1572 - Combination Cefuroxime and Sulopenem is active in vitro against Mycobacterium abscessus

Background: Mycobacterium abscessus (Mab) is a highly drug-resistant nontuberculous mycobacteria (NTM). Efforts to discover new treatments for Mab infections are accelerating with a focus on cell wall synthesis proteins (L, D-transpeptidases, Ldt_Mab1-5, and D, D-carboxypeptidase) that are targeted by combination β-lactam antibiotics. The US Food and Drug Administration (FDA) has granted Qualified Infectious Disease Product (QIDP) to the oral and intravenous (IV) formulations of Sulopenem (SUL). Data on SUL in vitro activity against Mab is currently unavailable. Here, we evaluated activity of SUL alone and in combination with Cefuroxime salt (CEF) against representative clinical isolates belonging to the Mab complex. Both CEF and SUL are available in oral formulation and can be considered as oral step-down therapy.

Methods: Minimum inhibitory concentrations (MICs) of SUL and CEF alone and in combination were determined using microdilution. Approximately 5 x 105 colony-forming units (CFU) per milliliter were inoculated into Middlebrook 7H9 Broth supplemented with 10% (vol/vol) oleic albumin dextrose catalase and 0.05% (vol/vol) Tween 80. CEF was added at fixed concentration of 4 µg/ml to serial dilutions of SUL. Mab isolates were incubated with test agents at 30 °C for 48 h, and MIC was defined as lowest antibiotic concentration that prevented visible bacterial growth.

Results: Fifty-five clinically derived and previously characterized isolates were tested in these assays. MIC₅₀ and MIC₉₀ of CEF is 16 and 32 ug/ml; MIC50 and MIC90 of SUL is 2 and 4 ug/ml, the range of MICs are as follows: CEF (8 → 64 ug/ml); SUL (1→8 ug/ml); and SUL and CEF at fixed 4 ug/ml (< 0.25 → 4 ug/ml).  Combination SUL and CEF lowered MIC to < 0.25 ug/ml in 52 clinical isolate (Figure).Fig. MIC distributions of cefuroxime salt, sulopenem, sulopenem with 4 μg/ml cefuroxime monohydrate against 55 Mab clinical strains


Conclusion: Our results support the emerging hypothesis that dual β-lactam therapy is a promising strategy in the treatment of serious Mab infections. Investigating the biochemical rationale for this combination will support the application to clinical trials.