## Icaac04- a-138

**ICAAC 2004**
**Use of Pharmacokinetic-Pharmacodynamic and Monte Carlo Simulation as Decision Support**
**for the Re-Evaluation of NCCLS Cephem Susceptibility Breakpoints for Enterobacteriaceae**
**PG AMBROSE, SM BHAVNANI, RN JONES, WA CRAIG, MN DUDLEY**
**Cognigen Corp., Buffalo, NY; University at Buffalo, Buffalo, NY; JONES Group/JMI Laboratories, North Liberty, IA;**
**University of Wisconsin, Madison, WI; and Diversa Corporation, San Diego, CA**
**Animal PK-PD Models**
Current, PK-PD-based, PK-PD-based-population distribution adjusted breakpoints

**A M E N D E D A B S T R A C T**
¥ Neutropenic murine-thigh infection models were used to study PK-PD indices that correlated
for antimicrobial agents in NCCLS M100-S14 Table 2A.

best with efficacy for Enterobacteriaceae, including both EBSL- and non-ESBL producing

**Background: **As cephem-resistant Enterobacteriaceae, including ESBL-producing strains,

have continued to emerge, the appropriateness of current NCCLS susceptibility breakpoints
Potential susceptibility breakpoints could be stratified into one of five groups
Table 2 shows current cephem NCCLS susceptibility breakpoints, PK-PD based
have been the focus of recent attention. In the face of limited clinical data, Pharmacokinetic-
¥ Indices of efficacy explored include: Duration of time (T) drug concentration remain above the
based upon probability of PK-PD target attainment and examination of
breakpoints, and MIC population-adjusted PK-PD breakpoints.

Pharmacodynamics (PK-PD) and Monte Carlo simulation have been increasingly used as
MIC (T > MIC), ratio of the peak concentration of the agent to the MIC of the pathogen (Cmax:MIC
decision support for establishing breakpoints. NCCLS susceptibility breakpoints for cephems
ratio), ratio of the 24-hour area under the concentration-time curve (AUC0-24) of the agent to
against Enterobacteriaceae were re-evaluated using this approach.

**Figure 3**. Fractional PK-PD target attainment of cefuroxime against

*Escherichia coli *and

**Methods:**
Susceptibility breakpoints did not bisect MIC distribution (Example, Figures
Using published mean PK parameter estimates and dispersion measures from
. The probability of PK-PD target attainment is greater than
¥ Non-linear regression using a Hill-type model was used to describe relationship between the
volunteer studies and PK-PD targets derived from a murine infection model (% free-drug (

*f*)
2A and 2B): Ceftazidime, Ceftriaxone, Cefotaxime, Cefepime, Cefamandole,
0.9 up to MIC values of 4 mg/L when cefuroxime is dosed 0.75 g every 8 hours
above PK-PD measures and response to therapy.

time > MIC ~50), Monte Carlo simulation (10,000 subjects) was used to evaluate the probability
and 8 mg/L when dosed 1.5 g every 8 hours.

of PK-PD target attainment (³ 90%) for standard cephem dosing regimens.

¥ Figure 1 shows the relationship between cephem exposure, as measured by %T > MIC, and

**Results:** Simulation results support lowering susceptibility breakpoints 2-16-fold for most

response in neutropenic murine-thigh infection models

* *involving Gram-negative bacteria.

Susceptibility breakpoints bisecting MIC population distributions could be
agents (see table below). Except for cefoxitin and cefazolin, breakpoints do not bisect
- 50% T>MIC was associated with a 0.8 to 2.4 log-unit reduction in bacterial burden.

avoided assuming higher of labeled doses used for serious infections
contemporary MIC population distributions (SENTRY Program).

**Monte Carlo Simulation**
¥ The following PK-PD structural model was used in the simulations:

*T *>MIC = (ln Dose/(

*V*§/

*f*) Ð ln MIC)/(CLT/

*V*§) where

*V*§ is the volume estimated from the

**MIC Probability**
Susceptibility breakpoints bisect MIC distribution (Example, Figure 4):
terminal elimination phase half-life (§) for a two-compartment model, CL

*f *is the fraction of unbound drug.

**Probability of Target Attainment**
¥ Pharmacokinetic parameters for each simulated patient were based on mean pharmacokinetic
Contemporary MIC populations not available: Ceftizoxime, Cefotetan,

**MIC (mg/L)**
parameter estimates and measures of dispersion.

- A log-normal distribution was assumed for clearance and volume terms.

¥ 10,000 patients were simulated for each drug regimen.

Consider removal from NCCLS table 2A due to lack of use and unavailability

**Figure 4**. Fractional PK-PD target attainment of cefoxitin against

*Escherichia coli *and

*Klebsiella*
- Simulations were conducted using the computer software Crystal Ball 2000.1 by

*pneumoniae*. The probability of PK-PD target attainment is greater than 0.9 at a
of contemporary MIC data: Cephalothin, Cefonicid, Moxalactam

**C O N C L U S I O N S**
MIC of 2 mg/L when cefoxitin is dosed 1 g every 6 hours and 4 mg/L when dosed

**Susceptibility Breakpoint Determinations**
**Figure 2A**. Fractional PK-PD target attainment of ceftriaxone against

*Escherichia coli *and

¥ 50% T>MIC was utilized as the PK-PD goal of therapy.

*Klebsiella pneumoniae*. The probability of PK-PD target attainment is essentially
Simulation results suggest that susceptibility breakpoints for
1.0 up to MIC values of 1 mg/L when ceftriaxone is dosed 1 g every 24 hours and

**Conclusions:** Simulation results suggest that susceptibility breakpoints for most cephems

¥ The susceptibility breakpoint was the highest MIC value associated with at least a 90%
most cephems against Enterobacteriaceae should be reduced
2 mg/L when dosed 2 g every 24 hours.

against Enterobacteriaceae should be reduced to insure that most patients attain PK-PD
probability of PK-PD target attainment.

to insure that most patients attain PK-PD exposures associated
¥ Contemporary MIC population distributions were considered (

*Escherichia. coli* and

*Klebsiella*
**MIC Probability**
**I N T R O D U C T I O N**
- If a major portion of the MIC distribution was bisected by a PK-PD susceptibility breakpoint,

**Probability of Target Attainment**
alternative breakpoints were chosen to avoid division but ensure high probabilities of PK-
As cephem-resistant Enterobacteriaceae, including ESBL-producing strains, have continued to
PD target attainment. In these cases, only susceptible and resistant breakpoints chosen.

Adjustment of NCCLS breakpoints to lower values may negate

**MIC (mg/L)**
**MIC Probability**
emerge, the appropriateness of current NCCLS susceptibility breakpoints have been the focus
the clinical need for ESBL screening and confirmatory tests.

**Probability of Target Attainment**
**Figure 1.**
Relationship between T>MIC and change in bacterial density in thighs of mice at
- Re-evaluation of susceptibility breakpoints for MIC and
Information from animal infection models, as well as limited clinical data, suggest that ESBL-
24 hours. Each data point represents data for one mouse. The dotted line reflects
Pharmacokinetic parameters utilized for simulations.

**MIC (mg/L)**
producing strains with lower MIC values may be effectively treated using appropriate cephem
the number of bacteria at the beginning of therapy. The T>MIC required for efficacy
corresponding disk zone diameters to better predict
is not affected by ESBL-production status.

Pharmacokinetic Parameter Estimates (mean (SD or range))
presence of ESBLs while potentially eliminating separate

**Figure 2B**. Fractional PK-PD target attainment of cefepime against

*Escherichia coli *and

Given the paucity of clinical data, pharmacokinetics-pharmacodynamics (PK-PD) and Monte

*Klebsiella pneumoniae*. The probability of PK-PD target attainment is greater than
screening tests has been completed (see Poster D-303,
Carlo simulation have been increasingly used as decision support for establishing breakpoints.

0.9 for MIC values of 4 mg/L irrespective of the three regimens considered. When
cefepime is dosed 2 g every 12 hours or 1 g every eight hours, the probability of
In view of the above limitations, susceptibility breakpoints for cephems against Enterobacteriaceae
PK-PD target attainment is 0.9 and 0.77 for a MIC of 8 mg/L, respectively.

were re-evaluated using this approach.

- Current NCCLS Enterobacteriaceae susceptibility
breakpoints remain acceptable based on error rate analysis

**M AT E R I A L S A N D M E T H O D S**
for contemporary isolates. Lower breakpoints could eliminate

**Pharmacokinetic Parameter Estimates**
¥ Pharmacokinetic data from healthy volunteers were extracted from the medical literature
the routine need for separate ESBL screening tests and

**MIC Probability **0.3

disk diffusion zone correlates can be selected to maximize

**Probability of Target Attainment**
inter-method accuracy pending final approval by the NCCLS.

**Microbiological Susceptibility Data**
**MIC (mg/L)**
¥ Obtained from the SENTRY Antimicrobial Surveillance Program (2001-2003).

Source: http://www.icpd.com/files/ICAAC_04_A_138_Enterobacteriaceae_ceph_breakpoints.pdf

© 2003, 2009 “The Coils of Eternity (part 5)” “HI, Eve. This is Richard. I’m in town, over at Stein’s place — you remember him, chemistry — in Ladera Heights. I’m on my way to one of those independent publishing conventions in San Francisco. Maurey talked me into a visit, and we went over to the university and I wheedled your number out of the secretary in the alumni office

Ön az alábbiak közül mely problémákhoz kapcsolódó kiadásokkal szembesült már?Gyermekbetegségek – lázcsillapító (Panadol), lázmérő Háztartási baleset – sebtapasz, BetadinVédőoltások – infl uenza elleni oltás, agyhártyagyulladás Szakorvosi vizsgálatok – fogorvos, szemész stb. Magánorvosi vizsgálatok – fog