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.

Symmetry breaking of in-plane order in confined copolymer mesophases.

Packing of spherical-domain block copolymer mesophases confined to a thin film is investigated as a function of the number of layers n. We find an abrupt transition from hexagonal to orthorhombic in-plane ordering of domains when n is increased from 4 to 5. As n increases further (up to 23 in this study), the symmetry of the orthorhombic phase asymptotically approaches that of the body-centered cubic (110) plane. These results are interpreted in terms of the energetics of competing packings in the bulk and at the film interfaces. Detailed structural and thermodynamic properties are obtained with self-consistent field theory.

Single-crystal diffraction from two-dimensional block copolymer arrays.

The structure of oriented 2D block copolymer single crystals is characterized by grazing-incidence small-angle x-ray diffraction, demonstrating long-range sixfold orientational order. From line shape analysis of the higher-order Bragg diffraction peaks, we determine that translational order decays algebraically with a decay exponent eta=0.2, consistent with the Kosterlitz-Thouless-Halperin-Nelson-Young theory for a 2D crystal with a shear modulus mu=2 x 10(-4) N/m.

Standardization of broth microdilution and disk diffusion susceptibility tests for Actinobacillus pleuropneumoniae and Haemophilus somnus: quality control standards for ceftiofur, enrofloxacin, florfenicol, gentamicin, penicillin, tetracycline, tilmicosin, and trimethoprim-sulfamethoxazole.

Quality control (QC) standards for the in vitro antimicrobial susceptibility testing of two fastidious veterinary pathogens, Actinobacillus pleuropneumoniae and Haemophilus somnus, were developed in a multilaboratory study according to procedures established by the National Committee for Clinical Laboratory Standards for broth microdilution and disk diffusion testing. The medium recommended for the broth microdilution testing is cation-adjusted Mueller-Hinton broth supplemented with 2% lysed horse blood, 2% yeast extract, and 2% supplement C. This medium has been designated veterinary fastidious medium. The medium recommended for the disk diffusion testing is chocolate Mueller-Hinton agar. The recommended QC organisms are A. pleuropneumoniae ATCC 27090 and H. somnus ATCC 700025. The QC MICs of ceftiofur, enrofloxacin, florfenicol, gentamicin, penicillin, tetracycline, tilmicosin, and trimethoprim-sulfamethoxazole were determined for each isolate, as were the zone size ranges. Of the results from the participating laboratories, 94.0% of the zone diameter results and 97.0% of the MIC results fell within the suggested QC ranges for all compounds. These QC guidelines should allow greater accuracy in interpreting results when testing these antimicrobial agents against fastidious pathogens.

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.

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.

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.

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.

Newer oral antimicrobials for resistant respiratory tract pathogens. Which show the most promise?

As antimicrobial resistance to tried-and-true drugs continues to build, an arsenal of new drugs aimed at resistant respiratory tract pathogens is needed. Penicillin is now ineffective against several common pathogens, including many pneumococcal organisms. Newer antimicrobials, including macrolides, cephalosporins, and fluoroquinolones, have been developed to take its place. The authors of this article present a progress report of the fight against respiratory tract infection and an assessment of the most promising newer agents for use against multidrug-resistant pathogens.

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.

Single-dose treatment of acute cystitis with fosfomycin tromethamine.

OBJECTIVE: To review the clinical pharmacology of fosfomycin tromethamine, a new antimicrobial agent for the treatment of uncomplicated lower urinary tract infections (UTIs). DATA SOURCE: Publications in English on fosfomycin, fosfomycin tromethamine, and fosfomycin trometamol (MEDLINE, 1970-1997), as well as unpublished studies submitted to the Food and Drug Administration (FDA), were reviewed. STUDY SELECTION: Comparative, randomized, controlled studies were used to analyze the efficacy and safety of fosfomycin tromethamine. DATA SYNTHESIS: Fosfomycin tromethamine is an oral antimicrobial indicated for the treatment of uncomplicated lower 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 therapeutic concentrations in the urine for 2-4 days. Comparative clinical trials suggest that a single dose of fosfomycin tromethamine 3.0 g is as clinically effective as 7- to 10-day treatment regimens of standard agents used to treat UTIs, such as nitrofurantoin, norfloxacin, and trimethoprim/sulfamethoxazole. Fosfomycin tromethamine is well tolerated and appears safe to use during pregnancy. CONCLUSIONS: Fosfomycin tromethamine is the only antimicrobial to be approved by the FDA for single-dose therapy in women with acute cystitis. It is as effective and safe as multidose comparators and appears safe to use during pregnancy. The acquisition cost of this new drug will need to be weighed against the improved compliance and convenience associated with its use in the treatment of uncomplicated UTIs.

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.

Pharmacology of new antiherpes agents: famciclovir and valacyclovir.

Limitations of acyclovir in treating infections caused by herpes simplex virus include the development of resistant isolates and relatively poor oral bioavailability. Penciclovir and famciclovir may have added clinical utility in the treatment of herpes virus infections in humans. Intracellular pharmacokinetics differ for valacyclovir and famciclovir, but the importance of these differences is unknown. Animal studies suggest that famciclovir (but not valacyclovir) can affect subsequent latent infection with HSV-1; the relevance of these findings to humans requires further investigation. Famciclovir and valacyclovir appear to decrease time to resolution of pain compared with acyclovir in patients with herpes zoster infections.

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.

Pharmacokinetics and pharmacodynamics of newer fluoroquinolones.

Newer fluoroquinolones currently under development have excellent pharmacokinetic profiles, and several parameters have been improved compared with those of their predecessors. These compounds are well absorbed, have large volumes of distribution, and distribute into most tissues at concentrations equal to or greater than those observed in serum. Moreover, these newer agents have long serum elimination half-lives that allow for once-daily dosing. With the exception of complexes with multivalent cations that retard absorption, there is a relative lack of clinically significant drug-drug interactions with these antimicrobials. Increased microbiological potency against several important pathogens, along with an enhanced pharmacokinetic profile, will make these newer fluoroquinolones preferable over older compounds for the treatment of a variety of infections.

Prevention of recurrent vaginal candidiasis with weekly terconazole cream.

OBJECTIVE: To investigate the prophylactic use of weekly terconazole 0.8% cream to prevent recurrent episodes of candidal vaginitis. DESIGN: Women with a documented history of recurrent candidal vaginitis (> or = 4 recurrences/y) were enrolled into a secondary prevention trial. None of these women were HIV positive, pregnant, diabetic, or immunosuppressed. Patients were initially treated for a symptomatic episode of candidal vaginitis and then started on weekly applications of terconazole 0.8% cream for 26 weeks. These women were then followed for an additional 26 weeks after therapy. SETTING: A university-affiliated medical school. PARTICIPANTS: The study population consisted of 22 healthy women aged 19-41 years. MAIN OUTCOME MEASURES: Patients were interviewed by phone each week concerning symptoms and compliance. They were also reminded to notify the study investigators any time vaginal symptoms of candidiasis occurred. Patients were examined whenever they developed vaginal symptoms and were treated on the basis of microscopic and culture results. RESULTS: Ten patients had 14 symptomatic cases of vaginitis during the prophylactic phase of the study, but Candida spp. were isolated during only 4 of these episodes. One episode was due to bacterial vaginosis and no pathogenic organisms were found in 9 of these cases. Eighteen of the 20 patients who completed the prophylactic phase were followed after therapy and 14 (78%) of these patients had a current case of candidal vaginitis. This incidence of infection was statistically higher than that observed during the treatment period (p < 0.001). CONCLUSIONS: Weekly applications of terconazole 0.8% cream were effective in preventing recurrent episodes of candidal vaginitis and were well tolerated.

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.

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.