Clinical Application of Aminoglycosides

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Abstract
After its introduction in 1966 gentamicin rapidly became the drug of first choice for treating life-threatening sepsis, especially in patients with hospital-acquired infections and those with compromised host defences. This happened in spite of early problems with toxicity, especially ototoxicity. Gentamicin was rapidly bactericidal for the coliforms, Staphylococcus aureus and Pseudomonas aeruginosa which were the main pathogens implicated. Rapid serum assays were developed, at first to monitor drug dosage to guard against excessive accumulation and toxicity. It quickly became apparent that there was a tendency to under-dose patients and that adequate serum concentrations could not simply be predicted from the dose given in relation to the 's size. A major purpose of rapid assay was to ensure adequate dosage, especially in severe infections such as Gram-negative pneumonia. The successful use of gentamicin without major toxicity has led to widespread use, often for less than life-threatening infection, for prophylaxis and even for minor indications. Topical and oral gentamicin have also been employed and have undoubtedly been associated with the emergence of gentamicin-resistant coliforms, staphylococci and pseudomonads, especially in burns units. Newer aminoglycosides have been introduced and each must be scrutinized carefully to see if it offers advantages over gentamicin. Tobramycin appears more active against Pseudomonas in vitro and appears less nephrotoxic in most animal studies. However, there is little in vivo evidence in humans that tobramycin confers a real advantage either in treating Pseudomonas infections or avoiding nephrotoxicity. My own experience in terms of efficacy has been disappointing. Amikacin, a semi-synthetic aminoglycoside, is active against the majority of gentamicin-resistant Gram-negative rods and staphylococci and the equivalent clinical dose is probably as effective as gentamicin and appears no more toxic. It should be reserved for situations where there is no infection with a gentamicin-resistant strain or a strong suspicion that this is so. Sissomicin will probably not be made available in this country, but there is experimental and clinical work to suggest that it is more efficacious than gentamicin in vivo. Nevertheless, strains resistant to gentamicin are virtually always resistant to sissomicin too. Netilmicin is a semi-synthetic derivative of sissomicin which appears to offer advantages over gentamicin in terms of broader spectrum (although not as broad as amikacin); reduced oto- and probably nephrotoxicity; and increased efficacy, certainly for klebsiella infections. Prospective, blind, clinical trials are needed to compare the new broad spectrum-lactam antibiotics with aminoglycosides to see where these agents can replace aminoglycosides in clinical use. Aminoglycosides will probably be retained for life-threatening infections in patients with compromised defence mechanisms, but hopefully there will be a more restricted use of them which will help reduce problems of toxicity and resistance.

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