Using PK/PD Principles in Antibiotic Prescribing SAHD May 20, 2011

Using PK/PD Principles in Using PK/PD Principles in Antibiotic PrescribingAntibiotic PrescribingSAHD May 20, 2011SAHD May 20, 2011

Peter Gayo MunthaliPeter Gayo MunthaliConsultant MicrobiologistConsultant Microbiologist

UHCWUHCWHonorary Associate Clinical ProfessorHonorary Associate Clinical Professor

University of WarwickUniversity of Warwick

ObjectivesObjectivesBy the end of this session you should be able to:1. Appreciate the importance of prescribing antibiotics in a timely

manner2. Understand the right dosing for major classes of antibiotics 3. Select antibiotics according to the site of infection 4. Safely prescribe Gentamicin and Vancomycin,be able to

monitor levels logically and interpret them5. Select safe antibiotics for use in renal and hepatic failure6. Understand the consideration of antibiotic interactions with

other drugs

There are Three in this RelationshipThere are Three in this Relationship

Drug

Bacteria

Resistance

Pharmacodynam

ics

(PD)Infection

Host defence

Toxici

ty

Pharm

acok

inet

ics

(PK)

Host

Improving the probability of Improving the probability of positive outcomespositive outcomes

• Window of opportunity– Early recognition and treatment of infection

– Selection of appropriate antibiotic(e.g. through in vitro susceptibility determination)

– Optimization of DOSE using Pharmacodynamic principles

– Use optimized dosing that would allow for the minimization of selecting further resistance

Early recognition of infection Early recognition of infection (Sepsis)(Sepsis)

• Systemic inflammatory response syndrome (SIRS)Systemic inflammatory response syndrome (SIRS)Systemic activation of the immune responseSystemic activation of the immune response 2 of the following in response to an insult:2 of the following in response to an insult:

• T > 38 .C or < 36.CT > 38 .C or < 36.C• HR > 90 bpmHR > 90 bpm• RR > 20 bpm or PaCO2 < 32 mmHgRR > 20 bpm or PaCO2 < 32 mmHg• WBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bandsWBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bands

• SepsisSepsisThe systemic response to infectionThe systemic response to infectionSIRS + suspected or confirmed infectionSIRS + suspected or confirmed infection

(Bone et al Crit Care med 1989.;17 :389) (Bone et al Crit Care med 1989.;17 :389)

SepsisSepsis• Severe sepsis

– Sepsis + organ dysfunction, hypoperfusion or hypotension

• Septic shock– Severe sepsis +

• unresponsive to fluid resuscitation • need for vasopressor agents

• Multiple organ dysfunction syndrome– Organ dysfunction – Homeostasis cannot be maintained without intervention

Severe Sepsis BundlesSevere Sepsis BundlesSepsis Resuscitation Bundle(To be completed as soon as possible and scored over first 6

hours)1. Serum lactate measured2. Blood culture obtained prior to antibiotic administration3. From presentation, broad spectrum antibiotics administered

within 3 hours for ED admission and 1 hour for non-ED ICU admission

4. In the event of hypotension and /or lactate >4mmol/l (36mg/dl):

a. Deliver an initial minimum of 20ml/Kg of crystalloid (or colloid equivalent)

b. Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure >65mmHg

5. In the event of persistent hypotension despite fluid resuscitation (septic shock) and /or lactate >4mmmol/L (36mg/dl):

a. Achieve central venous pressure (CVP) of >8mmHgb. Achieve central venous oxygen saturation (ScvO2) of > 70%

Early treatment of infectionEarly treatment of infection prospective observational study on 101 consecutive adult patients with

severe sepsis or septic shock

• The rate of compliance with the 6-hour sepsis bundle was 52%.

• non-compliant group had a more than twofold increase in hospital

mortality

– (49% versus 23%, RR 2.12 (95% CI 1.20 to 3.76), P = 0.01)

– similar age and severity of sepsis both groups

• Compliance with the 24-hour sepsis bundle in only 30% (21/69).

Hospital mortality was increased in the non-compliant group from 29%

to 50%,

– 76% increase in risk for death(RR 1.76 (95% CI 0.84 to 3.64), P =

0.16).

Critical Care 2005, 9:R764-R770

•2,000 consecutive patients admitted to surgical or medical ITU655 patients (33%) had either CA or HA infection 169 infected patients (25.8%) received inadequate antimicrobial treatment

•All Cause Hospital Mortality (All Cause Hospital Mortality (RR 4.26, 95% CI 3.52-5.15, p < 0.001)•Adequate antimicrobial treatment

•Mortality 12.2%•Inadequate antimicrobial treatment

•Mortality 52.1%

•Infection Related Mortality (Infection Related Mortality (RR 2.37, 95% CI 1.83-3.08, p < 0.001)

•Adequate antimicrobial treatment•Mortality 17.7%

•Inadequate antimicrobial treatment•Mortality 42.0%

•Most important independent determinant of hospital mortality was inadequate antibiotic treatment (OR 4.27, 95% CI 3.35-5.44, p < 0.001)

Role of Antibiotics (Kollef et al Chest 1999;115:462-474)

Timing of Antibiotics (Kumar A et al. Crit Care Med Kumar A et al. Crit Care Med

2006;34:1589–1596)2006;34:1589–1596)

•Retrospective, May 1999-June 2004, N=2731

•Outcome of antibiotic therapy after onset of recurrent or persistent hypotension

•Overall mortality 56.2%

•Survival decreased by 7.6% for each hour of delay

•Applied to all subgroups of infections regardless of the source of infection or causative pathogens

Key Message 1Key Message 1

• Diagnose sepsis early and give antibiotics promptly to reduce mortality from sepsis

PharmacodynamicsPharmacodynamics

Drug Absorption CurveDrug Absorption Curve

MIC CalculationMIC Calculation

MIC

Beta-LactamsBeta-Lactams

• The critical parameter is the time the antibiotic concentration remains above the MIC of the organism expressed as– T > MIC

BetaBeta-Lactams: -Lactams: Optimising ExposureOptimising Exposure

• The optimum level of exposure varies for different agents within the beta-lactam class

• Required %T>MIC for efficacy:– ~ 50%–70% for cephalosporins– ~ 50% for penicillins– ~ 40% for carbapenems

Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.

Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media

Craig et al, Ped Infect Dis 15: 255, 1996

Conventional (three-times daily regimen)Conventional (three-times daily regimen)

Nicolau DP et al. Antimicrob Agents Chemother. 1995;39:650–655

Once-daily vs. Conventional Once-daily vs. Conventional Three-times Daily Aminoglycoside Three-times Daily Aminoglycoside

RegimensRegimens

Once-daily vs. Conventional Once-daily vs. Conventional Three-times Daily Aminoglycoside Three-times Daily Aminoglycoside

RegimensRegimensConcentration (mg/L)Concentration (mg/L)

00

88

1414

44

66

1010

1212

Time (hours)00 1212 2424202044 88 1616

Once-daily regimenOnce-daily regimen

22MIC

Cmax:MIC modelFor optimal response,

Peak concentration: MIC ratio should be between 8-12.1

Aminoglycosides—Aminoglycosides—Relationship Between CRelationship Between Cmaxmax:MIC :MIC

Ratio and Clinical ResponseRatio and Clinical Response

55

6570

8389 92

0

10

20

30

40

50

60

70

80

90

100

2 4 6 8 10 12+

CCmaxmax:MIC:MIC

Clinical Clinical responseresponse

(%)(%)

Moore RD et al. J Infect Dis. 1987;155:93-99.

Key Message 2Key Message 2• Beta lactams need frequent dosing for

successful therapeutic outcome– Missing doses will lead to treatment failure

• Aminoglycosides should be given as a large single dose (except in infective endocarditis) for a successful therapeutic outcome– Multiple small doses will lead to treatment failure

and likely to lead to renal toxicity

PharmacokineticsPharmacokinetics

Where do bugs Hide?Where do bugs Hide?

CytosolListeria monocytogenesShigella flexeneriRickettsia spp

ER

Legionella pneumophila

Mycobacterium spp

Endosomes

Lysosomes

Legionella pneumophilaCoxiella brunetiStaphylococcus aureus

Phagosomes

Brucella sppSalmonella sppFrancisella tularensis

Inclusions

Chlamydia spp

Early Endosomes

Nucleus

Use of Pharmacokinetics in Treatment

Aminoglycosides

Good

Circulating organisms

Poor

Soft tissue

Bone and joints

Abscesses

Lungs

CSF

Beta lactams

Good/variable (Dependant on individual antibiotic)

Soft tissue

Bone and joints

Lungs

CSF

Poor

Abscesses

Examples of good Tissue Penetrators

Tetracyclines

Macrolides

Quinolones

Clindamycin

Extra and Intracellular PharmacokineticsExtra and Intracellular PharmacokineticsAntibiotic Influx Efflux Accumulation Factor Accumulate

s

Beta lactams Fast Variable < 1 Cytosol

Erythromycin Fast Fast 4-10 Two Thirds

Lysosomes/one third cytosol

Clarithromycin Fast Fast 10-20

Azithromycin Fast Slow-v. slow 40-300

Telithromycin Fast to slow 15-50

Fluoroquinolones Fast-v.fast

Very fast 4-10 Cytosol

Aminoglycosides V.slow Very slow 2-4 (after several days) Lysosomes

Clindamycin Fast Fast 5-20 Unknown

Tetracyclines Fast ? 1-4 Unknown

Vancomycin slow ? 8 (after 24 hrs) Lysosomes (in kidneys)

Teicoplanin Fast ? 60 Unknown

Accumulation factor =Cellular conc /extracellular concV.fast < 3min, Fast 3-15min, slow 15min-3hrs, V.slow >3hrs

Infect Dis Clin N Am 17(2003) 615-634

Key Message 3Key Message 3

• When selecting an antibiotic consider the following;– Where is the infection?– Which antibiotics will reach the site of

infection

• Match the two and select your antibiotic

Antibiotics, Renal Function and Hepatic Antibiotics, Renal Function and Hepatic FunctionFunction

Renal FunctionEstimated Creatinine clearance (Cockcroft-Gault formula) 140-AgexMass (Kg) x ConstantSerum Creatinine in µmol/l

Constant 1.04 for Women, 1.23 for Men

Stage GFR(ml/min/1.73m²) Description I 90+ Normal

II 60-89 Mild reduction

IIIa 45-59 Moderate reduction

IIIb 30-44 Moderate reduction

IV 15-29 Severe reduction

V <15 Very severe (End-stage)

Effect of Creatinine Clearance on the Half Life of an Antibiotic with a Normal Half Life of 1 Hour

1 24

20

0

5

10

15

20

25

Normal 50% Normal 25% Normal 5% Normal

Creatinine Clearance

Hal

f Life

in H

ours

Excretion Less than 15% in urine and

Generally innocuous

Examples

•Macrolides (erythromycin)

•Sodium fusidate

•Clindamycin

Generally no dosage adjustment required

•Exception

•Chloramphenicol-not innocuous

Major Renal Excretion i.e. ≥ 50%

Generally innocuous

Examples

•Penicillins

•Cephalosporins

•Carbapenems

•Tetracyclines

Not Innocuous

Examples

•Aminoglycosides

•Polymyxin B, Colistin

•Vancomycin

•Amphotericin

Antibiotic Renal Handling

Excretion Less than 15% in urine and

Generally innocuousDose adjustment required only at moderate to severe renal impairment

Examples

Antibiotic Creatinine Clearance

Dose adjustment

Clindamycin Any None

Erythromycin Any None

Major Renal Excretion i.e. ≥ 50% Generally innocuous

Antibiotic Creatinine Clearance (CrCl)

Dose Adjustment

Amoxicillin >30 Nil

Co-amoxiclav >15 Nil

Tazocin >40 Nil

Ceftriaxone Any Nil

Meropenem >50 Nil

Doxycycline and Minocycline (All other tetracyclines to be avoided)

Any Nil

Major Renal Excretion i.e. ≥ 50% AND Poisonous

Antibiotic Creatinine Clearance (CrCl)

Dose Adjustment

Aminoglycosides (Gentamicin 5mg/Kg trough levels after 1st dose)

In all cases monitor levels

Reduced

Severe

<20

↑ dose interval

↑ dose interval and ↓dose

Avoid

Vancomycin (1g BD, trough levels before 4th Dose)

In all cases monitor levels

Reduced

Severe

Monitor Trough levels

Give only after trough levels known

Amphotericin Reduced Avoid

Gentamicin monitoring 1Gentamicin monitoring 1

Hartford Nomogram

7 mg/Kg OD

•Precise Times of collection required

•Collection 6-12Hrs after dose

Gentamicin monitoring 2Gentamicin monitoring 2• Gentamicin 5-7mg/Kg OD

– Collect around 24Hrs post dose– Aiming for <1mg/l

• Checking if patient is clearing gentamicin

• High levels• Blood collected too early• Patient not clearing Gentamicin• Blood collected from lumen used to infuse

Gentamicin earlier on

Gentamicin monitoring 2Gentamicin monitoring 2

• Corrective measures– Re-check levels– Stop, look for alternative antibiotic– Omit dose and repeat levels after 12 Hrs

• Frequency– 2-3x/week after steady state

• More frequently if renal function changing or concurrent nephrotoxic drugs

Vancomycin trough level• Collect serum specimen 30 minutes or less before next dose

• Frequency of collection:

•First level at steady state (3rd - 5th dose)

•Subsequent levels once or twice/week

•More frequently if renal function changing or concurrent

nephrotoxic drugs

Vancomycin MonitoringGlycopeptide

•ONLY active against Gram-positive bacteria including MRSA

•IV only except for Clostridium Difficile associated diarrhoea when oral route is used (NOT absorbed from GI and not enough levels get into GI by IV route)

•1g BD IV standard dose

Therapy Trough Level (mg/L)

Dosing Interval Adjustment

Vancomycin <5 •On ≥q24h , decrease interval by 12 hours

•On q12h, consult microbiology/pharmacist

5-15 No change

15-20 Increase interval by 12 hours

>20 Consult microbiologist/pharmacist/Stop

Vancomycin with Aminoglycoside

<5 •On ≥q24h , decrease interval by 12 hours•On q12h, consult microbiology/pharmacist

5-10 No change

10-20 Increase interval by 12 hours

>20 Consult microbiologist/pharmacist/Stop

Hepatic failureHepatic failure

Antibiotic Handling Comments

Penicillins Kidneys Generally safe in liver failure, check individual drug for possible cholestatic jaundice

Tetracyclines Concentrated in the liver and excreted via bile and reabsorbed in the intestine. Eliminated in urine

Avoid or use with caution

Aminoglycosides Kidneys Safe

Macrolides Liver metabolism May worsen liver dysfunction, avoid

Chloramphenicol 85-95% conjugated in the liver

Avoid, increased probability of bone marrow toxicity

Glycopeptides Kidneys Safe

Co-trimoxazole Significant metabolism by liver

Avoid

Key Message 4&5Key Message 4&5• Aminoglycosides are toxic drugs and require

monitoring– Avoid use in renal failure but safe in liver failure– Avoid concomitant use with other renal toxic drugs – Check renal clearance, frequency according to renal function

• Vancomycin dosing should be BD dose and adjusted according to levels at steady state– Frequency of monitoring depends on renal function

• Beta lactams are the safest antibiotics in renal and hepatic failure– Adjustments to dose may still be required in severe failure

Antibiotic InteractionsAntibiotic Interactions

Antibiotic Interacting Drug

Comments

Penicillins MethotrexateAllopurinol

reduce excretion of MethotrexateIncreased risk of rash when given with

amoxicillin or Ampicillin

Tetracyclines RifampicinCarbamazepine,

barbiturates (Cytochrome P450 Inducers)

Plasma Doxycycline levels reducedAccelerates metabolism of

Doxycycline

Aminoglycosides Amphotericin, loop diuretics, Taccrolimus

Neostigmine

Increased nephrotoxicity /ototoxicityAntagonise effect

Macrolides Many Check BNF

Rifampicin (Cytochrome P450 Inducer)

Too many Check BNF

Key Message 6Key Message 6

• Always check the impact of an antibiotic on other drugs that a patient is on– Consult BNF

And So!And So!

Necrotising Fascitis

Beta haemolytic Streptococcus group A

Patient•Severe sepsis with septic shock

•Acute renal failure

•On Gentamicin, Clindamycin,

•co-amoxiclav

Beta haemolytic Streptococcus group A isolated from tissue

Sensitive to:

Amoxicillin, meropenem, Clindamycin

Gentamicin, doxycycline, Vancomycin, Erythromycin, Gentamicin

What would you do?

a. Stop Gentamicin

b. Switch Co-amoxiclav to Benzylpenicillin

c. Continue with the same treatment

d. Add meropenem to the current treatment

What would you do?On 11/05/11 you are called by a nurse at 2300hrs to make a decision whether to give gentamicin or not since the level was not done that day.

Date Urea (mmol/L) (Normal Ref 2.5-7.8)

Creatinine µmol/L ( Normal Ref 50-90)

Gent Levels

09/05/11 6 99 <1

07/05/11 7 98 <1

04/05/11 8 102 <1

30/04/11 8 103 <1

Previous Renal Function and Gentamicin Levels

How do you proceed?How do you proceed?

a) Send urgent Gentamicin levels before giving it

b) Change to another antibiotic until you get levels back the following day

c) Omit Gentamicin dose

d) Give the Gentamicin and check levels the following day

What would you do?On 11/05/11 you are called by a nurse at 2300hrs to make a decision whether to give gentamicin or not since the level was not done that day.

Date Urea (mmol/L) (Normal Ref 2.5-7.8)

Creatinine µmol/L ( Normal Ref 50-90)

Gent Levels

09/05/11 15 110 Not done

07/05/11 9 90 <1

04/05/11 3 60 <1

31/04/11 2.7 53 <1

Previous Renal Function and Gentamicin Levels

How do you proceed?How do you proceed?

a. Send urgent Gentamicin levels before giving it

b. Change to another antibiotic until you get levels back the following day

c. Omit Gentamicin dose

d. Give the Gentamicin and check levels the following day

A 40 year old engineer comes in with SOB and fever of 40ºC. What is your diagnosis?

Which antibiotics would you use?

a. Benzylpenicillin

b. Amoxicillin

c. Erythromycin

d. Clarithromycin

Patient says she is allergic to Penicillin. What next?

Ask type of allergy

a. Pneumothorax

b. Community acquired pneumonia

c. Pulmonary embolus

It made my pint taste funny and my fish and chips were not the same. Which statements are correct?

a. Penicillin is safe

b. I would avoid the use of penicillin

It made me itchy all over and I had a rash. Which of these is correct ?

a. Amoxicillin can be given safely

b. Ertapenem can be given with caution

c. Doxycycline can be given safely

d. Ceftriaxone can be given safely

The laboratory phones and informs you that they have grown a pneumococcus

Sensitive to:

Gentamicin

Penicillin

Vancomycin

Chloramphenicol

Ciprofloxacin

Which antibiotics can be safely used to treat Chidongo who has severe penicillin allergy?

a) All of the above

b) Gentamicin

c) Vancomycin

d) Chloramphenicol

e) Ciprofloxacin

What would you do?What would you do?You are called at night to prescribe warfarin for a patient with PE.

Her INR has fallen below therapeutic range since Rifampicin was prescribed 5 days ago for Staphylococcus aureus bacteraemia

a. Reduce Rifampicin dose

b. Increase warfarin dose

c. Wait and see

d. Stop Rifampicin and replace it with something else

A patient on furosemide for CCF has been started on Gentamicin for UTI. Two days later her renal function has become severely deranged,

a. Stop furosemide

b. Stop Gentamicin

c. Stop Gentamicin and replace with another antibiotic