The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital

Purpose: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options. Patients and Methods: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). Results: The most common genotypes of CRKP were bla(OXA-48) (53.1%) and bla(OXA-48)+bla(NDM) (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC50 and MIC90 of CZA against CRKP were 2 and >256 mu g/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved >= 90% of the target of free ceftazidime plasma concentration over MIC (%/Time>MIC) >= 50% and 100% against isolates MICs of <= 8 and <= 8 mu g/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 mu g/mL. Based on CFR >= 90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48. Conclusion: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying bla(OXA-48).

Automated summary

This study in Thailand found that CZA exhibited a fairly susceptible rate among CRKP isolates carrying the OXA-48 gene, with the recommended dose of 2.5 g infused every 8 hours for 2-3 hours.