Oral erythromycin and the risk of sudden death from cardiac causes.

BACKGROUND: Oral erythromycin prolongs cardiac repolarization and is associated with case reports of torsades de pointes. Because erythromycin is extensively metabolized by cytochrome P-450 3A (CYP3A) isozymes, commonly used medications that inhibit the effects of CYP3A may increase plasma erythromycin concentrations, thereby increasing the risk of ventricular arrhythmias and sudden death. We studied the association between the use of erythromycin and the risk of sudden death from cardiac causes and whether this risk was increased with the concurrent use of strong inhibitors of CYP3A. METHODS: We studied a previously identified Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. The CYP3A inhibitors used in the study were nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin; each doubles, at least, the area under the time-concentration curve for a CYP3A substrate. Amoxicillin, an antimicrobial agent with similar indications but which does not prolong cardiac repolarization, and former use of erythromycin also were studied, to assess possible confounding by indication. RESULTS: The multivariate adjusted rate of sudden death from cardiac causes among patients currently using erythromycin was twice as high (incidence-rate ratio, 2.01; 95 percent confidence interval, 1.08 to 3.75; P=0.03) as that among those who had not used any of the study antibiotic medications. There was no significant increase in the risk of sudden death among former users of erythromycin (incidence-rate ratio, 0.89; 95 percent confidence interval, 0.72 to 1.09; P=0.26) or among those who were currently using amoxicillin (incidence-rate ratio, 1.18; 95 percent confidence interval, 0.59 to 2.36; P=0.65). The adjusted rate of sudden death from cardiac causes was five times as high (incidence-rate ratio, 5.35; 95 percent confidence interval, 1.72 to 16.64; P=0.004) among those who concurrently used CYP3A inhibitors and erythromycin as that among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications. In contrast, there was no increase in the risk of sudden death among those who concurrently used amoxicillin and CYP3A inhibitors or those currently using any of the study antibiotic medications who had formerly used CYP3A inhibitors. CONCLUSIONS: The concurrent use of erythromycin and strong inhibitors of CYP3A should be avoided.

Serum sickness like illness and antimicrobials in children.

AIM: To determine which antimicrobials are associated with the development of serum sickness like reactions in children admitted to hospital in Christchurch. METHOD: A retrospective case note review of children admitted with serum sickness like reactions over a 10 year period was carried out. 59 children were identified and 30 of these were eligible for inclusion in the study. RESULTS: Of the 30 children with serum sickness like reaction, 19 had received cefaclor alone, six penicillin V, two amoxycillin, and one each flucloxacillin cotrimoxazole and triacetylolendomycin (TAO). Children received these antimicrobials for 3-10 days. CONCLUSION: In this study cefaclor was commonest antimicrobial agent associated with the development of serum sickness like reaction. This association should receive consideration prior to prescribing cefaclor to children.

[A new cause of torsades de pointes: combination of terfenadine and troleandomycin]. / Une nouvelle cause de torsades de pointes: association terfénadine et troléandomycine.

The authors report a case of wave-burst arrhythmia which occurred during combined treatment with terfenadine and troleandomycin. After the treatment had been stopped and the QT interval returned to normal, terfenadine treatment was reintroduced with no major change in repolarization. However, as soon as troleandomycin was associated, there was a significant and progressive prolongation of QT. Normal repolarization was restored again with troleandomycin alone. These findings suggest drug interaction between terfenadine and troleandomycin. Although it is not possible to carry out serum assays of terfenadine, one possible physiopathological hypothesis would be an overdose of terfenadine. Terfenadine undergoes hepatic oxidative metabolism involving the cytochrome P450 pathway and troleandomycin inhibits cytochrome P450. In the literature, a case has already been described of wave-burst arrhythmia related to terfenadine overdose when associated with a cytochrome P450 inhibitor.

Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma.

BACKGROUND: Troleandomycin (TAO), a macrolide antibiotic, was studied as an alternative treatment in 18 children with severe, steroid-requiring asthma. METHODS: In this investigation three treatment arms were used in randomized, double-blind, parallel fashion: combination TAO and methylprednisolone (MPn), combination TAO and prednisone, and MPn alone. RESULTS: All groups tolerated a considerable reduction in glucocorticoid dose over the 12 weeks of the study: 80% +/- 6% for TAO-MPn, 55% +/- 8% for TAO-prednisone, and 44% +/- 14% for MPn alone. These reductions are all statistically significant (p < 0.05) within groups, and the differences between groups were statistically significant between the TAO-MPn and MPn alone groups. The concentration of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second and pulmonary function were not significantly improved in any treatment group. Safety parameters including blood chemistry and hematology, adrenal function assessment; bone densitometry, and muscle strength testing, were not altered significantly. Two patients who received TAO had elevated liver enzyme levels; one required discontinuation of TAO and one experienced spontaneous resolution without intervention. Lack of statistically significant changes in the efficacy parameters were likely a result of small sample size and effects of the glucocorticoid dose taper. CONCLUSIONS: TAO is safe and may be a reasonable treatment alternative in a limited trial for patients who are unable to tolerate tapering of their glucocorticoid dosage. Therapy should be guided by the goal of treatment, that is, glucocorticoid dose reduction or improvement of pulmonary function with appropriate monitoring of pulmonary function and adverse effects.

A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids.

A group of 75 subjects with asthma requiring daily corticosteroids for control were enrolled in a 2-yr, double-blind, placebo-controlled study of the use of troleandomycin combined with methylprednisolone, compared with methylprednisolone alone, for the management of their asthma. The primary outcome variables were determination of the lowest stable methylprednisolone dose and assessment of corticosteroid side effects. Methylprednisolone dose was adjusted to maintain optimal control of asthma symptoms. A total of 30 patients receiving TAO and 27 patients receiving placebo completed 1 yr; 17 on TAO and 8 on placebo completed 2 yr of double-blind participation. Control of asthma was equivalent in both groups. The vast majority of patients in both groups achieved alternate-day dosing (29 of 30 on TAO and 23 of 27 on placebo in the first year). The lowest stable doses of methylprednisolone achieved were 10.4 mg/day (placebo) versus 6.3 mg/day (TAO) in the 1-yr group (p = 0.03). However, the baseline dose was also significantly higher in the placebo group (22.8 versus 17.6 mg/day in the TAO group). Therefore, the reductions in methylprednisolone dose were not significantly different between treatment groups. Differences were observed between the two treatment groups in serum IgG, fasting blood sugar, serum cholesterol, and progression of osteoporosis. In each instance the more unfavorable response occurred in those subjects receiving TAO. We conclude that the addition of TAO to methylprednisolone was not accompanied by a reduction in corticosteroid side effects compared with treatment with methylprednisolone alone. Furthermore, no evidence was found for a subset of "TAO responders."(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-inflammatory drugs in the treatment of allergic disease.

The treatment of asthma is undergoing significant change with an emphasis on anti-inflammatory therapy. While glucocorticoids are the most potent anti-inflammatory agent, certain patients fail to respond. These patients may be candidates for alternative anti-inflammatory therapy, such as troleandomycin, methotrexate, gold, hydroxychloroquine, or dapsone. In addition, the application of immunomodulator therapy, such as intravenous gamma globulin or cyclosporine, may be useful.

Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma.

In nine children with steroid-dependent asthma, ranging in age from 2 and 11/12 to 14 and 4/12 years, troleandomycin (TAO) was administered at a dose of 250 mg po QD or BID, along with oral methylprednisolone. Both medications were then rapidly changed to a QOD schedule. Baseline daily steroid dosage requirements decreased from 15.3 +/- 9.1 mg methylprednisolone to 1.4 +/- 0.7 mg (P less than 0.01, paired t-test), and the number of steroid bursts (1-2 mg/kg/day) per year decreased from 12.2 +/- 4.8 to 4.1 +/- 2.0 (P less than 0.01, paired t-test). There was also a significant decrease in the number of hospitalizations per year from 3.4 +/- 4.6 to 0.6 +/- 0.7 (P less than 0.05, paired t-test). The incidence of steroid side effects increased, despite the decrease in the amount of steroid required. Specifically, the prevalence of cataracts increased from 11% to 33% (chi 2 = 4.5, P = 0.15) and the prevalence of hypercholesterolemia increased from 22% to 78% (chi 2 = 16.67, P less than 0.001). There was no elevation of serum transaminases in any of our patients on TAO. Although TAO appears to be efficacious, caution is warranted when TAO is considered for use in younger children with steroid-dependent asthma.

Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children.

Fifteen hospitalized asthmatic children (8 to 18 years old) completed a 2-week randomized, parallel, double-blind placebo-controlled comparison of combination methylprednisolone and placebo troleandomycin, prednisone and troleandomycin (P-TAO) or methylprednisolone-TAO (MPn-TAO). Troleandomycin (250 mg once daily or every other day) and glucocorticoid doses were reduced by a standard protocol. Symptom scores, blood chemistries, pulmonary function tests, airway response to methacholine, and glucocorticoid pharmacokinetics were compared. In each group, a steroid dose reduction of 50% was achieved without a deterioration in symptom scores. Methacholine response was unchanged in all five on methylprednisolone alone, but decreased 3-fold to 30-fold in two of five on combination P-TAO, and four of five on combination MPn-TAO. Troleandomycin decreased MPn clearance by an average of 62% but did not alter prednisolone clearance. Low-dose TAO combined with MPn has a significant effect on methylprednisolone clearance in children, an effect equivalent to that reported with higher dose TAO (1000 mg/d) therapy. In addition, this preliminary study suggests that TAO may decrease bronchial hyperresponsiveness to methacholine in severely asthmatic children.

Fatal varicella in a corticosteroid-dependent asthmatic receiving troleandomycin.

Long-term use of corticosteroids (CSs) may result in an increased risk of disseminated varicella. Concurrent administration of troleandomycin (Tao) to treat CS-dependent asthmatics can potentiate steroid effects. We present the first case of fatal varicella in a patient concurrently receiving methylprednisolone and Tao therapy. At the time of her death she had been receiving CSs for 2 years and Tao for 1 year. She had a 2-day history of fever, lower back and abdominal pain, dysuria, and constipation. Later, when pox lesions were evident, it was learned she had been exposed to varicella 2 weeks previously. While hospitalized she developed hepatitis, gastrointestinal hemorrhage, disseminated intravascular coagulopathy, and pneumonitis, resulting in respiratory failure. She succumbed despite treatment with stress doses of steroids, intravenous acyclovir, fresh frozen plasma, and ventilatory support. Autopsy findings revealed evidence consistent with disseminated varicella. This case suggests that concurrent therapy with CSs and Tao may increase the risk for disseminated varicella, possibly by enhancing CS-induced immunosuppressive effects. We suggest that other immunologic parameters in addition to serum varicella titers might be helpful in identifying those CS-dependent patients at risk. Any CS-dependent asthmatic, whether or not receiving Tao, should receive varicella-zoster immune globulin within 96 hours of exposure and acyclovir once varicella is clinically apparent. Varicella vaccine should be considered for those not yet exposed.

The incidence of corticosteroid side effects in chronic steroid-dependent asthmatics on TAO (troleandomycin) and methylprednisolone.

The purpose of this study was to determine the effect of troleandomycin (TAO)-methylprednisolone (MP) regimens on the incidence of corticosteroid-induced side effects. Retrospective analysis was performed on the charts of 29 adult chronic steroid-dependent asthmatics on regimens of TAO-MP. These 29 met our criteria of a minimum of 1 year on TAO-MP and at least 6 to 12 months on daily or alternate-day corticosteroids before TAO-MP was instituted. Charts were reviewed for nine known corticosteroid (CS) side effects, all previously identified side effects were excluded. Charts were also reviewed for TAO dose, MP dose, and dose/duration on CS therapy before TAO-MP regimen began. Patients on TAO at an average dose of 250 mg/d were able to wean to an average MP dose of 10.8 mg every other day from an average MP equivalent dose of 16.8 mg every other day before TAO. In spite of lower MP doses on TAO we found that 35% showed an increase in CS-induced side effects, some (three) had more than one side effect. Three patients developed cataracts (10%), two become hypertensive (6.8%), one developed diabetes (3%), one had a psychotic episode (3%), and one patient developed TB (3%) and had a spinal compression fracture. Sixty percent of these patients were on 8 mg or less of MP on an alternate-day basis. We found that in this group of 29 chronic steroid-dependent asthmatics the incidence of corticosteroid-related side effects was increased on TAO-MP regimens despite a reduction in corticosteroid dose.

[Psychotic disorders linked to the inhibition of benzodiazepine catabolism]. / Accidents psychiques liés à l'inhibition du catabolisme des benzodiazépines.

Five clinical cases of interaction between benzodiazepines on one hand and erythromycin, troleandomycin, josamycin and cimetidine on the other hand have been analyzed. These interactions resulted in severe disorders of behaviour, amnesia (including amnesia-automatism syndrome in one case), disturbances of consciousness and withdrawal syndrome. These disorders were consecutive to inhibition of the hepatic cytochrome P-450 system. Practical means of avoiding this risk consists in limiting such drug combinations, reducing benzodiazepine dosage and, if a combined treatment is necessary, using by preference either benzodiazepines degraded by conjugation instead of oxidation, or macrolides, or anti-H2 compounds with reduced inhibitory effect on microsomes.

Prolonged cholestasis after troleandomycin-induced acute hepatitis.

We report the case of a patient in whom troleandomycin-induced hepatitis was followed by prolonged anicteric cholestasis. Jaundice occurred after administration of troleandomycin for 7 days and was associated with hypereosinophilia. Jaundice disappeared within 3 months but was followed by prolonged anicteric cholestasis marked by pruritus and high levels of alkaline phosphatase and gammaglutamyltransferase activities. Finally, pruritus disappeared within 19 months, and liver tests returned to normal 27 months after the onset of hepatitis. This observation demonstrates that prolonged cholestasis can follow troleandomycin-induced acute hepatitis.

An improved protocol for the use of troleandomycin (TAO) in the treatment of steroid-requiring asthma.

An improved protocol was developed for the use of troleandomycin (TAO) in severe, steroid-requiring subjects with asthma. Compared to previous reports, this protocol uses a lower starting dose of TAO and a rapid steroid taper. Fifteen patients were treated with TAO following the new guidelines. Steroid requirements in the 15 patients dropped by 68% within 2 weeks, and 13 of the 15 patients were able to be maintained on alternate day steroids. In spite of rapid steroid taper, both FEV1 and mean FVC increased significantly (p less than 0.001). There was a low incidence of side effects and, in contrast to previous reports on TAO, no patient had even a transient increase in cushingoid appearance. Glucose intolerance was observed initially in three patients but resolved with continued steroid taper. Transient liver-enzyme elevation was noted in four patients and in each case reversed with a reduction in TAO dosage. The revised protocol is associated with an improved risk-benefit ratio. New guidelines are presented for the use of TAO in severe steroid-requiring subjects with asthma.