Anti-anaerobic activity of serum from patients treated with tigecycline for skin/soft tissue infections.

To gain additional data concerning the anti-anaerobic activity of tigecycline in serum, we analyzed blood samples from six patients with a complicated skin/soft tissue infection who were receiving IV tigecycline 50 mg every 12 h. Venous blood samples were obtained after multiple doses of tigecycline at 1, 6 and 12 h after the initiation of a 1 h IV infusion. Sera from these samples were tested to determine serum inhibitory and bactericidal activity over time against 4 anaerobic bacteria (Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia and Finegoldia magna). An analysis of serum titers found that tigecycline exhibited early (1 h) and prolonged (12 h) inhibitory activity against each study isolate. Moreover, it provided bactericidal activity for 12 h against these strains with the exception of F. magna. Tigecycline was found to exhibit antibacterial activity at serum concentrations below the MICs of the anaerobic bacteria tested. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of drug and that serum appears to enhance this antibacterial activity.

A multicenter comparative trial of three-day norfloxacin vs ten-day sulfamethoxazole and trimethoprim for the treatment of uncomplicated urinary tract infections.

Two-hundred nine patients with symptoms of acute urinary tract infection and pyuria were randomized to 400 mg of administered norfloxacin twice daily for three days, or 800 mg of sulfamethoxazole and 160 mg of trimethoprim administered twice daily for ten days. Therapeutic outcome was assessed five to nine days and four to six weeks after treatment. The cure rates were 71/74 (96%) with norfloxacin and 81/81 (100%) with sulfamethoxazole and trimethoprim five to nine days after treatment. Only seven patients had a recurrence at the second follow-up visit; four in the norfloxacin group and three in the sulfamethoxazole and trimethoprim group. No isolates were resistant to norfloxacin, but three Escherichia coli were resistant to sulfamethoxazole and trimethoprim. Fifteen patients in each group reported a side effect during treatment. Two patients in the norfloxacin group and four patients in the sulfamethoxazole and trimethoprim group discontinued therapy due to an adverse effect. In this multicenter study, a three-day course of norfloxacin was as effective and safe as a ten-day regimen of sulfamethoxazole and trimethoprim in the treatment of acute uncomplicated urinary tract infections.

Review of the bioavailability and pharmacokinetics of oral norfloxacin.

The pharmacokinetic profile of norfloxacin, an oral fluoroquinolone, is more complex than that of many antibacterial agents. Following administration of a 400-mg dose, peak serum concentrations of 1.5 to 2.0 micrograms/ml are achieved within one to two hours. The drug is widely distributed throughout the body, achieves high ratios of tissue to serum concentrations in both renal and prostatic tissue, and undergoes metabolic conversion. Six metabolites of norfloxacin have been identified. Approximately 30 percent of an administered dose is excreted as unchanged drug by glomerular filtration and tubular secretion. Following a single dose of norfloxacin, therapeutic levels of drug in the urine are achieved rapidly and maintained for at least 12 to 24 hours. Norfloxacin has a terminal elimination half-life of approximately three hours, although the presence of a reduced glomerular filtration rate increases the elimination half-life. Dosage modification is, therefore, necessary when the glomerular filtration rate falls below 20 ml/minute.

Drug interactions with fluoroquinolones.

The fluoroquinolones are a new class of antimicrobial agents that are now widely prescribed for a number of bacterial infections. Because of their complex pharmacokinetics, there is a potential for several types of drug interactions. Currently, only two drug interactions have been well studied. These involve a decrease in absorption when fluoroquinolones are given in combination with multivalent metal cations and an inhibition in the metabolism of methylxanthines by fluoroquinolones such as ciprofloxacin, enoxacin, and norfloxacin. These drug interactions can be easily avoided. Significant decreases in the absorption of fluoroquinolones by metal cations can be prevented by staggering the doses of these drugs. To avoid alterations in methylxanthine metabolism, newer fluoroquinolones, such as lomefloxacin, ofloxacin, and temafloxacin, should be utilized; alternatively, theophylline serum levels can be carefully monitored. Several other potentially serious drug interactions involving cyclosporine, warfarin, and nonsteroidal anti-inflammatory drugs have been reported, but additional investigations are required before their overall clinical significance can be fully determined. Since the use of fluoroquinolones will continue to escalate over the next decade, continued patient surveillance is necessary so that potential drug interactions can be recognized, described, and prevented.

Comparative serum bactericidal activity of clarithromycin and azithromycin against macrolide-sensitive and resistant strains of Streptococcus pneumoniae.

The serum pharmacodynamics of clarithromycin and azithromycin were studied against isolates of S. pneumoniae, including efflux resistant (M. phenotype) strains, by analyzing their serum bactericidal activity (SBA) over time. Normal healthy subjects were given a single 500 mg oral dose of these macrolides and serum samples were collected over 12 hrs. Paired isolates with MICs ranging from 0.25 ug/ml to 8.0 ug/ml were analyzed. Prolonged (at least 6 hrs) SBA was observed with clarithromycin for strains with MICs < or = 2.0 ug/ml. No SBA was observed in strains with MICs >or = 4.0 ug/ml. Azithromycin exhibited SBA for at least 6 hrs for strains up to a MIC = 0.5 ug/ml. No SBA was observed for isolates with MICs > or = 1.0 ug/ml. In contrast to azithromycin, clarithromycin exhibited SBA for at least one-half of its normal dosing interval against S. pneumoniae strains well above its current susceptibility breakpoint concentration of 0.25 microg/ml. These findings may have relevance to the ongoing debate as to the appropriate susceptibility breakpoints for the newer macrolides.

Urinary pharmacodynamics of low-dose ciprofloxacin and ofloxacin.

The incidence of resistant uropathogens to the fluoroquinolones is increasing, but their effectiveness in the urine against these strains is unknown. In this investigation, we studied the urinary pharmacodynamics of ciprofloxacin (100 mg) and ofloxacin (200 mg) against urinary isolates that were moderately resistant to ciprofloxacin (Escherichia coli, MIC = 4; Klebsiella pneumoniae, MIC = 4. Staphylococcus saprophyticus, MIC = 8) and ofloxacin. Seven healthy female volunteers received three doses (one dose every 12 h) of ciprofloxacin and ofloxacin in a randomized, crossover design with a 1-week washout period between regimens. Urine bactericidal activity was determined after the first and third dose of each drug. Both ciprofloxacin and ofloxacin exhibited prolonged (> or = 6 h) urine bactericidal activity against the E. coli and K. pneumoniae isolates after the first dose. No bactericidal activity was demonstrated for ciprofloxacin against the S. saprophyticus strain. In contrast, ofloxacin exhibited urine bactericidal activity for 8 h against this isolate. Similar findings were observed after the third dose, with the exception that ciprofloxacin exhibited a short period (4 h) of bactericidal activity against the S. saprophyticus strain. In summary, low-dose regimens of ciprofloxacin and ofloxacin exhibited prolonged bactericidal activity against moderately resistant strains of common bacterial uropathogens. Only ofloxacin demonstrated bactericidal activity in the urine during the first dosing interval against a moderately resistant isolate of S. saprophyticus.

Use of rDNA restriction fragment length polymorphisms to differentiate strains of Candida albicans in women with vulvovaginal candidiasis.

Epidemiologic studies in women with recurrent Candida vaginitis have been hampered in the past by the lack of a reproducible typing system. Several molecular probes have now been developed that have the ability to differentiate strains of Candida albicans and give reproducible results. In this investigation, 24 women with Candida vaginitis were studied in a longitudinal fashion for 30 days following short-course antifungal therapy. Seven women with either recurrent vaginitis or with multiple culture-positive sites with C. albicans were included in an epidemiological study. A total of 18 isolates of C. albicans (12 vaginal and six rectal) were typed utilizing restriction fragment length polymorphisms of rDNA. This technique was able to differentiate five different strains of C. albicans. Our epidemiologic study revealed that vaginal and rectal strains recovered from the same women were usually different. None of our patients had a similar vaginal and rectal strain prior to treatment, and only one patient had the same strain isolated from both the rectum and the vagina at the time of recurrence. On the other hand, we found that the same strain of C. albicans was initially and later recovered from the vagina in four of five women who failed treatment or developed recurrent vaginitis. These results suggest that recurrent episodes of C. albicans vaginitis, following short-course antifungal therapy, are often due to relapse of the original infecting strain and not due to autoinoculation from the rectum.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection.

This multicenter clinical trial compared single-dose fosfomycin tromethamine with a 7-day course of nitrofurantoin for the treatment of acute uncomplicated lower urinary tract infection (UTI) in female patients. Healthy females with symptoms of acute uncomplicated UTI were enrolled in a double-masked, randomized clinical trial. Assessable patients had >10(5) colony-forming units per milliliter of a uropathogen in a clean-voided midstream urine sample. Patients received a single 3-g dose of fosfomycin tromethamine plus 7 days of placebo capsules or a single 3-g dose of placebo plus 7 days of nitrofurantoin monohydrate/macrocrystal 100-mg capsules. Treatment efficacy was assessed by both bacteriologic and clinical response 5 to 11 days after the initial treatment dose (visit 2) and 5 to 11 days (visit 3) and 4 to 6 weeks (visit 4) after the last day of medication. Of the 749 patients initially enrolled in the study, 375 received fosfomycin and 374 received nitrofurantoin. There were no clinical differences in patient characteristics between the 2 groups at study entry. Overall, 94% of pretreatment isolates were susceptible to fosfomycin and 83% were susceptible to nitrofurantoin. Bacteriologic cure rates at the first follow-up visit (5 to 11 days after initiation of treatment) were 78% and 86% for fosfomycin and nitrofurantoin, respectively (P = 0.02). At visit 3 (1 week posttreatment), they were 87% and 81% for fosfomycin and nitrofurantoin, respectively (P = 0.17). Both treatment groups had an 80% overall clinical success rate (cure and improvement). Twenty patients (5.3%) who received fosfomycin and 21 patients (5.6%) who received nitrofurantoin reported an adverse effect related to study medication. The most common side effects related to fosfomycin treatment were diarrhea (2.4%), vaginitis (1.8%), and nausea (0.8%). Both bacteriologic and clinical cure rates observed with a single 3-g dose of fosfomycin were comparable to those achieved with a 7-day course of nitrofurantoin in female patients with acute uncomplicated UTI.

Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects.

The relative bioavailability and pharmacokinetics of ofloxacin tablets and a reference oral solution of ofloxacin were compared in 32 normal male subjects using a randomized two-way crossover design. After an overnight fast, subjects were randomized to receive a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) and blood samples were obtained prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose. After a 5-day wash-out period, subjects were administered the same dose but of the other formulation, and blood samples were collected in an identical manner. Plasma concentrations of ofloxacin were determined by high-pressure liquid chromatography. The results showed that ofloxacin tablets were more slowly absorbed when compared to the solution and mean peak plasma concentrations were obtained in about 1.5 hours for the tablet preparation. Maximum plasma concentrations were higher after administration of the solution (Cmax = 2.24 micrograms/ml, 200 mg; Cmax = 3.25 micrograms/ml, 300 mg) compared to the tablet (Cmax = 1.74 micrograms/ml, 200 mg; 2.61 micrograms/ml, 300 mg). The bioavailability of ofloxacin tablets was greater than 98% compared to the solution. The other pharmacokinetic parameters were similar between the two dosage formulations. Ofloxacin tablets revealed an apparent volume of distribution of 1.5 l/kg, an elimination half-life of 5.6 hours, and a total clearance of 251 ml/min. In addition, a linear increase in plasma concentrations was observed when the dose of ofloxacin was increased. In summary, ofloxacin tablets was found to be reliably bioavailable and bioequivalent to the reference solution.

The 4-quinolone antibiotics: past, present, and future.

During the past 5 years the 4-quinolone antibiotics have progressed from relative obscurity to a highly visible and intensely studied class of compounds. The zeal for developing and marketing newer fluoroquinolones closely parallels that of the cephalosporins for the last 10 years. All of these newer agents appear to have similar mechanisms of action, but numerous derivatives of the basic 4-quinolone structure have been synthesized in an effort to enhance the antimicrobial spectrum and pharmacologic properties of these antibiotics.

Sparfloxacin: potential clinical and economic impact in the treatment of respiratory infections.

Sparfloxacin is a new oral fluoroquinolone antimicrobial that is highly active against common respiratory pathogens, including multiresistant strains. It is well absorbed and has excellent penetration into upper and lower respiratory tissues. Sparfloxacin is administered once a day and does not interfere with the metabolism of other drugs. The agent is highly effective and safe in the treatment of acute sinusitis, exacerbations of chronic bronchitis, and community-acquired pneumonia. Due to its activity against multidrug-resistant respiratory pathogens, it has the potential to prevent hospitalization as well as decrease parenteral antibiotic therapy. Consequently, it may generate significant pharmacoeconomic benefits to patients and payers of medical care.

Pharmacodynamic activity of five oral cephalosporins against Haemophilus influenzae.

STUDY OBJECTIVES: To determine the time above minimum inhibitory concentration (T > MIC) and serum bactericidal activity of five oral cephalosporins against two strains of Haemophilus influenzae. DESIGN: Randomized, crossover study. SETTING: University-associated research center. SUBJECTS: Ten healthy volunteers. INTERVENTIONS: Each subject received a single dose of cefpodoxime 200 mg, cefuroxime 500 mg, cefaclor 500 mg, cefprozil 500 mg, or loracarbef 400 mg each week for 5 weeks. Blood for serum levels was obtained at time zero and 1, 2, 3, 4, 6, 8, and 12 hours after each dose. MEASUREMENTS AND MAIN RESULTS: Cefpodoxime produced serum concentrations above the MIC for more than 90% of the time for both beta-lactamase-negative and -positive strains of H. influenzae. Moreover, it had serum bactericidal activity for 12 hours against both isolates. Cefuroxime was the second most active cephalosporin, with serum concentrations above the MIC of both isolates for 60% of the time. Cefuroxime provided serum bactericidal activity for 12 hours against the beta-lactamase-negative strain and 6 hours against the beta-lactamase-positive strain of H. influenzae. Even though the T > MIC was less than 50% of the study period for the other cephalosporins, all but cefaclor provided serum bactericidal activity for 12 hours against the beta-lactamase-negative isolate. Cefaclor provided measurable serum bactericidal activity for only 3 hours. The duration of serum bactericidal activity of cefprozil, loracarbef, and cefaclor against the beta-lactamase-positive isolate was 4, 2, and 0 hours, respectively. CONCLUSION: Cefpodoxime was the most active cephalosporin studied based on T > MIC and serum bactericidal activity against isolates of H. influenzae.

Cost-effectiveness of sparfloxacin compared with other oral antimicrobials in outpatient treatment of community-acquired pneumonia.

We examined the cost-effectiveness of sparfloxacin compared with other selected oral antimicrobials in outpatient treatment of community-acquired pneumonia (CAP) using clinical pathway-based decision analysis. Cost estimates were obtained from medical claims databases and Medicare reimbursement schedules. Probability estimates were derived from published clinical trials, the medical literature, and clinical expert opinion. Overall adjusted efficacy rates were 89% for sparfloxacin, 79.4% for azithromycin, 77.8% for clarithromycin, 73% for cefaclor, 70.8% for amoxicillin-clavulanic acid, and 69% for erythromycin. The expected total cost/CAP episode of treatment with sparfloxacin was $216.07 compared with $258.97, $297.08, $345.75, $389.80, and $395.93 for azithromycin, clarithromycin, erythromycin, amoxicillin-clavulanic acid, and cefaclor, respectively. Therapy with sparfloxacin for managing CAP is cost effective-relative to other commonly prescribed antibiotics, resulting in net cost savings.

A preliminary study of clarithromycin versus doxycycline in the treatment of nongonococcal urethritis and mucopurulent cervicitis.

In a comparison of drug safety and efficacy, 40 adult outpatients with clinical signs and symptoms of nongonococcal urethritis or mucopurulent cervicitis were treated with either clarithromycin 250 mg or doxycycline 100 mg twice/day for 7 days. Clinical and laboratory evaluations were repeated during, at the end, and 3 weeks after the completion of therapy. Isolation and susceptibility tests of Chlamydia and Mycoplasma isolates were performed at each visit. All but one patient who received doxycycline were clinically cured or improved at the end of treatment. Two (10%) patients who received clarithromycin and three (15%) who received doxycycline had clinical relapses of the infection. All isolates of Chlamydia trachomatis were eradicated and did not recur in both groups. Doxycycline was more effective than clarithromycin in eradicating Ureaplasma urealyticum (p < 0.01). Both groups reported a high frequency of minor adverse effects, but no patient discontinued therapy. Overall, clarithromycin was clinically safe and effective treatment in patients with nongonococcal urethritis and mucopurulent cervicitis.

Safety of multiple doses of ofloxacin in healthy volunteers.

A safety profile of ofloxacin, a new fluoroquinolone antibiotic, was assessed in twelve healthy male volunteers. Ofloxacin was dosed at 400 mg twice daily over a 10-day course of treatment. This evaluation included chemistry and haematologic profiles, neurologic evaluations, ophthalmologic examinations, audiometric testing, and electrocardiogram before, during and the end of the study. In addition, plasma samples were analysed for ofloxacin prior to each morning dose and a complete plasma concentration profile was performed on day 6. Gastrointestinal complaints such as nausea, diarrhoea and upset were the most frequent side effects reported. The only other adverse event that occurred in more than one volunteer was headache. None of the subjects in this study developed a serious side effect and no physical or psychological changes were observed. Laboratory values remained in their normal ranges with the exception of one volunteer who developed a 3-fold rise in one liver function test at the end of the study. The subject was asymptomatic and this aberration resolved without sequelae. In summary, a 10-day course of ofloxacin was found to be safe and have a low potential for toxicity. The side effects observed in this study were mild and similar to those observed with other fluoroquinolones.

Fosfomycin tromethamine: single-dose treatment of acute cystitis.

Fosfomycin tromethamine is an oral antimicrobial indicated for the treatment of uncomplicated lower urinary tract infections (UTIs). This agent is active in the urine against common uropathogens that are associated with cystitis in women, including organisms resistant to other antibiotics. A single dose of fosfomycin tromethamine is well absorbed and produces a therapeutic concentration in the urine for one to three days. Comparative clinical trials suggest that a single 3.0-g dose of fosfomycin tromethamine is as clinically effective as 7- to 10-day treatment regimens of standard agents such as nitrofurantoin, norfloxacin, and trimethoprim/sulfamethoxazole used to treat UTIs. Fosfomycin tromethamine is well tolerated and appears safe for use during pregnancy. Quality-of-life advantages, such as enhanced compliance and convenience, are also important aspects of fosfomycin tromethamine therapy.

Pharmacokinetic evaluation of ceftiofur in serum, tissue chamber fluid and bronchial secretions from healthy beef-bred calves.

Ceftiofur is a new broad spectrum cephalosporin marketed for the treatment of acute bovine respiratory disease. In this investigation ceftiofur was administered by intramuscular injection, at 24 h intervals, to healthy beef-bred calves for four days at dosages of 2.2 and 4.4 mg/kg of body weight, with 4 wk intervals between dosing regimens. Serum, tissue chamber fluid (TCF), and bronchial secretion (BS) concentrations of ceftiofur were measured by microbiological assay after the first and fourth dose of each dosing regimen. Peak serum concentrations (Cmax) of 8.8 micrograms/mL and 17.3 micrograms/mL were obtained approximately 2 h (Tmax), the time of mean peak concentration) after single injections of 2.2 mg/kg and 4.4 mg/kg, respectively. The Cmax was increased approximately twofold following multiple doses of 2.2 mg/kg (Cmax = 13.1 micrograms/mL) and 4.4 mg/kg (Cmax = 24.1 micrograms/mL). Ceftiofur accumulated slowly into TCF and peak concentrations were found to be approximately 14% of those observed in serum after the first dose and approximately 24% after multiple dosing. Concentrations of ceftiofur in BS were obtained rapidly with peak concentrations reaching 45% of the serum Cmax after the first dose. After multiple dosing the Cmax for BS was approximately 25% of the serum Cmax. This study found that both the 2.2 mg/kg and 4.4 mg/kg dosing regimens resulted in continuous serum, TCF and BS concentrations of ceftiofur that exceeded the minimal concentration required to inhibit the bacteria most frequently isolated from calves with acute bovine respiratory disease.

Pharmacokinetics, nephrotoxicosis, and in vitro antibacterial activity associated with single versus multiple (three times) daily gentamicin treatments in horses.

Once-daily administration of aminoglycosides may be a safe and effective therapeutic regimen, on the basis of the microbiologic and pharmacokinetic characteristics of these antibiotics. This study was designed to determine serum and tissue concentrations following i.v. administration of gentamicin, at dosages of 6.6 mg/kg of body weight, every 24 hours, and 2.2 mg/kg, every 8 hours, for 10 days in adult horses. Nephrotoxicosis from these dosage regimens also was compared, and microbiologic effects, including postantibiotic effects, were determined with various concentrations of gentamicin against an equine clinical isolate of Pseudomonas aeruginosa. Treatment at the 6.6-mg/kg dosage resulted in maximal serum concentrations (77.93 +/- 19.90 micrograms/ml, mean +/- SEM) and area under the concentration-vs-time curves (83.79 +/- 14.97 micrograms.h/ml) that were significantly (P < 0.05) greater than those following treatment at the 2.2-mg/kg dosage (5.05 +/- 0.50 micrograms/ml and 6.03 +/- 0.66 micrograms.h/ml, respectively). Nephrotoxicosis was not induced with either dosage regimen, and postantibiotic effects were prolonged with a higher gentamicin concentration. This study provided evidence to support the use of once-daily gentamicin treatment in adult horses.

Pharmacokinetic evaluation of enrofloxacin administered orally to healthy dogs.

Enrofloxacin was administered orally to 6 healthy dogs at dosages of approximately 2.75, 5.5, and 11 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosage regimens. Serum and tissue cage fluid (TCF) concentrations of enrofloxacin were measured after the first and seventh treatments. The mean peak serum concentration occurred between 1 and 2.5 hours after dosing. Peak serum concentrations increased with increases in dosage. For each dosage regimen, there was an accumulation of enrofloxacin between the first and seventh treatment, as demonstrated by a significant (P = 0.001) increase in peak serum concentrations. The serum elimination half-life increased from 3.39 hours for the 2.75 mg/kg dosage to 4.94 hours for the 11 mg/kg dosage. Enrofloxacin accumulated slowly into TCF, with peak concentrations being approximately 58% of those of serum. The time of peak TCF concentrations occurred between 3.8 hours and 5.9 hours after drug administration, depending on the dosage and whether it was after single or multiple administrations. Compared with serum concentrations (area under the curve TCF/area under the curve serum), the percentage of enrofloxacin penetration into TCF was 85% at a dosage of 2.75 mg/kg, 83% at a dosage of 5.5 mg/kg, and 88% at a dosage of 11 mg/kg. All 3 dosage regimens of enrofloxacin induced continuous serum and TCF concentrations greater than the minimal concentration required to inhibit 90% (MIC90) of the aerobic and facultative anaerobic clinical isolates tested, except Pseudomonas aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)