Emergence of Resistance to Imipenem During Therapy for Pseudomonas aeruginosa Infections

Quinn, John P.; Dudek, Edward J.; DiVincenzo, Cathy A.; Lucks, David A.; Lerner, Stephen A.

doi:10.1093/infdis/154.2.289

Cited by 265 publications

(136 citation statements)

References 28 publications

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“…SDS-PAGE gel analysis of the OMPs of the representative mutant strain showed a marked reduction in a specific OMP with a molecular weight of about 48,000 (data not shown). These results indicated that the mutant resulted from the reduced expression of OprD and they exhibited reduced susceptibility or resistance to DRPM, MEPM, or IPM compared to the parent strain [3,6,7]. These results also suggested that both MEPM and IPM could specifically select for the carbapenem reduced susceptible mutants or carbapenem-resistant mutants of P. aeruginosa strains, and that DRPM could prevent growth of the mutants at a concentration that would inhibit cell growth.…”

Section: Appearance Of Colonies Of Carbapenem-resistant Mutants Withimentioning

confidence: 84%

“…This type of imipenem (IPM)-resistant P. aeruginosa mutant was first isolated during clinical trials of IPM for the treatment of serious infections caused by P. aeruginosa [3]. The IPM-resistant mutants of P. aeruginosa were found to lack a 45 KD to 49 KD protein [3ϳ6] in the outer membrane protein D2 (OprD), which forms a channel specific to IPM and its structural analogues [7].…”

Section: Introductionmentioning

confidence: 99%

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Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa

et al. 2006

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The potencies of the carbapenems; doripenem (DRPM), meropenem (MEPM) and imipenem (IPM) in preventing the emergence of carbapenem-resistant mutants were examined in Pseudomonas aeruginosa strains. The carbapenems predominantly selected carbapenem-resistant mutants or carbapenem mutants with reduced susceptibilities that were specifically resistant to carbapenems and had arisen as a result of the reduced level of expression of the outer membrane protein with a molecular weight of about 48,000 (OprD). The potency of carbapenems in preventing the growth of the mutants differed for DRPM, MEPM and IPM. The isolation frequency of the mutant was examined on agar plates containing each of the carbapenems at a concentration of 1/2 or 1/4 MIC of each carbapenem for that mutant. Mutants were not selected on agar containing DRPM at a frequency of greater than 10 Ϫ9 per cell per generation, whereas mutants of each strain were selected on agar containing MEPM or IPM at frequencies of 10 Ϫ7 to 10 Ϫ9 per cell per generation. The drug concentrations and the drug concentration range for the selective increase of carbapenem resistant mutants in the broth culture containing each carbapenem differed for each carbapenem. DRPM exhibited both the lowest drug concentration and the narrowest range of drug concentration for selection of the carbapenem-resistant mutants. The results shown in this report indicated that DRPM exhibited the greatest ability to prevent the emergence of the mutant.

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Section: Appearance Of Colonies Of Carbapenem-resistant Mutants Withimentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa

et al. 2006

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“…pHN4 is a recombinant plasmid (blaS tet Xcos+ incP); it codes for production of L-1 3-lactamase, which was originally derived from Xanthomonas maltophilia and is capable of hydrolyzing panipenem and imipenem (19). The recombinant plasmid was transferred to both 3-C and 3-B (19), which were both isolated from a single patient and which were identical in serotype and pyocin type (18). P. aeruginosa PAO1 and its OprD protein-deficient mutant DD-11 were used to determine uptake of ['4C]panipenem into the cells and for susceptibility testing.…”

Section: Methodsmentioning

confidence: 99%

Activity of the carbapenem panipenem and role of the OprD (D2) protein in its diffusion through the Pseudomonas aeruginosa outer membrane

Fukuoka¹,

Ohya²,

Narita³

et al. 1993

Antimicrob Agents Chemother

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Evidence of permeation of panipenem through the OprD (D2) channel of Pseudomonas aeruginosa outer membrane was shown by using OprD protein-producing and -nonproducing strains which contained plasmid pHN4, which codes for L-1 13-lactamase of Xanthomonas maltophilia. Permeation by panipenem was determined by measuring hydrolysis of the carbapenem by 13-lactamase in the periplasmic space. Permeation by panipenem was also determined by counting uptake of [14C]panipenem into P. aeruginosa PAO1 and its OprD protein-deficient mutant, and this permeation of PAO1 was inhibited by L-lysine. These results indicate that panipenem, as well as imipenem, uses the OprD channel, which functions as a specific channel for diffusion of basic amino acids. Panipenem and imipenem showed stronger activities against PAO1 and clinical isolates in human serum than in Mueller-Hinton broth, which contains more amino acids than human serum does. The activities of the carbapenems were reduced by addition of L-lysine to human serum. Similar results were obtained with mouse serum and ascitic fluid. In contrast, such a change in the activities of carbapenems was not observed with an OprD protein-deficient mutant, suggesting that the main reason for the strong activities of carbapenems in biological fluids is a decrease in competition between the antibiotics and basic amino acids for permeation through the OprD channel. Panipenem and imipenem showed much stronger therapeutic efficacies against experimental infections with P. aeruginosa in mice than did the reference antibiotics. Their in vivo activities were more consistent with their MICs in biological fluids than with those in Mueller-Hinton broth.Infections by Pseudomonas aeruginosa are serious clinical problems, particularly in compromised hosts. In recent years, many new extended-spectrum penicillins and cephalosporins have been introduced into clinical practice. Some of them show potent antipseudomonal activity in vitro. However, only a few antibiotics show adequate clinical efficacy against pseudomonal infections. Carbapenems, such as panipenem (formerly RS-533 or CS-533) and imipenem, have been shown to have potent antipseudomonal activity both in vitro and in vivo (2,4,8,9,12,14,15,17,22).We reported previously that panipenem and imipenem showed much stronger antipseudomonal activities in lowamino-acid media, such as a minimal medium, than in Mueller-Hinton medium (5). This mechanism was investigated by using P. aeruginosa PAO1 and its OprD (D2) protein-deficient mutants, and it was assumed that the increase in the antipseudomonal activities of the carbapenems in low-amino-acid media relates to lessened competition between the carbapenems and basic amino acids for permeation through the OprD channel of the P. aeruginosa outer membrane. Trias and Nikaido reported that imipenem permeated the outer membrane of P. aeruginosa through the OprD channel (20) and that the permeation was competitively inhibited by basic amino acids (21). Concentrations of free basic amino acids in human serum are ...

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“…However, several recent reports (Quinn et al, 1986;Buscher et al, 1987;Lynch, Drusano & Mobley, 1987) have documented the emergence of imipenem resistance during imipenem therapy of Pseudomonas aeruginosa infections. Such resistance emerged in six of ten cases of nosocomial pseudomonal pneumonia (Salata et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Novel resistance to imipenem associated with an altered PBP-4 in a Pseudomonas aeruginosa clinical isolate

Bellido

Veuthey

Blaser

et al. 1990

J Antimicrob Chemother

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Emergence of Resistance to Imipenem During Therapy for Pseudomonas aeruginosa Infections

Cited by 265 publications

References 28 publications

Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa

Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa

Activity of the carbapenem panipenem and role of the OprD (D2) protein in its diffusion through the Pseudomonas aeruginosa outer membrane

Novel resistance to imipenem associated with an altered PBP-4 in a Pseudomonas aeruginosa clinical isolate

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