Optimization and evaluation of piperacillin plus tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modeling [PublishAheadOfPrint]

Augmented renal clearance (ARC) in critically-ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa using the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically-ill patient and static concentration time-kill experiments (SCTK), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, at two inocula (10^5.8 and 10^7.6 CFU/mL) over 72h. We subsequently evaluated the effect of optimized piperacillin (4 g q4h, 0.5h infusion) plus tobramycin (5 mg/kg q24h, 7 mg/kg q24h and 10 mg/kg q48h as 0.5h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 mL/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin at low inoculum) achieved synergistic killing (≥2 log₁₀vs. the most active monotherapy at 48h and 72h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4 log₁₀ initial killing followed by regrowth at 24h with resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log₁₀ at 13h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5 log₁₀ killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin plus tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear highly promising for effective and early treatment, even in the near-worst case scenario of ARC.

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