Other inhibitors of cell wall synthesis

peptide chains. The abnormal proteins which result are fatal to the microbe, i.e. aminoglycosides are bactericidal and exhibit concentration-dependent bacterial killing (see p. 203).

Pharmacokinetics. Aminoglycosides are water-soluble and do not readily cross cell membranes. Poor absorption from the intestine necessitates their administration i.v. or i.m. for systemic use and they distribute mainly to the extracellular fluid; transfer into the cerebrospinal fluid is poor even when the meninges are inflamed. Their t'/2 is 2-5 h.

Aminoglycosides are eliminated unchanged mainly by glomerular filtration, and attain high concentrations in the urine. Significant accumulation occurs in the renal cortex unless there is severe renal parenchymal disease. Plasma concentration should be measured regularly (and frequently in renally-impaired patients) and it is good practice to monitor approximately twice weekly even if renal function is normal. With prolonged therapy, e.g. endocarditis (gentamicin), monitoring must be meticulous. The dose should be reduced to compensate for varying degrees of renal impairment, including that of normal aging. Numerous successful legal actions by patients against doctors for negligence in this area have resulted in large compensation payments, especially for ototoxicity.

Current practice is to administer aminoglycosides as a single daily dose rather than as twice or thrice daily doses. Algorithms are available to guide such dosing according to patients' weight and renal function, and in this case only trough concentrations need to be assayed. Single daily dose therapy is probably less oto- and nephrotoxic than divided dose regimens, and appears to be as effective. The immediate high plasma concentrations that result from single daily dosing are advantageous, e.g. for acutely ill septicaemic patients, as aminoglycosides exhibit concentration-dependent killing (see p. 203).

Antibacterial activity. Aminoglycosides are in general active against staphylococci and aerobic Gram-negative organisms including almost all the Enterobacteriaceae; individual differences in activity are given below. Bacterial resistance to aminoglycosides is an increasing but patchily-distributed problem, notably by acquisition of plasmids (see p. 209) which carry genes coding for the formation of drug-destroying enzymes. Gentamicin resistance is rare in community-acquired pathogens in many hospitals in the UK.

Uses include:

• Gram-negative bacillary infection, particularly septicaemia, renal, pelvic and abdominal sepsis. Gentamicin remains the drug of choice but tobramycin may be preferred for infections caused by Pseudomonas aeruginosa. Amikacin has the widest antibacterial spectrum of the aminoglycosides but is best reserved for infection caused by gentamicin-resistant organisms. As long as local resistance rates are low, an aminoglycoside may be included in the initial best-guess regimen for treatment of serious septicaemia before the causative organism(s) is identified. A potentially less toxic antibiotic may be substituted when culture results are known (48-72 h), and toxicity is very rare after such a short course.

• Bacterial endocarditis. An aminoglycoside, usually gentamicin, should comprise part of the antimicrobial combination for enterococcal, streptococcal or staphylococcal infection of the heart valves, and for the therapy of clinical endocarditis which fails to yield a positive blood culture.

• Other infections: tuberculosis, tularaemia, plague, brucellosis.

• Topical uses. Neomycin and framycetin, whilst too toxic for systemic use, are effective for topical treatment of infections of the conjunctiva or external ear. They are sometimes used in antimicrobial combinations selectively to decontaminate the bowel of patients who are to receive intense immunosuppressive therapy. Tobramycin is given by inhalation for therapy of infective exacerbations of cystic fibrosis. Sufficient systemic absorption may occur to recommend assay of serum concentrations in such patients.

Adverse effects. Aminoglycoside toxicity is a risk when the dose administered is high or of long duration, and the risk is higher if renal clearance is inefficient (because of disease or age), other potentially nephrotoxic drugs are co-administered (e.g.

loop diuretics, amphotericin B) or the patient is dehydrated. It may take the following forms:

• Ototoxicity. Both vestibular and auditory damage may occur, causing hearing loss, vertigo and tinnitus which may be permanent (see above). Tinnitus may give warning of auditory nerve damage. Early signs of vestibular toxicity include motion-related headache, dizziness or nausea. Serious ototoxicity can occur with topical application, including ear-drops.

• Nephrotoxicity. Dose-related changes, which are usually reversible, occur in renal tubular cells, where aminoglycosides accumulate. Low blood pressure, loop diuretics and advanced age are recognised as added risk factors.

• Neuromuscular blockade. Aminoglycosides may impair neuromuscular transmission and aggravate (or reveal) myasthenia gravis, or cause a transient myasthenic syndrome in patients whose neuromuscular transmission is normal.

• Other reactions include rashes, and haem-atological abnormalities, including marrow depression, haemolytic anaemia and bleeding due to antagonism of factor V.

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