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

BackgroundIDSA 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. MethodsWe performed minimum inhibitory concentrations (MICs) experiments followed by hollow fiber system model of MAB-LD (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 three different MAB 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 achieved target exposure were identified using Monte Carlo experiments. ResultsCeftriaxone reduced sulbactam-durlobactam MICs by 8-tube dilutions. In the HFS-MAB, 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 plus ceftriaxone killed without regrowth and demonstrated Bliss additivity.{gamma} of bacterial population in >95% of virtual subjects were 2.28 (0.97-4.80) log10 CFU/mL/day for sulbactam-durlobactam-ceftriaxone and 2.91 (1.65-4.93) log10 CFU/mL/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 [&ge;]30 to <60 mL/min, and 1G q24h for <30 mL/min. ConclusionSulbactam-durlobactam-ceftriaxone achieved the highest microbial kill encountered so far in the HFS-MAB. Sulbactam-durlobactam-ceftriaxone should be tested as the backbone for novel treatment shortening regimens.