___________________________________________________________________________ Antibiotics Review
DRUG INTERACTIONS Drug interactions are extensive. Erythromycin and clarithromy- cin are inhibitors and substrate for the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A4). If they are given with a drug that is primarily metabolized by CYP3A, the drug serum levels may be increased and/or prolonged [6]. Erythromycin is contraindicated with concurrent use of cis- apride, pimozide, dihydroergotamine, ergotamine, lovastatin, simvastatin, astemizole, or terfenadine. Clarithromycin is contraindicated with concurrent use of cisapride, pimozide, ergot alkaloids (e.g., ergotamine), or lomitapide [6]. Serum lev- els of theophylline, cyclosporine, ergotamine, carbamazepine, benzodiazepines, warfarin, amiodarone, and tacrolimus may also be affected by concurrent administration with erythromy- cin and clarithromycin. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors levels may also be elevated, with increased risk for rhabdomyolysis [6; 106]. Azithromycin is not likely to interact with drugs metabolized by CYP3A4. However, azithromycin interacts with pimozide, potentially resulting in QT interval prolongation and arrhyth- mia [107]. Co-administration with pimozide is therefore contraindicated. Levels of cyclosporine could potentially be increased and therefore should be monitored closely [6; 108]. SPECIAL POPULATIONS Erythromycin is pregnancy category B, with an erythromycin estolate preparation as the preferred form because it is less likely to cause hepatotoxicity. Surveillance studies have not shown any increase in adverse outcomes. Azithromycin is also category B [6]. The CDC recommends the use of azithromycin for the treatment of Chlamydia during pregnancy. Treatment with erythromycin is an approved alternative regimen [109]. Clarithromycin is pregnancy category C, based on the finding that it causes growth retardation in monkeys and adverse effects on other mammals, including fetal loss. A postmarketing sur- veillance study did not find any evidence of teratogenicity, but a Danish study found a doubling in the frequency of miscarriages among women treated with clarithromycin [110; 111]. The manufacturer recommends that clarithromycin not be used in pregnant women unless there are no alternative therapies [6]. Erythromycin is excreted in breast milk, but the AAP considers it usually compatible with breastfeeding [57]. Clarithromycin is excreted in breast milk, but breastfeeding is considered accept- able when the relative infant dose is less than 10% [112]. One systematic review and meta-analysis demonstrated a significant association between post-natal use of erythromycin and infan- tile hypertrophic pyloric stenosis [113].
Macrolides are relatively poorly absorbed orally. Fidaxomicin is minimally absorbed and active only locally in the gastrointes- tinal tract. Food increases absorption of extended-release clar- ithromycin but has little or no effect on the immediate-release preparation of the drug. Food causes decreased absorption of both azithromycin capsules and erythromycin (including base and stearate formulations) [104]. Erythromycin may also be given intravenously. All the macrolides have extensive tissue distribution, with less than adequate penetration into the brain tissue and the CSF [104]. Erythromycin is primarily excreted in feces and urine, with 2% to 15% unchanged [6]. Azithromycin is primarily excreted unchanged into the bile. Clarithromycin is excreted in the urine, both unchanged and as the hydroxy metabolite. It may be necessary to adjust the doses of the macrolides in the presence of severe hepatic insufficiency. Azithromycin should be used with caution in adults with hepatic impairment; no dosage adjustments are recommended for renal impairment [6]. A dosage adjustment of clarithromycin may be appropriate in patients with hepatic impairment and concomitant severe renal impairment; clarithromycin doses may have to be reduced in severe renal failure [6]. SIDE EFFECTS/TOXICITY While serious side effects with the macrolides are rare, milder side effects are common. Erythromycin stimulates motility in the GI tract, and this may cause abdominal cramping, diarrhea, nausea, and vomiting. Hepatic dysfunction with or without jaundice has occasionally been reported with erythromycin estolate. There have also been some reports of reversible hear- ing loss in patients treated with erythromycin in high doses or in the presence of renal insufficiency. With IV erythromycin, prolongation of the QT interval and ventricular tachycardia may occur [104]. Clarithromycin may cause nausea, diarrhea, abnormal taste, dyspepsia, and headache. There have been reports of tooth discoloration that is reversible with professional cleaning. Transient CNS changes with anxiety and behavioral changes, which resolve when the drug is discontinued, have also been reported [105]. Allergic reactions to macrolides are rare but may include rash and eosinophilia. Very rarely, severe reactions such as Stevens-Johnson syndrome have occurred. The drugs are contraindicated in patients with known hypersensitivity to the macrolides.
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MDTX2026
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