OBJECTIVES: In the clinical setting, the choice of definitive drug therapy is typically guided by the antimicrobial susceptibility profile of the infecting organism. We evaluated the activity of doripenem and ertapenem against Klebsiella pneumoniae isolates with similar MICs that exhibited KPC-based and non-KPC-based genotypes. METHODS: Five doripenem-non-susceptible K. pneumoniae isolates, three producing KPC carbapenemases and two exhibiting porin modifications plus AmpC β-lactamase production, were tested in a neutropenic murine thigh infection model. The ertapenem MIC for all isolates was >32 mg/L. Regimens of 2 g of doripenem every 8 h (4 h infusion) and 1 g of ertapenem every 24 h (0.5 h infusion) simulating human concentration-time profiles were administered 2 h after inoculation. The change in bacterial density was evaluated after 24 h of therapy. RESULTS: Consistent with the observed MICs, treatment with ertapenem resulted in minimal activity against all isolates tested. When comparing the activity of doripenem between the KPC and non-KPC producers with doripenem MICs of 8 mg/L, significantly better activity was noted for the non-KPC producer (P<0.001). Likewise, when comparing the two KPC-producing isolates with doripenem MICs of 24 mg/L and >32 mg/L with the non-KPC producer with an MIC of 32 mg/L, significantly greater activity was noted for the non-KPC producer (P<0.001). CONCLUSIONS: When doripenem MICs were similar, activity was greater for non-KPC-producing isolates when compared with KPC producers. While the in vitro MIC is typically the sole method utilized to aid in drug selection, these data suggest that the genetic driver behind these MICs may also play a role in predicting in vivo activity.
OBJECTIVES: In the clinical setting, the choice of definitive drug therapy is typically guided by the antimicrobial susceptibility profile of the infecting organism. We evaluated the activity of doripenem and ertapenem against Klebsiella pneumoniae isolates with similar MICs that exhibited KPC-based and non-KPC-based genotypes. METHODS: Five doripenem-non-susceptible K. pneumoniae isolates, three producing KPC carbapenemases and two exhibiting porin modifications plus AmpC β-lactamase production, were tested in a neutropenic murine thigh infection model. The ertapenem MIC for all isolates was >32 mg/L. Regimens of 2 g of doripenem every 8 h (4 h infusion) and 1 g of ertapenem every 24 h (0.5 h infusion) simulating human concentration-time profiles were administered 2 h after inoculation. The change in bacterial density was evaluated after 24 h of therapy. RESULTS: Consistent with the observed MICs, treatment with ertapenem resulted in minimal activity against all isolates tested. When comparing the activity of doripenem between the KPC and non-KPC producers with doripenem MICs of 8 mg/L, significantly better activity was noted for the non-KPC producer (P<0.001). Likewise, when comparing the two KPC-producing isolates with doripenem MICs of 24 mg/L and >32 mg/L with the non-KPC producer with an MIC of 32 mg/L, significantly greater activity was noted for the non-KPC producer (P<0.001). CONCLUSIONS: When doripenem MICs were similar, activity was greater for non-KPC-producing isolates when compared with KPC producers. While the in vitro MIC is typically the sole method utilized to aid in drug selection, these data suggest that the genetic driver behind these MICs may also play a role in predicting in vivo activity.
Entities:
Keywords:
antimicrobial susceptibility profiles; carbapenemases; genotypes; mechanism of carbapenem resistance
Authors: Islam M Ghazi; Jared L Crandon; Emil P Lesho; Patrick McGann; David P Nicolau Journal: Antimicrob Agents Chemother Date: 2015-09-28 Impact factor: 5.191