Meropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill Patients

Abstract

Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM). Pharmacokinetic profiles representing substantial ARC (creatinine clearance of 250 ml/min) were generated in the HFIM for meropenem (1 g or 2 g administered every 8 h as 30-min infusion and 3 g/day or 6 g/day as continuous infusion [CI]) and tobramycin (7 mg/kg of body weight every 24 h as 30-min infusion) regimens. The time courses of total and less-susceptible bacterial populations and MICs were determined for the monotherapies and all four combination regimens. Mechanism-based mathematical modeling (MBM) was performed. In the HFIM, maximum bacterial killing with any meropenem monotherapy was ∼3 log10 CFU/ml at 7 h, followed by rapid regrowth with increases in resistant populations by 24 h (meropenem MIC of up to 128 mg/liter). Tobramycin monotherapy produced extensive initial killing (∼7 log10 at 4 h) with rapid regrowth by 24 h, including substantial increases in resistant populations (tobramycin MIC of 32 mg/liter). Combination regimens containing meropenem administered intermittently or as a 3-g/day CI suppressed regrowth for ∼1 to 3 days, with rapid regrowth of resistant bacteria. Only a 6-g/day CI of meropenem combined with tobramycin suppressed regrowth and resistance over 7 days. MBM described bacterial killing and regrowth for all regimens well. The mode of meropenem administration was critical for the combination to be maximally effective against carbapenem-resistant P. aeruginosa.

Optimisation of alternative antibiotic dosing regimens for maximal antibacterial activity and suppression of emergence of resistance

“…Thus, the question on PTZ-aminoglycoside combination vs PTZ/meropenem monotherapy on clinical outcome remained unanswered in this study. However, in agreement with previous in vitro studies (51,52,139) on benefits of combination therapy, a clinical study reported that beta-lactam and aminoglycoside combination therapy reduced mortality in patients with sepsis caused by carbapenemase-producing Enterobacterales (328). Also, a meta-analysis reported that combination therapy in patients with septic shock improves the survival of patients > 25% (147).…”

“…Few studies have investigated the effect of combination therapy against Enterobacterales, with most studies investigating the effect of combination antibiotics against P. aeruginosa (51,52,139). In this context, differences in cell wall thickness, presence of efflux pumps and the presence of different beta-lactamases are likely key differences between these bacterial species that mediate beta-lactam resistance, which may explain the improved bacterial killing with clinically relevant doses of PTZ used in our study compared with others conducted using P. aeruginosa (321,322).…”

“…and in vivo studies have demonstrated that beta-lactam and aminoglycoside combination therapy can achieve effective bacterial killing and suppress the emergence of resistance against P. aeruginosa and Acinetobacter baumannii (51,52,139,140). Researchers suggested that the effect on protein synthesis and the disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations (131,141), and thereby prevent the emergence of antibiotic resistance by killing resistant bacteria or by suppressing the growth of resistant sub-population (51,52,142).…”

Evaluation of Meropenem‐Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance

“…30 Treatment failure with meropenem monotherapy against P. aeruginosa in previous HFIM studies simulating ARC was observed despite fT >MIC exceeding 40%. 9,11 In the first of those studies, meropenem dosing regimens (2, 1 and 0.5 g q8h as short-term infusions) failed to yield sustained bacterial killing and resistance suppression for a susceptible P. aeruginosa isolate (MIC of 0.25 mg/L). 9 In the second study evaluating a carbapenem-resistant P. aeruginosa isolate (MIC of 8 mg/L), in addition to short-term infusion regimens, meropenem at 3 or 6 g/ day CI produced ~ 3-log killing by 7 hours followed by extensive regrowth similar to the control arm.…”

“…7 In the dynamic hollow-fiber infection model (HFIM) simulating pharmacokinetic (PK) profiles typical of patients with ARC, approved doses of meropenem and piperacillin as monotherapy against a susceptible P. aeruginosa isolate failed to achieve sufficient bacterial killing and resistance suppression. 8,9 Beta-lactam and aminoglycoside combinations studied in the HFIM under ARC conditions demonstrated good bacterial killing and resistance suppression, 10,11 but this combination has the potential to cause aminoglycoside-associated nephrotoxicity. 12 Beta-lactam and quinolone combinations have been found to produce substantial bacterial killing and resistance suppression of P. aeruginosa; 13,14 however, these combinations have never been evaluated in the HFIM under conditions of ARC.…”