Generating signals of drug-adverse effects from prescription databases and application to the risk of arrhythmia associated with antibacterials.

BACKGROUND: Although it is well known that a variety of antibacterials may incidentally cause malignant arrhythmia, the list of drugs causing arrhythmia and the impact of these adverse effects are still uncertain. We investigated on this topic by using a large prescription database with different observational designs. METHODS: Prescription data on all incident users of several antibacterial and antiarrhythmic drugs over the period July 1997 through December 1999 were retrieved from the Drug Prescription Database (DPD) of the Italian Province of Varese. The association between the use of antibacterial and antiarrhythmic drugs was investigated by applying prescription sequence symmetry, cohort and nested case-control designs. RESULTS: Lower proarrhythmic effects were on an average obtained from prescription sequence symmetry approach with respect to both cohort and nested case-control. Evidence of association between exposure to drugs (erythromycin and ciprofloxacin) and the risk of arrhythmia was consistently found by the three approaches. No other signals were generated from the prescription sequence symmetry analysis. Two drugs (clarithromycin and levofloxacin) showed patterns compatible with an arrhythmic effect according to both cohort and nested case-control designs. CONCLUSIONS: Prescription databases are useful tools to explore drug safety through both conventional and emerging observational designs. In spite of its appealing features, prescription sequence symmetry design shows lower sensitivity with respect to conventional designs. Evidence about the association between the use of certain macrolides and fluoroquinolones and the onset of arrhythmia is confirmed by this study.

Immune tolerance to drugs. I. Long-term tolerability of rokitamycin in patients with antibiotics hypersensitivity.

Macrolides are considered one of the safest anti-infective groups in clinical use and are well-tolerated as alternative antibiotics in patients with a previous adverse reaction to other classes of antibiotics. However there is scarce information in the literature about their long-term tolerability. The present study was performed to determine whether the results of a challenge test with rokitamycin could predict the response to ingestion of rokitamycin during illness. The study was carried out on 335 patients, who experienced adverse reactions to one or more antibiotics. All patients received peroral challenges with rokitamycin (granules or capsules). On the first day patients received a number of placebo doses equivalent to the rokitamycin doses. One week later, the test was administered by increasing doses of rokitamycin at 60 min intervals until the common daily therapeutic dose of 406.25mg was reached (31.25-93.75-125-156.25mg). A questionnaire was distributed to all subjects. In particular, subjects were asked to clarify any reactive symptom they had developed after ingestion of the drug. It was found that only 3.1% (4/129) of subjects, who used this drug, reported adverse reactions: three experienced urticaria/angioedema and one patient experienced erythema multiforme during treatment. This study, points out a low percentage of adverse reactions to rokitamycin after a negative challenge test, thus, emphasizing both safety and good predictive value as a challenge test.

[Rokitamycin tolerance in patients with adverse reactions to chemotherapeutic agents]. / Tolleranza alla rokitamicina in pazienti con reazioni avverse a chemioterapici.

The main task in the drug intolerance reactions is the choice of "alternative" drug by oral challenge. The tolerance of rokitamycine (RKM), a new macrolide with a wide activity spectrum in 133 antibiotic-intolerant patients has been studied by open oral challenge with incremental dosage until a cumulative dose of 406 mg. The RKM in 96.2% of cases has been well tolerated. Only 5 patients (3.8%) have had reactions, mainly "atypical" and of minor clinical importance, at cumulative doses ranging from 31.25 to 250 mg. The RKM has been well tolerated also by 6 patients who have had reactions to macrolides belonging to the same group (16 membered). Finally, the use of RKM as alternative drug in chemotherapeutics-intolerant patients has been proposed.

Miocamycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Miocamycin is an orally administered 16-membered macrolide antimicrobial drug. It has a spectrum of in vitro activity similar to that of erythromycin, inhibiting a range of Gram-positive and Gram-negative organisms, atypical microbes and some anaerobes. Importantly, miocamycin demonstrates greater in vitro potency than erythromycin against several pathogens including Legionella pneumophila, Mycoplasma hominis, and Ureaplasma urealyticum. Equally noteworthy is its activity against erythromycin-resistant staphylococcal and streptococcal species expressing inducible-type resistance. Miocamycin possesses poor overall activity against Haemophilus influenzae and is inactive against Enterobacteriaceae. Penetration of miocamycin into body tissues and fluids is both rapid and extensive. The 3 major metabolites of miocamycin possess antimicrobial activity and may contribute to the therapeutic efficacy of the drug. Clinical data indicate that miocamycin is useful in the treatment of upper and lower respiratory tract infections in both adult and paediatric patients. Miocamycin is also effective in the treatment of urogenital tract infections caused by Chlamydia trachomatis or U. urealyticum. Several studies suggest that miocamycin is at least as effective as erythromycin in these indications; however, comparisons with newer macrolide agents have yet to be performed. In other studies, miocamycin proved to be a useful agent in the treatment of periodontal infections and as anti-infective prophylaxis in dental surgery. Miocamycin appears to have a tolerability profile qualitatively similar to that of other macrolides, with gastrointestinal and skin disorders being the most commonly reported adverse events. Current data suggest that the potential for drug interactions with miocamycin is low, with the possible exceptions of carbamazepine and cyclosporin. Thus, although further confirmation and elaboration of various aspects of its efficacy and tolerability profile is needed, at this stage miocamycin offers a useful alternative oral therapy to erythromycin for the treatment of uncomplicated community-acquired respiratory tract infections and nongonococcal urethritis.

Clinical efficacy of dirithromycin versus miocamycin in tonsillopharyngitis.

A single-blind, randomized, parallel-group study was conducted to compare the efficacy and safety of dirithromycin with miocamycin in the treatment of streptococcal pharyngitis/tonsillitis caused by Group A streptococci. The study population consisted of 60 patients: 30 were randomized to receive 500 mg dirithromycin od and 30 to receive 600 mg miocamycin bd. All 30 dirithromycin-treated patients were eligible for efficacy analysis. A favourable clinical response was observed in 100% of these patients at the post-therapy visit. In the miocamycin-treated group, 28 of 30 (93.3%) patients were eligible for efficacy analysis; a favourable clinical response was observed in 100%. Bacteriological cure of evaluable dirithromycin- and miocamycin-treated patients was 96.7% and 92.9%, respectively. No statistically significant post-therapy differences in clinical or bacteriological response rates were noted between the two groups. Adverse event analysis showed no significant differences between treatment groups. There were no serious adverse events during the study. Two miocamycin-treated patients were prematurely withdrawn from the study due to adverse events (diarrhoea). Analysis of clinical laboratory data revealed no statistically significant differences between the treatment groups that were considered to be drug related. The results of this study suggest that dirithromycin has comparable safety and efficacy to miocamycin in the treatment of streptococcal pharyngitis/tonsillitis infections caused by Group A streptococci.

Clinical efficacy of dirithromycin versus miocamycin in the treatment of acute bronchitis or acute exacerbations of chronic bronchitis.

A multicentre trial was carried out to compare the efficacy and safety of dirithromycin with miocamycin in the treatment of patients with acute bronchitis or acute exacerbations of chronic bronchitis. The study was a single-blind, randomized, parallel-group study. Dirithromycin was administered orally at a dosage of 500 mg once daily and miocamycin was administered orally at a dosage of 600 mg twice daily; the duration of therapy was five to seven days for both drugs. The results, in 161 assessable patients (78 taking dirithromycin; 83 taking miocamycin), show that dirithromycin and miocamycin have comparable efficacy and safety in the treatment of bronchitis caused by susceptible bacterial pathogens.

Dirithromycin in the treatment of skin and skin structure infections.

The efficacy and safety of dirithromycin were compared with those of erythromycin or miocamycin for the treatment of skin and/or skin structure infections in two double-blind, double-dummy, randomized, parallel group, multicentre studies conducted in North America and in Europe, and one single-blind, randomized, parallel group study conducted in Italy. The US and European study patients, in which bacterial infection was confirmed by culture, received either dirithromycin 500 mg once daily or erythromycin base 250 mg four times daily for seven days. Patients in the Italian trial were treated with either 500 mg dirithromycin once daily or with 600 mg miocamycin twice daily for seven days. A total of 156 of the 304 US patients treated with dirithromycin and 127 of the 274 patients treated with erythromycin qualified for efficacy analysis post-therapy. At the post-therapy evaluation, 112 (71.8%) dirithromycin-treated patients were cured and 34 (21.8%) improved compared with 94 (74.0%) and 25 (19.7%) patients treated with erythromycin. The pathogen was eliminated or presumably eliminated in 136 (87.2%) and 110 (86.6%) dirithromycin- and erythromycin-treated patients, respectively. A total of 100 of the 193 dirithromycin-treated patients qualified for efficacy analysis, as did 99 of the 198 erythromycin-treated patients in the European study at post-therapy. Favourable clinical responses (cure or improvement) at the post-therapy visit were recorded in 96 (96.0%) dirithromycin- and 98 (99%) erythromycin-treated patients, and pathogens were eliminated or presumed to have been eliminated in 87 (87.0%) and 88 (88.9%) patients respectively, in the dirithromycin and erythromycin treatment groups. Efficacy analysis was performed in 56 of the 70 Italian patients treated with dirithromycin and in 62 of the 71 patients treated with miocamycin. At post-therapy evaluation, a favourable clinical response was observed in 98.2% of the dirithromycin-treated patients compared with 95.1% of miocamycin-treated patients, whereas a favourable bacteriological response was observed in 52 (92.9%) dirithromycin- and 52 (83.9%) miocamycin-treated patients respectively. In all studies no serious treatment-related events were noted. Events most frequently reported were gastrointestinal in nature. Overall in the three studies, no statistically significant differences were observed between two treatment groups in the clinical and bacteriological outcomes.

[Evaluation of effectiveness of rokitamycin dry syrup in acute enteritis in pediatrics. A comparative study on rokitamycin and fosfomycin dry syrups].

Because Campylobacter jejuni is most frequently identified as a causative organism of bacterial enteritis in pediatrics, a study was done to evaluate the clinical efficacy against Campylobacter enteritis and the safety of a macrolide antibiotic, rokitamycin (RKM). In case of acute enteritis, RKM was used in a form of dry syrup at a dose level of approximately 30 mg (in potency)/kg body weight and its efficacy and safety were compared to those of fosfomycin (FOM) dry syrup which is currently in use at a dose level of 60 mg (in potency)/kg. Both drugs were administered, as a rule, in 3 divided daily dose (RKM before meal and FOM after meal) for 5 consecutive days. Comparisons of the drugs were made using a well-controlled method. Obtained results are summarized as follows. 1. No significant differences in background factors of the 2 drug groups were apparent, hence it was deemed that no obstacles existed in making comparative studies of the 2 groups with regard to their efficacies and safeties. 2. Overall efficacy rate against Campylobacter enteritis was 100% in the RKM group with a rate of excellent efficacy of 91.3% and the former was 94.4% in the FOM group with the latter of 72.2%. Though the RKM group apparently showed higher rates by 5.6% and 19.1%, respectively, for overall and excellent efficacies, they were not statistically significant as both drugs showed good efficacies. When acute cases of enteritis other than those caused by Campylobacter were included in the analysis, overall efficacy rates and rates of excellent efficacy were, respectively, 97.6% and 85.7% for the RKM group and 88.6% and 68.2% for the FOM group, thus RKM showed higher efficacy rates by 9.0% and 17.5%, respectively. These differences were deemed statistically significant using the U-test. 3. Numbers of days required for most of the major symptoms to subside were 3 days or less for the group for which RKM was used against Campylobacter enteritis. Similar results were observed for the FOM group also. In cases of acute enteritis due to other causes than Campylobacter, slower recoveries were observed for both the RKM and the FOM groups than in Campylobacter enteritis cases, with the latter group slower than the former. In cases of puruloid stool, the recovery in the RKM group was significantly faster by U-test than the FOM group, and a similar trend was observed overall. 4. Bacteriologically, the eradication rate of Campylobacter in the RKM group was very good at 91.3% with the FOM group showing a rate of 78.9%.(ABSTRACT TRUNCATED AT 400 WORDS)