Comparative efficacy of 5 days of dirithromycin and 7 days of erythromycin in skin and soft tissue infections.

We investigated the comparative efficacy and safety of dirithromycin and erythromycin in the treatment of skin and soft tissue infections in this double-blind, randomized, multicentre study, in which 439 patients were randomized to treatment with dirithromycin (500 mg daily for 5 days) or erythromycin (250 mg every 6 h for 7 days). All randomized patients were included in the termination analysis, which showed that 187 of 220 (85.0%) dirithromycin recipients and 177 of 219 (80.8%) erythromycin recipients were clinically cured or improved (95% confidence interval (CI) -3.0% to +11.4%). In the termination analysis of the 211 bacteriologically evaluable patients, clinical cure or improvement occurred in 83 of 100 (83%) dirithromycin recipients and in 89 of 111 (80.2%) erythromycin recipients (95% CI -7.8% to +13.4%), and bacteriological eradication occurred in 85 of 100 (85%) and 89 of 111 (80.2%), respectively. Adverse events were similar in incidence and nature between the two groups, except that there was less nausea with dirithromycin (3.6% versus 8.2%; P = 0.042). Ten of 220 (4.5%) dirithromycin recipients and 27 of 219 (12.3%) erythromycin recipients returned >20% of their prescribed medication (P = 0.033). In the treatment of skin and soft tissue infections, dirithromycin (500 mg daily for 5 days) was comparable in efficacy to, and caused significantly less nausea than, erythromycin (250 mg every 6 h for 7 days). Compliance with the dirithromycin regimen was superior to that with the erythromycin regimen.

Drug interactions of macrolides: emphasis on dirithromycin.

OBJECTIVE: To describe the drug interactions of dirithromycin, a new macrolide, and to compare them with those of other macrolides. DATA SOURCES: A literature search was performed using MEDLINE to identify articles published between January 1980 and July 1995 concerning the drug interactions of macrolides. Published abstracts were also examined. All studies using dirithromycin were performed under the sponsorship of Eli Lilly and Company. DATA SYNTHESIS: Erythromycin, the first macrolide discovered, is metabolized by the cytochrome P450 enzyme system. By decreasing their metabolism, erythromycin can interact with other drugs metabolized by the cytochrome P450 enzymes. The lack of such interactions would be a desirable feature in a newer macrolide. We describe studies performed to detect any interactions of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, and ethinyl estradiol. The studies showed that dirithromycin, like azithromycin, is much less likely to cause the interactions detected with clarithromycin and erythromycin. A review of the literature showed differences among macrolides in their abilities to inhibit cytochrome P450 enzymes and, thus, to cause drug-drug interactions. Erythromycin and clarithromycin inhibit cytochrome P450 enzymes, and have been implicated in clinically significant interactions. Azithromycin and dirithromycin neither inhibit cytochrome P450 enzymes nor are implicated in clinically significant drug-drug interactions. CONCLUSIONS: Dirithromycin, a new macrolide, does not inhibit the cytochrome P450 enzyme system. The concomitant use of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, or ethinyl estradiol was studied in pharmacokinetic and pharmacodynamic studies. In vitro, dirithromycin did not bind cytochrome P450. In healthy subjects, erythromycin increases the clearance of cyclosporine by 51%, whereas dirithromycin causes no significant changes in the pharmacokinetics of cyclosporine. In kidney transplant recipients, administration of dirithromycin was associated with a significant (p < 0.003) decrease of 17.4% in the clearance of cyclosporine. In patients taking low-dose estradiol, the administration of dirithromycin caused a significant (p < 0.03) increase of 9.9% in the clearance of ethinyl estradiol; escape ovulation did not occur. Unlike erythromycin and clarithromycin, dirithromycin had no significant effects on the pharmacokinetics of theophylline, terfenadine, or warfarin. The alterations typical of drug interactions that are based on inhibition of the cytochrome P450 system occurring with erythromycin and clarithromycin were not observed with dirithromycin.

A study of the interaction between dirithromycin and astemizole in healthy adults.

The effect of a standard regimen of dirithromycin, a macrolide antibiotic, on the single-dose pharmacokinetics of the H (1) receptor blocker astemizole was evaluated in a sample of 18 healthy young adults (nine males and nine females). The study was conducted in a two-way cross-over fashion after the subjects had been randomly given either dirithromycin (two 250 mg tablets) or placebo (two tablets) every morning for 10 days. On the morning of the fourth dose of either dirithromycin or placebo each subject ingested a single 30-mg oral dose (three 10-mg tablets) of astemizole. The disposition kinetics of both astemizole and its major metabolite, N-desmethylastemizole, were characterized after measuring the concentrations of both analytes in the serum fraction of serial blood samples collected for 14 days after the astemizole dose. In addition, corrected QT (QT(c) ) intervals were estimated from electrocardiogram rhythm strips that were run 24 hours prior to the astemizole dose, 12 hours after the astemizole dose, and after the last treatment (dirithromycin or placebo) dose in both study periods. Pharmacokinetic parameters that were measured for both astemizole and N-desmethylastemizole during each treatment were: C(max), t(max), AUC (0-infinity), CL(oral), half-life, and volume of distribution (V). None of the parameters for N-desmethylastemizole was different when comparing data by ANOVA from the dirithromycin treatment period with that of the placebo treatment period. On the other hand, during dirithromycin treatment astemizole CL(oral) was 34% slower, volume of distribution was 24% larger, and half-life was 84% longer. Generally, all QT ( c ) intervals did not appear to be affected by dirithromycin treatment. The changes in astemizole kinetics could not be attributed to its N-demethylation since the dispositional kinetics of N-desmethylastemizole were unaffected by dirithromycin. Therefore, it is difficult to ascertain the clinical significance of the changes in astemizole kinetics. Since there were no significant differences for mean QT(c) intervals and no effect of dirithromycin treatment on N-desmethylastemizole kinetics, it is unlikely that a standard regimen of dirithromycin would place a patient taking astemizole at an increased risk of torsade de pointes or related ventricular arrhythmias.

Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin.

To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period. Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks. By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020). The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy. We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin.

Vancomycin skin tests and prediction of "red man syndrome" in healthy volunteers.

The purpose of the present study was to assess the cutaneous response to intradermally administered vancomycin in healthy adults and to determine whether the magnitude of the cutaneous response correlated to the severity of "red man syndrome" (RMS) following intravenous administration of vancomycin to the same subjects. Eleven healthy males were skin tested with intradermally administered histamine and saline controls and intradermally administered vancomycin at different concentrations. Vancomycin caused a dose-dependent area of flare in all subjects. The sigmoidal maximal flare model was used to fit each dose-response curve, and cutaneous responsiveness to vancomycin was quantified by various methods, including the flare area at each dose, maximum flare area (maximal flare), dose required to produce 50% of maximum flare, dose required to produce a flare area of 400 mm2, and the slope of the dose-response curve. One week after skin testing, subjects received an infusion of vancomycin, 15 mg/kg of body weight over 60 min. For the assessment of the severity of RMS, we used previously described methods. Although all subjects experienced erythema from the intravenously administered vancomycin and 10 subjects had pruritus, there was no significant correlation between vancomycin skin test results and the severity of RMS. We conclude that vancomycin skin tests do not predict the severity of RMS. In addition, vancomycin skin tests may be of no benefit for assessing immunoglobulin E-mediated allergy to vancomycin, since all subjects had a positive reaction at concentrations of > or = 10 micrograms/ml.

The influence of chronic administration of calcium carbonate on the bioavailability of oral ciprofloxacin.

Six healthy male volunteers participated in a two-period, two-treatment study to determine the effect of chronic calcium carbonate administration on ciprofloxacin bioavailability. There was a mean reduction of 40% in Cmax and 43% in AUC when calcium carbonate was administered with ciprofloxacin, compared with ciprofloxacin alone (P < 0.05). There were no changes in either half-life or tmax. It is therefore recommended that patients being treated with ciprofloxacin for serious infections refrain from ingesting calcium supplements. If this is not possible, administration of ciprofloxacin 2 h before ingestion of the supplement is suggested.

Comprehensive safety profile of cefaclor AF in respiratory, urinary tract and skin infections.

The safety of cefaclor advanced formulation (cefaclor AF) was evaluated in 3,272 patients participating in 11 controlled clinical trials in comparison with cefaclor (2,210 patients) for a variety of infectious illnesses. Daily doses of cefaclor AF ranged from 500 to 1500 mg, with a mean duration of treatment of 8.1 days (range 1-18 days). There were no significant differences between the cefaclor AF- and cefaclor-treated groups in the frequency of adverse events by body system for all events reported. The majority of adverse events related to therapy were mild and transient. Severe adverse events occurred in 2.1% of the cefaclor AF group and 2.7% of the cefaclor group. The most frequently reported adverse events for cefaclor AF were diarrhoea (3.4%), headache (3.2%), nausea (2.5%) and vaginal moniliasis (2.5% of females). Drug-related adverse events led to early discontinuations in 1.7% of cefaclor AF-treated patients and 1.6% of cefaclor-treated patients. Overall, there were few significant differences in the frequency of adverse reactions between older and younger patients. Notably, elderly patients reported significantly less diarrhoea and fewer hypersensitivity-type reactions. There were, however, more therapy discontinuations due to adverse effects in patients aged 65 years or older than in those less than 65 years of age. Many of the discontinuations were thought to be unrelated to therapy. Alterations in laboratory values in patients treated with cefaclor AF were similar to those seen with other beta-lactam antibiotics. The comprehensive data indicate that cefaclor AF is a safe therapeutic option for a variety of common bacterial infections.

An analysis of blood and body fluid exposures sustained by house officers, medical students, and nursing personnel on acute-care general medical wards: a prospective study.

OBJECTIVE: To prospectively examine the epidemiology of blood and body fluid exposures sustained by medicine housestaff, medical school students, registered nurses (RNs), licensed practical nurses (LPNs), and nurses' aides (NAs) on general medicine wards and to define problem areas that may be amenable to change. DESIGN: Daily data collection during 9 months using a self-reporting questionnaire. SETTING: General medical wards in 2 tertiary referral hospitals. PARTICIPANTS: Medicine housestaff/students and nursing personnel. RESULTS: Physicians reported 644 exposures, of which 98 (15.2%), 296 (46.0%), and 250 (38.8%) were sustained by medicine residents, interns, and students, respectively. Blood contact occurred with 591 (91.8%) exposures. For physicians, 575 (89.3%) exposures occurred during venipuncture, intravenous catheter manipulation, and arterial punctures. Interns and students most commonly incurred exposures during venipunctures and intravenous manipulations; residents commonly were exposed during emergent intravenous catheter placements. Five-hundred-twenty-two (81%) exposures occurred between 7 A.M. and 7 P.M. During 524 (81.4%) exposures, physicians were not using barrier devices. Nurses reported 235 exposures, of which 140 (59.6%), 23 (9.8%), and 72 (30.6%) were sustained by RNs, LPNs, and NAs, respectively. RN exposures commonly occurred during intravenous manipulations and glucometer fingersticks. LPNs and NAs incurred a higher percentage of exposures during nonprocedural patient care. Blood contact and wound drainage accounted for 167 (71.1%) and 31 (13.2%) exposures, respectively. CONCLUSIONS: Exposures to blood and body fluids frequently are incurred by healthcare workers on general medical wards. Efforts to reduce these exposures should be directed not only at improving procedural skills of healthcare workers for venipunctures, intravenous catheter insertions, and glucometer fingersticks, but also in increasing barrier use during procedural and nonprocedural tasks.

Meningitis due to Neisseria mucosa: case report and review.

Neisseria mucosa is a species of gram-negative cocci that has a characteristic mucoid, adherent colonial morphology and includes pigmented and nonpigmented morphotypes. The ability of N. mucosa to reduce nitrates distinguishes it from other Neisseria species. N. mucosa is part of the normal human nasopharyngeal flora and infrequently causes human infections, including meningitis. We report a unique case of a patient with a cerebrospinal fluid shunt infection due to N. mucosa and review five other reports of cases of meningitis caused by this organism. Seven additional previously reported cases of presumed N. mucosa meningitis have been excluded from this review on the basis of the current criteria for identification of the organism. In the reports of established cases, female infants and children who often had predisposing conditions predominate. Although the outcome for such patients has been favorable, no clinical or laboratory findings are helpful in distinguishing meningitis due to N. mucosa from that due to other bacteria.

Klebsiella pneumoniae urinary tract infection complicated by endophthalmitis, perinephric abscess, and ecthyma gangrenosum.

We have reported the case of an immunocompromised patient with a K pneumoniae bacteremia admitted with endophthalmitis. The source of the infection was an asymptomatic left renal calculus associated with a perinephric abscess. Persistent bacteremia resulted in the development of ecthyma gangrenosum, which has not previously been associated with Klebsiella spp infection.

Lack of interaction between lomefloxacin and caffeine in normal volunteers.

Sixteen healthy, nonsmoking adult males participated in a randomized, double-blind, placebo-controlled, two-way crossover study to evaluate the influence of chronic lomefloxacin administration on the disposition of caffeine and its major metabolite, paraxanthine, at steady-state conditions. Lomefloxacin (400 mg) or placebo was administered orally once daily for 5 days to xanthine-free volunteers after an overnight fast. Caffeine (200 mg orally) was administered simultaneously with lomefloxacin on days 3 through 5. After a 2-day washout period, subjects were crossed over to the alternate 5-day regimen with caffeine, which was again given on the final 3 days. Blood samples for caffeine, paraxanthine, and lomefloxacin concentration determinations were serially collected for 48 h following the last dose of each regimen. All compounds were analyzed by high-performance liquid chromatography. For the placebo versus lomefloxacin-containing treatments, maximum caffeine concentrations in plasma (4.35 +/- 0.63 versus 4.07 +/- 0.56 micrograms/ml), areas under the concentration-time curve from time zero to 24 h at steady state (30.3 +/- 6.9 versus 29.7 +/- 6.6 micrograms.h/ml), and elimination half-lives of caffeine (4.8 +/- 1.1 versus 4.8 +/- 1.2 h) were not significantly different. In addition, there were no significant changes in the disposition parameters of paraxanthine as a result of lomefloxacin administration. The frequencies of central nervous system-related effects for the two treatments were not statistically different. We conclude that lomefloxacin has no significant effect on the disposition of caffeine in young healthy volunteers.

Are universal precautions effective in reducing the number of occupational exposures among health care workers? A prospective study of physicians on a medical service.

Using a daily questionnaire, we prospectively studied 277 physicians from two hospital medical services for incidents of exposure to blood and body fluids and barrier use before and after the implementation of universal precautions. We found that implementation significantly increased the frequency of barrier use during exposure incidents from 54% before implementation to 73% after implementation of universal precautions. Implementation led to a decrease in the number of exposure incidents that resulted in direct contact with blood and body fluids (actual exposures), from 5.07 to 2.66 exposures per physician per patient care month, and to an increase in averted exposures in which direct contact was prevented by the use of barrier devices, from 3.41 exposures per patient care month before implementation to 5.90 exposures per patient care month after implementation. Implementation affected neither the types of body fluid or procedures involved nor the overall rate of exposure incidents (8.5 per patient care month) but, through an increase in barrier use, it did prevent direct contact with blood and body fluids and thus converted what would have been an actual exposure into an averted one. We conclude that universal precautions were effective in reducing the risk of occupational exposures among physicians on a medical service.

Pericardial effusion and tamponade due to Kaposi's sarcoma in acquired immunodeficiency syndrome.

We describe a 29-year-old homosexual man with acquired immunodeficiency syndrome who developed pericardial effusion and tamponade. Pericardiocentesis resulted in clinical improvement. All diagnostic tests on pericardial fluid were negative. At autopsy, extensive plaques and nodules of Kaposi's sarcoma were found studding the epicardium, and no other cause of effusion was found. To our knowledge there has been no previous case of Kaposi's sarcoma associated with pericardial effusion and tamponade reported in patients with AIDS. Kaposi's sarcoma should be considered in the differential diagnosis of pericardial effusion in these patients.