Safety and pharmacokinetics of multiple doses of intravenous ofloxacin in healthy volunteers

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.

Section: Materuils and Methodssupporting

confidence: 72%

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

“…This phenomenon was also observed in the single-dose studies (5,15). As expected, these slight differences in absorption rate (3,4) suggests that the current findings can be extrapolated to the 200-and 300-mg once-a-day or ql2h regimens.…”

Section: Methodssupporting

confidence: 56%

Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers

Flor¹,

Rogge²,

Chow³

1993

The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens.Ofloxacin is a synthetic carboxyquinolone antimicrobial agent with potent broad-spectrum bactericidal activity against gram-positive and gram-negative aerobic and facultatively anaerobic bacteria (8 Washout was performed during days 6 to 8. On day 9, the crossover took place and subjects again received p.o. or i.v. ofloxacin (400 mg ql2h) during days 9 to 12. On day 13, they received the last p.o. or i.v. morning dose. All subjects entered the study center at least 12 h prior to administration of the first dose and remained at the center until the last procedure was completed. Subjects were not allowed to eat within 2 h of a dose. For the morning doses, subjects fasted from at least midnight of the previous day. On days 5 and 13, food was not consumed after the prior evening meal until 2 h after the morning dose. Venous blood samples (5 ml) were drawn from each volunteer immediately prior to each dose on days 1, 3, 4, 9, 11, and 12. On days 5 and 13, blood samples were drawn immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 16, and 24 h after dosing began.Analytical procedures. Plasma samples were analyzed for ofloxacin by a sensitive and specific high-pressure liquid chromatographic method previously described (3). After extraction at pH 7 with dichloromethane, the extract was injected onto a C18 ,uBondapak column (25 cm by 4.6 mm [inner diameter]; Waters Associates Inc., Milford, Mass.). The mobile phase consisted of 1.74 g of potassium dihydrogen phosphate and 20 mg of 1-hexanesulfonic sodium salt (Eastman Kodak Co., Rochester, N.Y.) dissolved in 650 ml of distilled water, combined with 350 ml of methanol, and adjusted to pH 3 with phosphoric acid. The imidazolic derivative of ofloxacin (Daiichi Seiyaku) was used as the internal standard. Detection was done with a UV detector at 313 nm. The limit of quantitation was 0.01 mg/liter, and the extraction efficiency was more than 75%. The assay was linear over the concentration range of 0.025 to 9 mg/liter. The intra-and interday coefficients of variation ranged from 3 to 6% over the standard curve concentration range of 0.025 to 9 mg/liter.

“…The early concentrations of each of the seven antibiotics measured in the sera of the mice at 30 min (or 60 min for doxycycline) were of the same order as those found in the sera of humans (14,18) at approximately the same time following administration of the usual doses ( Table 2). The pharmacokinetic characteristics of the drugs in mice infected with Y pestis, especially the short elimination half-lives, were in Fig.…”

Section: Methodsmentioning

confidence: 58%

Assessment of a fluoroquinolone, three beta-lactams, two aminoglycosides, and a cycline in treatment of murine Yersinia pestis infection

Bonacorsi

Scavizzi

Guiyoule

et al. 1994

Amoxicillin, cefotaxime, ceftriaxone, gentamicin, doxycycline, and ofloxacin were active in vitro, like the reference drug streptomycin, against the virulent strain Yersinia pestis 6/69M. The comparative efficacies of these drugs in vivo were evaluated in a standardized and reproducible mouse model of systemic infection. Each antibiotic was injected intravenously once, at 24 h postinfection, and then repeatedly during 48 h. In vivo results were measured by counting the viable bacteria recovered from the whole spleens of mice sacrificed at selected times. All the drugs were manifestly successful; ceftriaxone, ofloxacine, and the reference drug were the most effective. Therefore, gentamicin and doxycycline could be used, depending on the clinical forms of the Y. pestis infection. Further investigations on beta-lactams, especially those used in the present study, could be carried out to confirm or not confirm their activities against Y. pestis. Ofloxacin appeared to be as active and to perform as rapidly as streptomycin in the treatment of murine Y. pestis infection, which is in agreement with the previous successes obtained with the use of fluoroquinolones in the treatment of murine infections caused by other pathogenic yersiniae.Three pathogenic species are included in the genus Yersinia. Y enterocolitica and Y pseudotuberculosis essentially cause gastroenteritis and occasionally septicemia. Y pestis, which was discovered in 1894 by Alexandre Yersin, is the agent of plague.Despite the efforts of public health workers to control plague, this infection still has a widespread distribution in the world (7,20,22,25,35). During the last decade (1980 to 1989), 21 countries notified the World Health Organization of almost 10,000 cases of plague, and the global fatality rate was 11.5%, with peaks in some countries exceeding 35% (35). If, at the moment, the worldwide incidence seems to be stable, a few countries regularly report an increasing number of cases. In the four past decades (the 1950s, 1960s, 1970s, and 1980s), the United States has recorded 10, 28, 105, and 179 cases of plague, respectively (6, 35). Septicemic plague, which is difficult to recognize, may represent 20 to 25% of the cases of plague in the United States (17, 34). Secondary localizations, for example, pulmonary or meningeal, may complicate 6% of cases of bubonic or septicemic plague (3, 5) and up to now have been characterized by a high death rate, in some reports rising to 33% (2, 17).Forty years ago, Meyer (23) considered streptomycin, chloramphenicol, and tetracyclines to be reference drugs for the treatment of plague, and they are still recommended for that use today (3). This limited antibiotic choice can be a serious handicap because of (i) localization of the disease (e.g., meningitis), (ii) underlying disease, or (iii) antibiotic side effects.In the face of this dilemma, it seemed to us that it would be useful to evaluate the in vivo comparative efficacies of newer antibiotics like fluoroquinolones and extended-spectrum cephalosporins agains...