Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

Abstract

Hypermutable organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔ (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable .

Pharmacodynamic Drug–Drug Interactions

“…The synergy was concluded to arise from enhanced penetration of the β‐lactam to its molecular target site as a result of outer membrane disruption by the aminoglycosides. A PD DDI model, based on the in vitro evaluation of bacterial killing using a hollow‐fiber infection model system, was translated in vivo to a murine thigh infection model and to patients simply by integrating the PK models of the antibiotics in those species. Simulations with the PK/PD model suggested that the continuous infusion of a high‐dose β‐lactam combined with an aminoglycoside would constitute a promising regimen for optimal bacterial killing without regrowth.…”

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

“…Serial samples were collected at 5 to 10 min predose (0 h) and at 1.5, 5, 24, 29, and 48 h. The bacterial suspensions were centrifuged at 24 h, the supernatant carefully removed, and bacteria resuspended in fresh, prewarmed medium that contained the targeted antibiotic concentration(s). As previously described, supplemental meropenem doses corresponding to 30% of the original dose were added at 6 and 30 h to further offset the known thermal degradation of meropenem (52,67). The samples for viable counting were washed twice in sterile saline, and counts determined by manually plating 100 l of undiluted or appropriately diluted suspension in saline onto agar plates.…”

Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling

“…The first-order growth rate constant (k12,IR) was defined as 60/MGT IR , with MGT IR denoting the mean generation time for the bacterial population. We used a direct killing process [25,26,27] for both tobramycin and ciprofloxacin. The KC 50,TOB and KC 50,CIP were the tobramycin and ciprofloxacin concentrations required to achieve 50% of the maximum killing rate constant ( K max ).…”