XDR P. aeruginosa has now spread worldwide and has become a severe challenge to clinical work, especially the treatment of immunocompromised patients with severe infections . Furthermore, CDC (Centers for Disease Control and Prevention) classified MDR/XDR P. aeruginosa infections as a serious antibiotic resistance threat . Several studies demonstrated that clinical and microbiology responses of CZA against MDR/XDR P. aeruginosa pulmonary infections were inferior to other gram-negative bacteria [4, 5]. However, most of these researches were case series or retrospective studies and confined to small sample sizes. The main resistance mechanisms of P. aeruginosa are intrinsic resistome, mutational resistome, and horizontally acquired resistome . Furthermore, CZA is a novel β-lactam/ β-lactamase inhibitors (BL/BLIs) and has been regarded as a new treatment option for XDR P. aeruginosa . By the way, in vitro studies showed that the susceptibility rate of CZA to XDR P. aeruginosa ranged from 73.7–76.2% [8, 15, 16].
Based on the above research background, our team conducted a PK/PD analysis. In our study, we used OTAT and TI to evaluate the efficacy of different CZA dosing models to treat XDR P. aeruginosa pulmonary infections. MCSs have been performed to study CZA dosing models and define the optimal dosing regimen of CZA therapy for XDR P. aeruginosa pneumonia, testing various renal function statuses and doses.
And we found that all OTAT dosing regimens (ie: 2.5 g [e.g., 1.25 g (0.5h) + 1.25 g (2h)] q6h, 2.5 g [e.g., 1.25 g (0.5h) + 1.25 g (2h)] q8h, 4g [e.g., 2 g (0.5h) + 2 g (2h)] q6h, 4g [e.g., 2 g (0.5h) + 2 g (2h)] q8h for normal renal function patients. 1.25 g [e.g., 0.675 g (0.5h) + 0.675 g (2h)] q6h, 1.25 g [e.g., 0.675 g (0.5h) + 0.675 g (2h)] q8h for patients with CLCR range 30 to 50 ml/min. 0.94 g [e.g., 0.47 g (0.5h) + 0.47 g (2h)] q12h for patients with CLCR > 16 to ≤ 30 ml/min.) with adequate PK exposures (CZA concentration decreased to 5\(\times\)MIC after the second step infusion) can obtain favorable response. Compared with TI, we considered that OTAT can be an ideal strategy for XDR P. aeruginosa with MICs of 16 to 32 mg/L.
Eguchi et al. (2010)  conducted a PK/PD analysis, and they found that OTAT can significantly improve the initial killing rate of meropenem. Another study demonstrated that meropenem monotherapy is competent for meropenem-nonsusceptible bacterial infections if administered rational OTAT . These were similar to the results of our study. As with other time depended antibiotics (i.e., meropenem, ceftazidime), administration by OTAT is a potential treatment option for improving the probability of attaining the PK/PD target.
In clinical setting, drug-resistant P. aeruginosa in the respiratory tract is often found in patients with chronic lung disease states such as cystic fibrosis, immunosuppression, and so on. Considering that patient population can affect treatment decision and has varying PK/PD parameters, I suggest that the application of OTAT regimens should be considered the variation of PK parameters.
From the pharmacoeconomic perspective, our study has great significance for some developing countries with poor healthcare situations. At the same dosing model (i.e., same medical expenses), OTATs with sufficient PK exposures were more effective than TI. CZA is a novel antibiotic with high prices. In case of poor efficacy of CZA therapy for XDR P. aeruginosa pneumonia, doctors can use an OTAT rather than increasing the dose or frequency blindly. This can significantly reduce the burden on patients.
From the perspective of safety of CZA, our study helps to reduce toxic reactions caused by overdose. At the standard dose of CZA (2.5 g q8h), the TI does not provide good bactericidal effect for XDR P. aeruginosa pulmonary infections, but the OTAT provides good bactericidal effect for XDR P. aeruginosa pneumonia. There are limits to the effectiveness of attempts to increase doses to achieve therapeutic goals, and the risk of overdose should be taken into account.
Our work had several limitations, as follows. Firstly, PK parameters of ceftazidime and avibactam were obtained from critically ill patients’ serum samples and confined to its small sample size. Nevertheless, our study aimed to evaluate the efficacy of CZA for the treatment of XDR P. aeruginosa pneumonia. Epithelial lining fluid (ELF) samples of patients with pneumonia would be the best .
Secondly, local surveillance and epidemiology should always be considered when deciding a therapy for drug-resistant organisms. Knowing resistance patterns is a key to control antimicrobial resistance as well as to avoid any antibiotic misuse or overuse. Therefore, applicability of MICs from a different country should be considered with caution as the strategies against multi-drug organisms (MDRO) may differ country by country, state by state, and even city by city. XDR P. aeruginosa was isolated from the United States from 2012 to 2015. XDR P. aeruginosa were collected in recent years would be better, but MIC distributions of these strains were unavailable.
Alternative regimens included longer dosage interval, prolonged infusions of the full dose for both drugs and OTAT. In addition, those regimens could reduce dosing errors, drug cost and nurse labor. Clinical investigation of those alternative dosage regimens would be required before implementation.
The treatment of XDR P. aeruginosa pulmonary infections is a massive challenge in our future work. In this study, we conducted Monte Carlo simulations to evaluate the efficacy of CZA for the treatment of XDR P. aeruginosa pulmonary infections. We found that OTAT dosing regimens can vastly improve the PTA at MIC ≥ 16mg/L. Moreover, all OTAT dosing regimens can obtain favorable CFR values.