Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models

Abstract

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC 24 ) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three Klebsiella pneumoniae strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC 24 /MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant K. pneumoniae mutants were intensively enriched at an AUC 24 /MIC ratio of 60 to 360 h (AUC 24 /MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC 24 /MIC and AUC 24 /MPC ratios, in accordance with the MSW hypothesis. AUC 24 /MPC and AUC 24 /MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBC M ) were bell shaped. These relationships predict highly variable "antimutant" AUC 24 /MPC ratios (20 to 290 h) compared to AUC 24 /MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC 24 /MPC ratio as an interstrain predictor of K. pneumoniae resistance is lower than that of the AUC 24 /MIC ratio.A n increasing number of reports on the isolation of resistant pathogens (1, 2) combined with a weak antibiotic pipeline suggests that optimization of antibiotic therapy should be aimed at the suppression of resistance (3, 4). In this regard, dynamic models that mimic antimicrobial pharmacokinetics in vitro have been proven to be a useful tool in predicting the amplification of resistant mutants at clinically achievable antibiotic concentrations (5). Using these models, bell-shaped relationships have been established between the emergence of resistance to fluoroquinolones and the ratios of 24-hour area under the concentration-time curve (AUC 24 ) to the MIC (6-17). Such relationships have been reported with moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, the investigational fluoroquinolone ABÒ492, pazufloxacin, tosufloxacin, and garenoxacin against Staphylococcus aureus (6-8, 14-16); moxifloxacin against Streptococcus pneumoniae (12, 13); garenoxacin against Klebsiella pneumoniae (15); ciprofloxacin and moxifloxacin against Pseudomonas aeruginosa (11, 12); and ciprofloxacin, marbofloxacin, and enrofloxacin against Escherichia coli (9,10,17). In some of these studies (6-15, 17, 18), changes in susceptibility of antibiotic-exposed bacteria and/or their enrichment with resistant mutants was observed at fluoroquinolone concentrations above the MIC but below the mutant prevention concentration (MPC), i.e., inside the mutant selection window (MSW) but not outside the MSW, in accordance with the MSW hypo...

Time inside the mutant selection window as a predictor of staphylococcal resistance to linezolid

“…Since the MSW hypothesis predicts the enrichment of resistant mutants at antibiotic concentrations above the MIC, but below the mutant prevention concentration (MPC) the concentration-resistance relationship can be described by an extremum-containing function. This also has been confirmed in further in vitro studies with fluoroquinolones [6,[8][9][10][11][12][13][14][15][16], glycopeptides and lipopeptides [17], and oxazolidinones [18] that demonstrate bell-shaped relationships between the amplification of resistant mutants or loss in susceptibility of antibiotic-exposed bacteria and AUC 24 or AUC 24 /MIC. It was this ratio that allows prediction of strain-independent resistance thresholds, i.e., the "antimutant" AUC 24 /MIC ratios, which were surprisingly less variable than the respective AUC 24 /MPC ratios among fluoroquinolone-exposed Gram-negative bacteria [12,15,16] but not such exposed Gram-positive bacteria [19].…”

Testing the mutant selection window hypothesis with meropenem: In vitro model study with OXA-48-producing Klebsiella pneumoniae

“…The Figs show that accurate bell-shaped relationships fitted with Gaussian function were observed. Similar bell-shaped "PK/PD index-resistance" relationships were previously reported in several studies with non-beta-lactam antibiotics with an account of the mutant selection window (MSW) hypothesis [10][11][12][13][14][15][16][17]; in this regard, beta-lactam antibiotics were not well described. Interestingly, despite meropenem degradation throughout time-kill experiments and the resultant pharmacokinetic profiles that differed significantly from targets, T MSW values, calculated with desired meropenem concentrations, were consistent with the enrichment of the bacterial population with resistant cells.…”

“…To address these issues we tested the well-known mutant selection window hypothesis with meropenem. The mutant selection window (MSW) hypothesis is applicable [10] to explain resistance patterns of several classes of antibiotics [11][12][13][14][15][16][17]; however, only a few such studies have been reported with beta-lactams [12,17].…”

Synergistic Combination of Linezolid and Fosfomycin Closing Each Other’s Mutant Selection Window to Prevent Enterococcal Resistance

“…The MSW comprises a specific drug concentration range in which mutant strains with reduced susceptibility can be selected ( Drlica and Zhao, 2007 ; Blondeau, 2009 ). It has been confirmed in many antibiotics such as fluoroquinolones ( Strukova et al, 2016 ), oxazolidinones ( Alieva et al, 2018 ), aminoglycosides ( Ni et al, 2016 ). MPC is defined as the lowest concentration that blocks the emergence of first-step resistant mutants in a large susceptible population, usually more than 10 10 colony forming unit (CFU)/mL bacteria ( Drlica, 2003 ).…”