Risks & adverse effects

Aminoglycosides, like all other antibiotics, have possible adverse effects that require careful monitoring. We provided a brief overview of the main ones earlier this week.

Nephrotoxicity

One such adverse effect is nephrotoxicity, defined as the drug-induced deterioration of kidney function. Aminoglycosides have the ability to accumulate in renal tubular epithelial cells. The toxicity can affect the kidneys. The reported incidence of nephrotoxicity varies widely due to variations in study design, toxicity definitions, patient population, and concomitant risk factors.

Aminoglycoside nephrotoxicity usually presents as a reduced urine output. In most cases, aminoglycoside nephrotoxicity is reversible.

There are a few risk factors that contribute to clinical aminoglycoside nephrotoxicity such as:

• patient-related factors – older age and pre-existing renal diseases
• hepatic dysfunction
• large aminoglycoside doses and treatment duration of longer than 3 days
• aminoglycoside choice, e.g. gentamicin
• concomitant drugs such as vancomycin, amphotericin B, furosemide, clindamycin, piperacillin, cephalosporins, methoxyflurane, foscarnet

This is summarised in the image below:

Ototoxicity

Another known toxic effect is ototoxicity, caused by aminoglycoside-induced damage of the auditory and vestibular portions of the eighth cranial nerve. They have the ability to accumulate in vestibular and cochlea hair cells, triggering apoptosis (cell death).

In some cases ototoxicity is transient; however, there is also a risk that the nerve damage is irreversible.

Common symptoms of cochlear toxicity are tinnitus and hearing loss. Vestibular toxicity can manifest in several ways, such as:

• Vertigo
• Disequilibrium
• Light-headedness
• Nausea
• Vomiting
• Ataxia

These symptoms will usually present after the acute infection that the aminoglycosides have been used for has resolved.

Ototoxicity is more likely to occur when aminoglycosides have been co-prescribed with furosemide (a loop diuretic) or vancomycin.

To avoid toxicity, serum drug concentrations, blood urea, nitrogen, and creatinine should be measured. In addition to monitoring, a possible preventive strategy in patients receiving long-term aminoglycoside therapy and/or with end-stage kidney disease is the co-administration of agents that may have a protective effect (such as N-acetylcysteine). Patients should be informed of the symptoms and counselled to report any auditory symptoms such as ringing in the ears.

Unfortunately, some patients may have genetic variations, which means that they are at higher risk of developing aminoglycoside-induced hearing loss. We will learn more about these genetic factors in the next step.

Neuromuscular blockade

Another risk involved is neuromuscular blockade, a rare but serious adverse effect induced by aminoglycoside therapy. Neuromuscular blockade is a failure in neuromuscular transmission which results in relaxed/paralysed muscles.

Aminoglycosides interfere with calcium ion movements and inhibit acetylcholine release at the synaptic cleft. The muscle-relaxant effect is very serious if it affects respiratory muscles such as the diaphragm.

Most patients experiencing such reactions have disease states and/or concomitant drug therapy that interferes with neuromuscular transmission. Myasthenia gravis is an absolute contraindication to aminoglycoside use.

You should note that the adverse drug reaction profiles of different aminoglycosides vary slightly with each other. For example, gentamicin is more ototoxic compared to amikacin. In contrast, amikacin is considered more nephrotoxic.

The toxicity of aminoglycosides can be linked to their levels in the body and this link, along with the importance of monitoring those levels using therapeutic drug monitoring (TDM), will be discussed next week.