Methods: Six CR-ACBN clinical isolates, including 5 isolates expressing OXA-23 or OXA-24, were studied. FEP and WCK 5222 MICs were 128 - >512 and 16 - 64 mg/L, respectively. The ZID MIC was >512 mg/L for all isolates. ICR mice were rendered transiently neutropenic via cyclophosphamide prior to thigh inoculation with bacterial suspensions of 107 CFU/mL. Treatment mice received either FEP HSR (equivalent to a clinical dose of 2 g IV q8h as a 1h infusion), ZID HSR (equivalent to a clinical dose of 1 g IV q8h as 1h infusion), or WCK 5222 HSR (FEP HSR + ZID HSR). Control mice were vehicle-dosed. Changes in log10 CFU/mL at 24h compared with 0h controls were measured to assess efficacy.
Results: The average log10 CFU/thigh at 0h across all isolates was 5.85 ± 0.22. Compared with 0h control, the mean bacterial growth at 24h in the untreated control mice, FEP HSR, and ZID HSR were 2.34 ± 0.93, 1.36 ± 1.40, and 2.04 ± 0.80 log10CFU/thigh, respectively. The WCK 5222 HSR produced a decline in bacterial burden for all isolates [mean reduction of -2.09 ± 1.01 log10CFU/thigh]; 4/6 isolates achieved ≥ 2-log reduction while ≥ 1-log reduction was attained with the remaining 2 isolates.
Conclusion: HSR of WCK 5222 showed potent in vivo activity against CR-ACBN expressing OXA carbapenemases in the murine thigh model which is attributed to the β-lactam enhancing effect of ZID, driven by the complementary PBP binding of FEP and ZID. These results support the clinical evaluation of WCK 5222 for the management of infections due to CR-ACBN.
S. Almarzoky Abuhussain,
K. Abdelraouf, None
D. P. Nicolau, Wockhardt: Investigator , Research support .