Antibiotics i

Antibiotics

Dr. Nabila HassanTropical medicine MD

Zagazig university

Objectives1. What are antibiotics?2. Bacteria targeted.3. Antibiotics classification4. Mode of action5. Pharmacokinetics6. Side effects and dose7. New antibiotics8. Antibiotics resistance

Antibiotics• Antibiotics, also called antibacterials, are a type of antimicrobial

drug used in the treatment and prevention of bacterial infections.

• They may either kill or inhibit the growth of bacteria.

• A limited number of antibiotics also possess antiprotozoal activity

Bacterial cell structure• Cell wall - G +ve cell wall - G –ve cell wall

• Plasma membarene• Extra cellualr structure• Intra cellular structure• Endospore

Medical important bacteria

Lack cell wall

mycoplasma

ureaoplasma

flexiable spirochetes

BorrelialeptospirallisTreponema

rigid cell wall

filamentousactinomycesmycobacteri

nocardia

simple unicellular

obligate intra cellular

ChylamadiaCoxilla

EhrlichiaRickettsia

free living

gram positive gram negative

Gram positive

StaphStrept

enterococcipeptostreptoc

occus

Bacilli

bacillusClostradium

coyrneubacteriumEriseplothirixLactobacillus

Listeriapropnionibacterium

cocci

Gram negative organisms

cocciNiesseriamorexalle

acinobacter

Bacillinon enteric

bacilli

HaemophilusBordetellaLegionella

Brucella

Francisella tularensisPasteurella

Yersinia PestisBartonella

pseudmons

enteric rodsenterobacilliEcherechia

fuseobacteriumhelicobacter

kleibacilliprevotellaproteus

ProvendeicaPseudomonossallemonella

serratiashigellia

VibrioYersinia

Microbial Sources of Antibiotics

Antibiotics classification Bactericidal antibiotics and bacteriostatic antibiotics. Bactericidals

kill bacteria directly, whereas bacteriostatics prevent them from dividing (laboratory behavior). In practice, both can effectively treat a bacterial infection.

Commonly classified based on their mechanism of action, chemical structure, or spectrum of activity.

Based on their target specificity. "Narrow-spectrum" antibiotics target specific types of bacteria, such as gram-negative or gram-positive, whereas broad-spectrum antibiotics affect a wide range of bacteria.

This difference is relative, as bacteriostatic drugs are often bactericidal at high concentrations and in the presence of host defence mechanisms.

In clinical practice, the distinction is seldom important unless the body’s defence mechanisms are depressed.

Bacteriostatic Bactericidal

Erythromycin Tetracyclines Chloramphenicol Sulphonamides Trimethoprim

Penicillins Cephalosporins Aminoglycosides Co-trimoxazole

Antibacterial agent Mechanism of actionPenicillinsCephalosporinsMonobactamsVancomycinPolypeptide Antibiotics

Inhibition of cell wall synthesis

Cell wall and cell membrane

Quinolones Inhibition of DNA gyrase

Rifampicin Inhibition of RNA polymerase

AminoglycosidesTetracyclinesErythromycinChloramphenicol

Inhibition of protein synthesis

TrimethoprimSulphonamides

Inhibition of folic acid metabolism

New Classes of AntibioticsFour new classes of antibiotics have been brought into clinical use in the late 2000s and early 2010s:

• Cyclic lipopeptides (such as daptomycin), • Glycylcyclines (such as tigecycline), • Oxazolidinones (such as linezolid),• Lipiarmycins (such as fidaxomicin)

Antibacterial drug, dose and route of administration choice

Depend on: The infection (in particular the responsible pathogen(s), but

also anatomical site and severity). Absorption characteristics of the drug, The dose may be guided

by plasma concentration measurements of drugs with a narrow therapeutic index (e.g. aminoglycosides).

Patient factors (in particular age, weight, renal function). The duration of therapy depends on the nature of the infection

and response to treatment.

Adjusted body weight(ABW)

Estimated adjusted body weight (kg) If the actual body weight is

greater than 30% of the calculated IBW, calculate the adjusted body

weight.

ABW = IBW + 0.4(actual weight - IBW)

Creatinine Clearance

MIC is the minimal concentration of a particular agent below which bacterial growth is not prevented.

Although the MIC provides useful information for comparing the

susceptibility of organisms to antibacterial drugs, it is an in vitro test

in a homogenous culture system, whilst in vivo the concentration at

the site of infection may be considerably lower than the plasma

concentration which one might predict to be bactericidal.

Minimum Inhibitory Concentration (MIC)

(e.g. drug penetration and concentration in an abscess cavity are very low).

Antibiotics CombinationsMost infections can be treated with a single agent. However, there are situations in which more than one antibacterial drug is prescribed concurrently:

To achieve broad antimicrobial activity in critically ill patients with an undefined infection (e.g. aminoglycoside plus a penicillin to treat septicaemia).

To treat mixed bacterial infections (e.g. following perforation of the bowel) in cases where no single agent would affect all of the bacteria present.

Certain beta-lactams and aminoglycoside combinations, between tigecycline and colistin but not between tigecycline and meropenem in KPC bacteriae to achieve an additive or synergistic effect (e.g. use of co-trimoxazole in the treatment of Pneumocystis carinii pneumonia).

Chances of emergence of resistance against two drugs are lower as compared with a single drug. Polymyxin and tigecycline are the two most commonly used antibiotics for carabemenase resistant enterococci (CRE).

1. Broadening antibacterial spectrum:

2. Polymicrobial infections:

3. Synergy:

4. Emergence of resistance:

Prophylactic Use Of Antibioticsa few occasions it is appropriate to use antibacterial drugs prophylactically. Wherever possible a suitably specific narrow spectrum drug should be used.

PROPHYLAXIS OF INFECTIVE ENDOCARDITIS

PROPHYLACTIC PREOPERATIVE ANTIBIOTICS

PROPHYLACTIC RHEUMATIC FEVER

PROPHYLACTIC SBP

PROPHYLACTIC MENINGITIS

PROPHYLACTIC CELLULILATIS

COMMONLY PRESCRIBED ANTIBIOTICS

Antibiotics in this group include the penicillins, monobactams, carbapenems and cephalosporins.These drugs each contain a β-lactam ring. This can be broken down by β-lactamase enzymes produced by bacteria, notably by many strains of Staphylococcus and Haemophilus influenzae, which are thereby resistant. β-Lactam antibiotics kill bacteria by inhibiting bacterial cell wall synthesis. Penicillins are excreted in the urine. Probenecid blocks the renal tubular secretion of penicillin.

β-LACTAM ANTIBIOTICS

Penicillins

Natural penicillins

Β-lactamase resistant

Aminopenicillins

Carboxypenicillins

Ureidopenicillins

Penicillin G --Penicillin V

Methicillin – Nafcillin – Oxacillin – Cloxacillin - Dicloxacillin

Ampicillin-Amoxicillin-Pivampicillin-Hetacillin-Bacampicillin-Metampicillin-Talampicillin-Epicillin

Carbenicillin – Ticarcillin -Temocillin

Mezlocillin-Piperacillin

Penicillins• Mode of action: Same mode of action as other beta-lactam

antibiotics: disrupt the synthesis of the peptidoglycan layer of bacterial cell walls

• Wide range of infections; penicillin used for streptococcal infections, syphilis, and Lyme disease

1. Amoxicillin (Novamox, Amoxil)2. Ampicillin Principen (discontinued)3. Azlocillin4. Carbenicillin Geocillin (discontinued)5. Cloxacillin Tegopen (discontinued)6. Dicloxacillin Dynapen (discontinued)7. Flucloxacillin Floxapen 8. Mezlocillin Mezlin (discontinued)

8. Methicillin Staphcillin (discontinued)9. Nafcillin Unipen (discontinued)10. Oxacillin Prostaphlin (discontinued)11. Penicillin G Pentids (discontinued)12. Penicillin V Veetids (Pen-Vee-K) (discontinued)13. Piperacillin Pipracil (discontinued)

14. Penicillin G Pfizerpen15. Temocillin Negaban (UK) (discontinued)16. Ticarcillin Ticar (discontinued)

Adverse effects1- Common adverse drug reactions (≥ 1% of people) associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis).

2- Infrequent adverse effects (0.1–1% of people) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in people with epilepsy), and pseudomembranous colitis.

About 10% of people report that they are allergic to penicillin; however, 90% are not actually allergic. Serious allergies only occur in about 0.03%.Pain and inflammation at the injection site. Significantly, there is an immunologic reaction to Streptolysin S, a toxin released by certain killed bacteria and associated with Penicillin injection, that can cause fatal cardiac syncope.

The allergic reaction is a Type I hypersensitivity reaction.

Anaphylaxis will occur in approximately 0.01 - 0.03% of

patients.

It has previously been accepted that there was up to a 10%

cross-sensitivity between penicillin-derivatives,

cephalosporins, and carbapenems, due to the sharing of the β-

lactam ring.

Benzylpenicillin

• Penicillin G is noted to possess effectiveness mainly against Gram-positive

organisms. Some Gram-negative organisms such as Neisseria gonorrhoeae and

Neisseria meningitidis.

• Adverse effects can include hypersensitivity reactions including urticaria, fever,

joint pains, rashes, angioedema, anaphylaxis, serum sickness-like reaction.

• Rarely CNS toxicity including convulsions (especially with high doses or in severe

renal impairment), interstitial nephritis, haemolytic anaemia, leucopenia,

thrombocytopenia, and coagulation disorders. Also reported diarrhoea (including

antibiotic-associated colitis).

Benzylpenicillin (penicillin G) is the drug of choice for streptococcal, pneumococcal, gonococcal and meningococcal infections,and is also useful for treatment of anthrax, diphtheria, gas gangrene, leptospirosis, syphilis, tetanus, yaws and Lyme disease in children.

Limitations of benzylpenicillin include:

1. It is acid labile and so must be given parenterally (inactivated in gastric acid).2. It has a short half-life, so frequent injections are required.3. Development of resistant β-lactamase-producing strains can occur.4. It has a narrow antibacterial spectrum

USES

Two preparations with similar antibacterial spectra are used to overcome the problems of acid lability/frequent injection:

1. Procaine benzylpenicillin – this complex releases penicillin slowly from an intramuscular site, so a twice daily dosage only is required.

2. Phenoxymethylpenicillin (‘penicillin V’) – this is acid stable and so is effective when given orally (40–60%absorption). Although it is useful for mild infections, blood concentrations are variable, so it is not used in serious infections or with poorly sensitive bacteria.Tablets are given on an empty stomach to improve absorption.

• Procaine pencillin G : 600,000-1,200,000 units IM qDay

• penicillin G aqueous (Rx)Pfizerpen, penicillin G potassium: 50- 100,000 unit/ kg in childeren. in adult vary according to organism and site From 1- 30 million unit/day

• penicillin G benzathine (Rx)Bicillin LA, Permapen 1.2 million units IM monthly following acute attack, OR 600,000 units IM q2Weeks

Renal Impairment• CrCl 10-50 mL/min: Decrease dose by 25%• CrCl <10 mL/min: Decrease dose by 50-70%• Hemodialysis: Removed by hemodialysis; administer after dialysis

DOSES

Flucloxacillin was developed to overcome β-lactamase-producing strains. Otherwise, it has a similar antibacterial spectrum to benzylpenicillin. It is effective against β-lactamase-producing organisms.

It is used for the treatment of staphylococcal infections (90% of hospital staphylococci are resistant to benzylpenicillin and 5–10% are resistant to flucloxacillin).

Flucloxacillin

EXTENDED-RANGE PENICILLINSAMPICILLIN/AMOXICILLIN

UsesIn addition to streptococcal (including pneumococcal) strains, ampicillin and amoxicillin are also effective against many strains of Haemophilus influenzae, E. coli, Streptococcus faecalis and Salmonella. They are used for a variety of chest infections (e.g. bronchitis, pneumonia), otitis media, urinary tract infections, biliary infections and the prevention of bacterial endocarditis(amoxicillin). Amoxicillin is some what more potent than ampicillin, penetrates tissues better and is given three rather than four times daily. Both are susceptible to β-lactamases.

PharmacokineticsThe half-life of each drug is about 1.5 hours and they are predominantly renally excreted.

Adverse effectsRashes are common and may appear after dosing has stopped. There is an especially high incidence in patients with infectious mononucleosis or lymphatic leukaemia.

Penicillin combinations

Mode of action: The second component reduces the effectiveness of some forms of bacterial resistance to the first component.

- Clavulanate - Sulbactam- tazobactam

Penicillin combinations1. Amoxicillin/clavulanate Augmentin2. Ampicillin/sulbactam Unasyn3. Piperacillin/tazobactam Zosyn4. Ticarcillin/clavulanate Timentin

DOSEAmpicillin             Meningitis or endovascular infectionCrCl >50 10-50 CrCl <10 ml/min2 g IV q4h 2 g IV q6h 1 g IV q8h

Uncomplicated Infection2 g IV q6h 1 g IV q6h 1 g IV q12h

Ampicillin/sulbactam>30 15-30 <15mL/min3 g IV q6h 1.5 g IV q6h 1.5 g IV q12h

ANTIPSEUDOMONAL PENICILLINSStandard penicillins are not effective against Pseudomonas. This is not usually a problem, as these organisms seldom cause disease in otherwise healthy people. However, Pseudomonas infection is important in neutropenic patients (e.g. those undergoing cancer chemotherapy) and in patients with cystic fibrosis.

Penicillins with activity against Pseudomonas have been developed and are

particularly useful in these circumstances. These include piperacillin, azlocillin and ticarcillin.

ANTIPSEUDOMONAL PENICILLINSUsesThese expensive intravenous penicillins are not used routinely. Their efficacy against Gram-positive organisms is variable and poor. They are useful against Gram-negative infections, particularly with Pseudomonas and they are also effective against many anaerobes.

These drugs have a synergistic effect when combined with aminoglycosides in Pseudomonas septicaemias.

Combinations of ticarcillin or of piperacillin with β-lactamase inhibitors designed to overcome the problem of β-lactamase formation by Pseudomonas are commercially available.

PharmacokineticsAbsorption of these drugs from the gut is inadequate in the life-threatening infections for which they are mainly indicated.

They are given intravenously every 4–6 hours. Their half-lives range from 1 to 1.5 hours and they are renally excreted.

Adverse effectsPredispose to superinfection, Rashes, sodium overload. Thrombocytopenia and platelet dysfunction can occur.

Piperacillin/tazobactama combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam.

It is commercially available as Tazocin and Zosyn. The combination has activity against many Gram-positive and Gram-negative pathogens and Pseudomonas aeruginosa.

Uses main uses are in intensive care medicine (pneumonia, peritonitis), some diabetes-related foot infections, and empirical therapy in febrile neutropenia (e.g., after chemotherapy (first line therapy )).PharmakokineticsThe drug is administered intravenously every 6 or 8 hr, typically over 3-30 min. It may also be administered by continuous infusion over four hours. Prolonged infusions are thought to maximize the time that serum concentrations are above the minimum inhibitory concentration (MIC) of the bacteria implicated in infection.

Adverse reactions

The most common adverse reaction is diarrhea (7% to 11%).One study showed Clostridium difficile-associated diarrhea happened in 4.9% of the patients on piperacillin/tazobactam.One other side effect is inhibition of platelets (thrombocytopenia)

DoseDosage Forms & Strengths piperacillin/tazobactam powder for injection

(2g/250mg)/vial: 2.25g(3g/375mg)/vial: 3.375g

(4g/500mg)/vial: 4.5g(36g/4.5g)/vial: 40.5g

Severe Infections:3.375 g (IV) q6hr; total of 13.5 g; administer over 30 minfor 7-10 days

Nosocomial Pneumonia:4.5 g IV q6 hr; add aminoglycoside; total of 18 g for 7-14 days; continue aminoglycoside in P. aeruginosa patients

Community-aquired Pneumonia: 3.375 g IV q6hr for 7-10 days

Diverticulitis/Intra-abdominal Abscess/ Peritonitis:3.375 g IV q6hr for 7-14 days or until clear

Complicated Intra-abdominal Infection:3.375 g IV q6hr for 4-7 days

Skin and Soft Tissue Infection: 3.375 g IV q6-8hr for 7-14 days

Dosing range3.375 g IV q6hr, OR 4.5 g IV q6-8hr; not to exceed 18 g/day

Renal impairmentCrCl >40 mL/min:

Dose adjustment not necessaryCrCl 20-40 mL/min:

2.25 g IV q6hr, OR 3 g/0.375 g IV q6hr (for nosocomial pneumonia), OR extended infusion of 3.375 g IV over 4 hr q12hr (off-label)CrCl <20 mL/min: 2.25 g IV q8hr, OR 2.25 g IV q6hr (for nosocomial pneumonia)

Dosing Considerations:

Dosing Modifications:

CEPHALOSPORINS

Cefadroxil (Oral) DuricefCefazolin (IV,IM) AncefCefalotin or Cefalothin Keflin (discontinued)Cefalexin KeflexGood coverage against Gram-positive infections and some gram-negative bacteria.

Mode of action: as other beta-lactam antibiotics: disrupt the synthesis of the peptidoglycan layer of bacterial cell walls.

They have few absolute (i.e. uniquely advantageous) indications. Their pharmacology is similar to that of the penicillins and they are principally renally eliminated.

Cephalosporins (First generation)

DOSE & MODIFICATIONS(Adults): 1-2 grams per day divided qd or q12h. Renal Dosing: [CRCL >50 ]: No change. [25-50 ]: 1 gram x 1, then 500mg q12h. [10-25 ]: 1 gram po x 1, then 500mg q24h. [<10 ]: 1 gram x 1, then 500 mg q36h. Hemodialysis: 1 gram x 1, then 500 mg q36h. Dose should be given after dialysis on dialysis days. Alternatively, give 1 gram after each hemodialysis session plus an additional 1 gram dose q72h

CefadroxilDuricef (ORAL)

[Dosing -Usual]: 500mg to 1g IV q8h. [Moderate to severe]: 500mg – 1 gram q6-8h. [life-threatening]: 1–2 grams q6h. [Maximum dosage/day]: 12 grams.Renal dosing: [CRCL >55 ml/min]: no change. [35-54 ml/min]: Maximum interval: q8h. 500mg – 1.5g q8h. [11-34 ml/min]: 500mg – 1.5g x 1, then 0.5 - 1 gram q12h. [<10 ml/min]: 500 mg - 1 gram q18-24h. Hemodialysis: 500 mg – 1 gram IV q24h. (Give dose post-dialysis on dialysis days.) PD: 500 mg q12h

CefazolinAncef

DOSE & MODIFICATIONS (Adults): 250-500 mg every 6-12 hours Renal Dosing:[CRCL 10-50 ml/min]: Administer 50% of dose.[<10 ml/min]: Administer 25% of dose.

CephradineVelosef (ORAL)

(usual): 250 – 500mg po q6h. [Severe infections]: 1 gm q6h. (Maximum: 4 g/day).Other: Streptococcal pharyngitis, skin and skin structure infections: 500 mg orally q12h. Uncomplicated cystitis: 500 mg orally q12h. Renal Dosing:[CRCL >30 ]: no changes. [10-30 ]: 250-500 mg q8-12h. [<10 ]: 250-500mg q12-24h. Hemodialysis: 250-500mg q12-24h (Dose should be given after dialysis on dialysis days).

CephalexinKeflex (ORAL)

Cefaclor DistaclorCefamandole Mandol (discontinued)Cefoxitin Mefoxin (discontinued)Cefprozil CefzilCefuroxime Ceftin, Zinnat, Zinacef (oral)Less Gram-positive cover, improved Gram-negative cover.

The pharmacology of the cephalosporins is similar to that of the penicillins, excretion being principally renal. Cephalosporins penetrate the cerebrospinal fluid poorly unless the meninges are inflamed.

Cefuroxime. Unlike most other second-generation cephalosporins, cefuroxime can cross the blood-brain barrier.

Cephalosporin (second generation)

DOSE & MODIFICATIONSDosing (Adults): 250–500 mg orally every 8 hours or if the extended release form is used: 375–500 mg every 12 hours. Renal dosing: [CRCL >10 ]: no change. [<10 ]: Give 50% of usual dose at same interval. Hemodialysis: 250mg q8-12 hours. Make sure dose is given after dialysis.

CefaclorCeclor

Dosing (Adults): 1-2 grams q12h. [Life-threatening]: 3 grams IV q12h.Renal Dosing:[CRCL >30 ml/min]: No changes. [10-30 ]: 1-2g q24h or 500mg-1g q12h. [<10 ]: 1-2 grams q48h or 250-500mg q12h. Hemodialysis: 250 - 500 mg q24h on non-HD days and 500 mg - 1 gm q24h on HD days. PD: 1 gram q24h

Cefotetan

Dosing (Adults): 250 – 500 mg po q12h. Specific guidelines: Pharyngitis/tonsillitis: 500 mg orally every 24 hours x 10 days. Secondary or acute exacerbation of chronic bronchitis: 500 mg orally every 12 hours x 10 days.Renal Dosing:[CRCL >30 ]: No changes. [<29 ]: 50% of usual dosage q12-24h. Hemodialysis: 50% of usual dosage q12-24h. (Administer after the completion of hemodialysis on dialysis days)

CefprozilCefzilORAL

Dosing (Adults): 750 mg to 1.5 gm IV q8h.Renal Dosing:[CRCL >20 ml/min]: no changes (750 mg to 1.5 gm IV q8h). [10-20 ]: 750 mg q12h. [<10 ]: 750 mg q24h. Hemodialysis: 750mg q24h. Repeat the dose at the end of dialysis. PD: 750 mg q24h.

CefuroximeZinacef

Dosing (Adults): 250 – 500mg orally q12h. Renal Dosing:[CRCL >10 ml/min]: no changes. [<10 ]: give 250mg q24h. Hemodialysis: Give 250 mg q24h. Repeat the dose after dialysis.

Cefuroxime axetilCeftin ORAL

Dosing (Adults): Skin and soft tissue infections: 200 mg orally every 12 hours x 7 days. Uncomplicated urinary tract infections: 200 mg once daily for 7 days. Uncomplicated pyelonephritis: 400 mg orally every 12 hours for 14 days. Pharyngitis/tonsillitis: 200 mg orally every 12 hours for 10 days. Sinusitis: 400 mg orally every 12 hours for 10 days. Upper/lower respiratory tract infection: 400 mg orally every 12 hours for 7-14 days.Renal Dosing:[CRCL >50 ml/min]: no changes. [CRCL 10-49 ml/min]: Administer 50% of usual dose at usual interval or usual dose given half as often.[CRCL <10 mL/min]: Administer usual dose every 3-5 days.[Hemodialysis]: Doses should be administered after dialysis sessions.Supplied: 200 mg, 400 mg capsule. Powder for oral suspension: 100 mg/5 ml (100 ml); 200 mg/5 ml (100 ml).

loracarbef Lorabid

ORAL

Cefoperazone (cefobid)Unlike most third-generation agents, cefoperazone is active against Pseudomonas aeruginosa], combination Cefoperazone with Sulbactam makes more effective antibiotic, because Sulbactam avoid degeneration of Cefoperazone.

Ceftazidime (Fortaz – fortam) + Tazobactam ( Fobidime -TZ)(Unlike most third-generation agents, ceftazidime is active against Pseudomonas aeruginosa, but less active against Staphylococci and Streptococci compare to other 3rd generation of cephalosporins)

Ceftriaxone (Rocephin ) (IV and IM, not orally, effective also for syphilis and uncomplicated gonorrhea)

Cephalosporin (Third generation)

Cefixime (antagonistic with Chloramphenicol) - Cefdinir – Cefdiel –Cefpodoxime - Ceftibuten - Ceftizoxime - Cefizox (discontinued)- Cefotaxime (Claforan) - Cefoperazone (cefobid)

Improved coverage of Gram-negative organisms, except Pseudomonas. Reduced Gram-positive cover. But still not cover Mycoplasma and Chlamydia

DOSE & MODIFICATIONSDosing (Adults): 1) Acute exacerbations of chronic bronchitis, pharyngitis , tonsillitis: 300 mg orally twice daily for 5-10 days or 600 mg once daily for 10 days. 2) Community-acquired pneumonia, uncomplicated skin and skin structure infections: 300 mg orally twice daily for 10 days. 3) Acute maxillary sinusitis: 300 mg orally twice daily or 600 mg once daily for 10 days Renal Dosing: [CRCL >30 ml/min]: no change. [<30 ]: 300 mg q24h. Hemodialysis: Give 300mg qod. On dialysis days, give 300mg after dialysis.

Cefdinir: Omnicef ORAL

Dosing (Adults): 400 mg orally once daily or 200mg twice daily. Uncomplicated cervical/urethral gonorrhea due to N. gonorrhoeae:400 mg orally x 1.Renal Dosing: [CRCL >60 ml/min]: no change. [21-60]: Administer 75% of the standard dose. [<20 ml/min]: Administer 50% of the standard dose.

CefiximeSuprax®ORAL

Dosing (Adults): 400 mg orally q24h.Renal Dosing:[CRCL > 50 ]: no changes. [30-49 ]: 200 mg q24h. [0-29 ]: 100 mg q24h. Hemodialysis: Give 400mg after each hemodialysis session.

CeftibutenCedax ORAL

Dosing (Adults): [Uncomplicated]: 1 gram IV/IM q12h. [Moderate to severe]: 1-2 grams IV/IM q8h. [Severe]: 2 grams IV q6-8h. [Life-threatening]: 2 grams IV q4hRenal Dosing:[CRCL >50 ml/min]: no change. [10-50 ]: 1-2 grams q8-12h. [<10 ] : 1-2 grams q24h. Hemodialysis: 500mg to 2 grams q24h, plus give a supplemental dose post-dialysis. PD: 1 gram q24h

CefpodoximeVantinORAL

Dosing (usual): 1 gram IV q8-12 hours. [Severe / Life-threatening]: 2 grams q8 hours. (Max 6 grams/day).Bone and joint infections: 2 grams IV q12h.Intra-abdominal or gynecologic infection: 2 g IV q8h.Meningitis: 2 g IV q8h.Skin and soft tissue infections: 0.5 to 1 g IV q8h.UTI: 250-500mg IV q8-12 hoursRenal Dosing:[CRCL >50 ]: No changes. [31-50 ]: 1 gram q12h. [16-30 ]: 1 gram q24h. [6-15 ]: 500 mg q24h. [<5 –dialysis]: 500 mg q48h. Note: all dosages listed for renal insufficiency may be increased by 50% in severe infections. Hemodialysis: Loading dose: 1 gram x 1, then 1 gram after each hemodialysis session. [Alternatively]: Give 1 gram q48h, plus give an additional 1 gram dose after each dialysis session. CAPD: 1 gram x 1, followed by 500mg q24h.

CeftazidimeFortaz ®

Dosing (Adults): 1-2 grams IV/IM q8-12 hours. [Life-threatening]: 3-4 gm IV q8h or 2 gm q4h.Renal Dosing:[CRCL >79 ]: no changes. [50-79 ]: 500 mg to 1.5 gm q8h. [5-49 ]: 250mg – 1 gm q12h. [0-4 – dialysis pt]: 250-500 mg q24h or 500mg to 1 gm q48h. Hemodialysis: 250-500 mg q24h or 500mg to 1 gram q48h (dosages should be timed after hemodialysis on dialysis days.) PD: 500mg – 1 gram q24h.

CeftizoximeCefizox ®

Dosing (Adults): 1-2 grams q8-12 hours. Renal dosing: no changes needed. Hemodialysis: No changes needed. (Ideally, dosage should be scheduled following a dialysis period).

CefoperazoneCefobid ®

Dosing (Adults): [Uncomplicated]: 1 gram IV/IM q12h. [Moderate to severe]: 1-2 grams IV/IM q8h. [Severe]: 2 grams IV q6-8h. [Life-threatening]: 2 grams IV q4hRenal Dosing:[CRCL >50 ml/min]: no change. [10-50 ]: 1-2 grams q8-12h. [<10 ] : 1-2 grams q24h. Hemodialysis: 500mg to 2 grams q24h, plus give a supplemental dose post-dialysis. PD: 1 gram q24h

CefotaximeClaforan ®

Dosing (Adults): 1-2 grams q12-24h.[Meningitis]: Give 100 mg/kg/day (not to exceed 4 grams) qd or in divided doses q12h.Other: Gonococcal infection (uncomplicated): 125-250 mg IM x1. PID: 250 mg IM x 1. Renal Dosing:No adjustments are necessary.

CeftriaxoneRocephin ®

Cefepime Maxipime Covers pseudomonal infections.

Dosing (Adults): [Mild to moderate]: 500 mg to 1 gram IV q12h. [Moderate to severe]: 1-2 grams IV q12h. [Febrile neutropenic patients]: 2 grams IV q8h.

Renal Dosing: [CRCL >60 ml/min]: no change. [30-60 ]: 500mg to 2 grams q24h.

Neutropenic: 2 grams q12h. [11-29 ]: 500 mg to 1 gram q24h.

Neutropenic: 2 grams q24h. [<11 ]: 250 – 500 mg q24h.

Neutropenic: 1 gram q24h. Hemodialysis: 250 – 500 mg q24h.

Neutropenic: 1 gram q24h. // Give additional dose post dialysis. PD: 1-2 grams q48h

Cephalosporin (Fourth generation)

Ceftaroline fosamil TeflaroUsed to treat MRSA

Ceftobiprole ZefteraUsed to treat MRSA (methicillin-resistant Staphylococcus aureus), penicillin-resistant Streptococcus pneumoniae, Pseudomonas aeruginosa, and enterococci

Cephalosporin (Fifth generation)

DOSAGE AND ADMINISTRATIONThe recommended dosage of Teflaro is 600 mg administered every 12 hours by intravenous (IV) infusion over 1 hour in patients 18 years of age

Estimated CrCla (mL/min)Teflaro> 50 No dosage adjustment necessary 30 to 50 400 mg IV (over 1 hour) every 12 hours 15 to 30 300 mg IV (over 1 hour) every 12 hours End-stage renal disease,including hemodialysisb 200 mg IV (over 1

hour) every 12 hour

SIDE EFFECTS• The principal side effect of the cephalosporins is hypersensitivity.

Penicillin-sensitive patients will also be allergic to the cephalosporins, depending on the cephalosporin generation. The previous percentage of 10% cross reactivity rates are often overestimated. Allergic reactions may present as, for example, rashes, pruritus (itching), urticaria,

serum sickness-like reactions with rashes, fever and arthralgia, and anaphylaxis.

• gastrointestinal disturbances (e.g. diarrhea, nausea and vomiting, abdominal discomfort, disturbances in liver enzymes, transient hepatitis and cholestatic jaundice),

• headache, and Stevens–Johnson syndrome. • Rare side effects include eosinophilia and blood disorders (including

thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia);

• reversible interstitial nephritis; hyperactivity, nervousness, sleep disturbances, hallucinations, confusion, hypertonia, and dizziness.

Interactions with other medications

• CoumarinsCephalosporins possibly enhance the anticoagulant effect of coumarins (e.g. Warfarin) - change in patient's clinical condition, particularly associated with liver disease, intercurrent illness, or drug administration, necessitates more frequent testing of INR, and dose adjustment as necessary• ProbenecidExcretion of cephalosporins is reduced by probenecid (resulting in increased concentrations of drug in the blood plasma)• AntacidsAbsorption of cefaclor is reduced by H2 blockers (a type of antacid); therefore antacids should not be taken at the same time as cefaclor

MONOBACTAMS• Monobactams (e.g. aztreonam) contain a 5-monobactam ring

and are resistant to β-lactamase degradation.AZTREONAM (Azactam)

Uses:Aztreonam is primarily active against aerobic Gram- negative organisms and is an alternative to an aminoglycoside. It is used in severe sepsis, often hospital acquired, especially infections of the respiratory, urinary, biliary, gastro-intestinal and female genital tracts.

It has a narrow spectrum of activity and cannot be used alone unless the organism’s sensitivity to aztreonam is known.

Mechanism of actionThe 5-monobactam ring binds to bacterial wall transpeptidases and inhibits bacterial cell wall synthesis in a similar way to the penicillins.

PharmacokineticsAztreonam is poorly absorbed after oral administration, so it is given parenterally. It is widely distributed to all body compartments, including the cerebrospinal fluid. Excretion is renal and the usual half-life (one to two hours) is increased in renal failure.

Adverse effectsRashes occur, but there appears to be no cross-allergenicity with penicillins.

DoseAztreonam

CrCl >30 15-30 <15mL/min 2 g IV q8h 2 g IV q12h 1 g IV q12

carbapenemImipenem: the first clinically used carbapenem, MeropeneErtapenem is administered once daily as an intravenous infusion or intramuscular injection. Doripenem has a spectrum of activity very similar to that of meropenem. Its greater stability in solution allows the use of prolonged infusions and it is somewhat less likely to produce seizures than other carbapenems.Panipenem/betamipron (Japanese approval 1993)

Biapenem (Japanese approval 2001) exhibits similar efficacy and adverse event rates as other carbapenems.

IMIPENEM–CILASTATIN AND MEROPENEM

UsesImipenem, (Tienam) a carbapenem, is combined with cilastatin, which is an inhibitor of the enzyme dehydropeptidase I found in the brush border of the proximal renal tubule. This enzyme breaks down imipenem in the kidney.

Imipenem has a very broad spectrum of activity against Gram-positive, Gram-negative and anaerobic organisms. It is β-lactamase stable and is used for treating severe infections of the lung and abdomen, and in patients with septicaemia, where the source of the organism is unknown.

Meropenem is similar to imipenem, but is stable to renal dehydropeptidase I and therefore can be given without cilastatin.

Adverse effects

Imipenem is generally well tolerated, but seizures, myoclonus, confusion, nausea and vomiting, hypersensitivity, positive Coombs’ test, taste disturbances and thrombophlebitis have all been reported.

Meropenem has less seizure-inducing potential and can be used to treat central nervous system infection.

DoseDue to the high antimicrobial activity of TIENAM I.V., it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4.0 g/day, whichever is lower.

Fully susceptible organisms including gram-positive and gram-negative aerobes and anaerobes

Moderately susceptible organisms, primarily some strains of P. aeruginosa

Mild (TOTAL DAILY DOSE = 1.0 g)250 mg q6h

500 mg q8h

Moderate 500 mg q8h (TOTAL DAILY DOSE = 1.5 g) or500 mg q6h (TOTAL DAILY DOSE = 2.0 g)

500 mg q6h (TOTAL DAILY DOSE = 2.0 g)

Severe, life threatening

500 mg q6h (TOTAL DAILY DOSE = 2.0 g) 1 g q8h (TOTAL DAILY DOSE = 3.0 g) Or 1 g q6h (TOTAL DAILY DOSE = 4.0 g)

Uncomplicated urinary tract infection

TOTAL DAILY DOSE = 1.0 g250 mg q6h

(TOTAL DAILY DOSE = 1.0 g)250 mg q6h

Complicated urinary tract infection

500 mg q6h (TOTAL DAILY DOSE = 2.0 g) 500 mg q6h (TOTAL DAILY DOSE = 2.0 g)

Infection

Severe pneumonia including hospital and ventilator-associated pneumonia.

Broncho-pulmonary infections in cystic fibrosis

Complicated urinary tract infections

Complicated intra-abdominal infections

Intra- and post-partum infections

Complicated skin and soft tissue infections

Acute bacterial meningitis

Management of febrile neutropenic patients

Dose to be administered every 8 hours

500-1gm

2 g

500-1gm

500-1gm

500-1gm500-1gm

2 g

1 g

Reduced Intravenous Schedule for Adults with Impaired Renal Function and/ or Body Weight <70 kg

Patients with creatinine clearance of ≤70 mL/min/1.73 m2 and/or body weight less than 70 kg require dosage reduction of TIENAM I.V. as indicated in the tables below.

Creatinine clearance may be calculated fromserum creatinine concentration by the following equation:Tcc (Males) = (wt. in kg) (140 − age) (72) (creatinine in mg/dL) ̸̸ Tcc (Females) = 0.85 × above value

REDUCED INTRAVENOUS DOSAGE OF TIENAM I. V. IN ADULT PATIENTS WITHIMPAIRED RENAL FUNCTION AND/ OR BODY WEIGHT <70 kg

andBodyWeight(kg)is:

1 gm / dayand creatinine clearance(mL/min/1.73 m2) is:≥71 41- 70 21- 40 6- 20

1.5 gm / dayand creatinine clearance(mL/min/1.73 m2) is:≥71 41- 70 21- 40 6- 20

2gm / dayand creatinine clearance(mL/min/1.73 m2 ) is:

≥71 41- 70 21- 40 6- 20

≥70 then the reduced dosage regimen (mg) is:250 250 250 250q6h q8h q12h q12h

then the reduced dosage regimen (mg) is:500 250 250 250q8h q6h q8h q12h

then the reduced dosage regimen (mg) is:500 500 250 250Q6h q8h q6h q12h

60 250 125 250 125q8h q6h q12h q12h

250 250 250 250q6h q8h q8h q12h

500 250 250 250Q8h q6h q8h q12h

50 125 125 125 125q6h q6h q8h q12h

250 250 250 250q6h q8h q12h q12h

250 250 250 250q6h q6h q8h q12h

40 125 125 125 125q6h q8h q12h q12h

250 125 125 125q8h q6h q8h q12h

250 250 250 250q6h q8h q12h q12h

30 125 125 125 125q8h q8h q12h q12h

125 125 125 125q6h q8h q8h q12h

250 125 125 125q8h q6h q8h q12h

If TOTAL DAILY DOSE from TABLE I is:andBodyWeight(kg)is:

3 gm / dayand creatinine clearance(mL/min/1.73 m2) is:≥71 41- 70 21- 40 6- 20

4gm / dayand creatinine clearance(mL/min/1.73 m2) is:≥71 41- 70 21- 40 6- 20

≥70 then the reduced dosage regimen (mg) is:1000 500 500 500q8h q6h q8h q12h

then the reduced dosage regimen (mg) is:1000 750 500 500q6h q8h q6h q12h

60 750 500 500 500q8h q8h q8h q12h

1000 750 500 500q8h q8h q8h q12h

50 500 500 250 250q6h q8h q6h q12h

750 500 500 500q8h q6h q8h q12h

40 500 250 250 250q8h q6h q8h q12h

500 500 250 250q6h q8h q6h q12h

30 250 250 250 250q6h q8h q8h q12h

500 250 250 250q8h q6h q8h q12h

Patients with creatinine clearances of 6 to 20 mL/min/1.73 m2 : should be treated with TIENAM I.V. 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients.Patients with creatinine clearance ≤5 mL/min/1.73 m2 should not receive TIENAM I.V. unless hemodialysis is instituted within 48 hours.There is inadequate information to recommend usage of TIENAM I.V. for patients undergoing peritoneal dialysis.

HemodialysisWhen treating patients with creatinine clearances of ≤5 mL/ min/ 1.73 m2 who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 6-20 mL/min/1.73 m2Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive TIENAM I.V. after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, TIENAM I.V. is recommended only when the benefit outweighs the potential risk of seizures.

Ertapenem (Rx) Invanz

Ertapenem has been designed to be effective against Gram-negative and Gram-positive bacteria. It is not active against MRSA, ampicillin-resistant enterococci, Pseudomonas aeruginosa, or Acinetobacter species. Ertapenem also has clinically useful activity against anaerobic bacteria.

Mechanism of Action1-beta methyl-carbapenem; inhibits cell-wall synthesis by binding to penicillin-binding proteins; resistant to most beta- lactamases

Pharmacokinetics[ertapenem is highly protein-bound, which results in a longer half-life (4 hours).Ertapenem is excreted primarily (80%) by the kidneys. Metabolism by the liver is not clinically important and does not affect dosing.Patients on haemodialysis should be given ertapenem at least 6 hours before dialysis. If it is given less than six hours before dialysis, the patient should be given an additional dose of 150 mg IV after dialysis. Ideally, patients on haemodialysis should be given ertapenem immediately following dialysis.

DosageErtapenem is dosed as 1 g given by intravenous injection over 30 minutes, or 1 g diluted with 3.2 ml of 1% lidocaine given intramuscularly. There is no oral preparation of ertapenem available.

DosageCommunity-Acquired Pneumonia 1 g/day IV/IM up to 14 days; after ≥3 days of parenteral therapy, may be switched to appropriate PO regimen if patient improves clinically

Complicated Urinary Tract Infections (Including Pyelonephritis) 1 g/day IV/IM up to 14 days; after ≥3 days of parenteral therapy, may be switched to appropriate PO regimen if patient improves clinically

Acute Pelvic Infections 1 g/day IV/IM for 3-10 daysComplicated Intra-abdominal Infections 1 g/day IV/IM for 5-14 days

Complicated Skin/Skin Structure Infections 1 g/day IV/IM for 7-14 days; may be continued up to 4 weeks for diabetic foot infections, depending on severity of infection and response to therapy (treatment excludes diabetic foot infections with osteomyelitis)

Dosing ModificationsRenal impairmentCrCl >30 mL/min/1.73 m²: Dosage adjustment not necessaryCrCl <30 mL/min/1.73 m² and end-stage renal disease (ESRD): 500 mg/day IVDialysis: 500 mg/day IV; if given ≤6 hr before dialysis, supplemental dose of 150 mg afterward

GlycopeptidesActive against aerobic and anaerobic Gram-positive bacteria including MRSAInhibits peptidoglycan synthesis.Teicoplanin Targocid (UK)Vancomycin VancocinTelavancin VibativDalbavancin DalvanceOritavancin Orbactiv

VANCOMYCINUses and antibacterial spectrumVancomycin is valuable in the treatment of resistant infections due to Staphylococcus pyogenes. It is also rarely used to treat other infections, for example Staphylococcus epidermidis endocarditis, and is given orally for pseudomembranous colitis caused by Clostridium difficile.

Mechanism of actionVancomycin inhibits bacterial cell wall synthesis.

PharmacokineticsVancomycin is not absorbed from the gut and is usually given as an intravenous infusion (except for the treatment of pseudomembranous colitis). It is eliminated by the kidneys. Because of its concentration-related toxicity, the dose is adjusted according to the results of plasma concentration monitoring.

TEICOPLANINTeicoplanin has a longer duration of action, but is otherwise similar to vancomycin

Adverse effects

These include:• hearing loss;• venous thrombosis at infusion site;• ‘red man’ syndrome due to cytokine/histamine releasefollowing excessively rapid intravenous administration;• hypersensitivity (rashes, etc.);• nephrotoxicity.

1.The dose should be calculated based on patient’s actual body weight:

Weight (in kg) Dose (in mg)< 50 75050-74 100075-90 1250>90 1500

2. The dosing interval should be based on creatinine clearance (CrCl):

CrCl (mL/min) Dosing Interval>50 q12h

30-50 q24h <30 One dose,

then check a random vancomycin level in 24-48 hours, redose when level is <15-20 mcg/mL

Hemodialysis 500-750 mg after each hemodialysis session

Vancomycin Dosing Guidelines for Adults

Vancomycin Dosing Guidelines for Adults

3. Vancomycin trough (pre-dose) levels should be checked:A. On the fifth day of therapy and weekly thereafter for most patientsB. Prior to the fourth dose for patients with:

i. Morbid obesity (BMI >40) or severe malnutrition (weight <45 kg)ii. Acute renal failure (change in serum creatinine by more than 0.5 mg/dL)iii. Central nervous system infectionsiv. Endocarditisv. Persistent gram-positive bacteremia