2 December 1951Bukit Tinggi

PhD in Clinical PharmacologyFUSA-Flinders Medical Centre Australia, 1988

ProfessorHead of DepartmentPharmacology & TherapeuticSchool of Medicine, USUJln. Tridharma 22Kampus USU, Medan

SpFK, Clinical PharmacologistPB-IDI & FK UI, 1995

MD, FK USU, 1978

Email: aznanlelo@yahoo.com

PK-PD ANTIBIOTICS IN CRITICALLY ILL

PATIENTSAznan Lelo

Dep. Farmakologi & Terapeutik,Fakultas Kedokteran

Universitas Sumatera Utara2 November 2007, PIRDICI, Medan

Critically ill patientsSYSTEMIC INFLAMMATORY RESPONSESYNDROME (SIRS)– Systemic activation of the immune response– >/= 2 of the following in response to an insult:

• T > 38 .C or < 36

.C

• HR > 90 bpm• RR > 20 bpm or PaCO2 < 32 mmHg• WBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bands

SEPSIS– The systemic response to infection– SIRS + suspected or confirmed infection

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

Why do we differentiate?

The Importance of Initial Appropriate Antibiotic TherapyMortality* Associated with Initial Inadequate Therapy

in Critically Ill ICU Patients with HAP or Sepsis

0% 20% 40% 60% 80% 100%

Luna, 1997

Ibrahim, 2000***

Kollef, 1998

Harbarth, 2003***

Rello, 1997

Alvarez-Lerma, 1996** Initial adequatetherapy

Initial inadequatetherapy

*Mortality refers to crude or infection-related mortality. **Includes patients with HAP.***Patients had blood stream infections rather than pneumonia as in the other studies.Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.; Luna CM et al. Chest 1997;111:676-685.; Rello J et al. Am J Respir Crit Care Med 1997;156:196-200.; Kollef MH et al. Chest 1998;113:412-420.; Ibrahim EH at al. Chest 2000;118:146-155.; Harbarth S et al. Am J Med 2003;115:529-535. & Valles J et al. Chest 2003;123:1615-1624.

Mortality

Valles, 2003***

24.7%

91%

37%

38%

15.6%

33.3%60.8%

28.4%61.9%

24%39%

63%31%

16.2%

Antibiotic use

Pathogen

Infection

Antibioticuse

Antibioticresistance

Preventinfection

Effective diagnosis

and treatmentOptimizeuse

Preventtransmission

Antibioticresistant pathogen

SusceptiblePathogen

Selection of Antimicrobial Therapy:Host Factors

Allergies, age, pregnancy, hepatic and renal function, concomitant drug therapy, immunocompentence, and co-morbiditiesSite of infection– Must cover common pathogens for specific infectious

diagnosis until culture results return• Must consider temporal relationships

– Organisms differ with early vs late onset hospital-acquired pneumonia

– Organisms may reflect selective pressure if antibiotics previously administered (Antimicrobial history taking is extremely important!)

Selection of Antimicrobial Therapy: Drug Factors

Variable antibiotic tissue penetration– Protected sites: pulmonary secretions, the central nervous

system, eye, prostate, abscess, boneDrug clearance: many are renally cleared– Exceptions: the macrolides, amphotericin, caspofungin,

voriconazole, clindamycin, tetracyclines, moxifloxacin, linezolid, ceftriaxone, and the antistaphylococcal penicillins

Bioavailability – Good absorption for most quinolones, linezolid, cotrimoxazole,

metronidazole, fluconazole, voriconazole, clindamycin, cephalexin, doxycycline, minocycline

Toxicity profileCost truths: – generic cheaper than brand name and oral/enteral cheaper than

parenteral, BUT: antimicrobial costs represent a small fraction of infection treatment

Selection of Antimicrobial Therapy:Pathogen Factors

Susceptibility patterns– Vary from institution to institution and even among nursing units– Change quickly if resistant clone becomes established and

spreads– Antibiograms are available from the laboratory at most hospitals

and updated regularly, and are essential to choose appropriate empirical therapy

Using MIC (minimum inhibitory concentration) data– Requires knowledge of achievable drug concentrations at the

site of infection– Comparisons within a class of antibiotics can be helpful;

example = Tobramycin with an MIC of <1mcg/ml for P aeruginosa is preferred over gentamicin with MIC of 4 for that organism

Drug Factors for Selection of Antibiotic

Pharmacokinetics– tissue penetrationPharmacodynamicsToxicityCost

What is PK and PD ?Pharmacokinetics (PK) – is what the body does to a drug. – This includes absorption, distribution,

metabolism, and excretion Pharmacodynamics (PD) – the biochemical and physiologic effects of the

drug and – its mechanism of action i.e. what the drug

does to the body (or micro-organism in the case of antibiotics)

Dosageregimen

Concentration vs time in plasma Concentration

vs time in site of

infection

Antibioticeffect vs time

Concentration vs time in tissue and

other body fluids

Pharmacologicor toxicologic

effect

Relationship between PK and PD

pharmacodynamicspharmacokinetics

AbsorptionProtein bindingDistributionBiotransformationExcretion

Craig WA. Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis. 26:1–12,1998

Bacterial Targets for Antibiotics

PK/PD and Antibiotic Efficacy3 patterns of bacterial killing– Concentration dependent with prolonged persistent

effect• Aminoglycosides, quinolones• Correlated with AUC/MIC , Cmax/MIC

– Time dependent with no persistent effect• Betalactams• Correlated with Time above MIC (T>MIC)

– Time dependent with moderate to prolonged persistent effect• Macrolides, azalides, clindamycin, tetracyclines,

glycopeptides, oxazolidinones• Correlated with AUC/MIC

PAECraig, 4th ISAAR, Seoul 2003

Important PK/PD Parametersconcentration dependent

Ant

ibio

tic

conc

entra

tion

Time

Cmax

MIC

Area under the curve Area under the curve over MICover MIC

• AUC/MIC is the ratio of the AUC

to MIC• Cmax/MIC is the

ratio of the peak concentration

to MIC

Important PK/PD Parameterstime dependent

Time above MIC Time

Ant

ibio

tic c

once

ntra

tion

(ug/

ml)

2

Drug A

B

4

6

8

0

Drug B

A

MIC

Time above MICProportion of the Proportion of the

dosing interval dosing interval when the drug when the drug concentration concentration

exceeds exceeds the MICthe MIC

PD parameters predictive of outcome

Maximize concentration exposure

Maximize concentration exposure

Optimise duration of exposure

Therapeuticgoal

Concentration-dependent

Concentration-dependent

Time-dependentOrganism kill

FluoroquinolonesAminoglycosidesMetronidazole

AzithromycinFluoroquinolonesKetolides

PenicillinsCephalosporinsCarbapenemsMacrolides

Representative Antimicrobial

Agents

Cmax:MICAUC:MICT>MICParameter correlating

with efficacy

Drusano & Craig. J Chemother ;9:3844,1997 Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S2741,1998

Vesga et al. 37th ICAAC 1997

Pharmacodynamics of Bacterial Killing Concentration-dependent (greater bacterial kill at higher

concentrations) vs. Concentration-independent (time dependent)

— Once-daily regimen— Conventional

(three-times daily regimen)

0

4

8

12

0 8 16 24

Con

cent

ratio

n (m

g/L)

Time (hours)

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

Concentration-dependant Effect on Bacterial Kill

Nicolau et al. Antimicrob Agents Chemother 39:650–5,1995

MIC

Relationship between the maximal peak plasma level to MIC ratio and the rate of

clinical response in 236 patients with Gram-

negative bacterial infection treated with

aminoglycosides(gentamicin, tobramycin, or

amikacin). Vertical bars represent SE values

High drug levels should be then the goal of therapy.

This approach, however, is not feasible for the fluoroquinolones

owing to dose-limiting CNS toxicity.

3

23

100

134

0

20

40

60

80

100

120

AUC:MIC <25 Peak:MIC <3

AUC:MIC 25-100 Peak:MIC 3-12

AUC:MIC >100 Peak:MIC >12

Success

Failure

Bacteriologicfailure rate 43% 11.5% 1%

Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated urinary

tract infections treated with 500 mg qd for 5-14 days

Preston et al., JAMA 279:125-9,1998

Bacteriologic outcome

No.

of p

atie

nt

LEVOFLOXACINOFLOXACINTROVAFLOXACINCIPROFLOXACINLOMEFLOXACIN

NORFLOXACINSPARFLOXACIN

Con

cent

ratio

n (m

g/L)

Time (hours)

Meropenem 500 mg administered as a 3 h infusion extends the time over the MIC

vs a 0.5 h infusionC

once

ntra

tion

(ug/

mL)

Time (h)0 2 4 6 8

0.1

1

10

100Rapid Infusion (30 min)

Extended Infusion (3 h)

MIC

Dandekar PK et al. Pharmacotherapy. 23:988-91,2003

PK problems in critically ill patientsDrug disposition in critically ill patients may be greatly altered for various reasons, including variations in– vascular permeability, – intravascular volume, and – the composition and distribution of plasma proteins.

increased distribution volume, this results in – inadequate serum levels of antibiotics.

protein binding is frequently reduced, this should be taken into account for highly bound drugs will alter

• the distribution volume and • drug clearance

The unbound serum concentration of the antibiotic should be above the MIC for at least 40% to 50% of the dosing intervalRenal and hepatic dysfunction is frequent.

PK-PD antibiotics in critically ill patients

patterns of bacterial killing are concentration dependent and time-dependentDrug disposition in critically ill patients may be greatly alteredGuidelines on critically ill patients should focus on antibiograms for each intensive care unit to ensure full coverage of initial therapy with a broad-spectrum antibiotic with

high tissue penetration, minimal organ toxicity and low risk of resistance development.

Future studies are needed in patients to assess the influence of selecting antibiotic therapy based on the impact of PK-PD antibiotics on

mortality, morbidity, and cost in critically ill patients.

KEBANGGAAN INDONESIA UNTUK DUNIAKEBANGGAAN INDONESIA UNTUK DUNIA