Killing Dynamics of Carbapenems against Pseudomonas aeruginosa Harboring Varied Determinants of Carbapenem Resistance
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Background: Ideal dose of the antimicrobials should be decided by considering their killing dynamics since sufficient elimination of the causative microorganisms is critical for proper antimicrobial treatment. In this study, the bactericidal activities of carbapenems by resistance mechanisms were assessed for carbapenem-resistant Pseudomonas aeruginosa. Methods: Minimal inhibition concentrations (MICs) of carbapenems were determined by broth dilution method and the resistance mechanisms were identified by PCR and DNA sequencing. The expression levels of efflux pumps were determined by reverse transcriptase real-time PCR. Time-kill curves were plotted by time-course numeration of the viable cells grown under imipenem and meropenem at 1× and 4×MICs, respectively. Results: One P. aeruginosa strain was susceptible, whereas three were resistant to carbapenems by defective OprD, efflux pump overproduction, and/or IMP-6 production. The susceptible strain had imipenem and meropenem MICs of 2 and 1 mg/L, respectively. The MICs were elevated by eight-fold by defective OprD, 16- and 32-fold by the pump overproduction, and four- and >64-fold by the combination of two determinants and the IMP-6 carbapenemase. While both the carbapenems showed time-dependent bactericidal activity to the susceptible isolate, either of the carbapenem-resistant determinants, such as decreased membrane permeability, carbapenemase production, or the defective OprD, presented concentration-dependent bacteriostatic activity. Conclusion: Different killing dynamics of the carbapenems were observed depending on the resistance determinants, and the results would guide a proper treatment strategy for the patients using these drugs.
Abstract
Background: Ideal dose of the antimicrobials should be decided by considering their killing dynamics since sufficient elimination of the causative microorganisms is critical for proper antimicrobial treatment. In this study, the bactericidal activities of carbapenems by resistance mechanisms were assessed for carbapenem-resistant Pseudomonas aeruginosa. Methods: Minimal inhibition concentrations (MICs) of carbapenems were determined by broth dilution method and the resistance mechanisms were identified by PCR and DNA sequencing. The expression levels of efflux pumps were determined by reverse transcriptase real-time PCR. Time-kill curves were plotted by time-course numeration of the viable cells grown under imipenem and meropenem at 1× and 4×MICs, respectively. Results: One P. aeruginosa strain was susceptible, whereas three were resistant to carbapenems by defective OprD, efflux pump overproduction, and/or IMP-6 production. The susceptible strain had imipenem and meropenem MICs of 2 and 1 mg/L, respectively. The MICs were elevated by eight-fold by defective OprD, 16- and 32-fold by the pump overproduction, and four- and >64-fold by the combination of two determinants and the IMP-6 carbapenemase. While both the carbapenems showed time-dependent bactericidal activity to the susceptible isolate, either of the carbapenem-resistant determinants, such as decreased membrane permeability, carbapenemase production, or the defective OprD, presented concentration-dependent bacteriostatic activity. Conclusion: Different killing dynamics of the carbapenems were observed depending on the resistance determinants, and the results would guide a proper treatment strategy for the patients using these drugs.
참고문헌 (22)
- Poole K, "Pseudomonas aeruginosa : resistance to the max", Front Microbiol, 2, pp.65~ (2011)
- Lee H, "Antimicrobial resistance of major clinical pathogens in South Korea, May 2016 to April 2017: first one-year report from Kor-GLASS", Euro Surveill, 23, pp.1800047~ (2018)
- Livermore DM, "Of Pseudomonas, porins, pumps and carbapenems", J Antimicrob Chemother, 47, pp.247~250 (2001)
- 홍덕진, "Epidemiology and Characteristics of Metallo-β-Lactamase-Producing Pseudomonas aeruginosa", Infection and Chemotherapy, 47(2), pp.81~97 (2015), 대한감염학회[DOI]
- Quale J, "Interplay of efflux system, ampC , and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates", Antimicrob Agents Chemother, 50, pp.1633~1641 (2006)
- Mattoes HM, "Optimizing antimicrobial pharmacodynamics : dosage strategies for meropenem", Clin Ther, 26, pp.1187~1198 (2004)
- Clinical and Laboratory Standards Institute (CLSI), "Performance standards for antimicrobial susceptibility testing. CLSI Document M100S", ~ (2016)
- Nordmann P, "Global spread of carbapenemase-producing Enterobacteriaceae", Emerg Infect Dis, 17, pp.1791~1798 (2011)
- Hong JS, "Clonal dissemination of Pseudomonas aeruginosa sequence type 235 isolates carrying bla IMP-6 and emergence of bla GES-24 and bla IMP-10on novel genomic islands PAGI-15 and-16 in South Korea", Antimicrob Agents Chemother, 60, pp.7216~7223 (2016)
- Stratton CW, "Dead bugs don't mutate : susceptibility issues in the emergence of bacterial resistance", Emerg Infect Dis, 9, pp.10~16 (2003)
- Pankey GA, "Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections", Clin Infect Dis, 38, pp.864~870 (2004)
- Dantas RC, "Pseudomonas aeruginosa bacteraemia : independent risk factors for mortality and impact of resistance on outcome", J Med Microbiol, 63, pp.1679~1687 (2014)
- Castanheira M, "Epidemiology and carbapenem resistance mechanisms of carbapenem-non-susceptible Pseudomonas aeruginosa collected during 2009-11 in 14 European and Mediterranean countries", J Antimicrob Chemother, 69, pp.1804~1814 (2014)
- Seok Y, "Dissemination of IMP-6 metallo-betalactamase-producing Pseudomonas aeruginosa sequence type 235 in Korea", J Antimicrob Chemother, 66, pp.2791~2796 (2011)
- Huang H, "Genetic definition of the substrate selectivity of outer membrane porin protein OprD of Pseudomonas aeruginosa", J Bacteriol, 175, pp.7793~7800 (1993)
- Masuda N, "Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-oprM efflux pumps in Pseudomonas aeruginosa", Antimicrob Agents Chemother, 44, pp.3322~3327 (2000)
- Yano H, "Plasmid-encoded metallobeta-lactamase (IMP-6) conferring resistance to carbapenems, especially meropenem", Antimicrob Agents Chemother, 45, pp.1343~1348 (2001)
- Nordmann P, "Superbugs in the coming new decade; multidrug resistance and prospects for treatment of Staphylococcus aureus , Enterococcus spp. and Pseudomonas aeruginosa in 2010", Curr Opin Microbiol, 10, pp.436~440 (2007)
- Woodford N, "Multiresistant gram-negative bacteria : the role of high-risk clones in the dissemination of antibiotic resistance", FEMS Microbiol Rev, 35, pp.736~755 (2011)
- Yoon EJ, "Mortality dynamics of Pseudomonas aeruginosa bloodstream infections and the influence of defective OprD on mortality : prospective observational study", J Antimicrob Chemother, 74, pp.2774~2783 (2019)
- Alcalde-Rico M, "Multidrug efflux pumps at the crossroad between antibiotic resistance and bacterial virulence", Front Microbiol, 7, pp.1483~ (2016)
- Yoon EJ, "Contribution of the Ade resistance-nodulation-cell division-type efflux pumps to fitness and pathogenesis of Acinetobacter baumannii", mBio, 7, pp.e00697-16~ (2016)