Selectivity of ertapenem for Pseudomonas aeruginosa mutants cross-resistant to other carbapenems

被引:57
作者
Livermore, DM [1 ]
Mushtaq, S [1 ]
Warner, M [1 ]
机构
[1] Hlth Protect Agcy, Ctr Infect, Antibiot Res Monitoring & Reference Lab, London NW9 5HT, England
关键词
OprD; efflux; mutations;
D O I
10.1093/jac/dki009
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
Objectives: 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 MIC50 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.
引用
收藏
页码:306 / 311
页数:6
相关论文
共 23 条
[1]   Determination of minimum inhibitory concentrations [J].
Andrews, JM .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2001, 48 :5-16
[2]   Growing group of extended-spectrum β-lactamases:: The CTX-M enzymes [J].
Bonnet, R .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (01) :1-14
[3]   Emergence of carbapenem-resistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 β-lactamases in New York City [J].
Bradford, PA ;
Bratu, S ;
Urban, C ;
Visalli, M ;
Mariano, N ;
Landman, D ;
Rahal, JJ ;
Brooks, S ;
Cebular, S ;
Quale, J .
CLINICAL INFECTIOUS DISEASES, 2004, 39 (01) :55-60
[4]   Risk factors for the development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized patients [J].
Colodner, R ;
Rock, W ;
Chazan, B ;
Keller, N ;
Guy, N ;
Sakran, W ;
Raz, R .
EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, 2004, 23 (03) :163-167
[5]  
FRIEDLAND I, 2003, 13 EUR C CLIN MICR I
[6]   In vitro activities of ertapenem (MK-0826) against clinical bacterial isolates from 11 North American medical centers [J].
Fuchs, PC ;
Barry, AL ;
Brown, SD .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (06) :1915-1918
[7]  
KOHLER J, 2001, 41 INT C ANT AG CHEM, P97
[8]   ROLE OF EFFLUX PUMP(S) IN INTRINSIC RESISTANCE OF PSEUDOMONAS-AERUGINOSA - RESISTANCE TO TETRACYCLINE, CHLORAMPHENICOL, AND NORFLOXACIN [J].
LI, XZ ;
LIVERMORE, DM ;
NIKAIDO, H .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1994, 38 (08) :1732-1741
[9]   In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia [J].
Livermore, DM ;
Carter, MW ;
Bagel, S ;
Wiedemann, B ;
Baquero, F ;
Loza, E ;
Endtz, HP ;
van den Braak, N ;
Fernandes, CJ ;
Fernandes, L ;
Frimodt-Moller, N ;
Rasmussen, LS ;
Giamarellou, H ;
Giamarellos-Bourboulis, E ;
Jarlier, V ;
Nguyen, J ;
Nord, CE ;
Struelens, MJ ;
Nonhoff, C ;
Turnidge, J ;
Bell, J ;
Zbinden, R ;
Pfister, S ;
Mixson, L ;
Shungu, DL .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (06) :1860-1867
[10]   Properties and potential of ertapenem [J].
Livermore, DM ;
Sefton, AM ;
Scott, GM .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2003, 52 (03) :331-344