Equis ISSN 2398-2977

Toxicity: aminoglycoside

Contributor(s): Nicola Menzies-Gow, Graham Munroe, Wilson Rumbeiha, Prof Alan Seawright

Introduction

  • Cause: aminoglycoside antibiotics Therapeutics: aminoglycosides, particularly gentamicin Gentamicin - an important group of drugs for the treatment of gram-negative bacterial infections in the horse. Aminoglycosides are well known causes of ototoxicity (deafness) and ataxia. This is a well known side-effect in man and in dogs and cats, although no reports in horses, it may still occur.
  • Signs: nephrotoxicity especially where glomerular filtration rate (GFR) is decreased, eg in association with hypovolemia.
  • Diagnosis: history, clinical signs, urinalysis, serum and aminoglycoside concentrations.
  • Treatment: supportive therapy and treatment of renal failure Kidney: renal failure.
  • Prognosis: usually signs are reversible if aminoglycosides are stopped early on in toxicity. Nephrotoxicity is reversible, ototoxicity is not.

Pathogenesis

Etiology

  • Aminoglycoside antibiotics most commonly used in equine practice includes gentamicin Gentamicin, amikacin Amikacin.

Predisposing factors

General

  • Concurrent renal disease - conventional dosage regimes are based on pharmacokinetic data from healthy animals - large individual and age-related variations exist in the volume of distribution and clearance of these drugs, especially in diseased animals.
  • Prematurity/immaturity Reproduction: prematurity / dysmaturity - premature or young neonatal foals particularly with hypoxia, azotemia and septicemia, have larger aminoglycoside clearance times due to renal hypoperfusion and decreased GFR.
  • Alteration in extracellular fluid (ECF) volume associated with dehydration, endotoxemia Endotoxemia: overview or sepsis, peritoneal/pleural effusion or the higher percentage of total body water in neonatal foals changes the volume of distribution; peak serum concentrations; decrease GFR; increase clearance times.
  • Simultaneous use of other nephrotoxic agents, eg NSAIDs Therapeutics: anti-inflammatory drugs.

Specific

  • Almost exclusive renal excretion of aminoglycoside antibiotics → larger clearance times → increased risk of nephrotoxicity.

Pathophysiology

  • Aminoglycoside antibiotics are not metabolized - are cleared almost exclusively by renal excretion.
  • Accumulation of these agents within the renal cortex, specifically proximal tubular cells → interference with function → toxicity.
  • Dehydration, pre-existing renal diseases, acidosis, endotoxemia, are predisposing factors.
  • After filtration at glomerulus, aminoglycosides bind to phospholipids on the brush border of proximal tubular cells and are subsequently resorbed.
  • Accumulation of the drugs in these cells interferes with lysosomal, mitochondrial and sodium pump function.
  • Further drug accumulation → frank necrosis of tubular cells.

Timecourse

  • Depends upon total dosage and dosing regimen.

All patients given aminoglycosides for >5 days should be monitored.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Raisis A L, Hodgson J L & Hodgson D R (1988) Serum gentamicin concentrations in copromised neonatal foals. Equine Vet J 30 (4), 324-328 PubMed.
  • Sweene R W, MacDonald M, Hall J, Divers T J & Sweeney C R (1988) Kinetics of gentamicin elimination in two horses with acute renal failure. Equine Vet J 20 (3), 182-184 PubMed.
  • Riviere J E et al (1983) Species dependent gentamicin pharmacokinetics and nephrotoxicity in the young horse. Fundam Appl Toxicol 3 (5), 448-457 PubMed.

Other sources of information

  • Geor R J (1997) Aminoglycoside dosing. In: Current Therapy in Equine Medicine IV. Ed: Robinson N E. W B Saunders Co, UK. pp 476-478.


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