Sulbactam-durlobactam plus ceftriaxone dosing and novel treatment regimens for Mycobacterium abscessus lung disease

The guideline-based therapy achieves sputum culture conversion rates in 20%-34% of patients with Mycobacterium abscessus (MAB) lung disease (LD). Double-β-lactam combinations have been proposed to improve cure based on time-kill curves. We tested MICs followed by hollow fiber system model of MAB (HFS-MAB) exposure-effect studies with sulbactam-durlobactam administered every 8 h (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). γ-slopes (kill-speed) were calculated for all regimens. The minimal sulbactam-durlobactam clinical doses that achieved target exposure were identified using Monte Carlo experiments. Ceftriaxone reduced sulbactam-durlobactam MICs by eight-tube dilutions. In the HFS-MAB, sulbactam-durlobactam microbial kill and antimicrobial resistance were linked to % time concentration persists above MIC (%T_MIC), with target exposure of 50%T_MIC. 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. The kill slope of bacterial population in >95% of virtual subjects was 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 (or 4G q12h for outpatients), 2G q12h for 60-90 mL/min, 1G q12h for ≥30 to <60 mL/min, and 1G q24h for <30 mL/min. Sulbactam-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.