___________________________________________________________________________ Antibiotics Review
TOXICITY The most common adverse effect associated with aminogly- coside usage is nephrotoxicity, occurring in 10% to 25% of therapeutic courses [84]. Aminoglycosides are freely filtered by the glomeruli and quickly taken up by the proximal tubular epi- thelial cells, where they exert their main toxic effect by altering phospholipid metabolism. Aminoglycosides also cause renal vasoconstriction [85]. Critical factors in the development of acute kidney injury secondary to aminoglycoside nephrotoxic- ity are dosing and duration of therapy. A single daily large dose is preferable to more frequent dosing, as it appears to cause less accumulation in the tubular cells once the saturation point is reached [84]. Additionally, extending the dose interval to more than 24 hours in patients with renal impairment has been found to be effective, with irreversible nephrotoxicity reported in only 1% of patients studied [86]. Vestibular and auditory toxicity may also complicate treatment with aminoglycosides, though this is less common now as clinical awareness and careful dosage adjustment in relation to renal function has improved. These effects are usually revers- ible, and because there is some data suggesting that there is a genetic predisposition to ototoxicity, this drug class should be avoided in patients who have a family history of ototoxicity with aminoglycosides [87]. When aminoglycoside therapy is expected to exceed five to seven days, baseline testing of audi- tory function should be performed and monitored weekly for the duration of treatment. Neuromuscular blockage has also been observed as a side effect. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disorders, such as myasthenia gravis and Parkinson disease, due to a curare-like effect on neuromuscular function [88]. Hypersensitivity reactions are not common with aminogly- cosides, but rash, fever, urticaria, angioneurotic edema, and eosinophilia may occur. Very rare reactions include optic nerve dysfunction, peripheral neuritis, arachnoiditis, encepha- lopathy, pancytopenia, exfoliative dermatitis, and amblyopia. Bronchospasm and hoarseness have been known to occur with tobramycin inhalation solution [89]. The aminoglycosides are contraindicated in patients with hypersensitivity to the drug. Cross-sensitivity between amino- glycosides does occur. Streptomycin also contains metabisulfite and should be avoided if the patient is allergic to sulfites (more common in asthmatics) [6; 90]. DRUG INTERACTIONS There are numerous drug interactions that should be taken into consideration when using the aminoglycosides. The risk of nephrotoxicity may be increased with co-administration of other drugs that are nephrotoxic or in patients receiving loop diuretics (e.g., furosemide). Respiratory depression may occur if aminoglycosides are given with nondepolarizing muscle relaxants. Neomycin may affect digoxin levels by altering the
bowel flora responsible for the metabolism of digoxin in the GI tract. Gentamicin may also cause increased serum digoxin levels [6; 91]. In vitro deactivation of penicillins due to acylation has been observed, so the drugs should not be mixed in vitro. Tobra- mycin inhalation solution cannot be mixed in the nebulizer with dornase alfa [6]. SPECIAL POPULATIONS Amikacin, gentamicin, neomycin, and streptomycin are pregnancy category D due to eighth cranial nerve toxicity that has occurred in the fetus with some aminoglycosides [6]. Plazomicin and tobramycin carry a boxed warning that states pregnant patients should be apprised of potential harm to the fetus with their administration [6]. Traces of amikacin, gentamicin, streptomycin, and tobramy- cin are excreted in breast milk, but they are compatible with breastfeeding because they are very poorly absorbed from the GI tract [6]. However, they may cause alterations in the normal bowel flora of the infant [6]. It is not known if neomycin or plazomicin are present in breast milk [6]. 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].
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MDTX2026
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