Selectivity of ertapenem for Pseudomonas aeruginosa mutants cross-resistant to other carbapenems.
OBJECTIVE
Ertapenem and other carbapenems will be used increasingly, as extended-spectrum beta-lactamases become more prevalent even among community-acquired pathogens. There is, however, concern that this use will select for resistances to imipenem and meropenem in nosocomial pathogens, notably Pseudomonas aeruginosa, and we investigated the validity of this concern.


METHODS
Single-step selection experiments were performed by plating P. aeruginosa cultures on to agar containing doubling dilutions of ertapenem. MIC patterns, outer membrane protein profiles and the effects of efflux inhibitors were examined for selected mutants.


RESULTS
At 2-8 x MIC, ertapenem selected (i) for OprD(-) mutants of P. aeruginosa, with cross-resistance only to carbapenems, (ii) for putative efflux types with broader cross-resistance, and also (iii) for various less familiar phenotypes. Efflux mutants were predominantly, but not exclusively, selected from carbenicillin-hypersusceptible strains and OprD(-) mutants largely from strains with normal levels of carbenicillin susceptibility. Whilst these data indicate potential cross-selectivity, they must be set against the observation that 20% serum raised the ertapenem MICs, and the drug concentrations needed for mutant selection, by over four-fold, reflecting the compound's strong protein binding. Since, following a 1 g intravenous dose the free ertapenem concentration in the serum falls below 4 mg/L--corresponding to the lower of two MIC(50) estimates--within 4 h (17% of the dosage interval) selectivity in vivo should be minimized.


CONCLUSIONS
Whilst ertapenem can select for P. aeruginosa mutants with cross-resistance to imipenem and ertapenem in vitro, this selectivity should be minimal under clinical conditions.
Livermore
David M
DM
Antibiotic Resistance Monitoring & Reference Laboratory, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5HT, UK. david.livermore@hpa.org.uk
Mushtaq
Shazad
S
Warner
Marina
M
D015780:Carbapenems / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D024881:Drug Resistance, Bacterial; D000077727:Ertapenem; D007769:Lactams / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D018272:Porins / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D047090:beta-Lactams
D015780:Carbapenems; D016895:Culture Media, Serum-Free; D007769:Lactams; D018272:Porins; D047090:beta-Lactams; C077157:OprD protein, Pseudomonas aeruginosa; D000077727:Ertapenem