Carbapenem Activities against Pseudomonas aeruginosa : Respective Contributions of OprD and Efflux Systems

Abstract

While meropenem MICs were strongly influenced by the presence or absence of the MexAB-OprM efflux pump in both OprD-proficient and -deficient strain backgrounds, MICs of imipenem and of ER-35786 remained unchanged, demonstrating that meropenem is a substrate of MexAB-OprM but not imipenem and ER-35786. In vitro, all three carbapenems selected loss of OprD as a first mechanism of resistance. However, in an OprD-deficient background, meropenem was able to select MexAB-OprM overproducers as a secondary resistance mechanism, while ER-35786 selected a mutant cross-resistant to sparfloxacin and cefpirome.

Correlation between meropenem and doripenem use density and the incidence of carbapenem-resistant Pseudomonas aeruginosa

“…We therefore believe that MEPM-resistant strains would develop by increasing the AUD of MEPM and DRPM, whilst IPM/CS insensitivity would be acquired as cross-resistance to MEPM insensitivity. This may be because MEPM resistance is caused by double mutation both of OprD and MexAB-OprM, whereas IPM/CS resistance is caused by only a mutation of OprD [5][6][7][8][9][10][11]. The isolation frequency of carbapenem-resistant P. aeruginosa clinically developed in Japan is ca.…”

“…The mechanisms of resistance to carbapenems differ among the drugs. IPM/CS-, PAPM/BP-and BIPM-resistant strains are the result of either a loss or decrease in the level of the outer membrane porin protein OprD, whereas MEPM-and DRPM-resistant strains are caused by the double mutation of both loss of OprD and overexpression of the MexAB-OprM efflux system [5][6][7][8][9][10][11]. However, there is little information about the relationship between antimicrobial use density (AUD) of carbapenems, resistance mechanisms and drug susceptibility.…”

Estimation of outer membrane permeability of carbapenem antibiotics to Pseudomonas aeruginosa

“…The permeablity coefficient of carbapenems in P. aeruginosa is considered to be the value which would be influenced by deficiency of the porin protein, OprD, or overproduction of MexAB-OprM efflux pump proteins. 15 From our results, it is suggested that both the higher rates of penetration of carbapanems, especially IPM and BIPM, and the high stabilities to chromosomallactamase 11 may contribute to the in potent antibacterial activities against P. aeruginosa strains, except for carbapenemase-producing strain. We are convinced that this finding will increasingly spur further research and the development of new carbapenem derivatives.…”

Susceptibility of Pseudomonas aeruginosa clinical isolates in Japan to doripenem and other antipseudomonal agents

“…However, various resistance mechanisms against antipseudomonal agents have been reported, e.g. overexpression of efflux pumps, deficiency of porins and antibiotic inactivation enzymes including ␤-lactamases [6][7][8][9]. Thus, in most surveillance studies clinical isolates of P. aeruginosa show broad susceptibility distributions and resistant strains appeared at high rates [3,[10][11][12].…”