Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens for Mycobacterium abscessus Lung Disease

Background. Guideline-based therapy achieves sputum culture conversion rates in 20-34% of patients with Mycobacterium abscessus (MAB) lung disease (LD). Double-beta-lactam combinations have been proposed to improve cure, based on time-kill curves. Methods. We performed minimum inhibitory concentrations (MICs) experiments followed by HFS-MAB exposure-effect studies with sulbactam-durlobactam administered every 8h (q8h), q12h, and q24h, to identify target exposures. Next, the sulbactam-durlobactam target exposure plus ceftriaxone was administered in the HFS-MAB inoculated with MAB clinical isolates, as was the sulbactam-durlobactam-ceftriaxone combination with epetraborole and omadacycline (SDCEO). gamma-slopes (kill-speed) were calculated for all regimens. The minimal sulbactam-durlobactam clinical doses that would achieve target exposure were identified using Monte Carlo experiments. Results. Ceftriaxone reduced sulbactam-durlobactam MICs by 8-tube dilutions. Sulbactam-durlobactam microbial kill and antimicrobial resistance were linked to % time concentration persists above MIC (%TMIC), with target exposure of 50%. Sulbactam-durlobactam killed 3.85 log10 CFU/mL below day 0 burden (B0) with regrowth. Sulbactam-durlobactam-ceftriaxone killed without regrowth. Sulbactam-durlobactam and ceftriaxone demonstrated Bliss additivity. The kill-speed of bacterial population in >95% of virtual subjects was 2.28 (0.97-4.80) log10 CFU kill/day for sulbactam-durlobactam-ceftriaxone and 2.91 (1.65-4.93) log10 CFU kill/day for SDCEO. The optimal sulbactam-durlobactam dose co-administered with ceftriaxone was 2G q8h for creatinine clearance >90 mL/min, 2G q12h for 60-90 mL/min, 1G q12h for ≥30 to <60 mL/min, and 1G q24h for <30 mL/min. Conclusion. Sulbactam-durlobactam-ceftriaxone achieved the highest microbial kill encountered so far in the HFS-MAB. Sulbactam-durlobactam-ceftriaxone should be tested in clinical trials as the backbone for novel treatment shortening regimens.