RESUMO
Abstract Determining the role of the immune response in preventing antimicrobial resistance and optimizing antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae (KPC) is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamics and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B_MIC: 0.5-64 mg/L; Fosfomycin MIC: 16-128 mg/L) to evaluate the pharmacodynamics of mono- and combination therapies in static time-kill studies. A mechanism based model was used to characterize the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared to monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect which resulted in an increase in fosfomycin's ability to reach its target site. The mechanism based model described the data well across all six strains with R2 values ranging from 0.705 to 0.935. The combination reduced K. pneumoniae-induced IL-6 and IL-8 but not TNF-α expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone, and combinations showed significantly greater reductions compared to monotherapies. Our findings suggest that further research is needed to understand immune-mediated killing to identify a strategy which harnesses the power of the immune response against these hard to treat bacteria in an in vivo system.
Assuntos
Fosfomicina , Klebsiella pneumoniae , Polimixina BRESUMO
Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (024 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.611.6) log10 CFU hour/mL and 7.08 (7.0411.9) log10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/ kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple combination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.
Assuntos
Combinação de Medicamentos , Klebsiella pneumoniae , TerapêuticaRESUMO
The multidrug resistance profiles of Klebsiella pneumoniae carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the in vitro activity of polymyxin B and minocycline combination therapy against six KPC-2-producing K. pneumoniae isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing K. pneumoniae is dependent on polymyxin B susceptibility...
Assuntos
Klebsiella pneumoniae , Minociclina , Polimixinas , Resistência a Múltiplos MedicamentosRESUMO
Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, ofpolymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniaeclinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatmentfor mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Timekillstudies were conducted over 24 h with PMB (0.516 mg/L) and meropenem (20120 mg/L) alone or incombination against an initial inoculum of ca. 106 CFU/mL. Scanning electron microscopy (SEM) was employedto analyse changes in bacterial morphology after treatment, and the log change method was usedto quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2 gene and were resistant tomeropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combinationwith meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenemresistant,both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidalagainst polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphologicalchanges following treatment with PMB in combination with meropenem compared with thechanges observed with each individual agent. Additionally, morphological changes decreased with increasingresistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects maynot only be a summation of the effects due to each antibiotic but also a result of differential action thatlikely inhibits protective mechanisms in bacteria...