Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis

Abstract

We examined the impact of dose fractionation and altered MICs on survivorship in a neutropenic rat model of Pseudomonas aeruginosa sepsis employing the new fluoroquinolone antibiotic lomefloxacin. Once-daily administration of a drug dose which produced a high peak concentration/MIC (peak/MIC) ratio (ca. 20/1) produced significantly better survivorship compared with regimens employing the same daily dose but on a more fractionated schedule. The use of a smaller dose, producing lower (< 10/1) peak/MIC ratios, did not show this effect, as once-daily and twice-daily regimens produced equivalent results (the area under the concentration-time curve/MIC ratio was linked to survivorship). Challenge with resistant mutants selected for altered MICs of fluoroquinolones (two and four times the MIC for the parent strain, respectively) resulted in markedly diminished survivorship. Challenge with the parent strain and use of a drug dose which produced a peak/MIC ratio identical to that for animals challenged with the mutant for which the MIC was four times that for the parent strain and treated with the larger drug dose produced survivorship curves which were not different. For this animal model, peak/MIC ratio was linked to survivorship, particularly when high ratios (10/1 to 20/1) were obtained. At lower doses, producing peak/MIC ratios <10/1, the area under the concentration-time curve relative to the MIC appeared to be most closelylinked to outcome. The time that levels in plasma exceeded the MIC did not influence survivorship. The hypothesis most likely to explain these findings is that higher peak/MIC ratios can suppress the parent strain and mutant organisms (gyrA and transport mutants) for which the MIC is higher but limited (no more than eight times that for the parent strain).Schedules of antibiotic dosing can be altered to improve the outcome for severely infected patients. Many years passed before convincing data indicating that different classes of antimicrobial agents (e.g., ,-lactams and aminoglycosides) require different schedules for optimal outcome for severely infected patients were generated (3,12,13,17). In general, in vitro and animal model systems have provided necessary insights which have guided the design of clinical trials to provide the data which have proven these hypotheses in the clinical arena (1,6,8).Fluoroquinolone antimicrobial agents have been recently introduced into the physicians' therapeutic armamentarium. These agents are highly active against aerobic or facultative gram-negative bacilli. They have been shown to be very concentration dependent in their rate of kill. This property makes them resemble aminoglycosides more than ,3-lactam antibiotics in their microbiological properties. As these drugs have become more widely used clinically, we felt it important to investigate the relationship between the concentration in plasma-time profile and survivorship in a model of Pseudomonas aeruginosa sepsis in neutropenic rats.MATERIALS AND METHODS Bacteria. Several blood culture isolates of P. a...

Patient stratification in the management of acute bacterial exacerbation of chronic bronchitis: the role of levofloxacin 750 mg

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Quinolones: a class of antimicrobial agents

“…Similar results were observed in an in vivo model of Streptococcus pneumoniae in mice with ciprofloxacin (Sullivan et al, 1993), indicating that the peak concentration/MIC ratio had to reach a value of 10.6 for optimum protection in that model. Drusano et al (1993) provided some additional insight by administering lomefloxacin to neutropenic rats with Ps. aeruginosa sepsis as a single daily dose which produced high peak concentration/MIC ratios (approximately 20/1) or as the same total daily dose fractionated into four daily injections, the latter producing a longer time above the MIC.…”

“…doses up to 11 mg/kg every 12 h) and for a variety of other infections, such as mycobacterial infections (Studdert and Hughes, 1992); prostatitis (Dorfman et al, 1995) and osteomyelitis (Duval and Budsberg, 1995) caused by susceptible bacteria. Higher recommended doses were calculated on the basis of an assumption that the concentrations of quinolones must exceed the MIC 90 for the entire dosing interval (Walker et al, 1992), this was later shown to be an incorrect assumption (Drusano et al, 1993;Forrest et al, 1993). In dogs, a therapeutically equivalent dose of ciprofloxacin has been suggested to be 4-5 times the dose (on a mg/kg basis) of enrofloxacin which is 2.5 mg/kg twice a day; however, the scientific justification for this recommendation is questionable.…”

Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models

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