Amaury O’Jeanson, Elisabet I. Nielsen, Lena E. Friberg
Department of Pharmacy, Uppsala Universitet, Uppsala, Sweden
Introduction: β-lactamase inhibitors (BLI) are an increasingly important group of drugs, used to restore the activity of β-lactam (BL) antibiotics against β-lactamase-producing bacteria. Ceftazidime (CAZ) – a BL – and avibactam (AVI) – a BLI – is one example of such a drug combination. The traditional PK/PD index approach is not directly applicable for dose finding of drug combinations, particularly if both compounds have an antibacterial effect of its own. Moreover, the limitations of using summary-indices for inter-species translation has earlier been demonstrated [1]. Free drug concentration remaining above a threshold concentration for a defined portion of the dosing interval (%fT>CT) has been previously suggested as the best predictor of efficacy for avibactam [2,3].
Objectives: The aim of this study was to use a mechanism-based PKPD model developed from in vitro static time-kill kinetics data to simulate the bacterial response following different exposures of ceftazidime-avibactam in mice and humans and compare with traditional PK/PD indices.
Methods: Previously described ceftazidime-avibactam PK models in mice [3] and in humans [4] were combined with a PKPD model [5] describing the efficacy of CAZ-AVI against β-lactamase-producing Enterobacteriaceae in order to simulate bacterial growth/killing responses to different dosing regimens. A fixed ceftazidime dosing regimen (in humans: 2g q8h; in mice: its translated equivalent dose as a continuous infusion) with fractionated avibactam dosing regimens were used to predict CAZ-AVI exposures. For mice, the impact on the resulting PK/PD index of various avibactam modes of administration (different frequency from q2h to q24h and/or length of infusion: 30min-, 2h-, 4h- and continuous-infusion) was also assessed. Three different strains of Enterobacteriaceae were used in this simulation framework: two strains of K.pneumoniae (strain NCTC13438 producing KPC-3 β-lactamases; strain KP981690 producing KPC-2 β-lactamases) and one strain of E.cloacae (EL871203 producing OXA-48 β-lactamases). The starting inoculum size was set to 6 log10 CFU/mL in mice and in humans. The relationship between the avibactam-derived PK/PD indices and the 24h-change in bacterial density was evaluated to establish the performance of the PK/PD indices. Simulations were performed using the R package mrgsolve [6].
Results: Overall, for a fixed dose of ceftazidime, the most predicitve PK/PD index of avibactam, determined from simulations in mice and in humans, was fAUC/MIC. However, the differences in the fit between the PK/PD indices (%fT>CT, fCmax/MIC and fAUC/MIC) to characterize avibactam efficacy were relatively small (for example in mice simulations with K.pneumoniae NCTC13438: r2 values of 0.847, 0.805 and 0.974, respectively). The avibactam exposure required to achieve a 2-log kill in bacterial density at 24h was dependent on the bacterial strain’s susceptibility to ceftazidime. For K.pneumoniae KP981690 and E.cloacae EL871203 (MICCAZ-AVI of 1 and 8mg/L, respectively), the E.cloacae isolate needed an 8 times
higher dose of ceftazidime than the K.pneumoniae isolate in order to achieve the same bacterial killing for the same fractionated avibactam dosing regimens. In mice, for the same total daily dose (TTD) of avibactam, a higher frequency of administration was not always associated with higher efficacy. Different modes of infusion were also assessed in mice: for any avibactam TDD yielding bacterial stasis or a net growth at 24h, a continuous mode of infusion resulted in less bacterial growth than any other mode of infusion. Conversely, for any avibactam TDD yielding bacterial killing at 24h, the best efficacy was obtained with short infusion (30 min) dosing regimens.
Conclusions: The PKPD model-based simulations resulted in similar PK/PD index results for avibactam acting in combination with ceftazidime against β-lactamase-producing Gram-negative bacteria in mice and in humans. These results are in conflict with what was previously reported by Sy et al. [3], identifying %fT>CT as the most predictive PK/PD index for P.aeruginosa. The small differences between indices and its dependency on study design highlights the limitations of the PK/PD index approach to characterize the antibacterial response, further supporting the use of a model-based approach in the selection of antibiotic dosing regimens, especially for drugs used in combination.
References:
[1] Kristoffersson AN, David-Pierson P, Parrott NJ, Kuhlmann O, Lave T, Friberg LE, Nielsen EI. Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs. Pharm Res. 2016 May 1;33(5):1115–25.
[2] Berkhout J, Melchers MJ, van Mil AC, Seyedmousavi S, Lagarde CM, Schuck VJ, Nichols WW, Mouton JW. Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection. Antimicrob Agents Chemother. 2015 Dec 31;60(1):368–75.
[3] Sy SKB, Zhuang L, Xia H, Schuck VJ, Nichols WW, Derendorf H. A model-based analysis of pharmacokinetic–pharmacodynamic (PK/PD) indices of avibactam against Pseudomonas aeruginosa. Clinical Microbiology and Infection. 2019 Jul 1;25(7):904.e9-904.e16.
[4] Li J, Lovern M, Green ML, Chiu J, Zhou D, Comisar C, Xiong Y, Hing J, MacPherson M, Wright JG, Riccobene T, Carrothers TJ, Das S. Ceftazidime‐Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019 Mar;12(2):151–63.
[5] Kristoffersson AN, Bissantz C, Okujava R, Haldimann A, Walter I, Shi T, Zampaloni C, Nielsen EI. A novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria. Journal of Antimicrobial Chemotherapy. 2020 Feb 1;75(2):400–8.
[6] Baron KT, Gastonguay MR. Simulation from ODE-based population PK/PD and systems pharmacology models in R with mrgsolve. :1.
Reference: PAGE 30 (2022) Abstr 10006 [www.page-meeting.org/?abstract=10006]
Poster: Drug/Disease Modelling - Infection