Use of modeling techniques to aid in antibiotic selection

Firsov, Alexander A.; Zinner, Stephen H.

doi:10.1007/s11908-001-0057-9

Cited by 15 publications

(10 citation statements)

References 36 publications

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“…For example, based on I E -log AUC/MIC relationships established in our in vitro study [21], the AUC/MIC breakpoint for grepafloxacin (78 h), equivalent to that of ciprofloxacin (125 h), appeared to be very close to the breakpoint of grepafloxacin reported in a clinical setting (75 h [22]). The AUC/MIC breakpoint of levofloxacin (130 h) predicted in another in vitro study [23] corresponds to C max /MIC of 13 that is also consistent with the C max /MIC breakpoint of 12 reported in patients [24].…”

Section: Discussionsupporting

confidence: 63%

Simulated in vitro Quinolone Pharmacodynamics at Clinically Achievable AUC/MIC Ratios: Advantage of IE over Other Integral Parameters

et al. 2002

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To compare the antimicrobial effects of clinically achievable ratios of area under the curve (AUC) to MIC, a clinical isolate of Moraxella catarrhalis was selected with MICs corresponding to the MIC₅₀s of four quinolones. Monoexponentially declining concentrations observed in human plasma after oral administration of 1,000 mg of ciprofloxacin (as two 500-mg doses at a 12-hour interval), 320 mg gemifloxacin, 500 mg levofloxacin or 400 mg moxifloxacin (each as a single dose) and were simulated in an in vitro dynamic model. The respective half-lives were 4, 7.4, 6.8 and 12.1 h, and the AUC/MICs were 730, 1,130, 920 and 690 h. The time-kill/regrowth curves yielded similar patterns with the four quinolones: a rapid reduction in bacterial numbers followed by bacterial regrowth that occurred later with moxifloxacin than with ciprofloxacin, gemifloxacin, and levofloxacin. The total antimicrobial effect of moxifloxacin as expressed by the I_E parameter (area between the control growth and time- kill curves from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of antimicrobial) was 30, 55, and 120% greater than gemifloxacin, levofloxacin and ciprofloxacin, respectively. Unlike I_E, the other integral indices determined over a fixed time (24 h) – the area between the control growth and time-kill curves, area above the time-kill curve and area under the time-kill curve were similar for the four fluoroquinolones, thus precluding their differentiation.

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Section: Discussionsupporting

confidence: 63%

Simulated in vitro Quinolone Pharmacodynamics at Clinically Achievable AUC/MIC Ratios: Advantage of IE over Other Integral Parameters

et al. 2002

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“…Moreover, these attempts were often incorrect: erroneous conclusions about the advantages of one predictor over another resulted from the use of inconsistent functions relating the effect to its predictors, inappropriate combining of data obtained with pharmacokinetically different antibiotics, etc. Methodological pitfalls in analysis of the predictor-response relationships have been discussed in detail elsewhere (12).…”

Section: Discussionmentioning

confidence: 99%

Comparative Pharmacodynamics and Antimutant Potentials of Doripenem and Imipenem with Ciprofloxacin-Resistant Pseudomonas aeruginosa in an In Vitro Model

Firsov¹,

Gilbert²,

Greer³

et al. 2012

Antimicrob Agents Chemother

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To compare the antipseudomonal efficacy of doripenem and imipenem as well as their abilities to restrict the enrichment of resistant Pseudomonas aeruginosa, multiple-dosing regimens of each drug were simulated at comparable values of the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T >MIC ) and ratios of the 24-hour area under the curve (AUC 24 ) to the MIC. Three clinical isolates of ciprofloxacin-resistant P. aeruginosa (MIC of doripenem, 1 g/ml; MICs of imipenem, 1, 2, and 2 g/ml) were exposed to thrice-daily doripenem or imipenem for 3 days at AUC 24 /MIC ratios of from 50 to 170 h (doripenem) and from 30 to 140 h (imipenem). The antimicrobial effects for susceptible and resistant subpopulations of bacteria were expressed by the areas between control growth and time-kill curves (I E s) and areas under the bacterial mutant concentration curves (AUBC M s), respectively. With each antibiotic, the I E and AUBC M versus log AUC 24 /MIC relationships were bacterial strain independent. At similar AUC 24 /MIC ratios, doripenem was slightly less efficient than imipenem against susceptible and resistant subpopulations of bacteria. However, doripenem appeared to be somewhat more efficient than imipenem at clinically achievable AUC 24 s related to the means of the MICs for the three studied strains and had higher antimutant potentials for two of the three strains. Pseudomonas aeruginosa remains an important cause of nosocomial infections of the lung, urinary tract, and bloodstream, especially within intensive care units (13,19). This organism is particularly problematic for critically ill, neutropenic, immunocompromised, and mechanically ventilated patients (21). Over the past decade, fluoroquinolone resistance among these organisms has increased, often requiring other antibiotics for successful treatment (20). Recent studies have suggested that beta-lactam monotherapy for serious pseudomonal infections is probably as effective as combination therapy, even though in vitro synergism can sometimes be demonstrated with the combinations (4, 15).Doripenem is a new carbapenem antibiotic active against Pseudomonas aeruginosa. The pharmacodynamics of doripenem have been studied in vivo using a murine thigh model of infection with 10 Gram-negative organisms (1) and a rabbit model of pseudomonal pneumonia (3). A species-independent relationship between changes in the logarithm of the number of CFU of Gramnegative organisms per thigh and the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T ϾMIC ) was established in the former study, and similar efficacies of doripenem, imipenem, and meropenem were reported in the latter. T ϾMIC relationships of doripenem and imipenem antipseudomonal effects were also observed with each of three isogenic strains in an in vitro study using a dynamic model (14). Because the simulated ranges of the T ϾMIC s and the ratios of carbapene...

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“…Gatifloxacin and moxifloxacin have elimination half-lives of 8 and 10 h, respectively, and are given once daily (29). In modeling techniques, the T Ͼ MIC measurement has been shown to be a good predictor of antimicrobial effects (time kill and regrowth) and useful in determining the most appropriate dosing regimen when comparing fluoroquinolones (8). Furthermore, concentration-independent killing has been observed with various fluoroquinolones against anaerobic bacteria (27).…”

Section: Discussionmentioning

confidence: 99%

Bactericidal Activities of Methoxyfluoroquinolones Gatifloxacin and Moxifloxacin against Aerobic and Anaerobic Respiratory Pathogens in Serum

Stein

Schooley

Tyrrell³

et al. 2003

Antimicrob Agents Chemother

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Gatifloxacin (Bristol-Myers Squibb) and moxifloxacin (Bayer) are new methoxyfluoroquinolones with broadspectrum activity against aerobic and anaerobic pathogens of the respiratory tract. In this investigation, we analyzed the bactericidal activity in serum over time of these antimicrobials against three aerobic (Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus) and four anaerobic (Peptostreptococcus micros, Peptostreptococcus magnus, Fusobacterium nucleatum, and Prevotella melaninogenica) bacteria associated with respiratory tract infections. Serum samples were obtained from 11 healthy male subjects following a single 400-mg oral dose of gatifloxacin and moxifloxacin. These samples were collected prior to and at 2, 6, 12, and 24 h after the dose of each drug. Gatifloxacin exhibited bactericidal activity for a median of 12 h against Streptococcus pneumoniae (MIC ‫؍‬ 0.5 g/ml), Peptostreptococcus micros (MIC ‫؍‬ 0.25 g/ml), and F. nucleatum (MIC ‫؍‬ 0.5 g/ml) and 24 h against H. influenzae (MIC ‫؍‬ 0.03 g/ml), Staphylococcus aureus (MIC ‫؍‬ 0.125 g/ml), Peptostreptococcus magnus (MIC ‫؍‬ 0.125 g/ml), and Prevotella melaninogenica (MIC ‫؍‬ 0.5 g/ml). Moxifloxacin exhibited bactericidal activity for a median of 24 h against Streptococcus pneumoniae (MIC ‫؍‬ 0.125 g/ml), H. influenzae (MIC ‫؍‬ 0.015 g/ml), Staphylococcus aureus (MIC ‫؍‬ 0.06 g/ml), F. nucleatum (MIC ‫؍‬ 0.5 g/ml), Prevotella melaninogenica (MIC ‫5.0؍‬ g/ml), Peptostreptococcus magnus (MIC ‫؍‬ 0.125 g/ml), and Peptostreptococcus micros (MIC ‫؍‬ 0.25 g/ml). The results from this pharmacodynamic study suggest that these fluoroquinolones would have prolonged killing activity against these organisms in vivo and may have clinical utility in the treatment of mixed aerobic-anaerobic respiratory tract infections.Gatifloxacin (Bristol-Myers Squibb) and moxifloxacin (Bayer) are new 8-methoxyfluoroquinolones with broad-spectrum antimicrobial activity which includes anaerobic bacteria (29). Both compounds have comparable in vitro activity against common aerobic and anaerobic respiratory pathogens (3). Moreover, they exhibit similar serum pharmacokinetics and penetration into respiratory tissues (9, 24). The ability of gatifloxacin and moxifloxacin to eradicate aerobic respiratory pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae, has been well documented in pharmacodynamic models and clinical trials (9, 24). Their effectiveness in the treatment of anaerobic infections is unknown.In contrast to studies with aerobic bacteria, where concentration-dependent killing has been observed, concentrationindependent killing was discovered against Bacteroides thetaiotaomicron with various fluoroquinolones in an in vitro pharmacodynamic model (27). This model further discovered that resistant strains of Bacteroides fragilis emerged when the area under the concentration-time curve from 0 to 24 h (AUC 24 )-to-MIC ratio was less than 40 (26). In time-kill assays, maximal bactericidal activity against various anaerobes (B. fragilis, ...

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Use of modeling techniques to aid in antibiotic selection

Cited by 15 publications

References 36 publications

Simulated in vitro Quinolone Pharmacodynamics at Clinically Achievable AUC/MIC Ratios: Advantage of <i>I</i><sub>E</sub> over Other Integral Parameters

Simulated in vitro Quinolone Pharmacodynamics at Clinically Achievable AUC/MIC Ratios: Advantage of <i>I</i><sub>E</sub> over Other Integral Parameters

Comparative Pharmacodynamics and Antimutant Potentials of Doripenem and Imipenem with Ciprofloxacin-Resistant Pseudomonas aeruginosa in an In Vitro Model

Bactericidal Activities of Methoxyfluoroquinolones Gatifloxacin and Moxifloxacin against Aerobic and Anaerobic Respiratory Pathogens in Serum

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