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            <funder>Pfizer; Institut de Médecine et d'Epidémiologie Appliquée, IMEA</funder>
            <funder>This study was supported by a grant from Pfizer.</funder>
            <funder>The authors would like to thank all their colleagues at Raymond-Poincare Teaching Hospital, especially Pierre De Truchis for his unfailing support. Authors would also like to thank Beatrice Gadaleta from l'Institut de Médecine et d'Epidémiologie Appliquée (IMEA) in Paris for her logistic assistance.</funder>
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                <title xml:lang="en">Efficacy of ceftazidime-avibactam in various combinations for the treatment of experimental osteomyelitis due to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae</title>
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                  <date type="datePub">2023</date>
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                <term xml:lang="en">Osteomyelitis</term>
                <term xml:lang="en">Ceftazidime-avibactam</term>
                <term xml:lang="en">Klebsiella pneumoniae</term>
                <term xml:lang="en">KPC</term>
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              <p>Background: : Optimal treatment of carbapenemase-producing Enterobacterales (CPE) bone infections is poorly defined. This study evaluated the efficacy of the novel beta-lactam-beta-lactamase inhibitor—ceftazidime-avibactam (CAZ-AVI)—with different antibiotic combinations in an experimental model of CPE osteomyelitis. Methods: : KPC-99YC is a clinical strain of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae with intermediate susceptibility to meropenem (MIC 4 mg/L), gentamicin (MIC 0.25 mg/L), colistin (MIC 0.25 mg/L), fosfomycin (MIC 4 mg/L) and ceftazidime-avibactam (MIC 1 mg/L). Time-kill curves were performed at 4x MIC. Osteomyelitis was induced in rabbits by tibial injection of 2×108 CFU of KPC-99YC. Six groups started treatment 14 days later for 7 days: control, colistin, CAZ-AVI, CAZ-AVI plus gentamicin, CAZ-AVI plus colistin and CAZ-AVI plus fosfomycin. Antibiotic dosages were selected to simulate plasma concentrations obtained in humans. Treatment was evaluated according to bone cultures quantified in log10 CFU. Results: : In vitro, CAZ-AVI plus colistin or gentamicin were rapidly bactericidal in contrast with CAZ-AVI plus fosfomycin. In vivo, compared with controls, colistin alone (P = 0.045) and CAZ-AVI alone or in combination significantly lowered bone bacterial counts (P &amp;lt; 0.001). Bone sterilisation was achieved in 67% and 100% of animals with combinations of CAZ-AVI plus colistin or gentamicin (P = 0.001 and P &amp;lt; 0.001, respectively) whereas other treatments were no different from controls. CAZ-AVI plus gentamicin provided greater bone bacterial reduction than CAZ-AVI plus colistin (P = 0.033). No CAZ-AVI-resistant strains emerged in treated rabbits, regardless of combination. Conclusions: : CAZ-AVI plus gentamicin was the best effective combination therapy. Combinations with CAZ-AVI appear to be a promising treatment of KPC-producing Klebsiella pneumoniae osteomyelitis.</p>
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