Drug-drug interactions with fluoroquinolones.

Antimicrobials of the fluoroquinolone class are involved in a number of clinically important drug-drug interactions. Many of these interactions occur with all the available agents and exhibit little interpatient variability. In contrast, others occur only with specific fluoroquinolones and their extent varies markedly among subjects. The oral absorption of all fluoroquinolones is significantly impaired when coadministered with aluminum- and magnesium-containing antacids and sucralfate, as well as with other metal cations such as calcium and iron. Concomitant use of these agents, even when dosed several hours apart, should be avoided. Enoxacin and ciprofloxacin impair the hepatic metabolism of theophylline and caffeine, leading to significantly increased serum concentrations. Ofloxacin and lomefloxacin have only minimal effects on xanthine metabolism. Case reports suggest that concomitant administration of several fluoroquinolones and warfarin, a drug that is also highly metabolized by the liver, leads to increased hypoprothrombinemic effects; prospective studies, however, failed to confirm this interaction. Clinicians must be aware of these and other potential drug-drug interactions with fluoroquinolones for optimal use of the agents.

Pharmacokinetics and safety of single rising doses of ofloxacin in healthy volunteers.

The pharmacokinetics, safety, and disposition of the new antimicrobial fluoroquinolone ofloxacin were evaluated after oral administration in 14 healthy, male volunteers in a double-blind, placebo-controlled study. Ofloxacin was administered as 100-, 300-, and 600-mg doses separated by 1 week. Plasma and urine concentrations after each administration were measured using a sensitive and specific high-performance liquid chromatographic procedure. The distribution of ofloxacin was modeled using a two-compartment open-body model with first-order absorption. Maximum plasma concentrations and area under the plasma concentration versus time curve increased in a linear, dose-proportional manner over the range studied. At all levels, within 36 hours after administration, approximately 70% of the dose was recovered in urine as unchanged ofloxacin and only minimal amounts (less than 4%) as metabolites. No significant changes in the distribution or elimination of the compound were found over the 6-fold dose range. No major laboratory toxicities or clinically significant adverse effects were noted in either the ofloxacin or placebo group.

Pharmacoepidemiology of ciprofloxacin: analysis of use patterns and cost impact.

The pharmacoepidemiology and cost impact of ciprofloxacin use were evaluated after unrestricted availability in a 238-bed community teaching hospital. The medical records on all patients treated with oral ciprofloxacin over 6 months were reviewed. To determine if the availability of ciprofloxacin altered antibiotic usage patterns and outcome variables, a group of control patients from a period prior to ciprofloxacin availability were matched and compared to patients who had received the drug. Ciprofloxacin was used as both initial and replacement for parenteral therapy in a variety of infections. A successful clinical outcome was achieved in approximately 90% of patients treated with ciprofloxacin and resulted in an estimated cost avoidance of approximately $165/course. However, comparisons with the matched-control group revealed no differences in overall antibiotic costs or length of hospital stay. These results suggest that unrestricted availability of oral ciprofloxacin does not ensure changes in outcome variables related to cost. Educational and patient targeting programs may be necessary to promote earlier conversion of appropriate patients to newer oral therapies.

Outpatient general anesthesia: a comparison of a combination of midazolam plus propofol and propofol alone.

STUDY OBJECTIVE: To compare the hemodynamics, efficacy, safety, and postoperative recovery of patients following the use of either midazolam plus propofol or placebo plus propofol for induction and maintenance of general anesthesia for outpatient surgical procedures of less than two hours' duration. DESIGN: Prospective, parallel, randomized, double-blind, placebo-controlled, multicenter study. SETTING: Ten outpatient surgery centers. PATIENTS: 203 ASA physical status I, II, and III patients undergoing various outpatient surgical procedures. INTERVENTIONS: Patients were randomly assigned to one of the two treatment groups. For induction of anesthesia, Group 1 received midazolam (0.077 +/- 0.0021 mg/kg) via slow intravenous (IV) push plus continuous infusion propofol (provided in a concentration of 5 mg/ml), and Group 2 received placebo plus full-concentration (10 mg/ml) propofol. Thereafter, Group 1 received half-concentration propofol and Group 2 received full-concentration propofol via continuous infusion for maintenance of anesthesia. Investigators administered doses of study medication in a blinded fashion as required to achieve the desired clinical effect. Drugs used to maintain anesthesia were restricted to study drug, short-acting opioids, and nitrous oxide. Succinylcholine chloride or vecuronium were used to facilitate intubation of study patients. MEASUREMENTS AND MAIN RESULTS: There were no statistically significant differences between the midazolam/propofol and placebo/propofol groups with respect to the mean (SE) decrease in mean arterial pressure from pre-dose to time of intubation or from time of intubation to initiation of surgery; the mean (SE) time required from initiation of study medication to completion of intubation [6.7 (0.23) minutes vs. 7.0 (0.26) minutes, respectively]; or the mean (SE) amount of propofol required to induce and maintain anesthesia [6.03 (0.329) mg/kg vs. 9.71 (0.489) mg/kg, respectively]. There was no significant difference between the two treatment groups in the time to recovery following the completion of surgery (as assessed by Aldrete Post Anesthesia Recovery Score). Most patients (approximately 79%) in both groups rated the quality of the anesthetic regimen as excellent; however, as assessed by patient questionnaires, fewer patients in the midazolam/ propofol group were able to recall the events surrounding their surgical procedure as compared with patients in the placebo/ propofol group (89.2% vs. 77.9%; p = 0.022). There were no differences between the two groups with respect to the frequency or severity of adverse events. CONCLUSIONS: Concomitantly administered midazolam and reduction-concentration propofol did not exacerbate the well-described hypotensive effects of full-strength propofol during induction of anesthesia. The time to intubation was equivalent with the combination of midazolam/propofol as compared with propofol alone. Recovery from the two regimens was not significantly different. However, reduced recall of perioperative events was observed more often in the midazolam/propofol regimen compared with propofol alone.

Interactions of fluoroquinolones with other drugs: mechanisms, variability, clinical significance, and management.

Several important interactions of fluoroquinolones with other drugs have been reported in the literature. The absorption of all fluoroquinolones is almost entirely inhibited by concomitant administration of di- and trivalent cations, such as aluminum and magnesium contained in antacids. The inhibition of absorption can be significant and can potentially lead to the failure of treatment, even when fluoroquinolone doses are separated from antacid doses by hours. Certain isozymes of the cytochrome P-450 system are selectively inhibited by some fluoroquinolones. The metabolism of theophylline and caffeine is inhibited by enoxacin and ciprofloxacin such that the dosage of theophylline may need to be reduced in order to avoid toxicity. In contrast, ofloxacin and norfloxacin cause less inhibition of the metabolism of these compounds, and reduction of the theophylline dosage is not routinely required. Evidence regarding the effect of fluoroquinolones on the disposition of other drugs known to be metabolized, such as warfarin and cyclosporine, is inconclusive. In summary, the safe and effective use of fluoroquinolone antibiotics requires careful consideration of concomitant drug therapy.

Cefotaxime stability during in vitro microbiological testing.

Cefotaxime is a broad-spectrum cephalosporin which is metabolized or degraded to less active or inactive metabolites by serum esterases, elevated temperatures, or a pH outside of its stability range. Cefotaxime instability during in vitro microbiological susceptibility tests may lead to an underestimation of the antibacterial activity of the compound. Cefotaxime and desacetylcefotaxime solutions were studied under MIC and serum inhibitory titer testing conditions. Cefotaxime concentrations, as measured by high-performance liquid chromatography, decreased 20 to 30% over the incubation period in various systems tested; the greatest decline occurred in systems containing serum in the media. Changes in the results of microbiological susceptibility tests interpreted after 6 and 18 h of incubation were consistent with changes observed in the high-performance liquid chromatography analysis. This study demonstrates cefotaxime instability under conditions of in vitro microbiological testing.

The effect of food or milk on the absorption kinetics of ofloxacin.

We have studied the effects of food or milk on the absorption of ofloxacin in 21 healthy male volunteers in a three-way crossover design. Milk did not alter the rate or extent of absorption of ofloxacin or its elimination. Food altered the onset and/or rate of absorption, but not the extent of absorption or the elimination rate. Thus, food reduced peak ofloxacin concentrations (Cmax) by 20% compared with fasting conditions and the time to reach maximum concentration (tmax) was prolonged on average by 1 h. However, the extent of absorption and the half-life (t 1/2) of ofloxacin were the same after each treatment. These data indicate that food and milk have a clinically insignificant effect on ofloxacin absorption.

In vitro postantibiotic effect following repeated exposure to imipenem, temafloxacin, and tobramycin.

The postantibiotic effect (PAE) following three consecutive 2-h exposures to imipenem, temafloxacin, and tobramycin was determined in Pseudomonas aeruginosa. A PAE and a bactericidal effect were consistently observed for imipenem following each cycle of drug exposure and regrowth. In contrast, the PAE increased with repeated exposure with temafloxacin (1.8 to > 5 h), but disappeared with tobramycin by the third exposure (0.9 to 0 h). These data show that the in vitro PAE may change within a strain following multiple cycles of drug exposure and bacterial regrowth.

Pharmacokinetics and bioavailability of intravenous-to-oral enoxacin in elderly patients with complicated urinary tract infections.

The pharmacokinetics of oral fluoroquinolone antibiotics in normal volunteers have been studied extensively; however, limited patient data exist. Enoxacin steady-state pharmacokinetics and bioavailability were determined following repeated 400-mg intravenous (i.v.) and oral dosing by using compartmental and noncompartmental methods in 10 elderly (mean age, 73.8 years) men with complicated urinary tract infections. Average peak enoxacin concentrations following i.v. and oral dosing were 8.15 and 5.45 mg/liter, respectively. Mean values for major pharmacokinetic parameters (noncompartmental) were similar following i.v. and oral administration, respectively: area under the concentration-time curve from 0 to 12 h, 47.6 and 41.0 mg.h/liter; volume of distribution or volume of distribution/bioavailability, 1.61 and 1.99 liters/kg; total body clearance or total body clearance/bioavailability, 2.58 and 3.01 ml/min per kg; and half-life, 8.2 and 9.1 h. Parameters from analysis of enoxacin plasma concentration data by using a two-compartment pharmacokinetic model also revealed marked similarities between the two administration routes. Enoxacin was highly bioavailable (mean, 86.97%) following oral administration.

Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge: a placebo-controlled study.

OBJECTIVES: To study the toxicology and pharmacology of the endotoxin-neutralizing agent, bactericidal/permeability-increasing protein. DESIGN: Prospective, randomized, placebo-controlled laboratory study. SETTING: Academic research laboratory. SUBJECTS: CD-1 mice (n = 259); Sprague Dawley rats (n = 26); New Zealand White rabbits (n = 19). INTERVENTIONS: Pharmacokinetics of intravenously injected bactericidal/permeability-increasing protein was assessed in mice. Toxicology was tested in mice and rats. Efficacy of intravenously administered bactericidal/permeability-increasing protein as an endotoxin-neutralizing agent was tested in mice, rats, and rabbits. MEASUREMENTS AND MAIN RESULTS: Administration of a single 10-mg/kg bolus injection of bactericidal/permeability-increasing protein resulted in no alterations in hematologic, renal, or hepatic function, activity level, or weight gain in animals observed over a 7-day study period. A single bolus injection (10 mg/kg) of bactericidal/permeability-increasing protein protected 15 of 16 mice from a lethal endotoxin challenge (mortality rate 1/16 [6.25%]) compared with a 100% (16/16) mortality rate in the saline-treated controls (p < .001). Bactericidal/permeability-increasing protein administered up to 1 hr after endotoxin provided significant protection against lethal endotoxin challenge. Furthermore, bactericidal/permeability-increasing protein reduced the induration and dermal necrosis observed in the localized dermal Shwartzman reaction. CONCLUSIONS: Bactericidal/permeability-increasing protein is a potent antiendotoxin that neutralizes endotoxin in vivo and prevents mortality in animal models of lethal endotoxemia.

Dose ranging and fractionation of intravenous ciprofloxacin against Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of infection.

The effect of dose or dose interval on the pharmacodynamics of simulated high-dose intravenous ciprofloxacin therapy on infection due to Pseudomonas aeruginosa and Staphylococcus aureus was studied in an in vitro hollow-fiber model of infection. Simulated doses of 1,200 mg of ciprofloxacin per day as either 400 mg every 8 h or 600 mg every 12 h against P. aeruginosa resulted in selection of ciprofloxacin-resistant bacteria. The results with one test strain that was isolated from a patient prior to administration of intravenous ciprofloxacin demonstrated selection of a gyrA mutant in the model, as had occurred in vivo. A single 1,200-mg dose every 24 h did not select for bacterial resistance; however, breakthrough regrowth of ciprofloxacin-susceptible bacteria occurred. Dosages of 400 or 600 mg of ciprofloxacin every 12 h effectively reduced bacterial counts of one strain each of methicillin-susceptible or -resistant S. aureus, with no bacterial resistance detected at the end of experiment; in contrast, 200 mg every 12 h resulted in bacterial regrowth due to the selection of drug-resistant bacteria. These data show the need for high-dose intravenous ciprofloxacin, particularly with regimens producing high peak levels, for treatment of infections where selection for bacterial resistance is a clinical problem.