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ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model
... Probabilities were determined for delafloxacin doses of 200-450 mg given intravenously every 12 hours, revealing high percent probabilities of TA for MIC values ≤0.5 mg/L with intravenous and oral doses of 300 mg and 450 mg respectively, which were chosen for the Phase 3 studies [53]. Several studies have evaluated the comparative PD of delafloxacin versus other fluoroquinolones, mainly levofloxacin and ciprofloxacin, against multiple clinically relevant pathogens including S. aureus, E. coli, S. pneumoniae, and K. pneumoniae in both in vitro and in vivo model systems [54][55][56][57][58]. Exposure of ciprofloxacin-susceptible and ciprofloxacin-resistant clinical isolates of S. aureus to clinically achievable ratios of AUC to MIC of delafloxacin and levofloxacin in a model simulating the PK of single and multiple doses of the 2 fluoroquinolones showed that delafloxacin was capable of producing greater anti-staphylococcal effects than levofloxacin at clinically achievable AUC/ MICs [54]. ...
... Probabilities were determined for delafloxacin doses of 200-450 mg given intravenously every 12 hours, revealing high percent probabilities of TA for MIC values ≤0.5 mg/L with intravenous and oral doses of 300 mg and 450 mg respectively, which were chosen for the Phase 3 studies [53]. Several studies have evaluated the comparative PD of delafloxacin versus other fluoroquinolones, mainly levofloxacin and ciprofloxacin, against multiple clinically relevant pathogens including S. aureus, E. coli, S. pneumoniae, and K. pneumoniae in both in vitro and in vivo model systems [54][55][56][57][58]. Exposure of ciprofloxacin-susceptible and ciprofloxacin-resistant clinical isolates of S. aureus to clinically achievable ratios of AUC to MIC of delafloxacin and levofloxacin in a model simulating the PK of single and multiple doses of the 2 fluoroquinolones showed that delafloxacin was capable of producing greater anti-staphylococcal effects than levofloxacin at clinically achievable AUC/ MICs [54]. Moreover, delafloxacin was more effective in the prevention of the selection of resistant mutants in S. aureus, as shown by appreciable differences in the clinically achievable AUC 24 /MIC ratios (for the same organism, delafloxacin was capable of reaching an AUC 24h /MIC ratio of 870 h, which significantly exceeded the protective value of 240 h, whereas levofloxacin achieved a value of only 70 h, which was considerably lower than its protective value of 200 h) [54]. ...
... Several studies have evaluated the comparative PD of delafloxacin versus other fluoroquinolones, mainly levofloxacin and ciprofloxacin, against multiple clinically relevant pathogens including S. aureus, E. coli, S. pneumoniae, and K. pneumoniae in both in vitro and in vivo model systems [54][55][56][57][58]. Exposure of ciprofloxacin-susceptible and ciprofloxacin-resistant clinical isolates of S. aureus to clinically achievable ratios of AUC to MIC of delafloxacin and levofloxacin in a model simulating the PK of single and multiple doses of the 2 fluoroquinolones showed that delafloxacin was capable of producing greater anti-staphylococcal effects than levofloxacin at clinically achievable AUC/ MICs [54]. Moreover, delafloxacin was more effective in the prevention of the selection of resistant mutants in S. aureus, as shown by appreciable differences in the clinically achievable AUC 24 /MIC ratios (for the same organism, delafloxacin was capable of reaching an AUC 24h /MIC ratio of 870 h, which significantly exceeded the protective value of 240 h, whereas levofloxacin achieved a value of only 70 h, which was considerably lower than its protective value of 200 h) [54]. Examination of the killing kinetics of E. coli and P. aeruginosa exposed to single and multiple doses of delafloxacin and ciprofloxacin at clinically achievable AUC/MIC ratios showed that the killing effect of delafloxacin on E. coli at its clinically achievable AUC/MIC ratio (1740 h) was significantly higher than that seen with ciprofloxacin at its clinically achievable AUC/MIC ratio (2200 h) [55]. ...
Fluoroquinolones have been in clinical use for over 50 years with significant efficacy. However, increasing resistance and emergence of some marked adverse events have limited their usage. The most recently approved class member, delafloxacin, is the only available anionic (non-zwitterionic) fluoroquinolone. Its unique molecular structure provides improved in vitro activity against most Gram-positive pathogens, including quinolone-resistant strains, which is further enhanced at acid pH. Delafloxacin shows favorable pharmacological properties, with about 60% bioavailability after oral administration, only mild inhibition of cytochrome P450 3A, and no evidence of cardiac- or phototoxicity in healthy volunteers (tested against positive controls). Its twice daily dosing, suitability for intravenous, oral, or switch dosing, the lack of many clinically significant drug-drug interactions, and acceptable adverse event profile in registration clinical trials supports its use in the treatment of acute bacterial skin and skin structure infections, and potentially in other infections, where resistance to other agents, safety, and/or the need for early discharge is of concern.
... This is well-verified in numerous studies. In fact a unimodal relationship between resistance emergence and drug concentration (often called an 'inverted-U' in the literature) is arguably the single-most robust finding in all of the empirical literature [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. ...
... Second, the position and shape of the hazard curve will vary widely among drugs and microbes, depending on how drug dose affects mutation rates and the strength of competition. Such wide variation is seen [23,24,28,29,35,38,39,42,43], presumably reflecting variation in the strength of the opposing processes highlighted by Eq (4). ...
... At the low end, increasing dose should increase resistance evolution; at the high end, increasing dose should decrease resistance evolution. Examples of both cases are readily seen, often even within the same study [15,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][44][45][46][47][48][49][50]. It is important to note that there are clear examples for which low-dose treatments can better prevent resistance emergence than high doses [15,39,42,[44][45][46][47][49][50][51], despite an inherent focus in the literature on experimental exploration of high-dose chemotherapy. ...
High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients.
... 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)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Such relationships have been reported with moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, the investigational fluoroquinolone ABÒ492, pazufloxacin, tosufloxacin, and garenoxacin against Staphylococcus aureus (6)(7)(8)(14)(15)(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). ...
... 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)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Such relationships have been reported with moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, the investigational fluoroquinolone ABÒ492, pazufloxacin, tosufloxacin, and garenoxacin against Staphylococcus aureus (6)(7)(8)(14)(15)(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 hypothesis (19,20). ...
... With each of three clinical isolates, the maximal amplification of mutants resistant to 4ϫ, 8ϫ, and 16ϫ MIC of ciprofloxacin was observed when antibiotic concentrations fell into the MSW for most of the dosing interval, and both AUC 24 /MIC and AUC 24 /MPC relationships with resistance expressed by the population analysis data (AUBC M ) or susceptibility testing (ratio of the postexposure MIC to preexposure MIC) were bell shaped. These observations are consistent with earlier findings reported in studies with fluoroquinolones (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). ...
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 inter-strain
predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) 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 AUC24/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 AUC24/MIC from 60 to 360 h (AUC24/MPC from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBCM) were bell-shaped. These relationships predict highly variable “anti-mutant” AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1310 to 2610 h). These findings suggest that the potential of the AUC24/MPC ratio as an inter-strain predictor of K. pneumoniae resistance is lower than AUC24/MIC.
... In this regard, dynamic models that mimic antimicrobial pharmacokinetics in vitro have been used to bridge the static determinations of MIC or MPC and the time-course of the antimicrobial effect at continuously changing drug concentrations. These models have been widely applied to human-use fluoroquinolones to describe drug exposures associated with the risk of resistance emergence in various species of bacteria (Zinner et al., 2003;Firsov et al., 2004;Olofsson et al., 2006). These studies have also established the relationship between pharmacokinetic-pharmacodynamic (PK-PD) indices, such as the area under the concentration-time curve (AUC)/MIC or AUC/MPC ratios, and development of resistance, as well as differing potential of fluoroquinolones in preventing selection of resistance. ...
... The MICs of enrofloxacin and marbofloxacin against E. coli strains isolated from dogs and a qualitycontrol strain (E. coli ATCC 25922) were determined in triplicate using the Clinical and Laboratory Standards Institute (CLSI) broth micro-dilution method (CLSI, 2002). The MPC was determined as described elsewhere (Dong et al., 2000;Firsov et al., 2004). Briefly, the Fluoroquinolone MPC and resistance in E. coli tested micro-organisms were cultured in Mueller-Hinton broth (MHB) and incubated for 24 h. ...
... In vitro dynamic model and simulated pharmacokinetic profiles. A previously described dynamic model (Zinner et al., 2003;Firsov et al., 2004) was used in this study. Single daily doses of marbofloxacin (half-life, 10 h) and twice daily doses of enrofloxacin (half-life, 4.5 h) administered every 12 h for 3 consecutive days were mimicked. ...
The antibacterial activity and selection of resistant bacteria, along with mechanisms of fluoroquinolone resistance, were investigated by integrating the static [MIC or mutant-prevention concentration (MPC)] and in vitro dynamic model approaches using Escherichia coli isolates from diseased dogs. Using the dynamic models, selected E. coli strains and enrofloxacin and marbofloxacin at a range of simulated area under concentration-time curve over a 24 h interval (AUC(24 h))/MIC ratios were investigated. Our results indicated increasing losses in susceptibility of E. coli upon continuous exposure to enrofloxacin and marbofloxacin in vitro. This effect was transferable to other fluoroquinolones, as well as to structurally unrelated drugs. Our results also confirmed an AUC(24 h)/MIC (AUC(24 h)/MPC)-dependent antibacterial activity and selection of resistant E. coli mutants, in which maximum losses in fluoroquinolone susceptibility occurred at simulated AUC(24 h)/MIC ratios of 40-60. AUC(24 h)/MPC ratios of 39 (enrofloxacin) and 32 (marbofloxacin) were considered protective against the selection of resistant mutants of E. coli. Integrating our MIC and MPC data with published pharmacokinetic information in dogs revealed a better effect of the conventional dosing regimen of marbofloxacin than that of enrofloxacin in restricting the selection of resistant mutants of E. coli. Target mutations, especially at codon 83 (serine to leucine) of gyrA, and overexpression of efflux pumps contributed to resistance development in both clinically resistant and in vitro-selected mutants of E. coli. We also report here a previously undescribed mutation at codon 116 of parC in two laboratory-derived resistant mutants of E. coli. Additional studies would determine the exact role of this mutation in fluoroquinolone susceptibility, as well as establish the importance of our findings in the clinical setting.
... The hypothesis of the mutant selection window (MSW), that is the concentration range from the MIC to the mutant prevention concentration (MPC), within which it is proposed that resistant mutants are enriched or selected 1 has passed the test successfully with Staphylococcus aureus [2][3][4][5][6] and Streptococcus pneumoniae 7 exposed to fluoroquinolones in dilution 2,4-6 and hollow-fibre in vitro models. 3,7 Despite the use of different dynamic models, the most pronounced loss in susceptibility of antibiotic-exposed organisms and the enrichment of resistant mutants were reported over a comparable range of simulated ratios of 24 h area under the concentration-time curve (AUC 24 ) to MIC (from 25 to 100-150 h), when antibiotic concentrations fell into the MSW for most of the dosing interval. ...
... The MSW hypothesis was shown to be relevant to the studied lipopeptide and glycopeptide antibiotics: both selection of organisms resistant to 2· and 4· MIC of daptomycin or vancomycin and decreased susceptibility of staphylococci occurred at antibiotic concentrations that fell into the MSWs. Antibiotic-and bacterial strain-independent bell-shaped relationships between MIC final /MIC initial and AUC 24 /MIC were similar to those reported in in vitro studies with fluoroquinolones [5][6][7] although AUC 24 /MIC plots of resistance of S. aureus to daptomycin and vancomycin were more scattered. However, maximal enrichment of resistant mutants and significant loss in susceptibility of daptomycin-or vancomycin-exposed S. aureus were observed at AUC 24 /MIC ratios (30-60 h) that are comparable with those reported with the fluoroquinolones and S. aureus: from 25 to 100 h 6 and from 30 to 150 h 3 for ciprofloxacin, from 25 to 100 h for gatifloxacin, 4,6 levofloxacin 5,6 and moxifloxacin 6 and from 60 to 120 h for ABT-492, 5 but not with findings reported in a recent study with levofloxacin-exposed staphylococci, 15 where the enrichment of resistant mutants was observed only at an AUC 24 /MIC of 30 h but not at 60 h. ...
... Antibiotic-and bacterial strain-independent bell-shaped relationships between MIC final /MIC initial and AUC 24 /MIC were similar to those reported in in vitro studies with fluoroquinolones [5][6][7] although AUC 24 /MIC plots of resistance of S. aureus to daptomycin and vancomycin were more scattered. However, maximal enrichment of resistant mutants and significant loss in susceptibility of daptomycin-or vancomycin-exposed S. aureus were observed at AUC 24 /MIC ratios (30-60 h) that are comparable with those reported with the fluoroquinolones and S. aureus: from 25 to 100 h 6 and from 30 to 150 h 3 for ciprofloxacin, from 25 to 100 h for gatifloxacin, 4,6 levofloxacin 5,6 and moxifloxacin 6 and from 60 to 120 h for ABT-492, 5 but not with findings reported in a recent study with levofloxacin-exposed staphylococci, 15 where the enrichment of resistant mutants was observed only at an AUC 24 /MIC of 30 h but not at 60 h. ...
To extend the mutant selection window (MSW) hypothesis to include antibiotics in addition to fluoroquinolones, the pharmacodynamics of daptomycin (DAP) and vancomycin (VAN) and their ability to prevent the selection of resistant Staphylococcus aureus were studied in an in vitro model that simulates antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC.
Two clinical isolates of S. aureus, S. aureus 866 (MIC(DAP) 0.35, MIC(VAN) 0.7, MPC(DAP) 1.1, MPC(VAN) 2.4 mg/L) and S. aureus 10 (MIC(DAP) 1.1, MIC(VAN) 1.3, MPC(DAP) 5.5, MPC(VAN) 11 mg/L), were exposed for five consecutive days to once-daily daptomycin (half-life 9 h) and twice-daily vancomycin (half-life 6 h) at the ratio of 24 h area under the concentration-time curve (AUC24) to MIC that varied over a 16- to 30-fold range. The cumulative antimicrobial effect was expressed by its intensity (I(E)). Changes in susceptibility and numbers of surviving organisms on agar plates containing 2x and 4x MIC of daptomycin or vancomycin were monitored daily.
The I(E)-log AUC24/MIC plots were bacterial strain- and antibiotic-independent. This allowed combination of data obtained with both antibiotics and both organisms. Based on the sigmoid relationship between I(E) and the AUC24/MIC (r2 = 0.9), the antistaphylococcal effect of the therapeutic doses of daptomycin (4 and 6 mg/kg) against a hypothetical S. aureus with MIC equal to the MIC90 (AUC24/MIC90 380 and 570 h, respectively) was predicted to be similar to the effect of two 1 g doses of vancomycin given at a 12 h interval (AUC24/MIC90 200 h). AUC24/MIC relationships of the final-to-initial MIC ratio and logarithm of the ratio of maximal-to-initial numbers of organisms resistant to 2x and 4x MIC of daptomycin or vancomycin were bell-shaped and bacterial strain- and antibiotic-independent. Based on these relationships, an AUC24/MIC ratio that protects against the selection of resistant mutants was predicted at > or = 200 h. This protective value is less than the AUC24/MIC90s provided by the 4 mg/kg dose and considerably less than the 6 mg/kg dose of daptomycin, but it is close to the AUC24/MIC90 provided by two 1 g doses of vancomycin.
These findings support the MSW hypothesis and suggest comparable antistaphylococcal effects of clinically achievable AUC24/MIC90s of daptomycin and vancomycin but slightly better prevention against the selection of resistant S. aureus by daptomycin.
... We define π as the 26 probability of avoiding loss (which we refer to as 'escape'). To simplify the present 27 analysis, we use a separation of timescales argument and assume that the fate of each 28 mutant is determined quickly (essentially instantaneously) relative to the dynamics of the 29 wild type and host state (we relax this assumption in all numerical examples). Thus, π for 30 any mutant will depend on the host state at the time of its appearance, x(t; c), and it will 31 therefore depend indirectly on c. ...
... Second, the position and shape of the hazard curve will vary widely among drugs and 331 microbes, depending on how drug dose affects mutation rates and the strength of 332 competition. Such wide variation is seen (e.g., 22, 23,27,28,34,37,38,41,42), presumably 333 reflecting variation in the strength of the opposing processes highlighted by equation(4).334 Third, the relationship found between drug concentration and resistance evolution in any 335 empirical study will depend on the range of concentrations explored. ...
High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical and theoretical studies have begun to challenge this view. We show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose always lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and greatly simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients.
... 7 Similar bell curves were observed with moxifloxacin-exposed Streptococcus pneumoniae, 2 garenoxacin-exposed Klebsiella pneumoniae 7 and enrofloxacin-and marbofloxacin-exposed Escherichia coli. 10 This pattern of AUC/MIC relationships with resistance is in concordance with the hypothesis of the mutant selection window (MSW), which predicts the selection of resistant mutants at antibiotic concentrations above the MIC and below the mutant prevention concentration (MPC). 11 Based on the AUC-resistance relationships, anti-mutant AUC/MIC ratios, i.e. the AUC/MICs required to prevent amplification and/or inhibit resistant mutants, were predicted in in vitro studies with fluoroquinolone-exposed Staphylococcus aureus, 1,3,7 S. pneumoniae, 2 K. pneumoniae 7 and E. coli. 10 Also, surrogate relationships that describe only the descending portion of the bell-shaped AUC/MIC-resistance curve have been used to compare the anti-mutant potentials of different ciprofloxacin dosing regimens. 12,13 A similar design was used in the present study to compare AUC/MIC-resistance relationships with Pseudomonas aeruginosa exposed to doripenem, a novel carbapenem antibiotic, and ciprofloxacin in an in vitro dynamic model. ...
... Previously, we reported pharmacokinetic profile-dependent differences in AUC 24 /MIC -resistance curves observed with levofloxacin and an investigational fluoroquinolone, ABT-492. 3 The impact of the shape of simulated pharmacokinetic profiles on fluoroquinolone pharmacodynamics has been reported in in vitro studies with S. aureus. 20 Unlike P. aeruginosa 8996 and 8997, AUC/MIC relationships of the AUBC M with P. aeruginosa 14051 exposed to doripenem and ciprofloxacin were virtually superimposed (Figure 3 Zinner et al. ...
Objectives:
To compare the abilities of doripenem and ciprofloxacin to restrict the enrichment of resistant Pseudomonas aeruginosa, multiple antibiotic dosing regimens were simulated in an in vitro model at comparable ratios of the 24 h AUC (AUC24) to the MIC.
Methods:
Three clinical isolates of ciprofloxacin-resistant P. aeruginosa (MIC of doripenem 1 mg/L, MIC of ciprofloxacin 4 mg/L) were exposed to thrice-daily doripenem or twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios from 50 to 170 h (doripenem) and from 55 to 180 h (ciprofloxacin).
Results:
Doripenem- and ciprofloxacin-resistant mutants were enriched at antibiotic concentrations that fell into the mutant selection window for ≥ 45% and ≥ 60% of the dosing interval, respectively. The anti-mutant effects of doripenem and ciprofloxacin expressed by the area under the bacterial mutant concentration-time curve (AUBCM) depended on the AUC24/MIC ratio, and the AUBCM-log AUC24/MIC relationships were antibiotic specific.
Conclusion:
Based on AUC24/MIC relationships with AUBCM, a greater anti-mutant potential was predicted for doripenem compared with ciprofloxacin.
... These including Streptococcus pneumoniae, Etienne et al., 2004;Negri et al., 1994;Zinner et al., 2003) Staphylococcus aureus, (Cui et al., 2006;Firsov et al., 2006Firsov et al., , 2004Firsov et al., , 2003Zhu et al., 2012) Mycobacterium tuberculosis, (Gumbo et al., 2007(Gumbo et al., , 2004) P. ...
Healthcare-associated infections are caused by a diversity of pathogenic micro-organisms, which together represent leading causes of global infectious disease morbidity and mortality. The objective of this thesis was to develop novel mathematical models to evaluate the transmission dynamics of antibiotic-resistant bacteria and SARS-CoV-2 in healthcare settings, and to provide evidence for the design and optimization of species-specific surveillance and control interventions. First, a modelling framework for the hospital epidemiology of antibiotic-resistant bacteria was formalized. This framework accounts for within-host mechanisms of ecological interaction between the host microbiome and bacterial pathogens in the context of antibiotic exposure. Microbiome-pathogen interactions, including microbiome-induced colonization resistance and the interspecific horizontal transfer of antibiotic resistance genes, were found to underlie trade-offs in how antibiotics select for the epidemiological spread of resistance. In a simulation study using this framework, contact precautions were effective for prevention of colonization with methicillin-resistant Staphylococcus aureus but not multidrug-resistant Enterobacteriaceae, while antibiotic stewardship interventions and microbiome-targeted therapies were broadly effective across species. Second, simulations from an individual-based SARS-CoV-2 transmission model were used to inform optimization of testing and screening interventions in long-term care facilities. In an early pandemic context, group testing (sample pooling) was the most efficient means to detect emerging outbreaks in resource-limited facilities, while hierarchical testing cascades were most effective given high testing capacity. In a later pandemic context, population screening using rapid antigen diagnostic testing was an effective but time-sensitive means to prevent nosocomial transmission. Overall, work from this thesis represents a first step in understanding how the microbiome influences nosocomial transmission risk of antibiotic resistance, and provides evidence for optimizing SARS-CoV-2 surveillance in the context of limited and imperfect testing resources.
... The predictive anti-mutant potential of T >MPC against both Gram-positive and Gram-negative organisms has been confirmed previously in in vitro and in vivo pharmacodynamic experiments with several antibacterial classes (fluoroquinolones, [39][40][41][42][43] b-lactams, 44,45 fosfomycin 46 and linezolid 47,48 ). Also, the reliability of T >MPC as a predictor of anti-mutant effects of antibiotic combinations against staphylococci was confirmed in a study with linezolid plus rifampicin, where the approach for determining MPCs of combinations at pharmacokinetically derived antibiotic concentration ratios was first introduced. ...
Objectives:
To explore whether linezolid/daptomycin combinations can restrict Staphylococcus aureus resistance and if this restriction is associated with changes in the mutant prevention concentrations (MPCs) of the antibiotics in combination, the enrichment of resistant mutants was studied in an in vitro dynamic model.
Methods:
Two MRSA strains, vancomycin-intermediate resistant ATCC 700699 and vancomycin-susceptible 2061 (both susceptible to linezolid and daptomycin), and their linezolid-resistant mutants selected by passaging on antibiotic-containing medium were used in the study. MPCs of antibiotics in combination were determined at a linezolid-to-daptomycin concentration ratio (1:2) that corresponds to the ratio of 24 h AUCs (AUC24s) actually used in the pharmacokinetic simulations. Each S. aureus strain was supplemented with respective linezolid-resistant mutants (mutation frequency 10-8) and treated with twice-daily linezolid and once-daily daptomycin, alone and in combination, simulated at therapeutic and sub-therapeutic AUC24s.
Results:
Numbers of linezolid-resistant mutants increased at therapeutic and sub-therapeutic AUC24s, whereas daptomycin-resistant mutants were enriched only at sub-therapeutic AUC24 in single drug treatments. Linezolid/daptomycin combinations prevented the enrichment of linezolid-resistant S. aureus and restricted the enrichment of daptomycin-resistant mutants. The pronounced anti-mutant effects of the combinations were attributed to lengthening the time above MPC of both linezolid and daptomycin as their MPCs were lowered.
Conclusions:
The present study suggests that (i) the inhibition of S. aureus resistant mutants using linezolid/daptomycin combinations can be predicted by MPCs determined at pharmacokinetically derived antibiotic concentration ratios and (ii) T>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations as studied using in vitro dynamic models.
... Combining all factors, the adopted schematic view is that the probability of resistance emergence follows an inverted U-curve [5,[18][19][20][21][22][23][24][25][26] (but more complicated shapes are conceivable): for very low doses, there is no selection for resistance, and for very high doses, resistance is either unlikely due to a large genetic barrier or even physiologically impossible. Kouyos et al. (2014) and Day and Read (2016) argue that, eventually, the range of the therapeutic window determines whether a harsh or a mild treatment is best to mitigate the evolution of resistance [5,12]. ...
Antimicrobial resistance is one of the major public health threats of the 21 st century. There is a pressing need to adopt more efficient treatment strategies in order to prevent the emergence and spread of resistant strains. The common approach is to treat patients with high drug doses, both to clear the infection quickly and to reduce the risk of de novo resistance. Recently, several studies have argued that, at least in some cases, low-dose treatments could be more suitable to reduce the within-host emergence of antimicrobial resistance. However, the choice of a drug dose may have consequences at the population level, which has received little attention so far.
Here, we study the influence of the drug dose on resistance and disease management at the host and population levels. We develop a nested two-strain model and unravel trade-offs in treatment benefits between an individual and the community. We use several measures to evaluate the benefits of any dose choice. Two measures focus on the emergence of resistance, at the host level and at the population level. The other two focus on the overall treatment success: the outbreak probability and the disease burden. We find that different measures can suggest different dosing strategies. In particular, we identify situations where low doses minimize the risk of emergence of resistance at the individual level, while high or intermediate doses prove most beneficial to improve the treatment efficiency or even to reduce the risk of resistance in the population.
Author summary
The obvious goals of antimicrobial drug therapy are rapid patient recovery and low disease prevalence in the population. However, achieving these goals is complicated by the rapid evolution and spread of antimicrobial resistance. A sustainable treatment strategy needs to account for the risk of resistance and keep it in check. One parameter of treatment is the drug dosage, which can vary within certain limits. It has been proposed that lower doses may, in some cases, be more suitable than higher doses to reduce the risk of resistance evolution in any one patient. However, if lower doses prolong the period of infectiousness, such a strategy has consequences for the pathogen dynamics of both strains at the population level. Here, we set up a nested model of within-host and between-host dynamics for an acute self-limiting infection. We explore the consequences of drug dosing on several measures of treatment success: the risk of resistance at the individual and population levels and the outbreak probability and the disease burden of an epidemic. Our analysis shows that trade-offs may exist between optimal treatments under these various criteria. The criterion given most weight in the decision process ultimately depends on the disease and population under consideration.
... Delafloxacin possesses a broad spectrum of activity that includes MRSA, Enterobacteriaceae, and Pseudomonas aeruginosa [4][5][6]. Because delafloxacin targets both DNA gyrase and topoisomerase IV, the development of resistance requires multiple mutations, and a favorable area under the curve to minimum inhibitory concentration (MIC) ratio is achieved [7][8][9]. As such, susceptibility and clinical response are demonstrable in clinical MRSA isolates resistant to other fluoroquinolones [5,10]. ...
Delafloxacin is an option for infections due to methicillin-resistant Staphylococcus aureus. In 2017, 22% of isolates from seven hospitals in Brooklyn, NY were nonsusceptible to delafloxacin. Isolates belonging to ST105, a strain associated with healthcare-related infections, predominated. Resistance was also found in ST8, a strain (USA300) associated with community-associated infections.
... Combining all factors, the adopted schematic view is that the probability of resistance emergence follows an inverted U-curve [5,[18][19][20][21][22][23][24][25][26] (but more complicated shapes are conceivable): for very low doses, there is no selection for resistance, and for very high doses, resistance is either unlikely due to a large genetic barrier or even physiologically impossible. Kouyos et al. (2014) and Day and Read (2016) argue that, eventually, the range of the therapeutic window determines whether a harsh or a mild treatment is best to mitigate the evolution of resistance [5,12]. ...
Antimicrobial resistance is one of the major public health threats of the 21st century. There is a pressing need to adopt more efficient treatment strategies in order to prevent the emergence and spread of resistant strains. The common approach is to treat patients with high drug doses, both to clear the infection quickly and to reduce the risk of de novo resistance. Recently, several studies have argued that, at least in some cases, low-dose treatments could be more suitable to reduce the within-host emergence of antimicrobial resistance. However, the choice of a drug dose may have consequences at the population level, which has received little attention so far. Here, we study the influence of the drug dose on resistance and disease management at the host and population levels. We develop a nested two-strain model and unravel trade-offs in treatment benefits between an individual and the community. We use several measures to evaluate the benefits of any dose choice. Two measures focus on the emergence of resistance, at the host level and at the population level. The other two focus on the overall treatment success: the outbreak probability and the disease burden. We find that different measures can suggest different dosing strategies. In particular, we identify situations where low doses minimize the risk of emergence of resistance at the individual level, while high or intermediate doses prove most beneficial to improve the treatment efficiency or even to reduce the risk of resistance in the population.
... The genome sequence of HG001 is of high quality. For the single step resistance assay (Firsov et al., 2004;Ling et al., 2015), S. aureus with inoculum of 10 10 CFU/ml was plated on TSA plates containing 2.5×, 5×, 10× MIC PPAP 23 and incubated at 37 • C for 48 h before the examination of the colonies. For the sequential passaging, overnight culture of S. aureus HG001 was diluted to OD 578 of 0.02 in 2.5 mL TSB containing 0.5× MIC PPAP. ...
Recently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of its bactericidal profiles and mode of action. PPAP 23 showed a better efficacy in killing methicillin resistant Staphylococcus aureus (MRSA) and decreasing the metabolic activity of 5-day-old biofilm cells than vancomycin. Moreover, S. aureus did not appear to develop resistance against PPAP 23. The antimicrobial mechanism of PPAP 23 was investigated by RNA-seq combined with phenotypic and biochemical approaches. RNA-seq suggested that PPAP 23 signaled iron overload to the bacterial cells because genes involved in iron transport were downregulated and iron storage gene was upregulated by PPAP 23. PPAP 23 affected the membrane integrity but did not induce pore formation; it inhibited bacterial respiration. PPAP 23 preferentially inhibited Fe–S cluster enzymes; it has a mild iron chelating activity and supplementation of exogenous iron attenuated its antimicrobial activity. PPAP 23 was more effective in inhibiting the growth of S. aureus under iron-restricted condition. The crystal structure of a benzylated analog of PPAP 23 showed a highly defined octahedral coordination of three PPAP ligands around a Fe (3+) core. This suggests that PPAPs are generally capable of iron chelation and are able to form defined stable complexes. PPAP 23 was found to induce reactive oxygen species (ROS) and oxidative stress. Fluorescence microscopic analysis showed that PPAP 23 caused an enlargement of the bacterial cells, perturbed the membrane, and dislocated the nucleoid. Taken together, we postulate that PPAP 23 interacts with the cytoplasmic membrane with its hydrophobic pocket and interferes with the iron metabolism to exert its antimicrobial activity in Staphylococcus aureus.
... The minimum protective concentration in the present study ranged from one to four times the initial MIC for all quinolones tested. Delafloxacin-resistant mutants maintained their reduced susceptibility following passage in drug-free media for 7 days, suggesting a stable phenotype [8,46]. ...
Delafloxacin (formerly WQ-3034, ABT492, RX-3341) is a novel fluoroquinolone chemically distinct from currently marketed fluoroquinolones with the absence of a protonatable substituent conferring a weakly acidic character to the molecule. This property results in increased intracellular penetration and enhanced bactericidal activity under acidic conditions that characterize the infectious milieu at a number of sites. The enhanced potency and penetration in low pH environments contrast what has been observed for other zwitterionic fluoroquinolones, which tend to lose antibacterial potency under acidic conditions, and may be particularly advantageous against methicillin-resistant Staphylococcus aureus, for which the significance of the intracellular mode of survival is increasingly being recognized. Delafloxacin is also unique in its balanced target enzyme inhibition, a property that likely explains the very low frequencies of spontaneous mutations in vitro. Delafloxacin recently received US Food and Drug Administration approval for the treatment of acute bacterial skin and skin structure infections and is currently being evaluated in a phase 3 trial among patients with community-acquired pneumonia. In the current era of a heightened awareness pertaining to collateral ecologic damage, safety issues and antimicrobial stewardship principles, it is critical to describe the unique properties of delafloxacin and define its potential role in therapy. The purpose of this article is to review available data pertaining to delafloxacin’s biochemistry, pharmacokinetic/pharmacodynamics characteristics, in vitro activity and potential for resistance selection as well as current progress in clinical trials to ultimately assist clinicians in selecting patients who will benefit most from the distinctive properties of this agent.
... 15 The ability of delafloxacin to retain susceptibility against GP bacteria compared with other FQs is hypothesized to be driven by the drug's molecular shape, polarity and dual-targeting activity. 13 Delafloxacin has shown to have lower mutant prevention concentrations compared with other FQs in isolates of S. aureus, 13,22 S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. 23 Despite this, delafloxacin resistance has been shown to emerge in vitro in previously delafloxacinsusceptible, FQ-resistant MRSA isolates. ...
Delafloxacin is a novel anionic fluoroquinolone (FQ) approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by a number of Gram-positive and Gram-negative organisms including MRSA and Pseudomonas aeruginosa. The unique chemical structure of delafloxacin renders it a weak acid and results in increased potency in acidic environments. In Phase III studies, delafloxacin had similar outcomes to comparator regimens for treatment of ABSSSIs, and was well tolerated overall. Similar to other FQs, delafloxacin is available in both intravenous and oral formulations, but differs in that delafloxacin exerts a minimal effect on cytochrome P450 enzymes and on the corrected QT interval. This novel FQ has the potential to be utilized across a wide variety of clinical settings; however, post-marketing surveillance and long-term safety and resistance data will be essential to identify optimal use scenarios.
... 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]. ...
To explore if the time inside the mutant selection window (TMSW) is a reliable predictor of emergence of bacterial resistance to linezolid, mixed inocula of each of three methicillin-resistant Staphylococcus aureus strains (MIC of linezolid 2 μg ml−1) and their previously selected resistant mutants (MIC 8 μg ml−1) were exposed to linezolid pharmacokinetics using an in vitro dynamic model. In five-day treatments simulated over a wide range of the 24-h area under the concentration–time curve (AUC24) to the MIC ratio, mutants resistant to 4 × MIC of antibiotic were enriched in a TMSW-dependent manner. With each strain, TMSW relationships with the area under the bacterial mutant concentration–time curve (AUBCM) exhibited a hysteresis loop, with the upper portion corresponding to the time above the mutant prevention concentration (MPC; T>MPC) of 0 and the lower portion—to the T>MPC > 0. Using AUBCM related to the maximal value observed with a given strain (normalized AUBCM) at T>MPC > 0, a strain-independent sigmoid relationship was established between AUBCM and TMSW, as well as T>MPC (r2 0.99 for both). AUC24/MIC and AUC24/MPC relationships with normalized AUBCM for combined data on the three studied S. aureus strains were bell-shaped (r2 0.85 and 0.80, respectively). These findings suggest that TMSW at T>MPC > 0, T>MPC, AUC24/MIC and AUC24/MPC are useful bacterial strain-independent predictors of the emergence of staphylococcal resistance to linezolid.
... 14,15 In animal models, DLX has been shown to reach these parameters against S. aureus, S. pneumoniae, Escherichia coli and P. aeruginosa. 21,[37][38][39] ...
Francisco Javier Candel, Marina Peñuelas Department of Clinical Microbiology and Infectious Diseases, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Universidad Complutense, Madrid, Spain Abstract: Delafloxacin (DLX) is a new fluoroquinolone pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with skin and soft tissue infections and community-acquired respiratory tract infections. DLX also shows good activity against a broad spectrum of microorganisms, including those resistant to other fluoroquinolones, as methicillin-resistant Staphylococcus aureus. Its pharmacokinetic properties and excellent activity in acidic environments make DLX an alternative in the treatment of these and other infections. In this manuscript, a detailed analysis of this new fluoroquinolone is performed, from its chemical structure to its in vivo activity in recently published clinical trials. Its possible place in the current antimicrobial outlook and in other infectious models is also discussed. Keywords: Delafloxacin, fluoroquinolones, methicillin-resistant Staphylococcus aureus, therapy
... Bell-shaped curves that reflect concentration -resistance relationships are associated with fluoroquinolone studies using in vitro dynamic models. 1 -8 Some of these studies examined changes in susceptibility of antibiotic-exposed Staphylococcus aureus and/or their enrichment with resistant mutants depending on the ratio of 24 h AUC (AUC 24 ) to the MIC. 1,2,4,6 The emergence of staphylococcal resistance was observed in the first such study 1 at fluoroquinolone concentrations above the MIC but below the mutant prevention concentration (MPC), i.e. inside the mutant selection window (MSW) 9,10 but not outside the MSW. In fact, the bell-shaped response had been a puzzle that was explained by the MSW hypothesis. ...
Objectives:
To examine the predictive power of the ratios of the 24 h AUC (AUC24) to the mutant prevention concentration (MPC) and the MIC, the selection of ciprofloxacin-resistant mutants of Pseudomonas aeruginosa was studied in an in vitro dynamic model.
Methods:
Four clinical isolates of P. aeruginosa with MPC/MIC ratios from 5.6 to 32 were exposed to twice-daily ciprofloxacin for 3 days over a 100- to 200-fold range of the AUC24/MIC ratio.
Results:
The emergence of P. aeruginosa resistance to ciprofloxacin was concentration dependent: mutants resistant to 2-16 × MIC were enriched at antibiotic concentrations between the MIC and MPC, but not at concentrations below the MIC or above the MPC. Both AUC24/MIC and AUC24/MPC relationships with the area under the bacterial mutant concentration-time curve (AUBCM) were bell-shaped. These relationships predict highly variable 'anti-mutant' AUC24/MIC and AUC24/MPC ratios: e.g. with mutants resistant to 2 × MIC the ratios ranged from 220 to 1100 and from 7 to 180 h, respectively. Using combined data for the four studied organisms, correlations between AUBCM and AUC24/MIC or AUC24/MPC were established (r(2) = 0.75 and 0.65, respectively). Much stronger correlation was observed between AUC24/MIC and the area between the cut-off level at 10(8) cfu/mL and the time-kill curve (ABBC) as an integral index of the antimicrobial effect of ciprofloxacin on the parental strains (r(2) = 0.93).
Conclusions:
Findings obtained with ciprofloxacin-exposed P. aeruginosa are consistent with the mutant selection window hypothesis. AUC24/MIC and AUC24/MPC relationships with resistance were more bacterial strain specific than AUC24/MIC relationships with fluoroquinolone-induced killing of susceptible cells.
... The MSW model has been extremely influential and has been subjected to numerous empirical tests, particularly in bacteria [23][24][25][26][27][28][29][30][31][32][33]. It is worth noting, however, that although this terminology is ingrained in the literature it is technically incorrect. ...
The emergence of drug-resistant pathogens is often considered a canonical case of evolution by natural selection. Here we argue that the strength of selection can be a poor predictor of the rate of resistance emergence. It is possible for a resistant strain to be under negative selection and still emerge in an infection or spread in a population. Measuring the right parameters is a necessary first step toward the development of evidence-based resistance-management strategies. We argue that it is the absolute fitness of the resistant strains that matters most and that a primary determinant of the absolute fitness of a resistant strain is the ecological context in which it finds itself.
Copyright © 2015 Elsevier Ltd. All rights reserved.
... 36,60,63,64 The argument has been mostly tested in in vitro studies for quinolones where the mutantrestrictive thresholds of AUC 0-24 /MPC were approximately one-third of those AUC 0-24 /MIC values. 39, 65 The MPC has been described mostly for quinolones, although data for other classes of antibiotics are emerging. 60,66,67 Quantifying MPC thresholds for individual antibiotics should be one of the priorities in the development of dosing guidelines especially earlier in the process of evaluation and screening of new compounds. ...
The recent surge in multidrug-resistant pathogens combined with the diminishing antibiotic pipeline has created a growing need to optimize the use of our existing antibiotic armamentarium, particularly in the management of intensive care unit (ICU) patients. Optimal and timely pharmacokinetic/pharmacodynamic (PK/PD) target attainment has been associated with an increased likelihood of clinical and microbiological success in critically ill patients. Emerging data, mostly from in vitro and in vivo studies, suggest that optimization of antibiotic therapy should not only aim to maximize clinical outcomes but also to include the suppression of resistance. The development of antibiotic dosing regimens that adheres to the PK/PD principles may prolong the clinical lifespan of our existing antibiotics by minimizing the emergence of resistance. This article summarizes the relevance of PK/PD characteristics of different antibiotic classes on the development of antibiotic resistance. On the basis of the available data, we propose dosing recommendations that can be adopted in the clinical setting, to maximize therapeutic success and limit the emergence of resistance in the ICU.
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... Проведенные исследования продемонстрировали селекцию устойчивых мутантов S. aureus при режимах введения ципрофлоксацина, моделирующих его уровни внутри ОСМ. Этот результат согла-суется с данными, полученными с фторхинолонами ранее [1,3,[14][15][16][17], что можно рассматривать как еще одно подтверждение применимости концепции ОСМ [6]. Вместе с тем, в отличие от описанных в цитируемых работах взаимосвязей между резистентностью и ПФК 24 24 /МПК М (r 2 = 0,88-0,97) в отличие от довольно слабых корреляций между AUBC М и ПФК 24 /МПК (r 2 0,33-0,49). ...
24 /МПК и ПФК 24 /МПК М исследовали процессы селекции резистентных мутантов метициллиноустойчи-вых штаммов Staphylococcus aureus ATCC 43300 и ATCC 6538, для которых отношения МПК М к МПК резко различаются (4 и 16 соответственно). В динамической системе in vitro были смодели-рованы такие фармакокинетические профили, при которых уровни ципрофлоксацина находи-лись в пределах ОСМ на протяжении большей части интервала дозирования. Рост резистент-ных мутантов S. aureus АТСС 43300 наблюдался при отношениях ПФК 24 /МПК, составляющих 30, 72 и 100 ч; время, на протяжении которого кон-центрация ципрофлоксацина находилась внутри ОСМ (Т ОСМ) – 56–63% интервала дозирования. Селекция мутантов S. aureus АТСС 6538 проис-ходила при отношениях ПФК 24 /МПК, равных 48, 140 и 260 ч (Т ОСМ – 75–100%). Применительно к каждому штамму она начиналась тем раньше, чем ниже было моделируемое отношение ПФК 24 / МПК. При этом величина AUBC M (площадь под кривой изменения численности устойчивых кле-ток) систематически снижалась по мере повы-шения моделируемого значения ПФК 24 /МПК. Несмотря на то что резистентность индивиду-ального штамма можно прогнозировать как по значениям ПФК 24 /МПК, так и по ПФК 24 /МПК М , взаимосвязь между развитием резистентности и ПФК 24 /МПК М , но не ПФК 24 /МПК, была инвари-антной относительно бактериального штамма. Так, при объединении данных, полученных со штаммами S. aureus ATCC 43300 и ATCC 6538, установлена четкая корреляция между AUBC M и логарифмом ПФК 24 /МПК М . Для мутантов, устой-чивых к 2×, 4× и 8×МПК ципрофлоксацина, зна-чения r 2 были значительно выше (0,88, 0,96 и 0,97 соответственно), чем для корреляций между AUBC M и логарифмом ПФК 24 /МПК (0,33 – 0,49). По результатам данного исследования можно заключить, что прогноз развития резистентно-сти по величине ПФК 24 /МПК М надежнее, чем по ПФК 24 /МПК. Ключевые слова: Staphylococcus aureus, резистентность, ципрофлоксацин, динамическая система in vitro.
... Since the mutant selection window is defined with static drug concentrations, either using agar plates [104] or using large volumes of liquid medium [142], it was important to determine how well the static boundaries apply when drug concentrations fluctuate. Measurements with in vitro dynamic models show that the window can be observed with fluctuating antimicrobial concentrations for fluoroquinolones, vancomycin, and daptomycin [143][144][145][146][147][148][149][150][151][152]. It is also readily seen in rabbits infected with S. aureus and treated with levofloxacin [153]; in both cases, static data fit well with dynamic measurements. ...
Fluoroquinolones trap gyrase and topoisomerase IV on DNA as ternary complexes that block the movement of replication forks and transcription complexes. Studies with resistant mutants indicate that resistance is due to alterations in drug permeability, drug efflux, gyrase-protecting proteins, drug-modifying enzymes, and target topoisomerases. Emergence (acquisition) of resistance is thought to arise when fluoroquinolone concentration falls inside a range in which resistant mutant subpopulations are selectively enriched and amplified. The lower boundary of the range (mutant selection window) is approximated by the minimal inhibitory concentration (MIC) of the bulk, susceptible population. The upper boundary is the MIC of the least susceptible resistant mutant subpopulation, a value called the mutant prevention concentration (MPC). MPC varies among fluoroquinolones and pathogens; when combined with pharmacokinetics, MPC can be used to compare compounds and dosing regimens for selective amplification of mutant subpopulations. Batteries of resistant mutants can be used to identify compounds that have a very narrow selection window and are likely to restrict the emergence of resistance. While most of the concepts behind the emergence of quinolone resistance are based on chromosomal mutations, plasmid-borne resistance also occurs. Thus studies of quinolones can address most aspects of antibiotic resistance.
... Thus, there is an inverse relationship between the efficacy of an antibiotic and the resistance induction potential of an antibiotic 103 . For several micro-organisms and antimicrobials the area under the curve of the unbound fraction over MIC (fAUC/MIC) has been investigated in the prediction of selecting resistant organisms [104][105][106][107] . However, since there are no data on prevention of resistance in GBS, dosing regimens used in the prevention of GBS-EOD can not be judged on their potential to select resistant organisms. ...
Groep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle zwangeren toegediend. Ondanks de toediening van antibiotica worden er soms kinderen ziek. Onderzoek naar de farmacokinetiek (lotgevallen van geneesmiddelen in het lichaam) en de huidige dosering van deze antibiotica tijdens de bevalling werd nog niet eerder verricht. Antibiotica zoals amoxicilline en clindamycine, die tijdens de bevalling worden toegediend, moeten bij de moeder een voldoende tijd een werkzame bloedspiegel hebben, de moederkoek passeren en ook bij het kind een voldoende tijd een werkzame bloedspiegel bereiken. Uit ons onderzoek blijkt, dat voor amoxicilline de farmacokinetiek bij vrouwen met gebroken vliezen voor aanvang van de bevalling vergelijkbaar is met die bij niet-zwangeren. Verschillende situaties bleken geen invloed te hebben op de farmacokinetiek van amoxicilline. Wanneer gebruik wordt gemaakt van een farmacokinetisch computermodel, waarin de bloedspiegels van amoxicilline van moeder, de navelstreng en het kind verwerkt zijn, lijkt de begin dosis van 2 gram amoxicilline afdoende voor het voorkomen van GBS-ziekte. Doseringen penicilline G die gebruikt worden voor de behandeling van GBS-ziekte bij vroegtijdig geboren kinderen zijn ook afdoende. Over clindamycine kunnen geen definitieve conclusies getrokken worden.
... Since the mutant selection window was derived from static measurements, either with agar plates [110] or with large volumes of liquid medium [111], it was important to determine whether the window also exists when drug concentrations fluctuate. Measurements with in vitro dynamic models show that the window can be observed with fluctuating antimicrobial concentrations for fluoroquinolones , vancomycin, and daptomycin112113114115116117118119120121. It is also readily seen in rabbits infected with S. aureus and treated with levofloxacin [122]. ...
The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.
... Enrichment of resistant mutants at antibiotic concentrations that fall inside the mutant selection window (MSW) [1] has been reported in studies with Staphylococcus aureus [2][3][4][5][6][7], Streptococcus pneumoniae [8] and Escherichia coli [9,10] exposed to fluoroquinolones in in vitro dynamic models. Generally speaking, such enrichment might depend on the shape of the simulated pharmacokinetic profile of a given antibiotic. ...
Enrichment of resistant mutants at antibiotic concentrations above the minimum inhibitory concentration (MIC) but below the mutant prevention concentration (MPC), i.e. within the mutant selection window (MSW), might be dependent on the shape of the pharmacokinetic profile. To address this issue, two strains of Staphylococcus aureus were exposed to fluctuating (bolus administration) and constant (continuous infusion) concentrations of ciprofloxacin. Staphylococcus aureus ATCC 43300 and ATCC 6538 exhibiting different MPC/MIC ratios (4 and 16, respectively) were exposed to ciprofloxacin twice daily by bolus administration and continuous infusion for 3 days. With each organism and mode of administration, a series of pharmacokinetic profiles was simulated to have the same 24-h area under the concentration-time curve (AUC24) to MIC ratio. The simulated AUC24/MIC ratios were designed to provide ciprofloxacin concentrations within the MSW over most of the dosing interval (bolus administration) or over the entire dosing interval (continuous infusion). In all simulations, ciprofloxacin-resistant staphylococci were enriched in a concentration-dependent manner, i.e. the higher the AUC24/MIC, the later the onset of mutant selection and the smaller the area under the bacterial mutant curve (AUBC M). The relationships between AUC24/MIC and AUBC M were independent of the shape of the simulated pharmacokinetic profiles that corresponded to the different modes of ciprofloxacin administration. For mutants resistant to > or = 4 x MIC of ciprofloxacin, the AUC24/MIC was less predictive of the AUBC M than the AUC24/MPC ratio. This study indicates the mode of ciprofloxacin administration does not influence selection of resistant staphylococci, which is better predicted by AUC24/MPC than by AUC24/MIC.
... DW286, a naphthyridone, is among several fluoroquinolones in development that have in vitro activity against MRSA [121]. Active against MRSA strains that are resistant to other fluoroquinolones, it selects fluoroquinolone-resistant mutants at a lower frequency than do older agents (as may another fluoroquinolone, ABT-492) [122,123]. ...
Methicillin-resistant Staphylococcus aureus, first identified just over 4 decades ago, has undergone rapid evolutionary changes and epidemiologic expansion. It has spread
beyond the confines of health care facilities, emerging anew in the community, where it is rapidly becoming a dominant pathogen.
This has led to an important change in the choice of antibiotics in the management of community-acquired infections and has
also led to the development of novel antimicrobials.
Introduction
Delafloxacin is a novel fluoroquinolone with peculiar characteristics such as a weak acid character, frequent in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), and a low potential for resistance selection compared with other fluoroquinolones.
Areas covered
The present narrative review summarizes the available data on the use of delafloxacin for the treatment of community-acquired bacterial pneumonia (CABP).
Expert opinion
Delafloxacin is novel fluoroquinolone with a unique profile and some interesting characteristics for the treatment of CABP, such as its marked activity against gram-positive bacteria, including MRSA, the possible use as monotherapy (owing to anti-Gram-negative and anti-atypical bacteria activity), the retained activity against many Gram-positive organisms resistant to other fluoroquinolones, and the availability of both oral and intravenous formulations. The results of the DEFINE-CABP phase-3 randomized controlled trial have shown noninferiority of delafloxacin vs. moxifloxacin for the treatment of CABP, thereby providing a further option for this indication. Against this background, future post-marketing experiences remain of crucial importance for further refining the place in therapy of delafloxacin in the real-life management algorithms of CABP, either as first-line option or step-down/outpatient treatment.
Antibiotics (from ancient Greek αντιβιοτικά, antiviotika), also called antibacterials, are a type of antimicrobials drug used in the treatment and prevention of bacterial infections. Cellulitis is an infection that involves the outer layers of the skin. It is commonly caused by bacteria known as beta-hemolytic streptococcus or Staphylococcus aureus. You may experience pain, swelling, tenderness, warmth, and redness in the infected area. Complicate skin and soft tissue infections (SSTIs) are common for both outpatient and hospitalized patients and traditionally include various clinical symptoms ranging from minor superficial infections to necrotizing fasciitis with high rates of mortality. Delafloxacin (DLX) is a new FQ pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with ABSSSIs and CA-RTIs. It also shows good activity against a broad spectrum of microorganisms, including those resistant to other FQ, and stability against multiresistant strains.
PK/PD (pharmacokinetic/pharmacodynamic) relationships with the emergence of bacterial resistance are a basis for designing “anti-mutant” antibiotic dosing regimens, i.e., regimens that are expected to prevent or restrict the enrichment of resistant mutant subpopulations. In vitro dynamic models provide a way to study the enrichment of resistant mutants while simulating human antibiotic pharmacokinetics. A key observation made using these models is that a bell-shaped curve is observed when the recovery of resistant mutants is plotted against AUC/MIC, an integrated measure of drug exposure. This observation strongly supports the window hypothesis, which predicts the selective enrichment of resistant mutants when antimicrobial concentrations fall between the MIC of the bulk population and the mutant prevention concentration (MPC). In most cases examined, doses used clinically place drug concentrations inside the window where mutant enrichment is observed. Reports that contradict the mutant selection window hypothesis are addressed, and flaws in the arguments are pointed out. When considering the time that antimicrobial concentrations are inside the window as a predictor of mutant enrichment, it is important to consider the position of drug concentrations inside the window, since they affect mutant subpopulation size. Plots of mutant enrichment against “time in the window” display a distinct hysteresis loop that explains previous failures to show that “time in the window” is predictive of mutant enrichment. Dynamic models are also suited for optimizing combination therapies. Overall, bacterial resistance studies with in vitro dynamic models provide a way to identify dosing conditions that are likely to severely restrict the emergence of new resistance, a feature that should be especially useful in the development of new compounds.
Delafloxacin has recently received approval by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. This article provides a balanced and comprehensive systematic critique of the literature in order to provide an up-to-date summary of its clinical pharmacology. Oral delafloxacin is rapidly absorbed and exhibits comparable exposure characteristics (300 mg intravenous versus 450 mg oral) between the two formulations, allowing easy transition from intravenous to oral therapy. The bioavailability is high (60–70%) and absorption is not affected by food intake, although further studies are required under clinically relevant conditions. Delafloxacin is primarily excreted renally (thus requiring renal dose adjustment in the setting of renal dysfunction), but also undergoes metabolism by uridine diphosphate-glucuronosyltransferase enzymes in the formation of a conjugated metabolite. Few drug-drug interaction studies have been identified, although more systematic characterizations in vitro and in vivo are warranted. Delafloxacin is a concentration-dependent bactericidal agent that has in vitro susceptibility for gram-positive (notably potent activity against methicillin-resistant Staphylococcus aureus), gram-negative, and anaerobic organisms. In addition to acute bacterial skin and skin structure infections, the clinical utility of delafloxacin has also been studied in community-acquired pneumonia, acute exacerbation of chronic bronchitis, and gonorrhea, with potentially promising findings. Given its mild side effect profile, including an apparent lack of association with clinically important QTc prolongation, delafloxacin is generally well tolerated.
The emergence of antimicrobial resistance threatens current clinical practice across a range of infection types. Delafloxacin, a non-zwitterionic fluoroquinolone recently approved by the US FDA for the treatment of acute bacterial skin and skin structure infections, has been developed to address some of these challenges. Uniquely delafloxacin has increased intracellular penetration and enhanced antibacterial activity under acidic conditions, an environment seen in many infection sites including abscesses. Delafloxacin is active against a wide range of Gram-positive and -negative species including methicillin-resistant Staphylococcus aureus and many fluoroquinolone-resistant strains. Additionally, according to preclinical and clinical trial data, well-known adverse events related to fluoroquinolone class do not appear to occur with this new molecule. Delafloxacin has been studied in acute bacterial skin and skin structure infections with >1400 patients exposed to both intravenous and oral formulation for up to 14 days and has shown noninteriority to vancomycin with or without aztreonam. For its interesting microbiological and pharmacokinetic/pharmacodynamics characteristics and for its safety profile, delafloxacin represents a very promising option for the treatment of infections caused by multidrug-resistant pathogens.
Antibiotics (from ancient Greek αντιβιοτικά, antiviotika), also called antibacterials, are a type of antimicrobials drug used in the treatment and prevention of bacterial infections. Cellulitis is an infection that involves the outer layers of the skin. It is commonly caused by bacteria known as beta-hemolytic streptococcus or Staphylococcus aureus. You may experience pain, swelling, tenderness, warmth, and redness in the infected area. Complicate skin and soft tissue infections (SSTIs) are common for both outpatient and hospitalized patients and traditionally include various clinical symptoms ranging from minor superficial infections to necrotizing fasciitis with high rates of mortality. Delafloxacin (DLX) is a new FQ pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with ABSSSIs and CA-RTIs. It also shows good activity against a broad spectrum of microorganisms, including those resistant to other FQ, and stability against multiresistant strains.
Objectives:
To test the mutant selection window (MSW) hypothesis applied to linezolid-exposed Staphylococcus aureus and to delineate the concentration-resistance relationship, a mixed inoculum of linezolid-susceptible S. aureus cells and linezolid-resistant mutants (RMs) was exposed to linezolid multiple dosing.
Methods:
Three S. aureus strains (MIC of linezolid 2 mg/L), S. aureus 479, S. aureus 688 and S. aureus ATCC 700699, and their RMs (MIC 8 mg/L) selected by passaging on antibiotic-containing media were used in the study. RMs of S. aureus 479 and S. aureus ATCC 700699 contained a G2576T replacement ( Escherichia coli numbering) in one of the copies of the 23S rRNA gene, which had been reported in clinically isolated mutants. Five-day treatments with twice-daily linezolid were simulated over a 32-fold range of the 24 h AUC (AUC 24 ) to the MIC ratio.
Results:
A pronounced enrichment of mutants resistant to 2×, 4× and 8× MIC was observed at AUC 24 /MIC ratios of 30 and 60 when linezolid concentrations were within the MSW for more than half of the dosing interval for each strain. The number of viable mutant cells decreased significantly at the simulated AUC 24 /MIC ratio of 120, while the AUC 24 /MIC ratio of 240 completely prevented mutant enrichment in vitro . Bell-shaped AUBC M -AUC 24 /MIC and AUBC M -AUC 24 /MPC relationships ( r 2 0.91 and 0.79, respectively) were strain independent.
Conclusions:
The bell-shaped pattern of AUC 24 /MIC and AUC 24 /MPC relationships with S. aureus resistance to linezolid is consistent with the MSW hypothesis. 'Antimutant' AUC 24 /MIC ratios were predicted based on the AUC 24 /MIC relationship with AUBC M .
To explore if the ‘anti-mutant’ ratios of 24-h area under the concentration–time curve (AUC24) to the MIC overlap the clinically attainable AUC24/MICs, the selection of ciprofloxacin-resistant Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae mutants was studied in dynamic model that simulates human pharmacokinetics of ciprofloxacin. Four strains each of E. coli and P. aeruginosa and three strains of K. pneumoniae were exposed to ciprofloxacin over a 50–400-fold range of the AUC24/MIC ratio. Based on population analysis data, areas under the bacterial mutant concentration–time curves (AUBCMs) were determined for subpopulations resistant to 4×, 8× and 16× MIC of the antibiotic. The emergence of resistance among three Gram-negative organisms was concentration dependent. Based on the AUBCM vs. AUC24/MIC curves, the predicted ‘anti-mutant’ AUC24/MIC ratios were clinically attainable with E. coli but not with P. aeruginosa and K. pneumoniae. The emergence of fluoroquinolone resistance in a clinical setting can be predicted using dynamic models.
Amidation of the end carboxyl group of eremomycin and vancomycin by pinacolinic 4- or 3-amino methyl phenyl boron acids esters in the presence of the condensing reagent PyBOP resulted in formation of novel carboxamides of the antibiotics (IIIa-VIa). After elimination of the pinacolinic group under mild hydrolysis in weak acid aqueous medium there formed the respective derivatives with a residue of the nonprotected boric acid (III-VI). It was shown that the activity of the 4-substituted derivatives of the borole-containing eremomycin and vancomycin practically was the same as that of the initial antibiotics, while higher than that of the respective 3-substituted derivatives of the borole-containing derivatives against 8 strains of grampositive bacteria.
Quinolone antibacterial agents are among the most attractive drugs in the field of anti-infective chemotherapy. Quinolones target the essential bacterial type II topoisomerases, which are involved in DNA replication and metabolism. Despite a large number of quinolones approved for the treatment of bacterial infections, there have been progressive efforts for the discovery of new quinolones to overcome the problem of growing bacterial resistance. Over the years, there has been growing concern surrounding the increased prevalence of drug resistance in Staphylococcus aureus, especially methicillin-resistant Staphylococcus aureus (MRSA). MRSA used to be susceptible to the fluoroquinolones when they were introduced in the early 1980s but a rapid emergence of resistance to these drugs was observed soon after the increasing use of fluoroquinolones from the mid 1980s. Progressive efforts have been made to optimize the biological activity of the quinolones against S. aureus and drugresistant strains including MRSA. Much of the improved potency of modern quinolones against MRSA has been achieved by modification of the N-1, C-7, and C- 8 substituents on the quinolone ring system. Several newly developed quinolones and related compounds exhibit enhanced activity against S. aureus and have proved useful against MRSA strains and are under rapid preclinical and clinical development. This chapter will discuss the structural requirements of quinolones for anti- MRSA activity and introduce the newly developed quinolones to manage MRSA infections, their in-vitro effectiveness based on recent studies and structure-activity relationships.
ABT-492 is a novel fluoroquinolone with potent activity against gram positive, gram negative and a typical pathogens making this compound an ideal candidate for the treatment of community-acquired pneumoniae. This fluoroquinolone demonstrate the potent activity against penicillin sensitive, penicillin-resistant and levofloxacin-resistant S. pneumoniae strains. ABT-492, 1-(6-amino-3, 5- difluropyridine -2-yl)-8-chloroquinolone, a novel antibiotic, a new fluoroquinolone with increased activity compared to levofloxacin, trovafloxacin and even ciprofloxacin against gram positive organisms and activity similar to that of ciprofloxacin against certain gram-negative , quinolone-susceptible and quinolone rasiatant organisms. This antimicrobial agent is known to be up to 64 times more active than other fluoroquinolones currently available for the use of S. pneumoniae. The invitro susceptibilities and various bactiricdal studies of ABT-492 shows that it is a broad spectrum quinolone displaying improved invitro and bactericidal activities against a variety of quinolone-susceptible and quinolone-resistant gram positive and gram negative organisms which suggests that it may be useful for treating many different types of infections. The in vitro antibacterial potency of ABT-492 was significantly greater than that of levofloxacin against quinolone-susceptible pathogens involved in CA-RTIs. In addition, ABT-492 had improved in vitro activity against antibiotic-resistant respiratory tract pathogens, including multidrug-resistant S. Pneumoniae strains, S. pneumoniae and H. influenzae strains. In the present review article we have discussed the synthetic approach, invitro activities and potency & spectrum of ABT-492. Pharmacodynamic of ABT-492 in comparison of levofloxacin for selected micro-organisms is also discussed in brief.
Emergence of bacterial antibiotic resistance is usually characterised either by population analysis or susceptibility testing. To compare these endpoints in their ability to demonstrate clear relationships with the ratio of 24-h area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC), enrichment of ciprofloxacin-resistant mutants of four clinical isolates of Pseudomonas aeruginosa was studied in an in vitro dynamic model that simulates mono-exponential pharmacokinetics of ciprofloxacin over a wide range of the AUC24/MIC ratios. Each organism was exposed to twice-daily ciprofloxacin for 3 days. Amplification of resistant mutants was monitored by plating on media with 2×, 4×, 8× and 16× MIC of ciprofloxacin. Population analysis data were expressed by the area under the bacterial mutant concentration-time curve (AUBCM). Changes in P. aeruginosa susceptibility were examined by daily MIC determinations. To account for the different susceptibilities of P. aeruginosa strains, post-exposure MICs (MICfinal) were related to the MICs determined with the starting inoculum (MICinitial). For each organism, AUC24/MIC relationships both with AUBCM and MICfinal/MICinitial were bell-shaped, but the latter were more strain-specific than the former. Using combined data on all four isolates, AUBCM showed a better correlation than MICfinal/MICinitial (r(2)=0.75 vs. r(2)=0.53). The shift of MICfinal/MICinitial relative to AUBCM vs. AUC24/MIC curves resulted in a weak correlation between AUBCM and MICfinal/MICinitial (r(2)=0.41). These data suggest that population analysis is preferable to susceptibility testing in bacterial resistance studies and that these endpoints should not be considered interchangeable.
Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
ABSTRACT Delafloxacin is a fluoroquinolone lacking a basic substituent in position 7. It shows MICs remarkably low against Gram-positive organisms and anaerobes and similar to those of ciprofloxacin against Gram-negative bacteria. It remains active against most fluoroquinolone-resistant strains, except enterococci. Its potency is further increased in acidic environments (found in many infection sites). Delafloxacin is active on staphylococci growing intracellularly or in biofilms. It is currently evaluated as an intravenous and intravenous/oral stepdown therapy in Phase III trials for the treatment of complicated skin/skin structure infections. It was also granted as Qualified Infectious Disease Product for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, due to its high activity on pneumococci and atypical pathogens.
The evolution of resistance to antimicrobial chemotherapy is a major and growing cause of human mortality and morbidity. Comparatively little attention has been paid to how different patient treatment strategies shape the evolution of resistance. In particular, it is not clear whether treating individual patients aggressively with high drug dosages and long treatment durations, or moderately with low dosages and short durations can better prevent the evolution and spread of drug resistance. Here, we summarize the very limited available empirical evidence across different pathogens and provide a conceptual framework describing the information required to effectively manage drug pressure to minimize resistance evolution.
Although remarkable advances in the development of antibacterial agents for infections
caused by Staphylococcus aureus began in the 1940s, treatment of this pathogen is still a challenge for
clinicians. The emergence of S aureus strains with resistance to penicillin and methicillin in 1948 and
1961 and the recent reports of vancomycin-resistant strains indicate that the battle against this versatile
pathogen is not yet over. This review discusses the newly developed antimicrobial agents, mechanisms
of action, in-vitro studies, and emerging trends in S aureus resistance to these antibacterial agents. The
availability of linezolid in intravenous and oral form is an advantage for the treatment of pneumonia
and skin and soft tissue infection. Daptomycin is recommended for the treatment of deep-seated infections,
such as endocarditis or osteomyelitis caused by methicillin-resistant S aureus. Tigecycline is a
promising antibacterial agent in cases of complicated intra-abdominal infections and complicated skin
infections in adults. Novel cephalosporins, quinolones, and conjugate vaccines are currently being
developed. Rational antimicrobial usage along with effective infection control measures are required to
avert the rapid emergence of resistant strains of S aureus to these new agents.
Within a susceptible wild-type population, a small fraction of cells, even <10(-9) , is not affected when challenged by an antimicrobial agent. This subpopulation has mutations that impede antimicrobial action, allowing their selection during clinical treatment. Emergence of resistance occurs in the frame of a selective compartment termed a mutant selection window (MSW). The lower margin corresponds to the minimum inhibitory concentration of the susceptible cells, whereas the upper boundary, named the mutant prevention concentration (MPC), restricts the growth of the entire population, including that of the resistant mutants. By combining pharmacokinetic/pharmacodynamic concepts and an MPC strategy, the selection of resistant mutants can be limited. Early treatment avoiding an increase of the inoculum size as well as a regimen restricting the time within the MSW can reduce the probability of emergence of the resistant mutants. Physiological and, possibly, genetic adaptation in biofilms and a high proportion of mutator clones that may arise during chronic infections influence the emergence of resistant mutants. Moreover, a resistant population can emerge in a specific selective compartment after acquiring a resistance trait by horizontal gene transfer, but this may also be avoided to some extent when the MPC is reached. Known linkage between antimicrobial use and resistance should encourage actions for the design of antimicrobial treatment regimens that minimize the emergence of resistance. Emergence of a resistant bacterial subpopulation within a susceptible wild-type population can be restricted with a regimen using an antibiotic dose that is sufficiently high to inhibit both susceptible and resistant bacteria.
To explore whether the duration of in vitro simulated antibiotic exposure influences bacterial resistance, time-dependent amplification of resistant subpopulations of Staphylococcus aureus was studied in 10 day simulations in a dynamic model with daptomycin as a prototypic agent.
S. aureus ATCC 43300 was exposed to once-daily dosing of daptomycin at subtherapeutic ratios of 24 h area under the curve (AUC(24)) to the MIC (32 and 64 h). To provide an integral presentation of the time course of mutants grown on agar plates containing 2x and 4x the MIC of daptomycin, areas under the bacterial mutant kinetic curves (AUBC(M)s) were calculated.
Daptomycin-resistant S. aureus mutants were enriched gradually over the entire treatment duration, with systematic increases in AUBC(M) and concomitant decreases in susceptibility. AUBC(M) analyses were also applied to resistance data reported from other studies with S. aureus exposed to daptomycin and garenoxacin over a wide range of AUC(24)/MIC ratios. Although the maximal AUBC(M)s were greater with longer than with shorter exposures, the treatment or observation durations did not influence the predicted anti-mutant AUC(24)/MIC ratios.
These findings suggest that the duration of in vitro simulated antibiotic exposure is important for estimates of the maximal enrichment of resistant mutants but not for the prediction of the anti-mutant AUC(24)/MIC ratio.
The killing kinetics of Escherichia coli and Pseudomonas aeruginosa were compared when exposed to ABT492 and ciprofloxacin. E. coli ATCC 25922 and a clinical isolate of P. aeruginosa 4226 were exposed to ABT492 (single dose) and ciprofloxacin (two 12 h doses) at the ratios of area under the curve (AUC) to MIC varying from 60 to 480 h and at clinically achievable AUC/MIC ratios of ABT492 (1,740 and 140 h, respectively) and ciprofloxacin (2,200 and 120 h, respectively) that correspond to a 400 mg dose of ABT492 and two 500 mg doses of ciprofloxacin. In addition, a double dose of ABT492 (800 mg; AUC/MIC 280 h) and two 12 h doses of ABT492 (2 x 400 mg) were used with P. aeruginosa. Maximal reductions in the starting inoculum of E. coli and P. aeruginosa were greater with ABT492 than with ciprofloxacin at a given AUC/MIC ratio (60-480 h), whereas the times to regrowth were shorter with ABT492. A specific AUC/MIC relationship of the antimicrobial effect was inherent in each quinolone-pathogen pair. With both E. coli and P. aeruginosa, AUC/MIC plots of the area between the control growth and the time-kill curves (I(E)) were steeper for ciprofloxacin than ABT492 and they were species-independent. The effect of ABT492 on E. coli at the clinically achievable AUC/MIC ratio (1740h) was more pronounced than the respective AUC/MIC of ciprofloxacin (2,200 h). With P. aeruginosa, a 140 h AUC/MIC of ABT492 (400 mg as a single dose) provided 1.8-fold less effect than a 120 h AUC/MIC of ciprofloxacin (2 x 500 mg). However, two 12 h doses of ABT492 (AUC/MIC 2 x 140 h) but not a double single dose (800 mg) were more efficient than ciprofloxacin. These findings predict comparable efficacies of clinically achievable AUC/MICs of ABT492 and ciprofloxacin against E. coli (q.d. versus b.i.d. quinolone dosing) and P. aeruginosa at b.i.d. but not at q.d. ABT492.
The kinetics of killing of Streptococcus pneumoniae exposed to ABT492 or levofloxacin were compared. S. pneumoniae ATCC 49619 and four ciprofloxacin-resistant clinical isolates, S. pneumoniae 1149, 391, 79 and 804, were exposed to ABT492 and levofloxacin as a single dose in a dynamic model that simulates human pharmacokinetics of the quinolones. With S. pneumoniae ATCC 49619 eight-fold ranging AUC/MIC ratios (60-500 h) were simulated for each quinolone. In addition, two larger AUC/MICs, i.e., 1080 and 2150 h for ABT492 and 1460 and 3660 h for levofloxacin which correspond to 100 and 200 mg doses of ABT492 and 200 and 500 mg doses of levofloxacin, respectively, were mimicked. Each ciprofloxacin-resistant organism was exposed to the clinical doses of ABT492 (400 mg) and levofloxacin (500 mg); the respective AUC/MIC ratios were from 580 to 3470 h and from 28 to 110 h. At comparable AUC/MICs (from 60 to 500 h), regrowth of S. pneumoniae ATCC 49619 followed initial killing, and the times to regrowth were longer with levofloxacin than ABT492. However, no regrowth of S. pneumoniae ATCC 49619 occurred at the higher AUC/MICs of ABT492 (1080 and 2150 h) and levofloxacin (1460 and 3660 h). Killing of S. pneumoniae 1149, 391 and 79 without bacterial regrowth, was provided by ABT492 (AUC/MIC 3470, 2310 and 1160 h, respectively) but not levofloxacin (AUC/MIC 55, 110 and 28 h, respectively). Regrowth of S. pneumoniae 804 was observed with both ABT492 and levofloxacin (AUC/MIC 580 and 55 h, respectively). Areas between the control growth curve and the time-kill curve (ABBCs) for ABT492 against S. pneumoniae 1149, 391 and 79 were 2.6-4.2 times larger than the respective ABBCs for levofloxacin, whereas similar ABBCs were found with S. pneumoniae 804 exposed to both quinolones. These findings predict significantly greater efficacy of ABT492 than levofloxacin at clinically achievable AUC/MIC ratios against ciprofloxacin-resistant S. pneumoniae and similar efficacies of the two quinolones against susceptible organisms.
Methicillin-resistant Staphylococcus aureus (MRSA) should no longer be regarded as a strictly nosocomial pathogen. During the past decade, community-acquired MRSA (CA-MRSA) infections among young persons without healthcare-associated (HCA) risk factors have emerged in several areas worldwide. These infections are caused by strains that almost exclusively carry the staphylococcal cassette chromosome mec type IV element and the Panton-Valentine leukocidin genes and, unlike HCA-MRSA strains, are not multiresistant. Although the majority of CA-MRSA infections are mild skin and soft tissue infections, severe life-threatening cases of necrotizing pneumonia, necrotizing fasciitis, myonecrosis and sepsis have been reported. Clindamycin is an effective agent for skin and soft tissue infections, however attention should be paid to the possibility of the emergence of resistance during treatment in strains with the macrolide, lincosamide and group B streptogramin (MLS(B))-inducible resistance phenotype. For patients with invasive infections that may be caused be CA-MRSA, vancomycin, teicoplanin and linezolid represent appropriate empirical therapeutic options.
Group B streptococcus is known to be a leading cause of neonatal infection, but less appreciated is the fact that it causes maternal infection also. Maternal group B streptococcal infections during pregnancy and delivery threaten not only the mother, but the child as well. Postpartum infection, such as mastitis, bacteremia, sepsis, meningitis, endometritis, and wound infections are hazards to the mother. We describe the various maternal group B streptococcal infections, their characteristics, associated neonatal morbidity, and prevention and treatment strategies during pregnancy, delivery, and in the postpartum period.
The mutant selection window hypothesis postulates that, for each antimicrobial-pathogen combination, an antimicrobial concentration
range exists in which selective amplification of single-step, drug-resistant mutants occurs. This hypothesis suggests an antimutant
dosing strategy that is keyed to the upper boundary of the selection window: the mutant prevention concentration. Correlations
are described between the mutant prevention concentration—a static parameter that is measured with agar plates—and fluctuating
drug concentrations that restrict mutant amplification in vitro and in animals. When drug resistance is acquired stepwise,
the mutant selection window increases, making the suppression of each successive mutant increasingly more difficult. For agents
that kill drug-resistant mutants in a drug concentration–dependent manner, the use of the area under the 24-h time–drug concentration
curve value divided by the value of the mutant prevention concentration is suggested as an index for designing antimutant
dosing regimens. The need for such regimens is emphasized by a clinical example in which acquisition of drug resistance occurs
concurrently with eradication of susceptible bacterial cells. These data support using the mutant selection window to optimize
antimicrobial dosing regimens.
Earlier efforts to search for pharmacokinetic and bacteriological predictors of fluoroquinolone antimicrobial effects (AMEs) have resulted in conflicting findings. To elucidate whether these conflicts are real or apparent, several predictors of the AMEs of two pharmacokinetically different antibiotics, trovafloxacin (TRO) and ciprofloxacin (CIP), as well as different dosing regimens of CIP were examined. The AMEs of TRO given once daily (q.d.) and CIP given q.d. and twice daily (b.i.d.) against Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied in an in vitro dynamic model. Different monoexponential pharmacokinetic profiles were simulated with a TRO half-life of 9.2 h and a CIP half-life of 4.0 h to provide similar eightfold ranges of the area under the concentration-time curve (AUC)-to-MIC ratios, from 54 to 432 and from 59 to 473 (microg x h/ml)/(microg/ml), respectively. In each case the observation periods were designed to incorporate full-term regrowth phases in the time-kill curves, and the AME was expressed by its intensity (IE; the area between the control growth and time-kill and regrowth curves up to the point at which the viable counts of regrowing bacteria are close to the maximum values observed without drug). Species-independent linear relationships were established between IE and log AUC/MIC, log AUC above MIC (log AUCeff), and time above the MIC (Teff). Specific and nonsuperimposed IE versus log AUC/MIC or log AUCeff relationships were inherent in each of the treatments: TRO given q.d. (r2 = 0.97 and 0.96), CIP given q.d. (r2 = 0.98 and 0.96), and CIP given b.i.d. (r2 = 0.95 and 0.93). This suggests that in order to combine data sets obtained with individual quinolones to examine potential predictors, one must be sure that these sets may be combined. Unlike AUC/MIC and AUCeff, the IE-Teff relationships plotted for the different quinolones and dosing regimens were nonspecific and virtually superimposed (r2 = 0.95). Hence, AUC/MIC, AUCeff and Teff were equally good predictors of the AME of each of the quinolones and each dosing regimen taken separately, whereas Teff was also a good predictor of the AMEs of the quinolones and their regimens taken together. However, neither the quinolones nor the dosing regimens could be distinguished solely on the basis of Teff whereas they could be distinguished on the basis of AUC/MIC or AUCeff. Thus, two types of predictors of the quinolone AME may be identified: intraquinolone and/or intraregimen predictors (AUC/MIC, AUCeff and Teff) and an interquinolone and interregimen predictor (Teff). Teff may be able to accurately predict the AME of one quinolone on the basis of the data obtained for another quinolone.
The clinical outcome in patients treated with ampicillin-sulbactam may not always be predictable by disc susceptibility testing or with the MIC as determined with a constant level (4 micrograms/ml) of the beta-lactamase inhibitor (MIC1). The enzyme activities (EA) and the MICs estimated at a constant ratio of ampicillin to sulbactam of 2:1 (MIC2) for 15 TEM-1 beta-lactamase-producing strains of Escherichia coli were examined as alternatives to MIC1 as predictors of the antibacterial effects of this combined drug as studied in an in vitro model which simulates ampicillin-sulbactam pharmacokinetic profiles observed in human peripheral tissues. Integral parameters describing the area under the bacterial count-time curve (AUBC), the area between the normal growth curve, and the killing curve of bacteria exposed to antibiotic (ABBC), and the second parameter expressed as a percentage of its maximal hypothetical value (ABBC/ABBCmax) were calculated. All three parameters correlated well with EA (AUBC, r = 0.93; ABBC, r = -0.88; ABBC/ABBCmax, r = -0.91) and with MIC2 (r = 0.94, -0.94, and -0.95, respectively) but not with MIC1. Both EA and MIC2 can be considered reliable predictors of the antibacterial effect of ampicillin-sulbactam in an in vitro model. These correlations suggest that in vitro kinetic-dynamic models might be useful to reexamine established susceptibility breakpoints obtained with data based on the MIC1 (MICs obtained with constant levels of beta-lactamase inhibitors). These data also suggest that quantitative determinations of bacterial beta-lactamase production and MICs based on the component concentration ratio observed in vivo might be useful predictors of the effect of ampicillin-sulbactam and other beta-lactam-inhibitor combinations.
The influence of age and gender on the pharmacokinetics of levofloxacin in healthy subjects receiving a single oral 500-mg dose of levofloxacin was investigated in this parallel design study. Six young males (aged 18 to 40 years), six elderly males (aged > or = 65 years), six young females (aged 18 to 40 years), and six elderly females (aged > or = 65 years) were enrolled and completed the study. The study reveals that the bioavailability (rate and extent) of levofloxacin was not affected by either age or gender. In both age (young and elderly) and gender (male and female) groups of subjects, peak concentrations in plasma were reached at approximately 1.5 h after dosing; renal clearance of levofloxacin accounted for approximately 77% of total body clearance, and approximately 76% of the administered dose was recovered unchanged in urine over the 36 h of collection. The apparent differences in the calculated pharmacokinetic parameters for levofloxacin between the age groups (young versus elderly) and between the gender groups (males versus females) could be explained by differences in renal function among the subjects. A single dose of 500 mg of levofloxacin administered orally to both young and old, male and female healthy subjects was found to be safe and well tolerated. As the differences in levofloxacin kinetics between the young and the elderly or the males and the females are limited and are mainly related to the renal function of the subjects, dose adjustment based on age or gender alone is not necessary.
This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.
The effects of food and sucralfate on the pharmacokinetics of levofloxacin following the administration of a single 500-mg oral dose were investigated in a randomized, three-way crossover study with young healthy subjects (12 males and 12 females). Levofloxacin was administered under three conditions: fasting, fed (immediately after a standardized high-fat breakfast), and fasting with sucralfate given 2 h following the administration of levofloxacin. The concentrations of levofloxacin in plasma and urine were determined by high-pressure liquid chromatography. By noncompartmental methods, the maximum concentration of drug in serum (Cmax), the time to Cmax (Tmax), the area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL/F), renal clearance (CLR), and cumulative amount of levofloxacin in urine (Ae) were estimated. The individual profiles of the drug concentration in plasma showed little difference among the three treatments. The only consistent effect of the coadministration of levofloxacin with a high-fat meal for most subjects was that levofloxacin absorption was delayed and Cmax was slightly reduced (Tmax, 1.0 and 2.0 h for fasting and fed conditions, respectively [P = 0.002]; Cmax, 5.9 +/- 1.3 and 5.1 +/- 0.9 microg/ml [90% confidence interval = 0.79 to 0.94] for fasting and fed conditions, respectively). Sucralfate, which was administered 2 h after the administration of levofloxacin, appeared to have no effect on levofloxacin's disposition compared with that under the fasting condition. Mean values of Cmax and AUC from time zero to infinity were 6.7 +/- 3.2 microg/ml and 47.9 +/- 8.4 microg x h/ml, respectively, following the administration of sucralfate compared to values of 5.9 +/- 1.3 microg/ml and 50.5 +/- 8.1 microg x h/ml, respectively, under fasting conditions. The mean t1/2, CL/F, CLR, and Ae values were similar among all three treatment groups. In conclusion, the absorption of levofloxacin was slightly delayed by food, although the overall bioavailability of levofloxacin following a high-fat meal was not altered. Finally, sucralfate did not alter the disposition of levofloxacin when sucralfate was given 2 h after the administration of the antibacterial agent, thus preventing a potential drug-drug interaction.
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 (AUC(24)) to the MIC varied from 13 to 244 h, and the starting inoculum was 10(8) CFU/ml (6 x 10(9) CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC(24)/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 AUC(24)/MIC values (15 to 16 h) of GAT and CIP, whose C(max) exceeded the MICs. No such increases were observed with the smallest AUC(24)/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 AUC(24)/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 AUC(24)/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These "protective" AUC(24)/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.
Levofloxacin is a fluoroquinolone antibiotic and is the optical S-(−) isomer of the racemic drug substance ofloxacin. It has a broad spectrum of in vitro activity against Gram-positive and Gram-negative bacteria, as well as certain other pathogens such as Mycoplasma, Chlamydia, Legionella and Mycobacteria spp. Levofloxacin is significantly more active against bacterial pathogens than R- (+) - ofloxacin. Levofloxacin hemihydrate, the commercially formulated product, is 97.6% levofloxacin by weight.
Levofloxacin pharmacokinetics are described by a linear 2-compartment open model with first-order elimination. Plasma concentrations in healthy volunteers reach a mean peak drug plasma concentration (Cmax) of approximately 2.8 and 5.2 mg/L within 1 to 2 hours after oral administration of levofloxacin 250 and 500mg tablets, respectively. The bioavailability of oral levofloxacin approaches 100% and is little affected by the administration with food. Oral absorption is very rapid and complete, with little difference in the serum concentration-time profiles following 500mg oral or intravenous (infused over 60 minutes) doses.
Single oral doses of levofloxacin 50 to 1000mg produce a mean Cmax and area under the concentration-time curve (AUC) ranging from approximately 0.6 to 9.4 mg/L and 4.7 to 108 mg·h/L, respectively, both increasing linearly in a doseproportional fashion. The pharmacokinetics of levofloxacin are similar during multiple-dose regimens to those following single doses. Levofloxacin is widely distributed throughout the body, with a mean volume of distribution of 1.1 L/kg, and penetrates well into most body tissues and fluids. Drug concentrations in tissues and fluids are generally greater than those observed in plasma, but penetration into the cerebrospinal fluid is relatively poor (concentrations approximately 16% of simultaneous plasma values). Levofloxacin is approximately 24 to 38% bound to serum plasma proteins (primarily albumin); serum protein binding is independent of serum drug concentrations.
The plasma elimination half-life (t½β) ranges from 6 to 8 hours in individuals with normal renal function. Approximately 80% of levofloxacin is eliminated as unchanged drug in the urine through glomerular filtration and tubular secretion; minimal metabolism occurs with the formation of no metabolites possessing relevant pharmacological activity. Renal clearance and total body clearance are highly correlated with creatinine clearance (CLcr), and dosage adjustments are required in patients with significant renal dysfunction. Levofloxacin pharmacokinetics are not appreciably affected by age, gender or race when differences in renal function, and body mass and composition are taken into account.
Important drug interactions exist with aluminium- and magnesium-containing antacids and ferrous sulfate, as with other fluoroquinolones, resulting in significantly decreased levofloxacin absorption when administered concurrently. These agents should be administered at least 2 hours before or after levofloxacin administration. Cimetidine and probenecid decrease levofloxacin renal clearance and increase t½β; the magnitudes of these interactions are not clinically significant. Levofloxacin appears to have only minor potential for significantly altering the pharmacokinetics of theophylline, warfarin, zidovudine, ranitidine, digoxin or cyclosporin; however, patients receiving these drugs concurrently should be monitored closely for signs of enhanced pharmacological effect or toxicity. Levofloxacin pharmacokinetics are not significantly altered by sucralfate when administration of these drugs is separated by at least 2 hours.
To demonstrate the impact of the different pharmacokinetics of moxifloxacin and levofloxacin on their antimicrobial effects (AMEs), killing and regrowth kinetics of two clinical isolates of Staphylococcus aureus and one each of Escherichia coli and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of single doses of moxifloxacin (T:1/2 = 12.1 h) and levofloxacin (T:(1/2) = 6.8 h) were simulated. The respective eight-fold ranges of the ratios of area under the concentration-time curve (AUC) to the MIC were 58-475 and 114-934. Species- and strain-independent linear relationships observed between the intensity of AME (I:(E)) and log AUC/MIC were not superimposed for moxifloxacin and levofloxacin (r(2) = 0.99 in both cases). The predicted AUC/MIC ratios for moxifloxacin and levofloxacin that might be equivalent to Schentag's AUC/MIC breakpoint for ciprofloxacin (125) were estimated at 80 and 130, respectively. The respective equivalent MIC breakpoints were 0.41 mg/L (for a 400 mg dose of moxifloxacin) and 0.35 mg/L (for a 500 mg dose of levofloxacin). Based on the I:(E)-log AUC/MIC relationships, equiefficient 24 h doses (D:(24)s) of moxifloxacin and levofloxacin were calculated for hypothetical strains of S. aureus, E. coli and K. pneumoniae with MICs equal to the respective MIC50s (weighted geometric means of reported values). To provide an 'acceptable' I:(E) = 200 (log cfu/mL)*h, the D:(24)s of moxifloxacin for all three organisms were much lower (150, 30 and 60 mg, respectively) than the clinically proposed 400 mg dose. Although the usual dose of levofloxacin (500 mg) would be in excess for E. coli and K. pneumoniae (D:(24) = 36 and 220 mg, respectively), it might be insufficient for S. aureus (the estimated D:(24) = 850 mg). Moreover, to provide the same effect as a 400 mg D:(24) of moxifloxacin against staphylococci, levofloxacin would have to be given in a 5000 mg D:(24), which is 10-fold higher than its clinically accepted dose. The described method of generalization of data obtained with specific organisms to other representatives of the same species might be useful to predict the AMEs of new quinolones.
To compare the antistreptococcal activity of five fluoroquinolone antibiotics, using a neutropenic murine model of pneumococcal pulmonary infection.
Animal experiment.
University-affiliated research center.
Neutropenic and control mice weighing 24-29 g.
After induction of neutropenia, renal failure, and infection with Streptococcus pneumoniae, the mice received one of five fluoroquinolones twice/day for 72 hours beginning 12 hours after infection. Dosages were selected to approximate 0.1 x AUC0-24 (area under the concentration-time curve from 0-24 hours) and AUC0-24 achieved in humans. Control mice received normal saline. Survival was assessed at regular intervals for up to 10 days. At least 10 mice were included in each cohort (range 10-34).
Ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, and moxifloxacin were studied at subtherapeutic and therapeutic dosages against three quinolone-susceptible isolates of S. pneumoniae that lacked mutations in parC, parE, and gyrA. Pharmacokinetic profile of each agent and dosing regimen was determined. A composite survival curve for all fluoroquinolones and isolates was constructed. Relationships between survival rate at 72 hours and AUC:MIC (minimum inhibitory concentration), peak:MIC, time above the MIC (percentage of dosing interval) for total and free drug concentrations were fit by using a sigmoid maximal effect (Emax) model. Survival was significantly better in the higher dosage group than in the lower dosage group. Time above MIC did not display a correlation with outcome. The AUC:MIC showed a greater correlation with outcome (R2 = 0.56 total, 0.54 free) than did peak:MIC (R2 = 0.52 total, 0.51 free). With use of composite data, total AUC:MIC ratios associated with 50%, 90%, and 99% of Emax were 34:1, 56:1, and 95:1, respectively
In this model, efficacy was achieved with the fluoroquinolone antibiotics at dosages yielding AUC0-24 comparable to those obtained in humans. One pharmacodynamic parameter (i.e., AUC:MIC) may be applied to various fluoroquinolones and isolates of S. pneumoniae. The AUC:MIC was more predictive of outcome than was time above the MIC or peak:MIC.
Pharma-cokinetics of oral ABT-492 are similar in male and female subjects
- L Gustavson
- S Schweitzer
- B Hosmane
Gustavson, L., Schweitzer, S., Hosmane, B. et al. (2003). Pharma-cokinetics of oral ABT-492 are similar in male and female subjects. In Programs and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, San-Diego, CA, 2003. Abstract A17, p. 4. American Society for Microbiology. Washington, DC, USA
In vitro activity of ABT-492 compared with other quinolone antibiotics
- J M Andrews
- J P Ashby
- G Jevons
Andrews, J. M., Ashby, J. P., Jevons, G. et al. (2003). In vitro activity of ABT-492 compared with other quinolone antibiotics. In Programs and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, San-Diego, CA, 2003. Abstract E147, p. 199. American Society for Microbiology. Washington, DC, USA.