Resistance to Imipenem in Pseudomonas aeruginosa: Clinical Experience and Biochemical Mechanisms

Quinn, John P.; Studemeister, Alex; DiVincenzo, Cathy A.; Lerner, Stephen A.

doi:10.1093/clinids/10.4.892

Cited by 82 publications

(37 citation statements)

References 33 publications

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“…The implication that OmpF is involved in resistance remains doubtful, and even its function as a porin in P. aeruginosa has been challenged; in P. aeruginosa this protein is viewed as having a structural role similar to that of OmpA in E. coli (14,47 in P. aeruginosa has been described as a channel that is responsible for the facilitated diffusion of imipenem (43). The absence or reduced expression of this protein has been associated with decreased penetration of imipenem (2,24,34,35). In this study, in strains PT1 and PT2, we observed a reduced expression of an OMP band migrating in the region of protein D2 (apparent molecular mass, 47 kDa) and a four-to eightfold increase in the imipenem MIC.…”

Section: Discussionmentioning

confidence: 99%

Resistance to pefloxacin in Pseudomonas aeruginosa

Michéa-Hamzehpour

Lucain

Péchère

1991

Antimicrob Agents Chemother

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Mechanisms of resistance to pefloxacin were investigated in four isogenic Pseudomonas aeruginosa strains: S (parent isolate; MIC, 2 ,ug/ml), PT1 and PT2 (posttherapy isolates obtained in animals; MICs, 32 and 128 ,ug/ml, respectively), and PT2-r (posttherapy isolate obtained after six in vitro subpassages of PT2; MIC, 32 ,ug/ml). [2-3H]adenine incorporation (indirect evidence of DNA gyrase activity) in EDTA-permeabilized cells was less affected by pefloxacin in PT2 and PT2-r (50% inhibitory concentration, 0.27 and 0.26 ,ug/ml, respectively) than it was in S and PT1 (50% inhibitory concentration, 0.04 and 0.05 ,ug/ml, respectively). Reduced [14C]pefloxacin labeling of intact cells in strains PT1 and PT2 correlated with more susceptibility to EDTA and the presence of more calcium (P < 0.05) and phosphorus in the outer membrane fractions. Outer membrane protein analysis showed reduced expression of protein D2 (47 kDa) in strains PT1 and PT2. Other proteins were apparently similar in all strains. The addition of calcium chloride (2 mM) to the sodium dodecyl sulfate-solubilized samples of outer membrane proteins, before heating and Western blotting, probed with monoclonal antibody anti-OmpF showed electrophoretic mobility changes of OmpF in strains PT1 and PT2 which were not seen in strain S. Calcium-induced changes were reversed with ethyleneglycoltetraacetate.Decreased [14C]pefloxacin labeling was further correlated with an altered lipopolysaccharide pattern and increased 3-deoxy-D-mannooctulosonic acid concentration (P < 0.01). These findings suggested that resistance to pefloxacin is associated with altered DNA gyrase in strain PT2-r, with altered permeability in PT1, and with both mechanisms in PT2. The decreased expression of protein D2 and the higher calcium and lipopolysaccharide contents of the outer membrane could be responsible for the permeability deficiency in P. aeruginosa.The activities of fluoroquinolones against Pseudomonas aeruginosa have been fully documented (45), but bacteria can develop resistance to these agents (12,18,19,36,38). This resistance results from reduced permeability of the outer membrane (OM), altered DNA gyrase, or a combination of the two processes (7,8,18,36,38). However, mechanisms of resistance at the molecular level are not yet entirely elucidated (45).In a pseudomonal peritonitis model, we showed previously that resistance emerges rapidly when mice are treated with pefloxacin or ciprofloxacin (26). In mice infected with a quinolone-susceptible P. aeruginosa isolate, posttherapy variants (strain PT1) emerged after a single dose of pefloxacin, showing an 8-to 16-fold decrease in susceptibility to quinolones. Subinoculation of a PT1 strain, followed by therapeutic exposure to ciprofloxacin, produced a highly resistant posttherapy variant (strain PT2) for which the MIC was increased 64-fold (26).We report here results of further studies on the mechanism of resistance of these strains. As expected, we observed involvements of DNA gyrase and permeability, but we were surprised by ...

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Section: Discussionmentioning

confidence: 99%

Resistance to pefloxacin in Pseudomonas aeruginosa

Michéa-Hamzehpour

Lucain

Péchère

1991

Antimicrob Agents Chemother

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“…OprD appears to serve as the preferred portal of entry for the carbapenems, and loss of OprD from the outer membrane significantly decreases the susceptibility of P. aeruginosa to available carbapenems (103,132,140,144,169,209,210,221,229,254). However, data presented later in this section highlight how much we have yet to learn about the dynamic interactions of carbapenems with P. aeruginosa.…”

Section: Oprd and P Aeruginosa Susceptibility To Carbapenemsmentioning

confidence: 99%

Antibacterial-ResistantPseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

2009

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SUMMARY Treatment of infectious diseases becomes more challenging with each passing year. This is especially true for infections caused by the opportunistic pathogen Pseudomonas aeruginosa, with its ability to rapidly develop resistance to multiple classes of antibiotics. Although the import of resistance mechanisms on mobile genetic elements is always a concern, the most difficult challenge we face with P. aeruginosa is its ability to rapidly develop resistance during the course of treating an infection. The chromosomally encoded AmpC cephalosporinase, the outer membrane porin OprD, and the multidrug efflux pumps are particularly relevant to this therapeutic challenge. The discussion presented in this review highlights the clinical significance of these chromosomally encoded resistance mechanisms, as well as the complex mechanisms/pathways by which P. aeruginosa regulates their expression. Although a great deal of knowledge has been gained toward understanding the regulation of AmpC, OprD, and efflux pumps in P. aeruginosa, it is clear that we have much to learn about how this resourceful pathogen coregulates different resistance mechanisms to overcome the antibacterial challenges it faces.

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“…In approximately 10 to 20% of P. aeruginosa infections treated with imipenem, resistance to this compound developed (1,6,31). Spontaneous carbapenem-resistant mutants were isolated infrequently, generally at frequencies of 10 Ϫ7 to 10…”

Section: Downloaded Frommentioning

confidence: 99%

Activity of carbapenem BMS-181139 against Pseudomonas aeruginosa is not dependent on porin protein D2

Fung‐Tomc

Gradelski

Kolek

et al. 1995

Antimicrob Agents Chemother

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The broad antipseudomonal spectrum of the carbapenem BMS-181139 includes clinical strains and laboratory mutants of Pseudomonas aeruginosa that are resistant to imipenem. Unlike other known carbapenems (meropenem, panipenem, biapenem, and BO-2727), which have reduced activity against imipenem-resistant strains of P. aeruginosa, BMS-181139 was equally active against imipenem-susceptible (D2-sufficient) and imipenem-resistant (D2-deficient) strains. Conversely, imipenem and meropenem activities were the same against the susceptible parental strains and their BMS-181139-resistant mutants. Whereas basic amino acids antagonized the antipseudomonal activities of imipenem and meropenem, they had no effect on the activity of BMS-181139. These results suggest that the uptake of BMS-181139 into pseudomonal cells occurs by a non-D2 pathway. Compared with imipenem and meropenem, BMS-181139 may have a slightly higher affinity for penicillin-binding protein 2 (PBP-2) of P. aeruginosa. The rates of resistance development to imipenem, meropenem, and BMS-181139 in P. aeruginosa strains were similar; resistance occurred at frequencies of approximately 10 ؊7 to 10 ؊8. Resistance to BMS-181139 in P. aeruginosa is presumed to be caused by its diminished permeability since no change in their penicillin-binding protein affinities or ␤-lactamase levels could be detected. In summary, BMS-181139 is a new carbapenem which differs from other known carbapenems in its lack of cross-resistance with imipenem. This difference could be explained by the permeation of BMS-181139 through a non-D2 channel, compared to the preferential uptake of other carbapenems by the D2 porin.The carbapenem BMS-181139 has a broad antipseudomonal spectrum. In addition to Pseudomonas aeruginosa, the geometric mean MICs and MICs at which 90% of strains tested are inhibited (MIC 90 s) of BMS-181139 for 10 non-aeruginosa Pseudomonas species were Յ4 g/ml (14). Data from this study indicated that BMS-181139 was also active against imipenemresistant, clinical isolates of P. aeruginosa. Unlike the carbapenem meropenem, which has diminished activity against imipenem-resistant strains of P. aeruginosa (39), the activity of BMS-181139 against these strains was unaffected.Essentially all imipenem-resistant P. aeruginosa isolates produce low or undetectable levels of the porin protein D2 (2,8,21,33,35,38), suggesting its role in the permeation of imipenem across the outer membrane. The D2 channel was shown to facilitate the specific permeation of basic amino acids and, because of their structural similarities to basic amino acids, also imipenem and meropenem (36). It has been suggested that at low concentrations, imipenem penetrates primarily through the D2 channel but as the drug concentration increases, it is also transported through nonspecific porin channels (35,36). In a D2-deficient P. aeruginosa strain, stably derepressed production of ␤-lactamase leads to even higher levels of resistance to imipenem (17).Meropenem is less active against imipenem-resistant strains of P. ...

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Resistance to Imipenem in Pseudomonas aeruginosa: Clinical Experience and Biochemical Mechanisms

Cited by 82 publications

References 33 publications

Resistance to pefloxacin in Pseudomonas aeruginosa

Resistance to pefloxacin in Pseudomonas aeruginosa

Antibacterial-ResistantPseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

Activity of carbapenem BMS-181139 against Pseudomonas aeruginosa is not dependent on porin protein D2

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