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                <term xml:lang="en">Pseudomonas aeruginosa</term>
                <term xml:lang="en">ceftazidime-avibactam</term>
                <term xml:lang="en">ampC/ampD mutation</term>
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              <p>BackgroundCeftazidime/avibactam (CZA) is commonly used against multidrug resistant Pseudomonas aeruginosa (Pa) although resistances are frequently reported. This study assesses the respective impact of AmpCG183D and AmpDH157Y mutations, found in a CZA-resistant clinical isolate, on ceftazidime (CAZ) and avibactam (AVI).MethodsSingle and double mutants ampC (AmpCG183D) and ampD (AmpDH157Y) were previously generated in a PAO1 reference strain1. Minimum inhibitory concentrations (MIC) of CAZ, AVI, and CZA were assessed by broth microdilution2. Time-kill curves (TKC) were performed on PAO1 and its mutant against CAZ and AVI, in monotherapy and in combination with variable concentrations of both molecules. Relative expression of ampC was evaluated using quantitative PCR (qPCR). ResultsqPCR showed no change in ampC expression in PAO1 and the AmpCG183D mutant but revealed overexpression in strains with AmpDH157Y. For all strains, AVI MIC exceeded 256 mg/L (Table 1). No differences were observed in CAZ and CZA MIC of AmpCG183D mutant compared to PAO1. AmpDH157Y single mutant showed increased CAZ MIC and moderately increased CZA MIC. Elevated CZA MICs occurred only in the double mutant. TKC against PAO1 and AmpCG183D mutant, displaying basal expression of ampC, both showed an initial CFU decay followed by regrowth at CAZ MIC (2 mg/L) for all AVI concentrations tested up to 64 mg/L. AmpDH157Y mutant, overexpressing ampC, showed bacterial decay without regrowth at CAZ MIC (16 mg/L) for weak concentrations of AVI from 0.5 mg/L. The double mutant, overexpressing mutated ampC, showed CFU decay without regrowth at CAZ MIC (32 mg/L) for concentrations of AVI from 2 mg/L. ConclusionsOur results demonstrated that the AmpCG183D mutation alone is not sufficient to confer resistance to CAZ and CZA. Moreover, inhibitory effect of avibactam is significant only when wild-type ampC is overexpressed, while it is reduced when mutated ampC (AmpCG183D) is overexpressed. A semi-mechanistic PK/PD model is being developed to characterize the respective contributions of these mutations to the efficacy of both CAZ and AVI.</p>
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