Pharmacodynamic Profile of Ertapenem against Klebsiella pneumoniae and Escherichia coli in a Murine Thigh Model

Abstract

The pharmacodynamic profile of ertapenem was evaluated in a neutropenic mouse thigh infection model. Extended-spectrum beta-lactamase (ESBL)-positive and ESBL-negative clinical strains of Escherichia coli and Klebsiella pneumoniae were studied. MICs ranged from 0.0078 to 0.06 g/ml with standard inoculum tests. Ertapenem doses were administered once to five times daily to achieve various exposures, reported as the percentage of the dosing interval that the concentration of free ertapenem was in excess of the MIC (%T>MIC free ). Mean values for the static exposure and 80% maximally effective exposure (ED 80 ) were 19% (range, 2 to 38%) and 33% (range, 13 to 65%) T>MIC free , respectively. Differences in exposure requirements based on the presence of an ESBL resistance mechanism or bacterial species were not evident. In addition, experiments using a 100-fold higher inoculum did not decrease the magnitude of the reduction in bacterial density from baseline achieved compared to lower-inoculum studies. The pharmacodynamic parameter of %T>MIC free correlated well with bactericidal activity for all isolates, and the static and ED 80 exposures are consistent with those reported previously for carbapenems.Ertapenem is presently approved in the United States to treat complicated intra-abdominal infections, complicated skin and skin structure infections, community-acquired pneumonia, complicated urinary tract infections, and acute pelvic infections (Invanz package insert; Merck & Co., Inc, Whitehouse Station, N.J.). These infections are often characterized as polymicrobial in nature. In addition, convincing data have associated inadequate empirical therapy with increased failure rates and increased mortality for many of these infections (8). Therefore, initiation of treatment with a potent, broad-spectrum agent is essential.Ertapenem has demonstrated considerable in vitro potency against a wide range of pathogenic gram-positive and gramnegative organisms, excluding nonfermentating organisms. In addition, the in vivo activity of ertapenem against Streptococcus pneumoniae has previously been described (10). However, many fewer data exist to describe the in vivo pharmacodynamics of this agent in gram-negative infections. The objective of this study was to evaluate the killing activity of ertapenem against Escherichia coli and Klebsiella pneumoniae clinical isolates, two of the most commonly recovered pathogens in the above-mentioned infections, in a neutropenic thigh infection model. Four isolates were extended-spectrum beta-lactamase (ESBL) producers. We focused the analysis on the percentage of the dosing interval that the concentration of free ertapenem was in excess of the MIC (%TϾMIC), since this parameter has been repeatedly identified as the parameter correlating best with carbapenem efficacy (9). In vivo efficacy at a high inoculum (10 7 CFU/ml) was additionally evaluated in a subset of isolates to assess the impact of a larger inoculum size on the pharmacodynamic characteristics of ertapenem. MATERIALS AND METHODSAnti...

Colistin offers prolonged survival in experimental infection by multidrug-resistant Acinetobacter baumannii: the significance of co-administration of rifampicin

“…Animals were rendered neutropenic by the intraperitoneal administration of two doses of cyclophosphamide (Aventis, Paris, France) [6]; the first dose of 150 mg/kg at 96 h and the second dose of 100 mg/kg 48 h prior the experiment. The adequacy of the dose regimen for the induction of neutropenia was assessed in four rats by blood sampling 48 h after the second dose.…”

Bactericidal Activities of Meropenem and Ertapenem against Extended-Spectrum-β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in a Neutropenic Mouse Thigh Model

“…For carbapenems, the breakpoint that correlates best with bacteriostasis is an fTϾMIC of 20%, where maximal bactericidal activity is Ն40% (8, 22, 31, 31a). Recent animal work has demonstrated that no alternative pharmacodynamic breakpoints are needed to ensure efficacy against ESBL-producing isolates (1,19). In other words, even if the MICs increase for ESBL-producing isolates, as long as the antimicrobial regimen is able to exceed the critical fTϾMIC, efficacy remains.…”

“…The achievement of adequate fTϾMICs of 30 to 45% for meropenem and 20 to 30% for ertapenem, respectively, is the most likely explanation for these findings. Alternatively, since the raised MICs at a higher inoculum have been described as an artifact of in vitro susceptibility testing, they may not be clinically relevant (4,19,20).…”

Pharmacodynamics of Razupenem (PZ601) Studied in an In Vitro Pharmacokinetic Model of Infection

“…(1, 15, 17, 19), but also depends on the bacterial strain being tested (13). The TϾMIC for bactericidal effects are larger; a TϾMIC of 30 to 55% is required for a 2-log-unit reduction in viable bacterial counts (15,17), and the maximum effect for some strains may require a TϾMIC of Ͼ60% (14,15). The relationships between carbapenem TϾMICs and antibacterial effect are less clear for S. aureus, including MRSA strains.…”