Dirithromycin increases ethinyl estradiol clearance without allowing ovulation.

OBJECTIVE: To use a novel, sensitive study design to detect a potential oral contraceptive (OC) and dirithromycin drug interaction by assessing the pharmacokinetics of the ethinyl estradiol (E2) component of a common OC and the potential failure of OC effectiveness. METHODS: In this nonblinded study, 20 healthy women using Ortho Novum 7/7/7-28 were selected for a three-OC-cycle study. Baseline measures included E2 and progesterone serum levels on days 21, 23, 25, and 27 of cycle one and days 1, 3, 5, and 7 of cycle two. During cycle two, 24-hour blood sampling and radioimmunoassay analysis for ethinyl E2 pharmacokinetics were performed on day 8 and pelvic ultrasound on day 13. Oral dirithromycin 500 mg/day for 14 days began on day 21 of cycle 2. After starting dirithromycin, cycle two and three serum E2, progesterone, and serial ethinyl E2 levels and pelvic ultrasound replicated the baseline schedule. Ovulation was assumed if E2 concentration was greater than 50 pg/mL, progesterone concentration was greater than 3 ng/mL, or if an ovarian cyst greater than 10 mm was present on ultrasound. RESULTS: Pharmacokinetic analysis demonstrated a small (7.6%) but statistically significant decrease (P = .03) in the mean ethinyl E2 24-hour area under the curve and an increase in apparent oral clearance. No woman ovulated, based on E2 levels and progesterone concentrations or ultrasound. CONCLUSION: Dirithromycin increased the apparent oral clearance of ethinyl E2. The clinical importance of the interaction may be negligible because no woman ovulated or had compromised OC effectiveness in this small series.

Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin.

The steady-state plasma concentrations and pharmacokinetic characteristics of theophylline were studied during intermittent treatment with dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 AM) to a sustained-release theophylline dosing regimen (200 mg every 12 hours) elicited small changes in the steady-state pharmacokinetics of theophylline. Mean steady-state plasma theophylline trough concentrations (Cmin) were invariant before, during, and after dirithromycin treatment; however, mean average steady-state plasma theophylline concentrations (Cav) declined by 18% during dirithromycin treatment (P less than .05), and mean peak plasma concentrations (Css,max) declined by 26% (P less than .01). Theophylline clearance (CL/F) exhibited an increase of comparable magnitude during dirithromycin treatment, although the increase in CL/F was not statistically significant (.05 less than P less than .1). Dirithromycin treatment alters the steady-state pharmacokinetics of theophylline; however, the magnitude of the changes is small and is not likely to modify treatment outcomes.

Tonsillar tissue penetration of dirithromycin after multiple doses.

Dirithromycin is a new macrolide antibiotic that is effective against group A beta-hemolytic streptococcal pharyngotonsillitis. This prospective, multicenter, randomized study compared the serum and tonsil tissue concentrations of erythromycylamine (to which dirithromycin is rapidly converted by nonenzymatic hydrolysis during absorption) and erythromycin after 5- and 10-day regimens of dirithromycin and erythromycin, respectively. Thirty-nine patients undergoing elective tonsillectomy but without active tonsillitis were assigned in randomized fashion to receive dirithromycin 500 mg orally once daily (n = 22) or erythromycin base 250 mg orally four times daily (n = 17). Data from 12 patients receiving dirithromycin and 10 receiving erythromycin were eligible for analysis. Mean serum concentrations (+/-standard deviation) of erythromycylamine and erythromycin were 0.20 +/- 0.07 microgram/mL and 0.12 +/- 0.25 microgram/mL, respectively, after the 5-day regimen and 0.17 +/- 0.10 microgram/mL and 1.57 +/- 3.16 micrograms/mL, respectively, after the 10-day regimen. The mean serum concentration of erythromycin after 10 days was skewed by the data for one of the six patients in the group (concentration of > 8 micrograms/mL). Mean concentrations of erythromycylamine in tonsil tissue were 4.62 +/- 0.97 micrograms/ g after 5 days and 3.47 +/- 2.84 micrograms/g after 10 days. Concentrations in tonsillar tissue were undetectable in all patients given erythromycin for 5 days and in 4 of the 6 patients given erythromycin for 10 days. The high concentrations of erythromycylamine in tonsillar tissue agree with the clinical efficacy seen in the treatment of group A beta-hemolytic streptococcal tonsillopharyngitis with dirithromycin.

Clinical efficacy of dirithromycin in patients with bacteremic pneumonia.

Dirithromycin is a new macrolide antimicrobial drug with a long half-life (44 hours) that reaches high tissue concentrations, thus permitting once-daily oral dosing and shorter courses of therapy. Soon after absorption, dirithromycin enters the tissue so rapidly that serum concentrations are comparatively low. It could be hypothesized that these low serum levels could endanger the outcome in patients with bacteremic pneumonia. We reviewed the database on dirithromycin pneumonia (consisting of 1108 patients randomized to receive dirithromycin or erythromycin in two double-masked trials) to ascertain its efficacy in patients with community-acquired pneumonia and concomitant bacteremia. Fourteen (2.5%) of 555 dirithromycin-treated patients and 10 (1.8%) of 553 erythromycin-treated patients had bacteremia. A favorable clinical response posttherapy was observed in 92.3% and 88.9% of these patients with a response assigned, respectively. Overall, favorable response rates were comparable between the two groups in the bacteremic subsets: patients with pneumococcal bacteremia, patients with nonbacteremic pneumococcal pneumonia, and all patients enrolled with acute pneumonia who had a posttherapy clinical response. In the treatment of patients with mild or moderate community-acquired pneumonia, including those with unsuspected and incidental bacteremia, dirithromycin is an effective macrolide antimicrobial drug.

Clinical efficacy of dirithromycin in acute exacerbations of chronic bronchitis.

The efficacy and safety of seven days treatment with oral dirithromycin 500 mg given once daily was compared with oral erythromycin 250 mg qid in patients with acute bacterial exacerbations of chronic bronchitis. A total of 393 patients received dirithromycin and 409 erythromycin. Of 101 dirithromycin-treated patients analysed for efficacy, 87 (86%) had favourable clinical responses compared with 72/81 (89%) of those treated with erythromycin. Proven or presumed pathogen elimination was noted in 85/101 (84%) dirithromycin-treated patients and 66/81 (82%) erythromycin treated patients. Late post-therapy responses were also similar between treatment groups. Favourable clinical responses were noted in 89% of patients treated with dirithromycin and 91% of those receiving erythromycin. A favourable bacteriological response was noted in 87.5% and 89.6% of the dirithromycin- and erythromycin-treated groups, respectively. Adverse events were also similar between treatment groups. Gastrointestinal events were the most common events in both groups of patients; erythromycin was associated with a significantly higher incidence of diarrhoea (P = 0.003). Dirithromycin was associated with a higher incidence of lung events (P = 0.043). It is concluded that dirithromycin given once a day is comparable in efficacy and safety to four-times-daily erythromycin in the treatment of acute bacterial exacerbations of chronic bronchitis.

New directions for macrolide antibiotics: pharmacokinetics and clinical efficacy.

Erythromycin and related macrolide antibiotics have recently enjoyed a resurgence of clinical interest. This is a result of activity against organisms which are becoming more prevalent, particularly in immunocompromised hosts and, in addition, better understanding of the unique tissue penetration properties and potential immunomodulating properties of macrolides. Other features of clinical interest possessed by certain of the newer macrolides include the potential for once-daily dosing, resistance to acid degradation in the stomach without enteric coating, and possibly reduced gastrointestinal side effects. The new macrolides are expected to retain the clinical indications of erythromycin, which include upper and lower respiratory tract infections, skin and skin structure infections, and genital tract infections caused by erythromycin-susceptible organisms. In addition, enhanced activity has been demonstrated in animal models and in vitro against toxoplasma, Legionella, Haemophilus, and Campylobacter spp. New macrolide derivatives also show promise to expand the antimicrobial spectrum of erythromycin to include Mycobacterium and Borrelia spp.

Safety profile of dirithromycin.

Dirithromycin is a recently developed oral antibiotic, and has been shown to be effective in the treatment of respiratory tract, skin and soft tissue infections. Dirithromycin is administered once daily which may contribute to patient compliance. In this paper we review the data from studies conducted in Europe, USA, Israel and South Africa over a six-year period to assess the safety and efficacy of dirithromycin in the treatment of a variety of acute infectious illnesses, and to compare it with structurally related antibiotics (erythromycin base, roxithromycin, and miocamycin) given orally. A total of 7437 patients have been enrolled from a total of 66 studies and trials, 4263 (57.3%) treated with dirithromycin and 3174 (42.7%) treated with a comparator antibiotic. Patients received either 500 mg dirithromycin (two tablets once daily), 1000 mg erythromycin base (250 mg qid), 300 mg roxithromycin (150 mg bid), or 1200 miocamycin (600 mg bid); the length of therapy ranged from 7 to 14 days. These studies have shown that dirithromycin has a safety profile similar to the comparator agents. The most frequently reported adverse events for both dirithromycin and comparator treatment groups were gastrointestinal in nature. The majority (99%) of adverse events reported from patients treated with dirithromycin were considered mild or moderate in severity. Early discontinuation of antibiotic therapy was infrequent (3-4%) in both treatment groups, and considered to be possibly drug-related in 2-3% of the population. The safety profile of dirithromycin in elderly patients was comparable to that recorded in the overall patient population. The incidence and nature of abnormal clinical laboratory evaluation were similar in dirithromycin and comparator groups. Notable alterations in laboratory tests of haematological or hepatic function were infrequent and were not associated with clinical manifestations. Routine monitoring of standard clinical laboratory tests in patients prescribed dirithromycin does not appear to be necessary.

Dirithromycin in the treatment of streptococcal pharyngitis.

A double-blind, double-dummy, randomized, multicentre study compared the safety and the efficacy of dirithromycin (two 250 mg tablets, once daily) to erythromycin base (four 250 mg tablets, four times daily) for ten days in the treatment of proven group A beta-haemolytic (GABHs) streptococcal pharyngitis. Five-hundred and fifty-three patients (265 dirithromycin, 288 erythromycin) were enrolled in the trial and analysed for efficacy and safety. Clinical and bacteriological evaluations were performed pre-therapy, during therapy (days 3-5), post-therapy (three to five days after completion of treatment), and late post-therapy (three to five weeks after treatment). All patients qualified for safety analysis. A negative pre-therapy culture was the predominant reason a patient did not qualify for analysis of efficacy. At post-therapy, favourable clinical responses (cure or improvement) were reported for 94.1% (159/169) of dirithromycin and 94.6% (158/167) of erythromycin patients who qualified for efficacy analysis. Post-therapy throat cultures were negative for GABH streptococci in 79.3% (134/169) of dirithromycin patients and 86.2% (144/167) of patients treated with erythromycin (P = 0.314). At late post-therapy 87.6% (134/153) of dirithromycin and 88.7% (134/151) of erythromycin patients reported a favourable clinical response; pathogens were absent in 69.9% (107/153) of dirithromycin and 86.1% (130/151) of erythromycin patients (P = 0.001). The adverse event profile of the two drugs was comparable although digestive and cutaneous adverse events were reported more frequently in the erythromycin treatment group. In this study, more dirithromycin patients had throat cultures positive for GABH streptococci at late post-therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Five-day dirithromycin therapy is as effective as seven-day erythromycin therapy for acute exacerbations of chronic bronchitis.

In a meta-analysis of two identically designed, well-controlled, randomized, double-blind clinical trials, we compared 5 days of dirithromycin with 7 days of erythromycin for acute exacerbations of chronic bronchitis. Five hundred and thirty-one patients were randomized to receive dirithromycin (500 mg od) for 5 days and 526 patients were randomized to receive erythromycin (250 mg qid) for 7 days. Clinical and bacteriological responses were assessed 3-5 days after therapy and at termination from the study. Adverse events were collected from both groups and compared with each other, before and after treatment. Of the 690 patients clinically appraisable at the post-therapy visit, 298 (84.2%) dirithromycin-treated patients and 270 (80.4%) erythromycin-treated patients showed a favourable response. At termination, 273 (77.1%) dirithromycin-treated patients and 243 (72.3%) erythromycin-treated patients showed a favourable response. The microbiological cure was equivalent in the two groups (75% of dirithromycin-treated patients and 74.1% of erythromycin-treated patients showed a favourable response at termination). After therapy, dirithromycin was as effective as erythromycin in eradicating Streptococcus pneumoniae (77.8% vs 90.9%), Haemophilus influenzae (71.7% vs 72.2%), Moraxella catarrhalis (93.3% vs 88.9%) and Staphylococcus aureus (81.8% vs 82.1%). Although not statistically significant, fewer dirithromycin-treated patients reported adverse events than did erythromycin-treated patients. Nausea (6.8% vs 7.8%), headache (7.3% vs 8.2%) and diarrhoea (6.6% vs 9.5%) were the most frequently reported adverse events in both groups. In the treatment of acute exacerbations of chronic bronchitis, 5 days of dirithromycin is as effective as 7 days of erythromycin.

Comparison of dirithromycin and penicillin for treatment of streptococcal pharyngitis.

In the treatment of group A beta-hemolytic streptococcal pharyngitis, penicillin is the drug of choice and erythromycin is the alternative. In a double-blind, randomized study, dirithromycin, a new macrolide, was compared with penicillin for the treatment of streptococcal pharyngitis. Of 121 patients who were treated with dirithromycin, 96.7% manifested a favorable clinical response, and of 136 patients treated with penicillin, 94.2% manifested a favorable clinical response. Streptococci were eradicated from the pharynges of 85.3% of 116 dirithromycin-treated patients and 82.5% of 126 penicillin-treated patients who returned for follow-up. There were no statistically significant differences in efficacy between the two groups. The incidence of abdominal symptoms was higher in dirithromycin-treated patients. Being as efficacious as penicillin and having the advantages over erythromycin of once-daily dosing and the lack of drug interactions, dirithromycin is an alternative to penicillin in the treatment of streptococcal pharyngitis for patients 12 years of age and older.

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.

Pharmacokinetics of dirithromycin.

Dirithromycin is a new member of the macrolide class of antibiotics and has been developed for oral administration. Dirithromycin is a 14-membered lactone ring macrolide and is the C9-oxazine derivative of erythromycylamine. The human pharmacokinetics and clinical pharmacology of dirithromycin have been studied. Dirithromycin has unique pharmacokinetics which distinguish it from erythromycin. In man, following an oral 500 mg dose of dirithromycin, a mean peak plasma concentration (Cmax) of 0.48 mg/L (range 0.1-1.97) was observed at 4 h. The mean area under the plasma concentration versus time curve (AUC0-24h) measured 3.37 mg.h/L (range 0.39-17.16). No plasma accumulation was observed with multiple-dose administration. Dirithromycin may be taken without regard to meals, although food and H2-receptor antagonists may increase the systemic bioavailability in some patients. Based upon drug interaction studies performed with antipyrine and theophylline, dirithromycin has shown less potential to interact with other drugs metabolized by the cytochrome P450 system that does erythromycin. Plasma concentrations and AUCs were low due to rapid movement of the drug from the vascular space to the extravascular compartment, as reflected by tissue concentrations, which exceeded plasma concentrations 4 h after dosing. Dirithromycin achieves relatively high tissue concentrations (approximately 0.8-5.0 mg/kg) 4-24 h after dosing. The extensive tissue penetration is reflected in a large mean apparent volume of distribution of 800 L (range 504-1041). Dirithromycin is rapidly converted by non-enzymatic hydrolysis during absorption to erythromycylamine, which is microbiologically active. In a 14C-radiolabelled study, 60-90% of the administered dose was hydrolysed to erythromycylamine within 35 min of infusion. After 1.5 h, conversion to erythromycylamine in serum was virtually complete. Plasma protein binding was determined to be 15-30% by ultracentrifugation. Dirithromycin is characterized by a plasma elimination half-life of 44 h (range 16-65 h) that permits once-daily administration. Total body clearance was 226-1040 mL/min in the 14C-radiolabelled study. The primary route of elimination of dirithromycin/erythromycylamine was faecal/hepatic. Following intravenous administration, approximately 17-25% of the radioactivity appeared in the urine and 62-81% appeared in the stool, indicating predominantly hepatic excretion. With oral administration 1.2-2.9% of the radioactivity appeared in the urine and 81-97% in the stool. The major part of urinary excretion occurs within the first 48 h post-administration; however, urinary excretion of radioactivity lasted longer than 240 h. The absolute bioavailability calculated from dose-corrected urinary excretion data was 10% (6-14%).