Pharmacodynamics of Trovafloxacin and Levofloxacin against
            <i>Bacteroides fragilis</i>
            in an In Vitro Pharmacodynamic Model

Peterson, Marnie L.; Hovde, Laurie B.; Wright, David H.; Brown, Gigi H.; Hoang, A. D.; Rotschafer, John C.

doi:10.1128/aac.46.1.203-210.2002

Cited by 23 publications

(15 citation statements)

References 28 publications

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“…This finding suggests that these newer fluoroquinolones could provide clinically significant antibacterial effects as well as prevention of regrowth against these various isolates (17). Our findings are also supported by other pharmacodynamic models of bacterial killing with fluoroquinolones (16,26). The isolates utilized in our study were representative bacteria associated with respiratory tract infections and had MICs at or near the median MIC for these methoxyfluoroquinolones (1,3,6).…”

Section: Discussionsupporting

confidence: 69%

“…Furthermore, concentration-independent killing has been observed with various fluoroquinolones against anaerobic bacteria (27). It may be that the AUC 24 /MIC ratio is not an inherent predictor of antimicrobial efficacy against anaerobes but useful in determining the likelihood of resistance development (26). These observations suggest that T Ͼ MIC can play an important role in bacteriologic eradication with once-daily fluoroquinolones.…”

Section: Discussionmentioning

confidence: 72%

“…These ratios have been correlated to bacterial killing for both aerobic and anaerobic bacteria in pharmacodynamic models (12). For example, an AUC 24 /MIC ratio of Ն30 has been shown to be sufficient for eradication of pneumococci, and an AUC 24 /MIC ratio of Ն40 provided maximal killing and prevention of regrowth in strains of Bacteroides fragilis (16,26).…”

Section: Discussionmentioning

confidence: 99%

“…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, B. thetaiotaomicron, Peptostreptococcus magnus, and Clostridium perfringens) was observed at twice the MIC with levofloxacin (25).…”

mentioning

confidence: 96%

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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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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

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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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“…Mutants were selected as described previously (5) from B. fragilis NCTC9343/ ATCC25285 (Z14) on Wilkins and Chalgren agar in a single step at 2ϫ MIC of trovafloxacin, moxifloxacin, and ciprofloxacin at mutation frequencies of 2.6 ϫ 10 Ϫ10 , 6.6 ϫ 10 Ϫ9 , and 4.5 ϫ 10 Ϫ9 , respectively. In vitro mutants were also selected in a PD model (11,12) from Z14, a clinical isolate (Z54), and ATCC 23745 (Z55). From Z14, three mutants (Z50, Z72, and Z73) were selected with trovafloxacin and two mutants (Z69 and Z70) were selected with moxifloxacin.…”

mentioning

confidence: 99%

Role of Topoisomerase Mutations and Efflux in Fluoroquinolone Resistance of Bacteroides fragilis Clinical Isolates and Laboratory Mutants

Ricci

Peterson

Rotschafer

et al. 2004

Antimicrob Agents Chemother

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Twelve laboratory mutants and 32 ciprofloxacin-resistant isolates of Bacteroides fragilis were examined for the mechanism(s) of fluoroquinolone resistance. Five mutants had mutations in gyrA. One mutant and two clinical isolates contained a mutation in gyrB. Eight mutants and five clinical isolates accumulated significantly less ciprofloxacin than did wild-type isolates; the mutants and clinical isolates were restored to wild-type characteristics when carbonyl cyanide m-chlorophenylhydrazone was used.DNA gyrase is the primary target of fluoroquinolones for most gram-negative bacteria (3,4,6). DNA topoisomerase IV is also a primary target for specific fluoroquinolones in certain gram-positive bacteria (15,16). Studies to explore mechanisms of fluoroquinolone resistance in Bacteroides fragilis have identified mutations in gyrA as well as active efflux of norfloxacin (2, 7, 9, 10). However, analysis of the literature suggests that gyrA is a secondary (not primary) target of fluoroquinolones in B. fragilis (2, 10). The aim of this study was to identify the mechanism(s) of resistance in fluoroquinolone-resistant B. fragilis selected in vitro from agar and a pharmacodynamic (PD) model compared with those of 32 ciprofloxacin-resistant clinical isolates from the United States.The MIC of each antibiotic was determined for each strain with the agar doubling-dilution method described by the British Society for Antimicrobial Chemotherapy (1). Mutants were selected as described previously (5) from B. fragilis NCTC9343/ ATCC25285 (Z14) on Wilkins and Chalgren agar in a single step at 2ϫ MIC of trovafloxacin, moxifloxacin, and ciprofloxacin at mutation frequencies of 2.6 ϫ 10 Ϫ10 , 6.6 ϫ 10 Ϫ9 , and 4.5 ϫ 10 Ϫ9 , respectively. In vitro mutants were also selected in a PD model (11, 12) from Z14, a clinical isolate (Z54), and ATCC 23745 (Z55). From Z14, three mutants (Z50, Z72, and Z73) were selected with trovafloxacin and two mutants (Z69 and Z70) were selected with moxifloxacin. From Z54, one mutant (Z51) was selected with levofloxacin and one mutant (Z52) was selected with trovafloxacin. From Z55, two mutants (Z48 and Z49) were selected with sparfloxacin.Except for garenoxacin and isolate Z72, the MICs of all agents were 2-to 16-fold higher for all mutants than those seen with their parent strain (Table 1). Mutants selected with trovafloxacin on agar (isolate Z56) had a smaller decrease in susceptibility to garenoxacin than mutants selected in the PD model (Z50 and Z72). To study any role of efflux in fluoroquinolone resistance, the efflux inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP) was used. For all parent strains and mutants (except Z69 and Z70), CCCP lowered the MIC of ciprofloxacin two-to fourfold. A total of 32 ciprofloxacin-resistant strains isolated in 1999 from a tertiary hospital in the United States were also investigated. Two isolates were inhibited by Ն8 g of ciprofloxacin/ml, 15 were inhibited by Ն16 g of ciprofloxacin/ml, 10 were inhibited by Ն32 g of ciprofloxacin/ml, and 5 were inhibited by Ն64 g...

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Pharmacodynamics of Fluoroquinolones

Elshaboury

Dilworth

Rotschafer

2016

Methods in Pharmacology and Toxicology

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Fluoroquinolones are a ubiquitous class of broad-spectrum antibacterials used to treat a multitude of bacterial infections in both the inpatient and outpatient settings. Pharmacodynamic research has played an integral role in the drug development and approval process for fl uoroquinolones. There exists a wealth of fl uoroquinolone pharmacodynamic literature and, despite considerable heterogeneity among studies, the results are almost universally the same: f -AUC 24 /MIC ratio is most predictive of microbiologic and clinical effi cacy; >30 for gram-positive and >125 for gram-negative organisms. However, rising rates of fl uoroquinolone resistance, particularly among gram-negative pathogens, may challenge these established pharmacodynamic indices. This chapter discusses the pharmacodynamics of fl uoroquinolones with particular focus on the commonly used agents in current clinical practice: ciprofl oxacin, levofl oxacin, and moxifl oxacin.

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Pharmacodynamics of Trovafloxacin and Levofloxacin against Bacteroides fragilis in an In Vitro Pharmacodynamic Model

Abstract: Over the past several years, clinicians have proposed an alternative method to predict antibiotic performance.

Cited by 23 publications

References 28 publications

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

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

Role of Topoisomerase Mutations and Efflux in Fluoroquinolone Resistance of Bacteroides fragilis Clinical Isolates and Laboratory Mutants

Pharmacodynamics of Fluoroquinolones

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