___________________________________________________________________________ Antibiotics Review
Half-life alterations occur in patients at extremes of age. The half-life in neonates and low-birth-weight infants may be considerably prolonged. The elderly may also have a longer aminoglycoside half-life due to an age-related decrease in renal function [92]. Geriatric dosing should be based on ideal body weight estimates [6]. MACROLIDES The original macrolide, erythromycin, was discovered in 1952 by J.M. McGuire. It is produced by Saccharopolyspora erythraea (formerly known as Streptomyces erythreus ). Semisynthetic deriva- tives (clarithromycin, azithromycin) have been produced from the original erythromycin, with modifications that improve acid stability, antibacterial spectrum, and tissue penetration. MECHANISM OF ACTION The macrolides are bacteriostatic, inhibiting protein synthesis by binding at the 50S ribosomal unit and by blocking trans- peptidation and translocation. At high concentrations or with rapid bacterial growth, the effects may be bactericidal [93]. Data challenge the view of macrolides as global inhibitors of protein synthesis. Evidence demonstrates that these agents selectively inhibit the translation of a subset of cellular proteins, that they impact protein synthesis in a context-specific manner, and that they manifest site specificity of action [94; 95; 96; 97; 98]. Many bacteria that are resistant to the penicillins are also resistant to erythromycin. Bacterial resistance may result from decreased permeability of the cell membrane; in addition, an increase in active efflux of the drug may occur by incorporating a transporter protein into the cell wall [98; 99; 100]. The gene for this mechanism is transferred on plasmids between bacteria. Mutations of the 50S ribosomal receptor site may also develop, preventing binding of the erythromycin [101]. Lastly, bacterial enzymes have been described that may deactivate erythromycin [102]. It is likely that this form of resistance is also transferred on plasmids. Many strains of H. influenzae are resistant to erythromycin alone but are susceptible to a combination with a sulfonamide [103]. Erythromycin ethylsuccinate and sulfisoxazole are manufac- tured as suspensions for use in treating acute otitis media in children older than 2 months of age [6]. They are useful for targeting H. influenzae , one of the common pathogens in otitis media in this age group. PHARMACOKINETICS Erythromycin has a wide spectrum of activity. Gram-positive bacteria that are usually susceptible to erythromycin include the Streptococcus species. Erythromycin is a second-line agent for gram-negative bacteria, such as H. influenzae (when used concomitantly with sulfonamides) and M. catarrhalis . Mac- rolides are particularly useful for their coverage of atypical
bacteria, such as Mycoplasma and Chlamydia . Some spirochetes and mycobacteria are also susceptible to the macrolides. These drugs are indicated for upper respiratory tract infections, such as sinusitis, otitis media, pharyngitis, and bronchitis. They are also useful in the treatment of pertussis, Legionnaires disease, and diphtheria. 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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