scholarly journals Pharmacodynamic evaluation of suppression of in vitro resistance in Acinetobacter baumannii strains using polymyxin B-based combination therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nayara Helisandra Fedrigo ◽  
Danielle Rosani Shinohara ◽  
Josmar Mazucheli ◽  
Sheila Alexandra Belini Nishiyama ◽  
Floristher Elaine Carrara-Marroni ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Combination Therapy ◽  
Polymyxin B ◽  
Dosage Interval ◽  
Combination Regimen ◽  
Mutant Selection ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Free Plasma

AbstractThe emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. This study determined the mutant selection window (MSW) of polymyxin B alone and in combination with meropenem and fosfomycin against A. baumannii strains belonging to clonal lineages I and III. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The MSW of polymyxin B varied between 1 and 16 µg/mL for polymyxin B-susceptible strains. The triple combination of polymyxin B with meropenem and fosfomycin inhibited the polymyxin B-resistant subpopulation in meropenem-resistant isolates and polymyxin B plus meropenem as a double combination sufficiently inhibited meropenem-intermediate, and susceptible strains. T>MPC 90% was reached for polymyxin B in these combinations, while %TMSW was 0 against all strains. TMSW for meropenem and fosfomycin were also reduced. Effective antimicrobial combinations significantly reduced MSW. The MSW-derived pharmacodynamic indices can be used for the selection of effective combination regimen to combat the polymyxin B-resistant strain.

scholarly journals In Vitro Resistance Selection in Shigella flexneri by Azithromycin, Ceftriaxone, Ciprofloxacin, Levofloxacin, and Moxifloxacin

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
George P. Allen ◽  
Kayla A. Harris
Keyword(s):  
Shigella Flexneri ◽  
Dosage Interval ◽  
Time Curve ◽  
Mutant Selection ◽  
Content Type ◽  
Selective Enrichment ◽  
Mutant Prevention Concentration ◽  
Time Kill

ABSTRACT Shigella flexneri continues to be a major cause of diarrhea-associated illness, and increasing resistance to first-line antimicrobials complicates the treatment of infections caused by this pathogen. We investigated the pharmacodynamics of current antimicrobial treatments for shigellosis to determine the likelihood of resistance promotion with continued global antimicrobial use. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, ciprofloxacin, levofloxacin, and moxifloxacin against a wild-type strain of S. flexneri (ATCC 12022) and an isogenic gyrA mutant (m-12022). Time-kill assays were performed to determine antimicrobial killing. Concentrations of approved doses of ciprofloxacin, levofloxacin, and moxifloxacin are predicted to surpass the MPC for a majority of the dosage interval against ATCC 12022. However, against m-12022, concentrations of all fluoroquinolones are predicted to fall below the MPC and remain in the MSW for a majority of the dosage interval. Concentrations of ceftriaxone fall within the MSW for the majority of the dosage interval for both strains. All agents other than azithromycin displayed bactericidal activity in time-kill assays. Results of pharmacodynamic analyses suggest that all tested fluoroquinolones would achieve a favorable area under the concentration-time curve (AUC)/MPC ratio for ATCC 12022 and would restrict selective enrichment of mutants but that mutant selection in m-12022 would be likely if ciprofloxacin were used. Based on pharmacodynamic analyses, azithromycin and ceftriaxone are predicted to promote mutant selection in both strains. Confirmation of these findings and examination of novel treatment regimens using in vivo studies are warranted.

scholarly journals Mutant Prevention Concentration of Garenoxacin (BMS-284756) for Ciprofloxacin-Susceptible or -Resistant Staphylococcus aureus

2003 ◽  
Vol 47 (3) ◽  
pp. 1023-1027 ◽  
Author(s):  
Xilin Zhao ◽  
William Eisner ◽  
Nathan Perl-Rosenthal ◽  
Barry Kreiswirth ◽  
Karl Drlica
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Time ◽  
Mutant Selection ◽  
Selective Enrichment ◽  
Drug Concentrations ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants

ABSTRACT The new quinolone garenoxacin (BMS-284756), which lacks a C-6 fluorine, was examined for its ability to block the growth of Staphylococcus aureus. Measurement of the MIC and the mutant prevention concentration (MPC) revealed that garenoxacin was 20-fold more potent than ciprofloxacin for a variety of ciprofloxacin-susceptible isolates, some of which were resistant to methicillin. The MPC for 90% of the isolates (MPC90) was below published serum drug concentrations achieved with recommended doses of garenoxacin. These in vitro observations suggest that garenoxacin has a low propensity for selective enrichment of fluoroquinolone-resistant mutants among ciprofloxacin-susceptible isolates of S. aureus. For ciprofloxacin-resistant isolates, the MIC at which 90% of the isolates tested were inhibited was below serum drug concentrations while the MPC90 was not. Thus, for these strains, garenoxacin concentrations are expected to fall inside the mutant selection window (between the MIC and the MPC) for much of the treatment time. As a result, garenoxacin is expected to selectively enrich mutants with even lower susceptibility.

scholarly journals Treatment Outcome of Bacteremia Due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial Regimens

2012 ◽  
Vol 56 (4) ◽  
pp. 2108-2113 ◽  
Author(s):  
Zubair A. Qureshi ◽  
David L. Paterson ◽  
Brian A. Potoski ◽  
Mary C. Kilayko ◽  
Gabriel Sandovsky ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapy Group ◽  
Polymyxin B ◽  
The United States ◽  
Combination Regimen ◽  
Content Type ◽  
Crude Mortality Rate ◽  
Definitive Therapy

ABSTRACTKlebsiella pneumoniaeproducingKlebsiella pneumoniaecarbapenemase (KPC) has been associated with serious infections and high mortality. The optimal antimicrobial therapy for infection due to KPC-producingK. pneumoniaeis not well established. We conducted a retrospective cohort study to evaluate the clinical outcome of patients with bacteremia caused by KPC-producingK. pneumoniae. A total of 41 unique patients with blood cultures growing KPC-producingK. pneumoniaewere identified at two medical centers in the United States. Most of the infections were hospital acquired (32; 78%), while the rest of the cases were health care associated (9; 22%). The overall 28-day crude mortality rate was 39.0% (16/41). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (odds ratio, 0.07 [95% confidence interval, 0.009 to 0.71],P= 0.02). The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (P= 0.01). The most commonly used combinations were colistin-polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despitein vitrosusceptibility, patients who received monotherapy with colistin-polymyxin B or tigecycline had a higher mortality of 66.7% (8/12). The use of combination therapy for definitive therapy appears to be associated with improved survival in bacteremia due to KPC-producingK. pneumoniae.

scholarly journals Pharmacodynamic Modeling of Ciprofloxacin Resistance in Staphylococcus aureus

2005 ◽  
Vol 49 (1) ◽  
pp. 209-219 ◽  
Author(s):  
Jeffrey J. Campion ◽  
Patrick J. McNamara ◽  
Martin E. Evans
Keyword(s):  
Staphylococcus Aureus ◽  
Resistance Mechanism ◽  
Viable Count ◽  
Pharmacodynamic Modeling ◽  
Mutant Selection ◽  
High Density Culture ◽  
Low Level ◽  
Selection Window ◽  
Mutant Prevention Concentration

ABSTRACT Three pharmacodynamic models of increasing complexity, designed for two subpopulations of bacteria with different susceptibilities, were developed to describe and predict the evolution of resistance to ciprofloxacin in Staphylococcus aureus by using pharmacokinetic, viable count, subpopulation, and resistance mechanism data obtained from in vitro system experiments. A two-population model with unique growth and killing rate constants for the ciprofloxacin-susceptible and -resistant subpopulations best described the initial killing and subsequent regrowth patterns observed. The model correctly described the enrichment of subpopulations with low-level resistance in the parent cultures but did not identify a relationship between the time ciprofloxacin concentrations were in the mutant selection window (the interval between the MIC and the mutant prevention concentration) and the enrichment of these subpopulations. The model confirmed the importance of resistant variants to the emergence of resistance by successfully predicting that resistant subpopulations would not emerge when a low-density culture, with a low probability of mutants, was exposed to a clinical dosing regimen or when a high-density culture, with a higher probability of mutants, was exposed to a transient high initial concentration designed to rapidly eradicate low-level resistant grlA mutants. The model, however, did not predict or explain the origin of variants with higher levels of resistance that appeared and became the predominant subpopulation during some experiments or the persistence of susceptible bacteria in other experiments where resistance did not emerge. Continued evaluation of the present two-population pharmacodynamic model and development of alternative models is warranted.

scholarly journals In Vitro Antimicrobial Activity and Mutant Prevention Concentration of Colistin against Acinetobacter baumannii

2010 ◽  
Vol 54 (9) ◽  
pp. 3998-3999 ◽  
Author(s):  
Yun Cai ◽  
Ran Li ◽  
Beibei Liang ◽  
Nan Bai ◽  
Youning Liu ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Plasma Concentration ◽  
Combination Therapy ◽  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Recommended Dosage ◽  
Mutant Prevention Concentration ◽  
Emergence Of Resistance

ABSTRACT The antimicrobial activities of colistin and other antibiotics against clinical Acinetobacter baumannii and the mutant prevention concentration (MPC) of colistin against multidrug-resistant A. baumannii were studied. All 70 stains tested were sensitive to colistin. The MPC range of colistin against 30 multidrug-resistant A. baumannii stains was approximately 32 to >128 μg/ml, and the MPC at which 90% of the isolates tested were prevented (MPC90) exceeded 128 μg/ml, which was much higher than the plasma concentration of colistin at the current recommended dosage. So, combination therapy for colistin treatment of A. baumannii would be prudent to slow the emergence of resistance.

scholarly journals In Vivo Validation of the Mutant Selection Window Hypothesis with Moxifloxacin in a Murine Model of Tuberculosis

2007 ◽  
Vol 51 (12) ◽  
pp. 4261-4266 ◽  
Author(s):  
Deepak Almeida ◽  
Eric Nuermberger ◽  
Sandeep Tyagi ◽  
William R. Bishai ◽  
Jacques Grosset
Keyword(s):  
Drug Exposure ◽  
Serum Concentrations ◽  
Mutant Selection ◽  
Drug Concentrations ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT Combination therapy is the most effective strategy to prevent emergence of resistance during tuberculosis (TB) treatment. Another strategy, albeit theoretical, is to limit the time that drug concentrations fall in the “mutant selection window” (MSW) between the MIC and the mutant prevention concentration (MPC). Drug concentrations above the MPC prevent selective amplification of resistant mutants in vitro even with a single drug exposure. The MSW concept has been validated using fluoroquinolones against Mycobacterium tuberculosis in vitro but not in vivo. Using a mouse model in which serum moxifloxacin (MXF) concentrations were maintained above the MPC, we tested whether this strategy prevents selection of MXF-resistant mutants. Beginning 2 weeks after aerosol infection with M. tuberculosis, when the mean lung log10 CFU count was 7.9 ± 0.2, mice received either no treatment or MXF in the diet at 0.25% to approximate the conventional human dose or 1.5% to maintain serum concentrations above the MPC (8 μg/ml). After 56 days of treatment, lung CFU counts were 3.5 ± 0.8 and 0.9 ± 0.6 in 0.25% and 1.5% of the MXF-treated mice, respectively. In mice given 0.25% MXF, MXF-resistant mutants were selected by day 28 and detected in 16% (3/19) of mice tested on day 56. No selection of MXF-resistant mutants was detected in mice given 1.5% MXF. We conclude that maintaining serum concentrations of MXF above the MPC prevents selection of MXF-resistant mutants. Although this target cannot be achieved clinically with MXF, it might be possible with new fluoroquinolones with more potent activity and/or improved pharmacokinetics.

scholarly journals In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against Staphylococcus aureus

2003 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Alexander A. Firsov ◽  
Sergey N. Vostrov ◽  
Irene Y. Lubenko ◽  
Karl Drlica ◽  
Yury A. Portnoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Half Life ◽  
Dynamic Models ◽  
Daily Administration ◽  
Human Pharmacokinetics ◽  
Mutant Selection ◽  
Dosing Interval ◽  
Selection Window ◽  
Mutant Prevention Concentration

ABSTRACT To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Staphylococcus aureus exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (C max) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.e., within or “inside” the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC24) to the MIC varied from 13 to 244 h, and the starting inoculum was 108 CFU/ml (6 × 109 CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC24/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC24/MIC values (15 to 16 h) of GAT and CIP, whose C max exceeded the MICs. No such increases were observed with the smallest AUC24/MIC values (13 to 17 h) of MOX and LEV, whose C max were close to the MICs. Also, less pronounced but significant increases in MIC occurred at AUC24/MIC values (107 to 123 h) that correspond to quinolone concentrations partly overlapping the MIC-to-MPC range. With all four drugs, no change in MIC was seen at the highest AUC24/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These “protective” AUC24/MIC ratios correspond to 66% of the usual clinical dose of MOX (400 mg), 190% of a 400-mg dose of GAT, 220% of a 500-mg dose of LEV, and 420% of two 500-mg doses of CIP. Thus, MOX may protect against resistance development at subtherapeutic doses, whereas GAT, LEV, and CIP provide similar effects only at doses that exceed their usual clinical doses. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the MSW and suggest that in vitro dynamic models can be used to predict the relative abilities of quinolones to prevent mutant selection.

scholarly journals The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both Pseudomonas aeruginosa Kill Rate and Resistance Suppression

2010 ◽  
Vol 54 (6) ◽  
pp. 2646-2654 ◽  
Author(s):  
Arnold Louie ◽  
Caroline Grasso ◽  
Nadzeya Bahniuk ◽  
Brian Van Scoy ◽  
David L. Brown ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Infection Model ◽  
Combination Regimen ◽  
Time Data ◽  
Kaplan Meier ◽  
Drug Concentrations ◽  
Cell Kill ◽  
The Impact

ABSTRACT New approaches are needed for the treatment of Pseudomonas aeruginosa infections. All available single agents are suboptimal, especially for resistance suppression. Classical β-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the P. aeruginosa PAO1 wild type and its isogenic MexAB pump-overexpressed mutant. The drugs were studied using an in vitro hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2- to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.

Sign in / Sign up

Export Citation Format

Share Document