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Updated: Jul 20, 2025
Mutagenesis and Functional Selection Protocols for Directed Evolution of Proteins in E. coli
Published on: March 16, 2011
Testing the mutant selection window hypothesis with meropenem: In vitro model study with OXA-48-producing Klebsiella
Kamilla N Alieva1, Maria V Golikova1, Svetlana A Dovzhenko1
1Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Moscow, Russia.
Abstract:
OXA-48 carbapenemases are frequently expressed by Klebsiella pneumoniae clinical isolates; they decrease the effectiveness of carbapenem therapy, particularly with meropenem. Among these isolates, meropenem-susceptible carbapenemase-producers may show decreased meropenem effectiveness. However, the probability of the emergence of resistance in susceptible carbapenemase-producing isolates and its dependence on specific K. pneumoniae meropenem MICs is not completely known. It is also not completely clear what resistance patterns will be exhibited by these bacteria exposed to meropenem, if they would follow the patterns of non-beta-lactamase-producing bacteria and other than beta-lactams antibiotics. These issues might be clarified if patterns of meropenem resistance related to the mutant selection window (MSW) hypothesis. To test the applicability of the MSW hypothesis to meropenem, OXA-48-carbapenemase-producing K. pneumoniae clinical isolates with MICs in a 64-fold range (from susceptible to resistant) were exposed to meropenem in a hollow-fiber infection model; epithelial lining fluid meropenem pharmacokinetics were simulated following administration of 2 grams every 8 hours in a 3-hour infusion. Strong bell-shaped relationships between the meropenem daily dose infused to the model as related to the specific isolate MIC and both the antimicrobial effect and the emergence of resistance were observed. The applicability of the MSW hypothesis to meropenem and carbapenemase producing K. pneumoniae was confirmed. Low meropenem efficacy indicates very careful prescribing of meropenem to treat K. pneumoniae infections when the causative isolate is confirmed as an OXA-48-carbapenemase producer.
Insights
Meropenem effectiveness against OXA-48 carbapenemase-producing Klebsiella pneumoniae is variable. The mutant selection window hypothesis accurately predicts meropenem resistance emergence, guiding careful prescribing practices.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- OXA-48 carbapenemases in Klebsiella pneumoniae reduce carbapenem effectiveness, impacting meropenem therapy.
- Meropenem-susceptible carbapenemase producers may exhibit reduced meropenem effectiveness, with unclear resistance emergence patterns.
Purpose of the Study:
- To investigate the emergence of meropenem resistance in OXA-48 carbapenemase-producing K. pneumoniae.
- To test the applicability of the mutant selection window (MSW) hypothesis to meropenem in this context.
Main Methods:
- Utilized a hollow-fiber infection model simulating epithelial lining fluid pharmacokinetics of meropenem.
- Exposed OXA-48 carbapenemase-producing K. pneumoniae isolates with a wide range of meropenem MICs to meropenem.
Main Results:
- Observed strong bell-shaped relationships between meropenem dose, isolate MIC, antimicrobial effect, and resistance emergence.
- Confirmed the applicability of the MSW hypothesis to meropenem and carbapenemase-producing K. pneumoniae.
Conclusions:
- Meropenem efficacy is low against OXA-48 carbapenemase-producing K. pneumoniae.
- Judicious meropenem prescribing is crucial for K. pneumoniae infections caused by OXA-48 producers, guided by MIC values and the MSW hypothesis.
