2 December 1951

Bukit Tinggi
MD, FK USU, 1978
PhD in Clinical Pharmacology
FUSA-Flinders Medical Centre
Australia, 1988
SpFK, Clinical Pharmacologist
PB-IDI & FK UI, 1995
Professor
Head of Department
Pharmacology & Therapeutic
School of Medicine, USU
Email: aznanlelo@yahoo.com

Jln. Tridharma 22
Kampus USU, Medan

PK-PD ANTIBIOTICS
IN CRITICALLY ILL
PATIENTS
Aznan Lelo
Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara
2 November 2007, PIRDICI, Medan

Critically ill patients

 SYSTEMIC INFLAMMATORY RESPONSE
SYNDROME (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 Therapy

Mortality* Associated with Initial Inadequate Therapy
in Critically Ill ICU Patients with HAP or Sepsis
Alvarez-Lerma, 1996**

16.2%
24.7%
38%

Luna, 1997
Rello, 1997

91%
15.6%
37%

Initial inadequate
therapy

33.3%

Kollef, 1998

60.8%

Ibrahim, 2000***

28.4%

Harbarth, 2003***

24%

Valles, 2003***

31%

0%

Initial adequate
therapy

61.9%
39%
63%

20%

Mortality
40%
60%

80%

100%

*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.

Antibiotic use
Susceptible
Antibiotic
Pathogen
resistant
pathogen
Pathogen
Prevent
transmission

Prevent
infection

Antibiotic
resistance

Infection
Effective
diagnosis
and treatment

Optimize
use

Antibiotic
use

Selection of Antimicrobial Therapy:

Host Factors
Allergies, age, pregnancy, hepatic and renal
function, concomitant drug therapy,
immunocompentence, and co-morbidities
Site 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 hospitalacquired 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, bone

 Drug 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 profile
 Cost 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 penetration

 Pharmacodynamics
 Toxicity
 Cost

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)

Relationship between PK and PD

Dosage
regimen

Concentration
vs time in
plasma
Absorption
Protein binding
Distribution
Biotransformation
Excretion

pharmacokinetics

Concentration
vs time in
tissue and
other body fluids

Pharmacologic
or toxicologic
effect

Concentration
vs time in
site of
infection

Antibiotic
effect vs time

pharmacodynamics

Craig WA. Pharmacokinetic/pharmacodynamic parameters:

Rationale for antibacterial dosing of mice and men. Clin Infect Dis. 26:112,1998

Bacterial Targets for Antibiotics

PK/PD and Antibiotic Efficacy

 3 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

 PAE

Craig, 4th ISAAR, Seoul 2003

Antibiotic
concentration

Important PK/PD Parameters

concentration dependent
Area under the curve
over MIC

Cmax
MIC

Time

AUC/MIC is the
ratio of the AUC
to MIC
Cmax/MIC is the
ratio of the peak
concentration
to MIC

Antibiotic concentration
(ug/ml)

Important PK/PD Parameters

time dependent
8
6

Drug A

Time above MIC

Proportion of the
dosing interval
when the drug
concentration
exceeds
MIC
the MIC

Drug B

4
2
0

B
A
Time above MIC

Time

PD parameters predictive of
outcome
Parameter
correlating
with efficacy
Representative

Antimicrobial
Agents

T>MIC
Penicillins
Cephalosporins
Carbapenems
Macrolides

AUC:MIC

Azithromycin
Fluoroquinolones
Fluoroquinolones Aminoglycosides
Ketolides
Metronidazole

Organism kill Time-dependent ConcentrationTherapeutic

goal

Optimise
duration of
exposure

Cmax:MIC

dependent

Concentrationdependent

Maximize
concentration
exposure

Maximize
concentration
exposure

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 vs. Conventional Three-times Daily

Aminoglycoside Regimens Optimizes
Concentration-dependant Effect on Bacterial Kill
Concentration (mg/L)

12

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

4
MIC

0
0

16

24

Time (hours)
Nicolau et al. Antimicrob Agents Chemother 39:6505,1995

Relationship between the

maximal peak plasma level
to MIC ratio and the rate of
clinical response in 236
patients with Gramnegative 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.

Levofloxacin PK/PD correlations

134 hospitalized patients with respiratory tract, skin or complicated urinary
tract infections treated with 500 mg qd for 5-14 days

No. of patient

120
100

100

Bacteriologic outcome
Success

80

Failure

60
40
20

23
3

Bacteriologic
failure rate

AUC:MIC <25
Peak:MIC <3

43%

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

AUC:MIC >100
Peak:MIC >12

11.5%

1%

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

LEVOFLOXACIN
OFLOXACIN

Concentration (mg/L)

TROVAFLOXACIN
CIPROFLOXACIN
LOMEFLOXACIN
SPARFLOXACIN
NORFLOXACIN

Time (hours)

Meropenem 500 mg administered

as a 3 h infusion extends the time over the MIC
vs a 0.5 h infusion

Concentration
(ug/mL)

100

Rapid Infusion (30 min)

Extended Infusion (3 h)

10

MIC
1

0.1
0

Time (h)
Dandekar PK et al. Pharmacotherapy. 23:988-91,2003

PK problems in critically ill patients

 Drug 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 interval
 Renal and hepatic dysfunction is frequent.

PK-PD antibiotics
in critically ill patients
 patterns of bacterial killing are concentration dependent
and time-dependent
 Drug disposition in critically ill patients may be greatly
altered
 Guidelines 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 DUNIA