Pharmacodynamics of ceftazidime/avibactam against extracellular and intracellular forms of Pseudomonas aeruginosa
(2017) Journal of Antimicrobial Chemotherapy — Vol. 72, n° 5, p. 1400-1409 (2017)
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- Abstract
- Objectives: When tested in broth, avibactam reverses ceftazidime resistance in many Pseudomonas aeruginosa that express ESBLs. We examined whether similar reversal is observed against intracellular forms of P. aeruginosa. Methods: Strains: reference strains; two engineered strains with basal non-inducible expression of AmpC and their isogenic mutants with stably derepressed AmpC; and clinical isolates with complete, partial or no resistance to reversion with avibactam. Pharmacodynamic model: 24 h concentration-response to ceftazidime [0.01-200 mg/L alone or with avibactam (4 mg/L)] of bacteria in broth or bacteria phagocytosed by THP-1 monocytes, with calculation of ceftazidime relative potency ( Cs : concentration yielding a static effect) and maximal relative effect [ Emax : cfu decrease at infinitely large antibiotic concentrations (efficacy in the model)] using the Hill equation. Cellular content of avibactam: quantification by LC-MS/MS. Results: For both extracellular and intracellular bacteria, ceftazidime Cs was always close to its MIC. For ceftazidime-resistant strains, avibactam addition shifted ceftazidime C s to values close to the MIC of the combination in broth. Emax was systematically below the detection limit (-5 log 10 ) for extracellular bacteria, but limited to -1.3 log10 for intracellular bacteria (except for two isolates) with no effect of avibactam. The cellular concentration of avibactam reflected extracellular concentration and was not influenced by ceftazidime (0-160 mg/L). Conclusions: The potential for avibactam to inhibit beta-lactamases does not differ for extracellular and intracellular forms of P. aeruginosa , denoting an unhindered access to its target in both situations. The loss of maximal relative efficacy of ceftazidime against intracellular P. aeruginosa was unrelated to resistance via avibactam-inhibitable beta-lactamases.
- Affiliations
UCLouvain SSS/LDRI/MCPB - Analyse clinique par spectrométrie de masse de métabolites et de composés d'int
Citations
Buyck, J., Luyckx, C., Muccioli, G., Krause, K. M., Nichols, W. W., Tulkens, P. M., & Van Bambeke, F. (2017). Pharmacodynamics of ceftazidime/avibactam against extracellular and intracellular forms of Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy, 72(5), 1400-1409. https://doi.org/10.1093/jac/dkw587 (Original work published 2017)