Comment on: pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of ceftazidime/avibactam administered by continuous infusion in patients with MDR Gram-negative bacterial infections

We read with interest the study by Fresan et al. who assessed therapeutic drug monitoring (TDM) and pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime-avibactam administered by continuous infusion (CI) in 31 patients with MDR bacterial infections.¹ In that study, the PK/PD therapeutic target of ceftazidime-avibactam was based solely on ceftazidime exposure and defined as 100%fT > 4 × MIC of the causative pathogen. Based on this, the authors concluded that administering ceftazidime-avibactam by CI enabled the desired PK/PD target to be achieved in a large proportion of patients, even with doses lower than recommended for 2 hours of extended infusion.

We agree with the authors that CI compared to scheduled administration over a period of 2 hour may result in improved PK/PD target attainment of ceftazidime-avibactam, and real-world evidence showed also that CI was associated with better clinical outcome in patients with carbapenem-resistant (CR) infections.^2,3

The authors acknowledged that lack of avibactam concentration measuring was a limitation of the study, and was based on the assumption that the concentration of avibactam would always be sufficient to exert its action.¹ However, we would argue that, according to recent findings, assessing avibactam concentrations could reveal fundamental for accurately defining the PK/PD target of ceftazidime-avibactam.

Although the desirable PK/PD target has not yet been definitely defined for avibactam, there is ever-growing evidence suggesting the remarkable role that increasing avibactam concentrations may have in maximizing clinical efficacy and in preventing resistance development among patients treated with ceftazidime-avibactam.

First, it was recently shown in a preclinical model that increasing avibactam concentrations may result in lowering of ceftazidime MIC against KPC isolates.⁴ This finding made possible the adoption of the innovative concept of effective MIC with an inhibitor (MIC_i) as a powerful strategy for attaining optimal PK/PD targets with ceftazidime-avibactam. It was shown that a ceftazidime-avibactam exposure threshold of 76.1% fT_>MICi was significantly associated with suppression of bacterial regrowth.⁴ This suggests that, in contrast to conventional susceptibility testing, more robust dosing guidance of ceftazidime-avibactam could be provided by capturing avibactam concentration-dependent changes in ceftazidime MIC.⁴

Second, the MIC_i concept was applied by our group to assess the microbiological outcome in a case series of eight patients affected by CR-Enterobacterales bloodstream infections treated with CI ceftazidime-avibactam.⁵ Patients with lower free ceftazidime steady-state concentrations (fC_ss)/MIC_i ratios had a trend towards higher microbiological failure and resistance development to ceftazidime-avibactam.⁵ Noteworthy, lower fC_ss/MIC_i ratio values were strictly dependent on lower avibactam C_ss values observed during treatment, which lead to less pronounced ceftazidime MIC reductions.⁵ This supports the notion that measuring both ceftazidime and avibactam concentrations may be fundamental for better understanding the PK/PD profile of ceftazidime-avibactam in the treatment of MDR Gram-negative infections. The MIC_i is surely an intriguing concept, which may help in turning on the lights over the relevant role that changeable beta-lactamase inhibitor concentrations may have on the PK/PD profile of the novel beta lactam-beta-lactamase inhibitor combinations. However, its feasibility in daily clinical practice could be challenging and time consuming.

Alternatively, we introduced the concept of joint PK/PD target for optimizing CI ceftazidime-avibactam treatment.⁶ Specifically, the joint PK/PD target was defined by taking into account both the C_ss/MIC ratio for ceftazidime and the C_ss/C_T ratio for avibactam, where C_T is the fixed concentration threshold of 4 mg/L adopted by the EUCAST for avibactam when testing ceftazidime-avibactam susceptibility. We defined the joint PK/PD target as optimal when both C_ss/MIC ratio for ceftazidime was ≥4 (equivalent to 100% fT_{>4 x MIC}) and C_ss/C_T ratio for avibactam was >1 (equivalent to 100% fT > C_T of 4.0 mg/L), quasi-optimal if only one of the two thresholds was achieved, and suboptimal if none of the two thresholds was achieved.⁶ By applying this concept to a case series of 10 critically ill renal patients with documented CR-Gram-negative infections, we found that TDM-guided CI ceftazidime-avibactam ensured optimal and quasi-optimal attainment of joint PK/PD target in eight and two cases, respectively, and that microbiological failure occurred in two patients.⁶ In this regard, it is worth mentioning that in our case series the ceftazidime-to-avibactam ratios ranged between 1.7:1 and 13.1:1, namely values greatly different from the fixed 4:1 ratio that is present in the vial of ceftazidime-avibactam. This means that the probability of optimal attainment of the joint PK/PD target may be highly variable between patients.⁶ We are well aware that measuring both ceftazidime and avibactam concentrations may not be possible by all centres/hospitals in the real world. However, we are convinced that performing TDM of both ceftazidime and avibactam, whenever feasible, could represent the best way for giving appropriate PK/PD interpretation and dosing recommendations for ceftazidime-avibactam in real-world scenarios.

Funding

This study was carried out as part of our routine work.

Transparency declarations

M.G. has received personal fees from Angelini and Shionogi, outside the submitted work. F.P. participated in the speaker bureau for Angelini, BeiGene, Gilead, Menarini, Merck Sharp & Dohme, Nordic Pharma, Pfizer and Sanofi Aventis, and on the advisory board for Advanz Pharma, Angelini, BeiGene, Gilead, Merck Sharp & Dohme, Nordic Pharma, Novartis and Pfizer, outside the submitted work.

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