Antibiotics Review _ __________________________________________________________________________
The aminoglycosides commonly used at present for treatment of systemic bacterial infection include gentamicin, tobramycin, and amikacin. Kanamycin is discontinued [17]. Aminoglyco- sides have negligible oral absorption and thus require paren- teral administration. They also can be administered directly into body cavities and have a role in the management of pleural and peritoneal infection. Tobramycin is particularly useful for treatment of recurrent Pseudomonas infection in patients with cystic fibrosis and can be administered by aerosolized inhala- tion to facilitate optimal local antimicrobial effect [79]. In a large randomized, placebo-controlled clinical trial involving critically ill adults who had undergone invasive mechanical ventilation, a three-day prophylactic regimen of inhaled amika- cin reduced the subsequent incidence of ventilator-associated pneumonia [174]. Neomycin is often used orally as part of a pre-operative bowel decontamination protocol. The aminoglycosides are widely distributed in extracellular fluid, including pleural fluid, synovial fluid, abscesses, and peritoneal fluid. They are relatively insoluble in lipid, so the volume of distribution is lower in obese patients. They have poor distribution in bile, aqueous humor, bronchial secretions, sputum, and the CSF [15]. Aminoglycosides are excreted unchanged by the kidneys [6]. There is no reduction of dosage necessary in liver failure, as there is no hepatic metabolism of these agents. In renal failure, the dosage must be carefully adjusted based on glomerular filtration rate and measured serum levels. Serum levels should be monitored in all patients with reduced renal function [83]. 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].
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