Pharmacodynamics of Once-Daily Amikacin in Various Combinations with Cefepime, Aztreonam, and Ceftazidime against
            <i>Pseudomonas aeruginosa</i>
            in an In Vitro Infection Model

An in vitro pharmacodynamic system has been successfuly adapted to simulate in vivo antimicrobial pharmacokinetics under anaerobic conditions. This system was used to perform time-kill kinetic studies which were designed to compare the activity of temafloxacin to ciprofloxacin and cefotetan against two strains of Bacteroides fragilis (ATCC 25285 and ATCC 23745 fragilis. Ciprofloxacin was not bactericidal (<3 log10 unit decline in bacterial numbers) to either strain of B.fragilis. Cefotetan was bactericidal (.3 log1o unit decline in bacterial numbers) to each strain but killed at a slower rate than temafloxacin. Times to 3 loglo unit declines of strain ATCC 25285 were 2, 4, and >24 h, whereas those of strain ATCC 23745 were 4, 4, and >24 h for temafloxacin, cefotetan, and ciprofloxacin, respectively. Total logarithmic declines of strain ATCC 25285 were >4.5, >4.5, and 2.9 log1o CFU/ml, whereas those of strain ATCC 23745 were 4.1, >4.5, and 1.2 log1o CFU/ml for each drug, respectively. These and other studies demonstrated that temafloxacin showed potential as an agent that could have been further developed for use in the treatment of anaerobic infections. However, the drug was removed from the market by its manufacturer because of toxicity issues. Although the release of newer fluoroquinolones that possess significant activity against anaerobic bacteria does not appear imminent, the time-kill studies performed in this study demonstrate that further research is warranted in the development of fluoroquinolones which possess significant antianaerobic activity.Bacteroides fragilis is an important human pathogen in intra-abdominal and gynecologic infections. Antimicrobial regimens for infections that involve B. fragilis have generally been limited to certain ,B-lactams, clindamycin, chloramphenicol, or metronidazole. The prevalence of severe adverse reactions to chloramphenicol and the development of significant resistance among B. fragilis strains to clindamycin have driven the search for safe and effective therapeutic alternatives. All of the currently available fluoroquinolones possess excellent activity against aerobic and facultative gram-negative bacteria. Temafloxacin, however, has been shown to have significant in vitro activity against anaerobic bacteria while retaining excellent activity against most members of the Enterobacteriaceae (6,9,17). The in vitro evaluation of the activity of the fluoroquinolones against anaerobic bacteria has been based on standardized MIC testing. MIC testing methods possess some inherent restrictions that limit the researcher's ability to optimally evaluate the activity of a drug in vitro.The purpose of this study was to use an in vitro pharmacodynamic system to evaluate the activity of temafloxacin, ciprofloxacin, and cefotetan against two strains of B. fragilis. Through time-kill curve analysis, this system can exploit the pharmacokinetic and pharmacodynamic differences between drugs and thereby evaluate their relative in vitro efficacies.

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Evaluation of activity of temafloxacin against Bacteroides fragilis by an in vitro pharmacodynamic system

Zabinski

Vance‐Bryan

Krinke

et al. 1993

“…For the combination regimens, the peristaltic pump was set to achieve a 3-h half-life for rifampin, with ofloxacin added as a bolus to a supplement model to serve as a reservoir and to maintain its 6-h half-life (2 h, and the colonies were counted. The reliable limit of detection was 100 CFU/ml, as described previously (27 Pharmacokinetics. The individual drug concentrations and half-lives achieved for the 400-mg i.v.…”

Section: Materuils and Methodsmentioning

confidence: 99%

“…A two-compartment glass model simulating the pharmacokinetics of drugs in humans was used as described previously (7,27). The central compartment volume was 1,000 ml, into which antibiotics were added as a bolus.…”

Section: Materuils and Methodsmentioning

confidence: 99%

Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model

Kang

Rybak

McGrath

et al. 1994

The pharmacodynamic properties of levofloxacin (an optically active isomer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combination with rifampin, were evaluated over 24 to 48 h against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) energy-dependent efilux process mediated by the norA gene appeared to be responsible for the resistance observed. Our data suggest that with levofloxacin there is a more rapid onset of bactericidal activity than with ofloxacin or ciprofloxacin against MSSA 1199 and that the activity of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even when the pharmacokinetics of the drug were set to equal those of ciprofloxacin, suggesting that ofloxacin differs from ciprofloxacin irrespective of time of exposure. The resistance to ciprofloxacin that developed in our in vitro model may be mediated by the cfxc-ofr locus, which has been shown to be associated with low-level fluoroquinolone resistance. Overall, levofloxacin demonstrated potent bactericidal activity against S. aureus, without the emergence of resistance in our infection model. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not synergistic but prevented the emergence of ciprofloxacin resistance.

“…In vitro pharmacokinetic and pharmacodynamic models have increasingly been used to study therapeutic issues in infectious disease pharmacotherapy (21,34,35). We described an in vitro model adapted to incorporate simulated endocardial vegetations.…”

Section: In Vitro Model Of Endocarditis a One-compartment In Vitromentioning

confidence: 99%

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis

McGrath

Kang

Kaatz

et al. 1994

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%o)