be separated into distinct components. The first of these is pharmacokinetics, which deals with the absorption, distribution, metabolism and elimination of antimicrobials. It is these factors that determine the time course of antimicrobial concentrations in serum and tissues for a given dosing regimen. Pharmacodynamics, the second component, is concerned with the relationship between concentration and the antimicrobial effect.

IMPORTANT PHARMACODYNAMIC PRINCIPLES 1. The minimum inhibitory concentration is the minimum in vitro concentration of

antibiotic required to prevent inoculum growth. The MIC predicts bacteriologic response to therapy.

2. Post-antibiotic effect is the recognised in vitro and in vivo inhibition of growth

despite sub-MIC levels of antibiotics. It is recognised that increasing the peak level of an antibiotic will also increase the post-antibiotic effect. The effect varies depending on class of antimicrobial agent and pathogen. An example of post-antibiotic effect is shown below.

Antibiotic Staphylococci Pseudomonas Beta-lactam 3 h 0 h Vancomycin 4 h N/A Aminoglycoside 3 h 6 h Quinolone 3 h 6 h

3. The relationship between tissue levels and serum levels. As most infections occur

in tissues and the common bacterial pathogens are extracellular, interstitial fluid concentrations at the site of infection are the prime determinants of efficacy. Most tissue sites within the body can be described as having a large capillary surface area across which antimicrobials diffuse into a relatively small volume of interstitial fluid. Drug concentrations at these sites will show little lag and therefore antibiotic levels will be very close to serum concentrations. Some tissue sites such as blister, pleural, peritoneal and synovial fluids have a lower ratio of surface area to volume than most other tissues. Concentrations at these sites will therefore lag behind those in serum, resulting in lower peak concentrations but higher trough levels.

4. Two major patterns of bactericidal activity are now recognised. These are termed

"concentration-dependent killing" and "time-dependent killing". An understanding of these concepts will have a major impact on how antibiotics are prescribed.

Concentration-dependent bactericidal activity is characterised by a greater extent

and rate of bactericidal activity with higher drug concentrations. Figure 1 demonstrates this characteristic. This pattern of killing is observed with the aminoglycosides, fluoroquinolones, and metronidazole.

92

Time

Fig 1: Concentration Dependent Bactericidal Activity Rate of Kill K3 > K2 > K1

Time-dependent bactericidal activity is characterised by a saturation of the rate of killing at concentrations near the MIC. Thus, high concentrations will not kill the organism faster or more extensively than low concentrations. The duration of exposure rather than the concentration is the major determinant of the extent of killing. This pattern of bactericidal activity is seen with beta-lactams, vancomycin, macrolides and clindamycin. Figure 2 demonstrates this characteristic. Furthermore, animal studies have revealed that maximal efficacy for an antibiotic with time-dependent bactericidal activity can be achieved when serum levels are above the MIC for only 60% of the dosing interval, and as low as 25% for some organisms.

Time

Fig 2: Time-Dependent Bactericidal Activity Rate of Kill K0 is constant

The pharmacodynamic characteristics described reveal that the time course of antimicrobial activity varies markedly for different antimicrobials and can not be based solely on half-life of the antibiotic or the MIC data for a particular organism. It is with this in mind that the dosing guidelines for various antibiotics have been defined. Much of this pharmacodynamic data is relatively new, differing from some of the traditional dosing approaches used in the past.

Con

cent

ratio

n

K3

K2

K1

………………………………….………..………….…..…… MIC

Con

cent

ratio

n

K0

…………………………………………..…………………….. MIC

K0

K0

93

AMINOGLYCOSIDES: PRINCIPLES OF USAGE AND DOSING The aminoglycosides demonstrate concentration-dependent killing. Clinical studies show that a high peak serum concentration relative to the Minimum Inhibitory Concentration (MIC) of the micro-organism being treated, is the major determinant of the clinical response to the aminoglycosides. This optimisation of the Peak : MIC ratio, can best be obtained by the “extended interval" administration of aminoglycosides, which result in high peak concentrations of the drug (peak target ~ 20 µg/ml). In addition, these drugs also exhibit a post-antibiotic effect, which is a period of time after complete removal of the antibiotic during which there is no growth of the target organism. Although "extended interval" dosing of aminoglycosides may result in a period of up to 12 hours during which there are no detectable serum concentrations of the drug, this property of the aminoglycosides allows for “extended interval” dosing without compromising therapeutic efficacy. The principal goal to achieve good efficacy in aminoglycoside therapy is therefore to achieve a peak of 10 – 20 mg/L. Some patients, such as children, have very rapid clearance. Other patients, such as those with burns, have unusually high volume of distribution and require higher mg/kg doses. These cases may be recognised when levels 8-12 hr post dose are unexpectedly low. A secondary alternative goal is to achieve an area under the curve of 70-100 mg/L.h. Toxicity Toxicity may still occur in some cases where target levels have been adhered to, particularly after prolonged courses and in pre existing renal failure. This obligatory small risk is usually offset by aminoglycosides’ high potency, relative absence of resistance, narrow spectrum, low cost and efficient once daily administration. However, for courses longer than 7 days, specialist advice should be sought to weigh the risks and benefits. The major determinant of aminoglycoside-induced renal and ototoxicity is the accumulation of these agents within both the renal cortex and the perilymph of the inner ear. Uptake and accumulation of aminoglycosides into renal cortical tissue demonstrates saturable kinetics. This makes peak aminoglycoside concentrations unimportant when considering tissue accumulation of the drug. Less frequent dosing of aminoglycosides allows for trough levels of the drug to fall well below the threshold for binding to their tissue receptors. This also allows for the back-diffusion of aminoglycosides from the renal cortex and inner ear, which may theoretically limit drug toxicity. The major goal for avoiding aminoglycoside toxicity is therefore to achieve a low trough level, preferably below 1 mg/L for gentamicin and tobramycin. AMINOGLYCOSIDES: DOSING AND MONITORING Contraindications

• Previous vestibular or auditory toxicity due to aminoglycoside • Serious hypersensitivity reaction to aminoglycoside (rare)

Precaution if used > 48-72 hr

• Pre existing conductive hearing problem or vestibular problem

94

• Neuromuscular disorders • Chronic liver disease or cholestasis (bilirubin > 90 micromole/L) • Chronic renal failure or deteriorating renal function

Alternative agents

• 3rd and 4th generation cephalosporins eg ceftriaxone, ceftazidime or cefepime (the latter two for Pseudomonas)

• Fluroquinolones eg ciprofloxacin (not moxifloxacin) • Carbapenems eg meropenem or ertapenem (use is restricted for ecological and

stewardship reasons). Dual agent therapy

• With another active agent for severe Pseudomonal infection • With penicillin or amoxicillin for endocarditis

Administration IV infusion over 30 min.

• Neuromuscular blockade may occur with rapid administration. The standard dose size is 5 mg/kg of “dosing weight”

• “Dosing weight” is “ideal body weight” or an adjusted “obese dosing weight” (see below).

• Round the dose to the nearest 20 or 40 mg for adults. • Adjustment within the range 3 – 7 mg/kg may be required for specific patients

(see below). • An initial stat dose of 5 mg/kg may be given safely to most patients and

subsequent doses adjusted the next day. The standard dose interval is 24 hr

• In most cases, adjusting the interval is the preferable way to manage dosing. • Use the nomogram below to adjust the interval. • Adjustment within the range 16-48 hr may be necessary, guided by monitoring

levels. • Intervals in multiples of 12 hr are most convenient and foolproof. • If intervals beyond 48 hr are indicated, change to another agent. • Renal function is the main determinant of dosing interval. • 8 hrly dosing may be used in specific situations such as endocarditis synergy

and for neonates, in pregnancy and >20% burns. • Close monitoring and dose by dose adjustment is required in renal failure (CrCl

< 0.5 mL/s) and alternative agents are preferred.

95

Monitoring Courses over 7 days: consult with infectious diseases specialist as to the benefits versus risks. Consider monitoring renal function, vestibular and auditory function. Toxicity (particularly ototoxicity) may occur with long term use even if serum gentamicin levels are satisfactory. It is not necessary to measure drug levels if renal function is normal and the course is < 48 hr. Frequency of monitoring

• Initial test: after 24-72 hr of treatment • Long term monitoring: weekly with additional 3 x weekly serum creatinine • Recheck aminoglycoside levels if renal function improves or declines

significantly. • Dose adjustment: remeasurement is often useful at 24 – 48 hr intervals until a

stable satisfactory dose is established. The preferred time to measure levels is 8 – 12 hr post dose.

• Suitable when renal function is mildly impaired ie CrCl > 0.5 mL/s • Usually gives a measurable non zero figure. • Will pick up cases with slow clearance and those with large Vd. • Minor errors in recording the administration and sampling times won’t severely

affect interpretation. • Target level 2-7 mg/L, depends on time of sampling relative to last dose. See

nomogram. Measure peak and trough levels if difficulty is encountered.

• eg unusual Vd or body composition, changing or unpredictable renal function, if significant drug accumulation is suspected

• Peak sample: 30 min after end of 30 min infusion. • Target: gent and tobra 10-20 mg/L, amikacin 40-60 mg/L • Trough sample: within 2 hr of next dose. • Target: gent & tobra < 1mg/L, amikacin < 4 mg/L • For 8 hrly dosing, gent & tobra targets are peak: 5-10, trough <2 (4x time this

for amikacin). How to adjust doses

• Try for simple, conventional dose sizes and intervals to minimise administration errors.

• The Clinical Microbiologist or Infectious Diseases Physician is available to discuss cases.

• First, try to adjust the interval, using the nomogram. • Second, adjust the dose size if necessary. • Third, take peak and trough levels if a satisfactory result is not achieved after a

couple of days (sooner if problems are anticipated). • Fourth, change to an alternative agent if satisfactory levels can’t be readily

achieved.

96

Calculation of Dose Size

• Use “Ideal Body Weight” (IBW) to calculate the dose, or the actual body weight (if less than IBW).

IBW (male) = 50kg + 0.9kg for each cm >150cm in height IBW (female) = 45.5kg + 0.9kg for each cm >150cm in height

• If an individual is > 20% above IBW, dosing should be based on the obese dosing weight (ODW) which is calculated: ODW = IBW + 0.4 (Actual BW - IBW).

Ideal Body Weight Chart Height Males

(kg) Females (kg)

155 cm / 5’2” 55 50 160 cm / 5’4” 60 55 165 cm / 5’6” 64 60 170 cm / 5’8” 68 64 175 cm / 5’10” 73 69 180 cm / 6’0” 78 73 185 cm / 6’2” 82 78 190 cm / 6’4” 87 82 195 cm / 6’6” 91 87 Aminoglycoside Starting Doses for Special Cases Special Cases Starting Dose for Extended

Interval Dosing (24 – 48 hrly) mg/kg/day for gent or tobra For amikacin, multiply by 4

Neonates incl premature 3 Infants and Children < 10 y 7 10 - 29 y 6 30 - 60 5 > 60 y 4 Endocarditis, Streptococcal and Enterococcal

3 (gentamicin only)

Determination of Initial Dosing Interval

• The initial dosing interval is determined from an estimate of creatinine clearance. An estimate of creatinine clearance (CrCl) is made using the modified Cockcroft formula (Intensive Care Med 1993, 19:39).

CrCl (ml/sec) = (140 - age) x ideal body weight (IBW) in kg ( x 0.85 if female) serum creatinine (µmol/L) x 50

97

A creatinine clearance calculator is also available on the Intranet under Clinical Guidelines/Utilities.

• The initial dose interval is then selected according to guidelines below: Creatinine Clearance (mL/s) Initial Dosing Interval

5mg/kg for gentamicin and tobramycin. Amikacin doses are 4x those.

>1.0 q24 h 0.7 – 0.99 q36 h 0.5 – 0.7 q48 h <0.5 Consider alternative antibiotic.

One stat dose then seek specialist advice. Nomogram for Dose Interval Adjustment

• Start with the time the sample was taken after the most recent dose, read up to the measured aminoglycoside level and adjust the dose interval to that shown.

• If the measured level is undetectable, next time measure the peak level; increasing to 7mg/kg may be helpful.

Note: This nomogram may be used for either gentamicin or tobramycin and is calibrated for a dose of 5 mg/kg. For amikacin, multiply mg by 4. Source: Therapeutic Guidelines Antibiotic 13th ed 2006.

98

Vancomycin Dosing Vancomycin’s bactericidal effect appears to depend on the area under the curve. Vancomycin’s reputation for lower potency compared to beta lactams may stem partly from under dosing with standard regimens in patients with good renal clearance. The practical way to assure optimum dosing is to measure trough levels. Current recommendations are that trough levels should be 10 – 20 µg/ml in those patients receiving 12-hourly dosing. The MIC values for most Staphylococcus aureus are 0.5-1 µg/ml and for Enterococci and Coagulase Negative Staphyloccci may range up to 2 µg/ml. In cases of serious infection, the MIC should be checked because at levels of 2 or 4 µg/ml vancomycin will not be so effective. With MRSA, small moderately resistant subpopulations (heterogenous Vancomycin Intermediate S aureus, hVISA) may occur, which are difficult to detect in the laboratory and may result in therapeutic failure. Prolonged, subtherapeutic vancomycin dosing appears to allow such strains to emerge in an individual patient during treatment. If the patient does not improve on vancomycin, repeat cultures should be obtained and the case discussed with the laboratory so the organism may be sent to a reference laboratory to check for occult resistance. Fully Vancomycin Resistant Enterococci (VRE) and S. aureus (VRSA) due to VanA or VanB have MIC ≥ 32 µg/ml. VRE has been recognised in recent outbreaks within Auckland hospital (2007) and Waikato hospital (2008). Vancomycin must be given intravenously for systemic infections. It is not absorbed when given orally and IM injections cause tissue necrosis. Ototoxic and nephrotoxic effects of this drug are now considered to be minimal and not related to specific serum concentrations. However, vancomycin appears to potentiate the ototoxicity and nephrotoxicity of aminoglycosides. Careful monitoring is required when administering vancomycin together with an aminoglycoside or other drugs that are known to be cause ototoxicity or nephrotoxicity.

Usual Dose The usual adult starting dose is 1g iv 12 hourly. Vancomycin should be infused slowly over at least one hour to avoid anaphylactoid reactions and the ‘red man’ syndrome.

Dosing Interval As vancomycin is cleared solely by the kidney, an assessment of the patient’s renal function is required for determining the appropriate dosing interval. The initial dosage interval will be determined from an estimate of creatinine clearance, based on the patient’s age, weight and serum creatinine.

Creatinine Clearance (ml/sec) Dosing Interval > 1.0 q12 h 0.35 – 1.0 q24 h < 0.35 Repeat dose when Vanc level is 10-

20μg/ml

99

Monitoring • The primary aim of vancomycin monitoring is to ensure that dosing is adequate. • Peak levels are not performed, since they are not useful in predicting efficacy and

do not predict toxicity. • Trough levels should only be performed in a few select patient populations who

have been on vancomycin therapy for greater than 72 hours, including: - Patients with high (e.g. burn patients) or low (<0.9ml/sec) creatinine clearance.

- Patients receiving concurrent treatment with other nephrotoxic drugs (e.g. aminoglycosides, amphotericin B). - Patients with infections at sites where there is reduced penetration of

vancomycin (e.g. endocarditis, meningitis, pneumonia). • When trough levels are taken, the aim is to maintain a trough level of

10-20 μg/ml. • Trough levels should be drawn immediately before the next dose.

Adjusting the Dose • If the trough level is < 10 μg/ml.

- Decrease the dosing interval by one step. - Steps: q12h, q24h, q36h, and q48h. - If patient is receiving the dose q12h, increase the dose by 250-500mg.

• If the trough level is > 20μg /ml

- Increase the dosing interval by one step.

Monitoring Renal Function Check renal function periodically during the therapy, if the duration of therapy exceeds 72 hours. If signs of renal impairment develop, or if drug accumulation occurs, or trough levels fall too low, the dose must be reassessed.

Metronidazole Dosing Metronidazole, a nitroimidazole derivative, is a well-established antimicrobial for the prevention and treatment of anaerobic infections. Despite having a long serum elimination half-life of about 8 hours (range 6-12 hours), metronidazole has traditionally been administered every 6-8 hours. It has never been determined that such a frequency is necessary. Furthermore, dosing metronidazole every 6-8 hours will lead to drug accumulation after prolonged use, especially if there is liver impairment. It has been shown that a dose of 500mg every 12 hours is sufficient to maintain serum concentrations of the drug above the minimal inhibitory concentration (MIC) of most anaerobic pathogens for the duration of the dosing interval. There is also some limited data to suggest that metronidazole may have a post-antibiotic effect against certain anaerobic bacteria. Metronidazole’s bactericidal activity is based on concentration-dependent killing. All dosing recommendations in this booklet are based upon daily or twelve hourly dosing of metronidazole. Metronidazole has excellent oral bioavailability (95-100%) and the iv route should only be used when oral or rectal administration is not possible.

100

Beta-Lactam Dosing Beta-lactam antibiotics are frequently given in inappropriately high dosages. The treatments of meningitis and endocarditis are the only indications for "high" dosage, as serum levels may not necessarily reflect levels in the infected tissue. For most other infections, the magnitude of the peak level is no longer deemed relevant. Time-dependent killing means that the time above the MIC is the determinant of success. Examples of this would include ceftazidime for a sensitive Pseudomonas aeruginosa where 1g 8 hourly is more than adequate and ceftriaxone for systemic gram-negative infections where 1g 24 hourly is satisfactory.

101

IMPAIRED RENAL FUNCTION The presence of renal impairment may lead to the accumulation of toxic levels of antimicrobial drugs and/or their metabolites that are excreted totally or in part by the kidneys. Hence the dosage of such antimicrobials may require adjustment. The following table contains dosage recommendations for the majority of antimicrobial agents in common usage. In order to make the best use of the recommendations, it is necessary to calculate creatinine clearance, if it has not been formally measured. The most widely recommended method for doing this is to use the Cockroft-Gault formula below: CrCl (ml/sec) = (140 - age) x ideal body weight (IBW) in kg x 0.85 (if female) serum creatinine (µmol/L) x 50 Note that serum creatinine levels are now reported in µmol/L at Waikato Hospital. The upper limit of normal is around 100 µmol/L. If the ideal body weight is not easily calculated, the actual weight is usually satisfactory except in the morbidly obese (See Ideal Body Weight Chart, page 118). This formula will not accurately predict clearance in patients with rapidly changing renal function. In the presence of diminished renal function, doses may be altered by reducing the dose or by extending the interval between doses.

Legend For Dosage Guidelines (See following tables) 1 Method of dosage adjustment:

D = Dose adjustment I = Dosage interval adjustment.

2 Monitoring of levels recommended to determine precise dosage requirements. 3 Dosage for intraperitoneal administration. 4 Dosage in mg/L of filtrate removed. 5 nd = no data. 6 n/a = not applicable. 7 No supplement means that the dose given is the same as for GFR< 0.2 ml/sec. 8 Dose after means that the dose given is the same as for GFR < 0.2 ml/sec and it

should be withheld until after dialysis on days of dialysis. * Agents (often) used in combination, see also companion agent + Monitor for myelosuppression HAEMO Intermittent Haemodialysis CAPD Continuous Ambulatory Peritoneal Dialysis

102

Antimicrobial Therapy In Patients With Impaired Renal Function (i)

Drug Adjustment for Renal Failure by GFR (ml/sec) Doses for Dialysis

Dose Adjustment

Method2 > 1 ml/sec 0.2-1.0 ml/sec < 0.2 ml/sec Supplement for

HAEMO Supplement or Dose (D)

for CAPD Aciclovir D&I 8 hourly 12-24 hourly 50% 24-hourly dose after8 no supplement7

Amikacin2 D&I 50-100% 50% 24 hourly2 to 30% 48 hourly2

30% 48 hourly2 dose after8,2 15-20 mg/L of dialysate3 (D)2

Amoxycillin I 6-8 hourly 8-12 hourly 24 hourly dose after8 dose for GFR 0.2-1 Amoxycillin/ Clavulanate

D&I normal 8-12 hourly 50% 12 hourly dose after8 dose for GFR 0.2-1 nd5

Amphotericin - normal normal normal no supplement7 no supplement7

Azithromycin - normal normal normal no supplement7 no supplement7

Aztreonam D normal 50-75% 25% dose after8 no supplement7

Benzylpenicillin D normal 75% 20-50% dose after8 no supplement7

Cefaclor D normal 50-100% 50% dose after8 dose for GFR 0.2-1 (D) Cefepime D normal 50% 12 hourly 25% 24 hourly dose after8 no supplement7 Cefotaxime I 6 hourly 12 hourly 24 hourly dose after8 no supplement7

Cefotetan I 12 hourly 24 hourly 48 hourly dose after8 dose for GFR 0.2-1 (D) Cefoxitin I 8 hourly 8-12 hourly 24 hourly dose after8 no supplement7

Cefpirome D&I 100% 12 hourly

50% 12 hourly 50% 24 hourly 50% dose after8 nd5

Ceftazidime D&I 8-12 hourly 12-24 hourly 50% 24 hourly dose after8 no supplement7

Ceftriaxone - normal normal normal normal normal Cefuroxime I normal 8-12 hourly 24 hourly dose after8 no supplement7 Cephalexin I 6 hourly 6 hourly 8-12 hourly dose after8 no supplement7

Cephalothin I 6 hourly 6-8 hourly 12 hourly dose after8 no supplement7

Cephamandole I 6 hourly 6-8 hourly 12 hourly dose after8 no supplement7

Cephazolin I 8 hourly 12 hourly 24 hourly dose after8 dose for GFR 0.2-1 Chloramphenicol - normal normal normal no supplement7 no supplement7

Chloroquine D normal normal 50% no supplement7 no supplement7

103

Antimicrobial Therapy In Patients With Impaired Renal Function (ii)


Dose Adjustment



for CAPD Ciprofloxacin I 12 hourly 12-24 hourly 24 hourly dose after8 250 mg 8 hourly (D) Clarithromycin D normal 75% 50-75% dose after8 no supplement7

Clindamycin - normal normal normal no supplement7 no supplement7

Co-trimoxazole2,+ D&I 12 hourly 50% 12 hourly 50% 24 hourly (on dialysis)

dose after8 no supplement7

Doxycycline - normal normal normal no supplement7 no supplement7

Erythromycin D normal normal 50-75% no supplement7 no supplement7

Ethambutol I 24 hourly 24-48 hourly 48 hourly dose after8 no supplement7

Flucloxacillin I 6 hourly 8 hourly 12 hourly no supplement7 no supplement7

Fluconazole D normal 50% 50% dose after8 no supplement7

Flucytosine I 6-8 hourly2 12-24 hourly2 24 hourly2 dose after8,2 no supplement7

Fusidic acid - normal normal normal no supplement7 nd5

Ganciclovir+ I 12 hourly 24-48 hourly 48 hourly dose after8 no supplement7

Gatifloxacin D normal 50% 50% Dose after as per 0.2-1.0ml/sec

As for 0.2-1.0mL/sec

Gentamicin2 D&I normal 100% 36-48 hourly avoid dose after8,2 4-8 mg/L of dialysate3,2 (D) Imipenem/cilastatin D&I normal 50% 8-12 hourly 50% 12 hourly dose after8 nd5

Isoniazid D normal normal normal dose after8 no supplement7

Itraconazole - normal normal 50% no supplement7 no supplement7

Ketoconazole - normal normal normal no supplement7 no supplement7

Mebendazole - normal normal normal no supplement7 nd5

Mefloquine - normal normal normal no supplement7 no supplement7

Metronidazole - normal normal 50% dose after8 no supplement7 Meropenem D&I 8 hourly 50-100% 12 hourly 50% 24 hourly dose after8 nd5

Minocycline - normal normal normal no supplement7 no supplement7

Moxifloxacin - normal normal normal no data no data

104

Antimicrobial Therapy In Patients With Impaired Renal Function (iii)


Dose Adjustment



for CAPD Nalidixic acid D normal avoid avoid avoid avoid Nitrofurantoin - normal avoid avoid avoid avoid Norfloxacin I 12 hourly 12-24 hourly 24 hourly no supplement7 no supplement7

Phenoxymethyl-penicillin

D normal normal normal dose after8 no supplement7

Piperacillin I normal 8 hourly 12 hourly dose after8 no supplement7

Piperacillin Tazobactam

I normal 8 hourly 12 hourly dose after8 no supplement7

Praziquantel - normal normal normal no supplement7 nd5

Pyrazinamide D normal normal normal no data no data Pyrimethamine+ - normal normal normal no supplement7 no supplement7

Quinine I 8 hourly 8-12 hourly 24 hourly dose after8 no supplement7

Rifabutin - normal 50-100% 50% no supplement7 no supplement7

Rifampicin - normal normal 50-100% no supplement7 no supplement7

Roxithromycin - normal normal normal no supplement7 no supplement7

Sulphadiazine+ I 6 hourly 8 hourly 12 hourly nd5 nd5 Sulphamethoxazole*,+ I 12 hourly 18 hourly 24 hourly dose after8 no supplement7

Teicoplanin2 After dose on day 4 (I)

24 hourly 48 hourly 72 hourly no supplement7 no supplement7

Terbinafine D normal 50% 50% no supplement7 no supplement7

Tetracycline I 8-12 hourly avoid avoid avoid avoid Ticarcillin I 4 hourly 8 hourly 12 hourly dose after8 no supplement7

Tinidazole - normal normal normal dose after8 normal Tobramycin2 D&I 50-100%

24 hourly2 50% 24 hourly to 30% 48 hourly2

30% 48 hourly2 dose after8,2 3-4 mg/L of dialysate3 (D)2

Trimethoprim - normal normal normal dose after8 no supplement7

Vancomycin2 I 12-24 hourly 24-48 hourly every 4-10 days no supplement7 no supplement7

105

HEPATIC INSUFFICIENCY Although many antibiotics are metabolised in the liver and a few are excreted, to a significant extent, in the bile, precise guidelines for dosing in hepatic insufficiency are unavailable. There is no test of hepatic function, equivalent to creatinine clearance for renal insufficiency, on which to base dosage adjustments. It is prudent to avoid drugs with known hepatotoxicity when possible in those with hepatic failure. For manufacturer’s recommendations consult www.medsafe.govt.nz

http://www.medsafe.govt.nz/�

106

OBESE PATIENTS Antibiotic dosing is routinely adjusted for weight, but does not often take account of the variable proportions of tissues that comprise the body’s mass. The effect of obesity on the pharmacokinetics of antimicrobials is not very well understood. The volume of distribution of antibiotics in fat is only about 0.3 to 0.4 that of other tissues. The dosing weight is therefore often calculated as the ideal body weight plus 0.3-0.4 the difference between actual and ideal body weight. Since there is likely to be considerable individual variation, in the case of potentially toxic drugs e.g. aminoglycosides, levels should be measured and doses adjusted accordingly.

107

PREGNANCY AND LACTATION

Drugs in Pregnancy During the first 2 weeks of development, the embryo is thought to be resistant to any teratogenic effects of drugs. The critical period of embryonic development, when the organ systems develop starts at about 17 days after conception and is complete by 60 to 70 days. Exposure to certain drugs during this period can cause major birth defects. However, some drugs can interfere with functional development of organ systems and the central nervous system in the second and third trimesters and produce serious consequences. All drugs should be avoided if possible in the first 12 weeks of pregnancy. If drugs are to be prescribed, the benefits to the mother and/or foetus must be considerable. Discrepancies between recommendations on the safety of antimicrobials in pregnancy are a reminder that all prescribing involves risks and benefits that are often difficult to quantify. Manufacturers' recommendations tend to err on the side of caution and their warnings frequently reflect theoretical concerns or insufficient data rather than proven toxicity. No antimicrobial is absolutely contraindicated in all circumstances in pregnancy but the table below may allow choice of a safer alternative or raise the possibility of deferring treatment. Refer to the Description of Foetal Risk Categories (below) when prescribing any antimicrobial medications for women who are pregnant or lactating.

Description Of Foetal Risk Categories A Controlled studies show no risk. Adequate, well-controlled studies in pregnant

women have failed to demonstrate risk to the foetus.

B No evidence of risk in humans. As experience of effects of drugs in this category in humans is limited, results of toxicological studies to date (including reproduction studies in animals) are indicated by allocation to one of three sub-groups:

B1 Studies in animals have not shown evidence of an increased occurrence of foetal damage.

B2 Studies in animals are inadequate or may be lacking, but available data show no evidence of any increased occurrence of foetal damage.

B3 Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

C Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for foetal risk or lacking as well. However, potential benefits may justify the potential risk.

D Positive evidence of risk. Investigational or postmarketing data shows risk to the foetus. Nevertheless, potential benefits may outweigh the potential risk.

X Contraindicated in pregnancy. Studies in animals or humans, or investigational or postmarketing reports have shown foetal risk that clearly outweighs any possible benefit to the patient. Drugs that have such a high risk of causing permanent damage to the foetus should not be used in pregnancy or when there is a possibility of pregnancy.

108

Drugs in Lactation The benefits of breastfeeding are sufficiently important to recommend that breastfeeding should be discontinued or discouraged only when there is substantial evidence that the drug taken by the mother will be harmful to the infant and that no therapeutic equivalent can be given. Most antimicrobial drugs are only excreted to a minimal extent in breast milk, and in most cases the dosage to which the infant is ultimately exposed is very low and is well below the therapeutic dose level for infants. For this reason there are few antimicrobial drugs that are totally contraindicated whilst breastfeeding.

109

Antimicrobial Drugs In Pregnancy And Lactation (i)

Drug Category Use in Pregnancy (Foetal Risk Category)

Use in Lactation

ANTIBACTERIALS Penicillins A/B1 Safe

Caution high dose IV Cephalosporins A/B1 Safe Beta-lactamase inhibitors (e.g. clavulanate)

B Safe Caution high dose IV

Erythromycin (Do not use estolate during pregnancy - increased risk of maternal hepatoxicity)

A Safe

Clindamycin A Safe, monitor infant for diarrhoea

Nitrofurantoin A Avoid in premature infants. Caution with G6PD deficiency infants

Roxithromycin B1 Safe Aminoglycosides (Potential for foetal 8th nerve toxicity)

D Safe

Chloramphenicol (Avoid near term - risk of Grey Baby syndrome)

A Not recommended

Clarithromycin (Foetal toxicity in primates)

B3 Safe

Fusidic acid C Safe Metronidazole and other nitroimidazoles (Avoid during first trimester)

B2 Produces a bitter taste in milk Withhold breast-feeding for 24hrs after high dose or IV

Rifampicin (Neonatal bleeding, give Vitamin K if used during last few weeks of pregnancy)

C Safe

Trimethoprim (Avoid use in first trimester-teratogenic)

B3 Safe

Nalidixic acid A Caution especially in neonatal period

Vancomycin B2 Safe Tetracyclines (Discoloration of teeth, inhibition of bone growth, maternal hepatotoxicity)

D Short course is safe

Sulphonamides e.g. cotrimoxazole, sulphamethoxazole (Avoid near term - risk of kernicterus)

C Safe

Fluoroquinolones e.g. ciprofloxacin, norfloxacin (Damage to developing cartilage in animal models)

B3 Caution, monitor infant for diarrhoea

110

Antimicrobial Drugs In Pregnancy And Lactation (ii)

Drug Category Use in Pregnancy (Foetal Risk Category)

Use in Lactation

ANTIFUNGALS Amphotericin B B3 Uncertain Fluconazole D Safe Itraconazole B3 Uncertain Ketoconazole B3 Uncertain ANTIVIRALS Aciclovir B3 Safe Ganciclovir D Insufficient data Antiretrovirals (Therapy for HIV infection has not been associated with foetal risk and prevents transmission. Expert advice recommended).

Contraindicated in HIV positive women

111

ORAL ANTIMICROBIAL THERAPY

Switch Therapy The excellent pharmacokinetics and spectra of activity of many oral antimicrobial agents now enable the physician to choose an alternate approach to the treatment of infection in selected patients without compromising clinical outcome. Timely conversion from intravenous to oral agents has been referred to as switch, step-down or sequential therapy. This has been shown to be successful in the management of infections including those of the respiratory tract, skin and soft tissue, and bone and joint. In addition to reducing the costs of treatment, this approach to the management of infectious disease can be an important component in the provision of optimal patient care. Oral agents are generally much less expensive than parenteral; in addition, hidden costs such as plasma drug and toxicity monitoring, IV sets and specialised equipment, nursing and pharmacy time and wastage are avoided. In some patients, the antimicrobial may be given by mouth from the outset of treatment; this will depend upon the disease state, its severity and patient characteristics.

Advantages • Eliminates the risk of adverse events associated with intravenous therapy, such as

phlebitis and increased fluid burden. • Increases patient comfort and acceptance of therapy and permits increased patient

mobility. • Increases the potential for completion of treatment as an outpatient, allowing earlier

discharge from hospital. • Decreases the risk and severity of allergic reactions. • Reduces treatment costs.

Guidelines Patients eligible for conversion from parenteral to oral therapy should meet the following criteria: • Patient is tolerating oral or NG nutrition or is receiving medication by mouth or NG

tube. • Patient has a functional gastrointestinal tract. • Signs and symptoms related to the infection have resolved or are improving. • Patient does not fall within the parameters of exclusion as described below. • Patients should be excluded from immediate consideration for Switch Therapy if

they meet any of the following criteria: - Patient has an infection in which the continuation of parenteral therapy is

indicated, such as endocarditis, meningitis, line sepsis or Staphylococcus aureus, or Enterococcus spp. bacteraemia.

- Patient has febrile neutropenia.

Response to oral medication may be unreliable e.g. in the presence of continuous NG suction, malabsorption syndrome, ileus, protracted vomiting and severe diarrhoea. Treatment should be reinstated with the original parenteral regimen if continued improvement in the patient's clinical status is not apparent on oral therapy.

112

Selecting an Appropriate Oral Antimicrobial Drug The choice of oral antimicrobial agent should reflect the sensitivities of the micro-organism(s) involved. In the absence of a cultured pathogen, the oral agent should be chosen with consideration of the most likely causative organism and its usual sensitivities. It is not necessary to choose an oral agent from the same antimicrobial class as the parenteral agent being replaced. The following examples of regimen conversion are representative only and are not intended to be comprehensive. Doses will vary according to the clinical circumstances and patient characteristics. IV Drug and Representative Dose Oral Drug and Representative Dose Amoxycillin 1g q6h Amoxycillin 500mg q8h Amoxycillin/ 1.2g q8h clavulanate

Amoxycillin/ 500mg q8h clavulanate

Cephazolin 1g q8h Cephalexin 500mg q8h Cefuroxime 750mg q8h Amoxycillin/ 500mg q8h

clavulanate Ciprofloxacin 400mg q12h Ciprofloxacin 500-750mg q12h Clindamycin 300-600mg q8h Clindamycin 300-450mg q6h Erythromycin 500-1000mg q6h Erythromycin 800mg q6h Flucloxacillin 1-2g q6h Flucloxacillin 500-1000mg q6h Gentamicin 400mg q24h Ciprofloxacin 500mg q12h Metronidazole 500mg q12h Metronidazole 400mg q12h

113

Bioavailability Of Oral Antimicrobials

Drug Oral Absorption

(%)

Dose (mg)

Peak (μg/ml)

Half-Life (hr)

Protein Binding

(%)

Taken with

Meals ANTIBACTERIALS Penicillins Amoxycillin 60-89 500 5.0 1 17 Yes Amoxycillin/clavulanate 60 500 4.8 1 18 Yes Flucloxacillin 50 500 7-14 0.5 95 No Penicillin V 35-70 500 3-5 0.5 35 No Cephalosporins Cephalexin 90 500 15-18 0.5-1.3 5-15 Yes Cephradine 90 500 16 1.3 6-20 No Cefaclor 50 500 13 0.8 22-25 No Fluoroquinolones Ciprofloxacin 69-85 750 4.0 3 - 5 20-40 Yes Gatifloxacin 96 400 4.2-4.6 7-8 20 No Moxifloxacin 89 400 4.5 10-14 50 No Macrolides Erythromycin base Erythromycin stearate

18-45 18-45

250 500

0.3-1.0 0.4-1.9

1.4 70-74 No Yes

Roxithromycin 80 150 6 12 90% No Tetracyclines Doxycycline 90-100 100

200 1.8-2.9 3.7-6.7

18 93 Yes

Minocycline 95-100 200 2-3 11-26 76 Yes Tetracycline 75-80 250

500 1.5-2.2 3.0-4.3

8.5 65 No

Miscellaneous Clindamycin 85-90 600 5.3 2.4 85-94 Yes Metronidazole 90-100 250

500 5 10

6-14 20 Yes

Trimethoprim / Sulphamethoxazole

85-90 160/ 800

2/40

11/9 44/ 70

Yes

ANTIVIRALS Aciclovir 15-30 200 0.3-0.9 2.2-5.0 9-33 Yes ANTIFUNGALS Fluconazole 90 100

200 4.5-8 10

24 11-12 Yes

Ketoconazole Variable 200 3-4.5 6.5-9.6 84-99 Yes

114

PROPHYLACTIC USE OF ANTIMICROBIAL

DRUGS

SURGICAL PROPHYLAXIS Appropriate antimicrobial prophylaxis significantly decreases the incidence of post-operative infection following certain surgical procedures. The antibiotic regimen chosen for these procedures should be directed against the most likely infecting organism(s) (and not necessarily against every potential pathogen) and be designed so that the total number of organisms is decreased but not necessarily eliminated. Most postsurgicalinfections are due to the patient’s own organisms. In hospitalised patients, this may include multiresistant organisms, so the following recommendations may need to be individualised. Prophylaxis is the use of antibiotics to prevent infections at the surgical site. This must be distinguished from their use in early treatment, where infection is already established although not necessarily evident preoperatively (eg removal of a perforated appendix).

Major Indications for use of Prophylactic Antibiotics • Operations in which the risk of post-operative wound infection are high e.g. clean-

contaminated surgical procedures. • Operations in which the wound infection rate is relatively low but the consequences

of infection are significant e.g. prosthetic implants.

Principles for timing of Antibiotic Administration For effective antimicrobial prophylaxis, the drug must be present in the tissues in adequate concentration at the onset and throughout the operative procedure. To achieve this goal, the initial dose must be administered parenterally in the immediate pre-operative period (within 30 minutes) before the operation. Delaying initial dosing until the post-operative period or giving the antibiotics too far in advance of the procedure are both associated with an increased wound infection rate. Rectally administered metronidazole should be given 2 to 4 hours before surgery. Vancomycin requires a slower infusion that should be completed just prior to induction.

Route(s) of Administration Intravenous administration is the optimal method to ensure adequate tissue levels during the operative procedure. In certain instances rectal or oral administration is appropriate.

Duration of Antibiotic Treatment The critical period for successful prophylaxis is the 4 hours following implantation of organisms into a wound. In general, a single dose of parenteral antibiotic is sufficient

115

for most surgical procedures lasting less than 4 hours. A second dose may be necessary under the following circumstances: • A delay in starting the operation. • If the operation is prolonged so that it continues beyond four hours. • In specific circumstances e.g. amputation of an ischaemic limb. Giving more than 1 or 2 doses postoperatively is not advised, except where specifically recommended. Established infection should of course be treated. Note: • Prophylactic antibiotics are only one factor that determines the risk of infection.

Other factors of equal or even greater importance are surgical technique, the duration of surgery, the duration of pre-operative stay, shaving the operation site (if this must be done, do so immediately pre-operatively), repeat surgical procedure, obesity, immune compromise and a variety of other host factors (eg diabetes).

• Excessively long courses of 'prophylactic' antibiotic, whether before or after surgery, select for resistant organisms and may increase the risk of infection. The practice of continuing prophylactic antibiotics until surgical drains have been removed is both illogical and of unproven benefit.

Choice of Antibiotic There are several considerations when selecting an antimicrobial regimen for prophylaxis: • Antibiotics should have a spectrum of activity, which includes the pathogens most

frequently responsible for wound infection following a given operation. • The antibiotics need not be active against every micro-organism present in the

initial bacterial inoculum, as some of the micro-organisms may not contribute to the development of wound infection.

• Consideration should be given to the serum half-life of the antibiotic and local hospital antimicrobial susceptibility patterns.

Routine use of vancomycin prophylaxis is strongly discouraged to prevent selection pressure for VRE and VRSA. However, vancomycin should replace the cephalosporin or penicillin component of a regimen when preoperative patients are infected or colonised with an MRSA strain either currently or in the recent past.

The following tables contain surgical prophylaxis regimens that have been approved for use by the respective Clinical Directors at Waikato Hospital.

116

Antibiotic Prophylaxis for Surgical Procedures (i)

Type of Surgery Likely Pathogens Suggested Regime(s)

GENERAL SURGERY Contaminated or potentially contaminated wounds Abdominal surgery, including upper and lower GI tract, appendix and biliary tract and laparoscopic surgergy

Anaerobic bacteria, Streptococci, Aerobic Gram-negative bacilli

Metronidazole (child:12.5mg/kg up to) 500mg IV, ending the infusion at the time of induction plus Cephazolin (child: 25mg/kg up to) 1g IV at the time of induction. A second dose of cephazolin is administered for prolonged procedures (greater than 4 hours), or if significant blood loss has occurred

Severe penicillin allergy Gentamicin 3mg/kg IV (based on lean body mass) and metronidazole 500mg IV at induction

Clean surgery Hernia (with prosthetic material), varicose veins

Staphylococcus aureus, Staphylococcus epidermidis

Cephazolin 1g IV at induction. A second dose is administered for prolonged procedures (greater than 4 hours) or if significant blood loss has occurred

Thyroid and Parathyroid surgery Staphylococcus aureus, Staphylococcus epidermidis

Flucloxacillin 1g IV at induction.

Breast surgery

Staphylococcus aureus, Staphylococcus epidermidis (occasional anaerobes)

Amoxycillin/clavulanate 1g/200mg IV at induction

Note: Not all GI surgery needs prophylaxis. There is no indication for prophylaxis in uncomplicated cholecystectomies in patients younger than 60 as the biliary tract is normally sterile when elective operations for stone-related disease are undertaken.

117

Antibiotic Prophylaxis For Surgical Procedures (ii)


VASCULAR SURGERY Staphylococcus aureus, Staphylococcus epidermidis (occasional gram-negative bacilli)

Cephazolin 1g IV at induction. A second dose is administered for prolonged procedures (greater than 4 hours) or if significant blood loss has occurred.

LOWER LIMB AMPUTATION This carries a small but important risk of clostridial infection.

Use Cephazolin 1g IV at induction plus metronidazole 500mg (child: 12.5mg/kg up to 500mg) IV ending at the time of induction and then 12 hourly for 24 hours.

CARDIOTHORACIC SURGERY Staphylococcus epidermidis, Staphylococcus aureus Aerobic Gram-negative organisms

Cephazolin 1g IV at induction. A second dose is administered for prolonged procedures (greater than 4 hours), or if significant blood loss has occurred.

NEUROSURGERY 1 Staphylococcus epidermidis, Staphylococcus aureus

Cephazolin 1g IV at induction only.

ORTHOPAEDIC SURGERY Staphylococcus epidermidis, Staphylococcus aureus

Cephazolin 1g IV at induction only. Allow 5 minutes to elapse between administration of antibiotic and application of a tourniquet. Severe penicillin allergy Vancomycin 500mg infused over at least one hour

EAR, NOSE AND THROAT SURGERY

Head And Neck Mixed anaerobic and anaerobic upper respiratory tract flora


Rhinoplasty +/- cartilage graft Staphylococcus species Flucloxacillin 1g IV at induction Ear or sinus surgery with potential for dural breach

Mixed aerobic and anaerobic upper respiratory tract flora


Contaminated major ear or sinus surgery

Mixed aerobes and anaerobic upper respiratory tract flora


1 The value of routine prophylaxis for the insertion of shunts, ventricular drains or pressure monitors remains unproven.

118

Antibiotic Prophylaxis For Surgical Procedures (iii)


OBSTETRIC & GYNAECOLOGICAL SURGERY

Hysterectomy Anaerobes, Gram negative bacilli, Group B Strep, and enterococci

Cephazolin 1g IV at induction plus metronidazole 500mg ending the infusion at the time of induction. Severe penicillin allergy Gentamicin 3mg/kg IV (based on lean body mass) and Metronidazole 500mg IV at induction or 1g PR 1 hour pre-operatively.

Caesarean section. There is now evidence that antibiotics are beneficial for prophylaxis of wound sepsis as well as endometritis for all caesarean sections, elective or nonelective.

Gram negative bacilli, Group B Strep, and enterococci

Cephazolin 1g IV immediately after clamping of the cord. The recommendation to delay the timing of antibiotics, therefore avoiding exposure to the neonate, may assist in the assessment of potential sepsis in the neonate. There is no evidence that Cephazolin given at induction causes either toxicity or allergy in the neonate.

UROLOGICAL SURGERY General Aerobic Gram-negative bacilli,

Enterococcus faecalis, Staphylococci Gentamicin 3mg/kg IV (based on lean body mass)

Cystectomy Aerobic Gram-negative bacilli, Enterococcus faecalis, Staphylococci and anaerobes

Gentamicin 3mg/kg IV (based on lean body mass) and Metronidazole 500mg IV at induction or 1g PR 1 hour pre-operatively

OPTHALMOLOGY SURGERY Orbital Trauma and Orbital Implants

Staphylococcus epidermidis, Staphylococcus aureus

Cephazolin 1g IV at induction only.

119

ENDOCARDITIS PROPHYLAXIS A revolution in the recommendations for endocarditis prophylaxis has occurred during the last few years highlighted by the 2007 publication of the American Health Association “Prevention of endocarditis” guidelines - Circulation 2007;116:1736-1754. These evidence based guidelines are radically different from previous guidelines and have markedly reduced the indications for endocarditis prophylaxis acknowledging that the frequency, magnitude and duration of bacteraemia from dental and other procedures is in fact very similar to that which occurs from everyday activities. As a result, the need for specific endocarditis prophylaxis around dental and other operative procedures has been markedly reduced. The Waikato DHB has therefore created new endocarditis prophylaxis guidelines, adapted from the recommendations made within the AHA guidelines and 2008 NICE guidelines (http://www.nice.org.uk/CG064). There are likely to be further refinements once Australasian guidelines have been developed.

Cardiac Conditions associated with the highest risk of adverse outcome from endocarditis for which prophylaxis is reasonable • Prosthetic cardiac valve or prosthetic material used for cardiac valve repair. • Prior episode(s) of infective endocarditis. • Specific congenital heart disease only

- Unrepaired cyanotic CHD, including palliatie shunts and conduits - Completely repaired congenital heart defect with prosthetic material or device

during the first 6 months after the procedure - Reparied CHD with residual defects at the site or adjacent to the site of a

prosthetic patch or prosthetic device • Cardiac transplantation recipients who develop cardiac valvulopathy Prophylaxis is not reasonable or recommended any longer in all of the following circumstances:

- Native valvular heart disease (except for those with previous infective endocarditis)

- Previous rheumatic fever - Mitral valve prolapse or Hypertrophic cardiomyopathy - Previous coronary artery bypass graft surgery - Presence of a cardiac pacemaker - There is also no role for antibiotic prophylaxis in those with prosthetic joints.

Dental Procedures for which Prophylaxis is reasonable when the above highest risk cardiac conditions are present

• All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa.

Respiratory Procedures for which Prophylaxis is reasonable when the above highest risk cardiac conditions are present are

• Invasive procedures of the respiratory tract that involves incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy

• Invasive respiratory tract procedures to treat an established infection eg drainage of abscess or empyema (Note: these individuals are likely to already be on antibiotics)

Endocarditis prophylaxis solely to prevent IE is no longer recommended for any GI or GU procedures. It is important to state that antibiotic therapy remains important in treating active infections.

120

Antibiotic Regimens Antibiotics are aimed at Streptococcus viridans species.

Standard regimen: Amoxycillin 2g (children 50mg/kg up to 2g) po 30 to 60 minutes before the procedure.

Patients with penicillin allergy: Clindamycin 600mg (children 20mg/kg up to 600mg) po 30 to 60 minutes before the procedure. “Until publication of the recent AHA (Wilson et al. 2007) guidelines, antibiotic prophylaxis was universally prescribed to cover dental and other interventional procedures in patients at risk of infective endocarditis (IE). There are, accordingly, a large number of patients with a long history of taking antibiotic prophylaxis against IE for dental procedures for whom it is no longer considered appropriate. The information and support needs for such patients are likely to be significant because they will need to be fully informed about the risks and benefits of antibiotic prophylaxis in order to make an informed decision not to continue to take it.” NICE guideline comment 2008

121

SPLENECTOMY After splenectomy, people are at risk of severe infection, particularly from a small range of encapsulated bacteria. About 70% of these post splenectomy sepsis episodes occur in the first 5 years. Adults may be at less risk than children. The most common organisms are Streptococcus pneumoniae and Haemophilus influenzae type B, with Neisseria meningitidis and S. aureus causing a few cases only. Malaria is a recognised risk which travellers should be warned about.

Prevention of Severe Infections Measures to prevent severe infections post-splenectomy include: • Use of spleen-sparing procedures in trauma. • Vaccination • Prophylactic antibiotics.

Vaccination This should ideally be done 2 weeks before an elective splenectomy. Post splenectomy, response is believed to be better if given more than 2 weeks after the operation.

Recommended vaccinations include: • Pneumococcal 23-valent, 5 yearly. For children, a 7-valent vaccine should soon be

available which is more efficacious, but the dose is too low for adults. • Haemophilus influenzae Type B. This should be given as per routine schedule for

children, but is unlikely to benefit adults who have a much lower incidence of disease, presumably due to pre-existing immunity. This vaccine doesn’t protect against the non-typable H. influenzae, which causes adult respiratory tract infections.

• Meningococcal vaccine. The incidence of serogroup C and A disease in New Zealand at present (2008) is very low, therefore vaccination against these strains is likely to be of very little benefit. It is possible that the New Zealand custom-made serogroup B vaccine would be beneficial and patients with splenectomy are eligible under the Meningococcal vaccination program.

• Influenza vaccine seems sensible and could be offered annually.

Prophylactic Antibiotics Penicillin for “a few years” has been used, but there is no consensus that it is worthwhile, particularly for adults. There are no guidelines for dose, but amoxycillin has theoretical advantages with better coverage of Haemophilus and better pharmacokinetics from oral dosing. For the motivated, informed patient who wishes to use prophylaxis, amoxycillin 250 mg daily (20mg/kg daily for children <5 years) for 3 - 5 years would be reasonable, although there is no evidence-based literature to support this.

Treatment Of Post-Splenectomy Sepsis It would be reasonable for a patient to hold a supply of oral amoxycillin for prompt treatment of sepsis, but immediate simultaneous presentation to hospital would also be necessary. Ceftriaxone would be the drug of choice at hospital presentation. Treatment of fulminant sepsis may be unsuccessful even when initiated promptly.

122

APPENDICES

Outpatient Intravenous Therapy To ensure the safe and co-ordinated care of a patient who is discharging into the community on IV therapy the Community Resource Nurse (CRN) must be contacted. (The ward Clinical Nurse Leader will be able to do this). The CRN will facilitate discharge planning. There are 23 District Nurses based within WDHB, and all are able to manage IV therapy.

Long Term IV Antibiotics e.g. Joint infections, Endocarditis. A District Nurse can administer once daily IV antibiotics e.g. ceftriaxone. If administration is more frequent than this, the patient/parent is required to self-administer, or have a continuous infusion pump. A central venous catheter line or PICC line is usually required. Only certain antibiotics are fully subsidised for patients in the community. Check with Pharmacy Department to see whether it will be necessary to make an application for funding through Hospital Exceptional Circumstances (HEC). Applications forms for HEC funding are available from Pharmacy. The WDHB IV Manual, Section A10, has a pre-discharge checklist and skills mastery list, essential for all IV discharges.

Short Term IV Therapy e.g. Completion of antibiotic course for meningitis (up to 7 days). As above, but a peripheral line is adequate.

Chronic/Speciality Patients Requiring IV Therapy e.g. Cystic Fibrosis, Haematology patients. Contact the ward Clinical Nurse Leader or Clinical Nurse Educator – specialist areas will have relevant protocols for chronic patients.

Community Cellulitis Protocol This is for short-term antibiotics (three days) in the community via a peripheral line for simple cellulitis. This protocol is used by Waikato and T Hospital Emergency Departments and is now available to all GPs in the region.

123

LOCAL RESISTANCE PATTERNS TO ANTIMICROBIAL DRUGS

Antimicrobial therapy is usually commenced before the causative organism is known with certainty. The choice of agent for this “empiric therapy” depends on knowing the likely organisms and their likely susceptibility. The Treatment Guidelines for Common Conditions section of this handbook includes notes on the anticipated etiologic organisms. Frequently, the organism is identified in the laboratory before susceptibility test results are available. Most organisms are reasonably predictable in their antimicrobial susceptibility and frequently the antibiotic spectrum used can be narrowed once their identity is known. Susceptibility results for the individual patient’s organism often allow it to be narrowed further. Definitions: • “Susceptible” means that recommended doses of the antibiotic should be effective

in commonly encountered conditions. Many other factors can influence therapeutic success, e.g. site of infection, presence of prosthetic material or immunosuppression.

• “Resistant” means that an alternative agent should be considered. • “Intermediate” or “reduced susceptibility” means that in favourable circumstances,

the antibiotic may be effective. Increased doses may be required. If antibiotic-organism combinations have not been reported, this implies that these combinations are not usually recommended. Advice and occasionally additional testing are available on request.

Susceptibility of Common Organisms in Blood Culture

The following data is presented as a guide to the most common organisms expected in severe sepsis. These organisms are grouped according to their predictable susceptibility patterns. The figures in brackets indicate their frequency of occurrence as a percentage of all blood culture isolates for 2005.

Gram-Negative Bacteria

E. coli (13.1%) A reasonably sensitive organism, reliably treated by gentamicin or ceftriaxone in critical cases. Strains resistant to aminoglycosides or cephalosporins (Extended Spectrum Beta Lactamase) are rare in the Waikato at present. Susceptibility of individual strains to oral agents varies markedly, with 45% being susceptible to amoxycillin, 70% to amoxycillin/clavulanate and 76% susceptible to cotrimoxazole.

Other Susceptible Coliforms (5.3%) The following organisms are usually sensitive to cephalosporins and aminoglycosides: Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Yersinia Enterocolitica, Yersinia. kristensenii, Salmonella sp. ESBL Klebsiella are rare in the Waikato.

Potential AmpC Producing Coliforms (5.8%) These organisms may yield derepressed mutants after a few days of therapy and are resistant to cephalosporins. Aminoglycosides or quinolones are therefore required. Enterobacter, Serratia, Citrobacter, Acinetobacter, Providencia and Morganella sp.

124

Pseudomonas species (2.6%) These are best treated with dual antibiotics, including an aminoglycoside, antipseudomonal penicillin or cephalosporin or a fluoroquinolone.

Acinetobacters (0.6%) These are frequently multiresistant and require aminoglycosides.

Stenotrophomonas maltophilia (0.4%) These organisms are often highly multiresistant. They are usually susceptible to cotrimoxazole.

Neisseria meningitidis (1.7%) Uniformly susceptible to ceftriaxone and all penicillins.

Gram-Positive Bacteria

Staphylococcus aureus (13.0%) Flucloxacillin remains the drug of choice. In recent years around 6% of our S. aureus isolates have been MRSA. Isolation of MRSA does not necessarily mean that vancomycin must be used. MRSA at Waikato Hospital are often sensitive to cotrimoxazole and a number of other oral agents.

Coagulase-Negative Staphylococci (32.2%) These are frequently contaminants. Although they are usually resistant to beta-lactams, the important question is whether any treatment is needed at all rather than going straight to vancomycin therapy.

Streptococcus pneumoniae (3.8%) These respond well to high dose penicillin or cephalosporins, unless their MIC is >8.0 µg/ml or >4.0 µg/ml for meningitis. No such isolates have been identified at Waikato Hospital in recent years.

Beta Haemolytic Streptococci (1.6%) These are uniformly susceptible to penicillin.

Viridans Streptococci (5.0%) These are also uniformly susceptible to penicillin. If MIC >0.1 µg/ml in endocarditis, gentamicin may be required in addition.

Enterococci (7.0%) These are intrinsically more resistant than streptococci. A penicillin is the agent of choice. There has not been any evidence of vancomycin resistance in the Waikato.

Yeast

Candida albicans (0.6%) Predictably susceptible to fluconazole. Other Candida species are often resistant to fluconazole e.g. C. glabrata and C. krusei.

125

CUMULATIVE SENSITIVITY STATISTICS WAIKATO HOSPITAL 1 JAN - 31 DEC 2006

Gram negative isolates

% s

usce

ptib

le

Tota

l No.

test

ed

Eshc

eric

hia

coli

Prot

eus

mira

bilis

Kle

bsie

lla

pneu

mon

iae

Serr

atia

m

arce

scen

s1

Ente

roba

cter

cl

oaca

e1

Pseu

dom

onas

ae

rugi

nosa

2

Sten

otro

phom

onas

m

alto

phili

a

Hae

mop

hilu

s in

fluen

zae

% neg 83 Beta-lactamase Total 254

% susc 43 88 0 0 0 0 BLNAR3 Ampicillin Total 1849 144 183 73 90 252 206

% susc 79 95 92 0 0 0 1004 Amoxicillin - clavulanate Total 1848 143 183 73 89 254 38

% susc 85 100 92 62 64 86 Ticarcillin - clavulanate Total 1838 141 182 73 89 253

%susc 98 100 97 62 87 98 Pipericillin-Tazobactam Total 1842 142 182 73 90 303

% susc 51 96 88 0 0 0 Cephalothin Total 1838 141 181 73 89 254

% susc 98 97 97 90 79 1 Cefotaxime / Ceftriaxone5 Total 1838 181 181 73 89 253

% susc 98 97 97 100 66 92 Ceftazidime5

Total 1839 181 181 73 89 329 % susc 98 97 97 100 100 95 Cefepime

Total 1840 181 181 73 89 304 % susc 100 100 100 100 100 97 Meropenem6

Total 1816 142 180 73 88 300 % susc 100 100 99 100 98 98 Amikacin

Total 1840 141 182 74 89 260 % susc 95 100 94 100 77 87 Gentamicin

Total 1853 145 184 74 91 334 % susc 96 99 93 80 79 97 Tobramycin

Total 1849 144 182 74 89 333 % susc 95 100 99 92 88 91 Norfloxacin

Total 1847 143 184 73 90 258 % susc 95 100 99 70 87 88 Ciprofloxacin

Total 1846 144 182 74 89 334 % susc 97 0 27 0 47 0 Nitrofurantoin

Total 1847 143 182 73 90 254 Tetracycline % susc 96 Total 220 Co-trimoxazole % susc 79 97 87 75 75 3 88 78 Total 1850 144 184 91 91 290 25 242 Trimethoprim % susc 77 94 84 74 74 0 Total 1848 143 184 90 90 252

126

1.Penicillin and cephalosporin susceptibilities are not routinely reported for these species because they have the ampC gene which can become derepressed leading to development of resistance. Results reported are from isolates tested at time of isolation. 2.Susceptibilities reported for P.aeruginosa include non mucoid isolates from cystic fibrosis patients. 3. Beta-lactamase negative isolates only tested. 2.0 % of 206 isolates were Beta Lactamase Negative, Ampicillin Resistant. 4. Beta-lactamase positive isolates only tested. 5. See notes on Extended Spectrum Beta Lactamase organisms. 6. Phenotypic testing by Vitek II. No genetic or EDTA inhibition testing for carbapenemases has been performed.

127

Gram positive isolates

% s

usce

ptib

le

Tota

l No.

test

ed

Stap

hylo

cocc

us

aure

us

Coa

gula

se

nega

tive

stap

hylo

cocc

us

Ente

roco

ccus

fa

ecal

is

Ente

roco

ccus

fa

eciu

m

Cor

yneb

acte

rium

sp

ecie

s

% susc 100 23 Ampicillin Total 69 13

% susc 3 1 41 Penicillin Total 2365 332 21

% susc 802 23 Flucloxacillin Total 2542 404

% susc 75 73 Norfloxacin Total 36 43

% susc 84 63 70 8 50 Ciprofloxacin Total 2397 363 67 12 10

% susc 84 51 Erythromycin Total 2545 336

% susc 98 59 Clindamycin Total 2368 332

% susc 100 100 100 921 100 Vancomycin Total 2407 438 68 12 37

% susc 99 60 74 Gentamicin Total 2396 401 35

% susc 63 31 Gentamicin Synergy Total 67 13

% susc 81 72 Fusidic acid Total 2560 365

% susc 983 Mupirocin

Total 455 % susc 99 65 Co-trimoxazole

Total 2392 339 % susc 100 93 Chloramphenicol

Total 249 54 % susc 100 88 Rifampin

Total 2394 340 % susc 99 99 100 25 Nitrofurantoin

Total 2202 314 64 12 Doxycycline % susc Total Tetracycline % susc 98 88 30 62 Total 2394 332 67 12

1. Note that this is just one isolate of Vancomycin Resistant Enterococcus. 2. This figure includes duplicate isolates from some patients. See notes on Resistant Isolates: MRSA. Methicillin resistance among patients with S.aureus bacteremia was 6.7% in 2006. Methods in routine use may fail to detect heterogenous vancomycin resistance. 3. Only MRSA were tested against mupirocin.

128

ANTIMICROBIAL RESISTANCE IN ORGANISMS OF SPECIAL INTEREST

Streptococcus pneumoniae Susceptibility to Penicillin (invasive sites) or Amoxycillin (non-invasive sites) is reported according to the following criteria: Susceptible Intermediate

susceptibility Resistant

Amoxycillin M.I.C <2 4 >8

Penicillin M.I.C <0.06 0.12-1 >2 Invasive Isolates (total = 48 ) Total No. of

Isolates tested

No. isolates susceptible (%)

No. isolates with intermediate susceptibility (%)

No. isolates resistant (%)

Penicillin 48 42 (87.5) 6 0 Ceftriaxone 8 8 (100) 0 0 Erythromycin 43 40 (93.0) 0 3 Non Invasive Isolates (total = 120) Total No. of

Isolates tested




Ampicillin 120 114 (95.0) 5 1 Erythromycin 118 92 (78.0) 1 25

Neisseria gonorrhoeae There were 158 isolates of N.gonorrhoeae cultured in 2006. This was an increase from 101 isolates in 2005. Total No. of

Isolates tested




Penicillin 154 71 (46.1) 80 (52.0) 3 (1.95) Ceftriaxone 153 153 (100.0) - - Ciprofloxacin 152 104 (68.4) - 48 (31.6) One isolate of N.gonorrhoeae was Beta Lactamase positive. Ciprofloxacin resistance has increased dramatically, from 3.5% in 2004 to 16.5% in 2005 and 31.6% in 2006. Mycobacterium tuberculosis

129

During 2006, 35 patients were culture positive for Mycobacterium tuberculosis. Critical concentration susceptibility for the first line agents Streptomycin, Isoniazid, Rifampicin and Ethambutol was performed using the Bactec MGIT 960. Pyrizinamide susceptibility is tested by Waynes method for pyrazinamidase detection. The only resistance found was one isolate with low level and one with high level resistance to Isoniazid.

MRSA The prevalence of MRSA infections and patient colonisation has been stable since 2003. In 2006, a total of 105 patients had culture positive S.aureus bacteraemia. Of these, 6.7% (7 patients) were MRSA. Six of these 7 bacteraemias were due to the EMRSA 15 strain. 2003 2004 2005 2006Total S. aureus bacteremia cases

124 130 107 105

MRSA 9 9 9 7 Percent 7.3% 6% 8.4

% 6.7%

At Emergency Dept, MRSA comprised 7.7% of the 433 cases of S. aureus infection diagnosed by culture. Strain Number of

patients Previously known MRSA

EMRSA 15 16 4/16 WSSP 11 4/11 WR/AK1 3 2/3 other 1 BORSA 1 Extended spectrum beta-lactamase producing organisms (ESBL) There were 23 patients with ESBL isolates in 2006. Organisms included E. coli, E. cloacae and Klebsiella pneumoniae. Isolates included blood cultures, CAPD fluid, urine, faeces and wound swabs. Antibiotic resistance data is not entered on to the database but most isolates in 2006 were multi-resistant. Over an 18-month period a cluster of highly resistant ESBL Enterobacter cloacae isolates were received from seven patients, six of whom were under the care of the one clinical service. ESBL are detected in clinical isolates by Vitek II and confirmed with ceftazidime and cefotaxime-clavulanic acid double disk or cefepime double disc for Enterobacter sp. Other Resistant Isolates (MDRO)

130

There were two multi-drug resistant organisms isolated during 2006. Both were community-acquired. One patient had a highly resistant E.coli from a urine specimen. This was not found to be an ESBL through further laboratory testing. The other isolate was a Morganella morganii in catheter urine from a patient with long term catheterisation.

Report prepared by: Kay Stockman Manager/Technical Advisor Microbiology Dept. With contributions from: Dr Chris Mansell, Microbiologist Kathryn Coley, Mycobacteria Laboratory Specialist Ruth Barratt, Infection Control

131

MRSA MANAGEMENT The control of MRSA is important because the alternatives to beta-lactams are more toxic, more expensive and less effective. New Zealand is in the fortunate position where beta lactams can be confidently used as initial treatment in conditions where S. aureus infection is suspected. In 2005, 6% of S. aureus from blood cultures at Waikato Hospital was MRSA, although this figure fluctuates depending on local outbreaks. In many parts of the world, over 30% of S. aureus is MRSA. Patients found to be positive are isolated or cohorted and receive appropriate treatment and follow up. Fortunately, only a limited number of strains of MRSA are currently circulating within the Waikato region. At the time of writing (August 2005) most MRSA encountered in the Waikato can be treated with cotrimoxazole if oral therapy is required.

Typical Antibiotic Susceptibility of MRSA Strains in the Waikato 2005

MRSA Strain

Fluc

loxa

cilli

n

Eryt

hrom

ycin

Cip

roflo

xaci

n

Cot

rimox

azol

e

Mup

iroci

n

Fusi

dic

Aci

d

Vanc

omyc

in

Comments

WSPP 1 & 2 R S S S S S S Common in the community. Readily controllable by standard MRSA procedures. Doesn’t cause outbreaks in our hospitals.

EMRSA 15 R R R S S S S Present in the community. Particularly transmissible and difficult to control. Causes the majority of hospital- acquired cases in the Waikato.

AKH4 R R R R S S S This strain caused outbreaks at Waikato Hospital in late 2004.

WR/AK1 R S S S V R S Uncommon at present, not endemic at Waikato Hospital. Often resistant to mupirocin. Prevalence has declined since mupirocin over the counter sales stopped.

The management of MRSA outbreaks is directed by the Infection Control Team and may vary for each particular outbreak. The location, type of clinical service, staffing and strain of MRSA will influence strategies for isolation, screening and decolonisation.

MRSA Screening Screening is directed by the Infection Control Team. Guidelines about how to collect specimens are available in the Infection Control Manual, which is held on each ward and on the hospital intranet. Frequently, MRSA is detected in routine clinical specimens and may reflect active infection or colonisation. To detect colonisation in staff or patients, request “MRSA screen” and the laboratory will test by a more sensitive method and not look for other organisms. Often, swabs from several sites on the one patient will be processed as one for this purpose.

132

Isolation Procedures Detailed instructions for managing MRSA-colonised or infected patients are in the Infection Control Manual, available on the Waikato Hospital intranet and in hard copy in clinical areas. The mainstay of isolation is “contact precautions”. Where appropriate, they may be cohorted into multibed rooms with other MRSA patients. Where their medical conditions allow, efforts are made to discharge carriers from hospital. Patients with infectious conditions such as MRSA may be placed at the end of operating lists to reduce the possibility of cross-infection. Management of specific patients may vary at the direction of the Infection Control Team.

Clearance It is seldom possible to clear MRSA completely from a person with active infection or unhealed lesions.

Management Of Staff Members Carrying MRSA Management of staff members carrying MRSA is organised by their line manager, with advice from the Infection Control Team. They may be stood down from work on special leave (at the discretion of infection control). An attempt is made to eradicate the organism, using antiseptic body washes, shampoo and nasal mupirocin ointment. This is usually successful and MRSA screening swabs are used to check. Colonisation may recur at a future date, particularly after a course of antibiotics.

133

BLOOD AND BODY FLUID EXPOSURES Needlestick injuries and mucous membrane splashes are the most common recognised incidents where healthcare workers may be exposed to infectious diseases. Pathogens of major concern include Hepatitis B, Hepatitis C and HIV. In some circumstances, prophylaxis or monitoring may be indicated after exposure to Neisseria meningitidis, Hepatitis A virus, bites, sexual assault, Tuberculosis, Varicella (non-immune pregnant or immunosuppressed people), Haemophilus influenzae type B, Influenza, Rabies, biological weapons. These cases should be discussed with an appropriate specialist.

Procedures for dealing with Needlestick and Mucous Membrane Exposures Similar procedures should be used for dealing with needlestick injuries and mucous membrane exposures, although risk of infection following mucous membrane exposure is much lower. Blood contact with intact skin is not a risk exposure. A “Body Fluid Exposure Pack” will be available to guide management.

First Aid Measures • Wash and gently encourage bleeding. Attend to injuries. • Document identity of source and exposed people. • Arrange for a doctor, Health and Safety advisor or other trained person (e.g.

Clinical Nurse Leader) to manage the incident, arranging collection of specimens, checking results and ensuring follow-up. In general, people should not manage their own exposure incident.

• Routinely obtain blood from both source and exposed people and test both for: - HBsAg - Anti-HBs - Anti-HBc - Anti-HCV - HIV antigen and antibody

• Assess risk status of source person. Are they likely to be early in acute infection with one of the 3 viruses or is blood not available for testing?

• Assess Hepatitis B immunisation status of the exposed person.

Management of Documented Exposures

HBV • Risk of infection for a non-immune exposed person is 5-30%, depending on the

HBeAg status of the source. • HBV immunoglobulin is given within 72 hrs if exposed person is non-immune. • HBV vaccination is commenced.

HCV • Risk of infection is approximately 3%. • Exposed person is monitored for development of Hepatitis C, particularly

asymptomatic infection. • If infection occurs, treatment of acute Hepatitis C may be initiated.

134

HIV • Risk of infection is approximately 0.3%, but less if the source is having effective

antiretroviral treatment. • Antiretroviral prophylaxis can have life-threatening complications, while HIV

infection can now be managed to preserve length of survival and quality of life. • Prophylaxis should generally not be given unless a definite exposure has occurred. • The ideal time frame for administration is thought to be within 2 hours, but

sometimes longer delays are unavoidable. • Only a “specialist experienced in the treatment of patients with HIV as approved

and named by the Ministry of Health” may prescribe antiretroviral prophylaxis. • The people to contact (through Waikato Hospital telephonist) are, in order:

- Dr Graham Mills, Infectious Disease Physician. - Dr Jane Morgan, Sexual Health Physician. - Auckland Hospital Infectious Disease Service (available 24hr).

Please persist in making contact with one person on this list if source blood is HIV positive.

135

NOTIFIABLE DISEASES IN NEW ZEALAND

Notifiable Infectious Diseases Under The Health Act 1956 And Tuberculosis Act 1948

Infectious Diseases Notifiable to a Medical Officer of Health and Local Authority (Public Health staff will notify the Local Authority where required). Acute gastroenteritis* Campylobacteriosis Cholera Cryptosporidiosis Giardiasis Hepatitis A Legionellosis

Listeriosis Meningoencephalitis = primary amoebic Salmonellosis Shigellosis Typhoid and paratyphoid fever Yersiniosis

* Not every case of acute gastroenteritis is necessarily notifiable - only those where there is a suspected common source or from a person in a high risk category, (e.g. food handler, child care worker, etc.) or single cases of chemical, bacterial, or toxic food poisoning such as botulism, toxic shellfish poisoning (any type) and disease caused by verocytotoxic E. coli.

Infectious Diseases Notifiable to Medical Officer of Health Acquired Immunodeficiency Syndrome Arboviral diseases Creutzfeldt Jakob Disease and other Spongiform encephalopathies Haemophilus Influenzae B Hepatitis C Hydatid disease Leptospirosis Measles Neisseria meningitidis invasive disease Plague Rabies Rickettsial diseases Severe Acute Respiratory Syndrome (SARS) Tetanus

Anthrax Brucellosis Diphtheria Hepatitis B Hepatitis (viral) - not otherwise specified Leprosy Malaria Mumps Pertussis Poliomyelitis Rheumatic fever Rubella Tuberculosis (all forms) Viral haemorrhagic fevers Yellow fever

Diseases Notifiable to Medical Officer of Health (Other than Notifiable Infectious Diseases) Cysticercosis Taeniasis Trichinosis Decompression sickness

Lead absorption equal to or in excess of 15µg/dL (0.72µmol/L) ** Poisoning arising from chemical contamination of the environment

**Blood lead levels to be reported to the Medical Officer of Health (15µg/dL or

0.72µmol/L) are for environmental exposure. Where occupational exposure is suspected, please notify OSH through the NODS network.

136

How To Notify A Notifiable Disease (Include Suspected Cases) During times of increased incidence practitioners may be requested to report with informed consent, to their local Medical Officer of Health cases of communicable diseases not on this list. Notification by phone is preferred, since the Ministry of Health notification forms have too little information.

Contact Phone Numbers: Normal Office Hours (0800 - 1700) Waikato Hospital ext 2065 Hamilton region (07) 8581065 Outside Hamilton region 0800 800 977 For specific advice, ring phone numbers above or contact On Call Medical Officer of Health 021 359 650 Dr Dell Hood 021 521 926 Dr Antia Bell 021 171 7703 Dr Felicity Dumble 021 359 646 Facsimile for Public Health 07 838 2382 After Hours and Weekends Phone Waikato Hospital operators and ask for the Medical Officer of Health on-call or phone 021 359650.

Antibiotics

Documents

dr jane morgan

forming grampositive

400mg po bd

lean body

herpes simplex

clenched fist

ideal body

randomised