Aminoglycosides - Antimicrobials

Aminoglycosides

Aminoglycoside antibiotics contain amino sugars linked to an aminocyclitol ring by glycosidic bonds.

Examples

·              Amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, paramomycin, streptomycin, , and trospecto-mycin.

·              The first of these compounds to be discovered was strepto-mycin which was isolated from the actinomycete Streptomycesgriseus, in1943bySchatz, Bugie,andWaksman. This wassoon followed by the isolation of other members of the group in rapid succession.

Uses

These antibiotics are mainly active against infections caused by aerobic, gram-negative bacilli— Citrobacter, Enterobacter,Escherichia, Klebsiella, Proteus, Providencia, Pseudomonas, Serratia, and Staphylococcus. Kanamycin and streptomycinhave a more limited spectrum compared to the other amino-glycosides.

In conjunction with penicillin or vancomycin, some of these agents (streptomycin, gentamicin), are also active against strains of Enterococci and Streptococci. Streptomycin is some-times used for the treatment of drug-resistant tuberculosis.

Toxicokinetics

The aminoglycosides being highly polar cations are poorly absorbed from the GI tract and hence are administered parenter-ally (IM). Peak plasma concentrations are achieved in 30 to 90 minutes. Binding to plasma albumin is negligible (except in the case of streptomycin), and the apparent volume of distribution is 25% of body weight. Concentrations of these drugs in tissues and secretions is generally low. However they can cross the placental barrier, and streptomycin in particular is known to produce toxic effects (hearing loss) in children born to mothers who have received the drug during pregnancy.

Excretion is mainly through the urine by glomerular filtra-tion. In the presence of renal impairment, these drugs must be used with great caution owing to the risk of accumulation and resultant toxicity.

Mode of Action

·              Aminoglycosides are bactericidal antibiotics which inhibit protein synthesis by interfering with the 30s ribosomal subunit of RNA.

·              In toxic doses, these drugs produce renal damage by binding to phospholipids on brush border membranes in the prox- imal renal tubules resulting in cellular dysfunction. Risk factors include genetic predisposition, advanced age, renal disease, female sex, previous aminoglycoside therapy, liver dysfunction, large doses, long duration of therapy, frequent doses, concomitant administration of other nephrotoxic drugs and presence of shock.

·              Ototoxicity of aminoglycosides is related to high cochlear and vestibular trough concentrations resulting in damage to sensory hair cells.

·              Rare instances of neuromuscular blockade produced by aminoglycosides is due to inhibition of acetylcholine release from presynaptic nerve terminals, as well as blockade of acetylcholine receptors.

Adverse Effects and Clinical (Toxic) Features

Ototoxicity—

·              Administration of any of the aminoglycosides can cause both vestibular and auditory dysfunction which may be irreversible, owing to destruction of vestibular and cochlear sensory cells.

·              Symptoms include tinnitus (high pitched and contin-uous), deafness, and dysequilibrium characterised by ataxic gait, stumbling, and loss of balance on turning. Onset may be sudden and severe, but is usually progres-sive over 6 to 10 months. Vertigo is a rare symptom.

·              With neomycin, ototoxicity is characterised by a latency of 2 to 6 weeks after onset of therapy, hearing loss often being noticed days to weeks after the drug has been discontinued.

·              Ototoxicity after acute single overdose is not well documented.

·              Streptomycin is predominantly vestibulotoxic; kana-mycin, neomycin, and amikacin are predominantly cochleotoxic; gentamicin and tobramycin are both vestibulo- and cochleotoxic.

·              Ototoxicity (deafness and vertigo) has been reported following use of topical neomycin and otic solutions containing gentamicin.

Nephrotoxicity—

·              About 8 to 26 % of patients receiving any aminoglyco-side for several days develop nephrotoxicity, which is fortunately usually reversible. Typically, acute tubular necrosis sets in after 7 to 10 days of therapy. Recovery on stoppage occurs over 4 to 6 weeks.

·              The following rank order of decreasing toxicity is generally accepted for aminoglycosides: neomycin > gentamicin > tobramycin > amikacin > netilmicin > streptomycin.

Neuromuscular blockade—

·              All aminoglycosides are capable (rarely) of causing neuromuscular blockade with consequent paralysis. The order of decreasing potency for blockade is neomycin >kanamycin>amikacin>gentamicin>tobramycin.

·              Risk factors for inducing neuromuscular blockade include concurrent use of curare-like drugs, succinylcho-line, and magnesium, as well as presence of botulinum toxin and disease entities such as myasthenia gravis.

Other effects—

·              Optic nerve toxicity has been reported with strepto-mycin, as also peripheral neuritis and paraesthesia. Intramuscular injections involving this drug are extremely painful.

·              Less common adverse effects associated with chronic aminoglycoside use include electrolyte abnormalities, allergic reactions, hepatotoxicity, anaemia, granulocy-topenia, thrombocytopenia, eosinophilia, reproductive dysfunction and toxic psychosis.

·              Acute ischaemic retinopathy has occurred from intraoc-ular administration of gentamicin.

·              Hypersensitivity reactions have been reported most frequently with neomycin, including skin rashes, eosinophilia, fever, blood dyscrasias, angioedema, exfoliative dermatitis, stomatitis and anaphylaxis.

Diagnosis

·              Ototoxicity can be detected in the early stages by full-tone audiometric testing which is capable of revealing high-frequency hearing loss. Vestibular dysfunction can be diagnosed at its inception by electronystagmography.

·    Monitor serum aminoglycoside concentration.

o     Gentamicin: Toxicity (primarily nephrotoxicity) mayoccur with persistent peak serum levels more than 12 mcg/ml, and/or trough levels more than 2 mcg/ml.

o     Amikacin: Toxicity (primarily nephrotoxicity) mayoccur with persistent peak serum levels more than 20 to 35 mcg/ml, and trough levels more than 8 mcg/ml.

o     Netilmicin: Toxicity (primarily nephrotoxicity) is asso-ciated with persistent peak serum levels greater than 16 mcg/ml, and trough levels greater than 4 mcg/ml.

o     Tobramycin: Toxicity (primarily nephrotoxicity) isassociated with persistent peak serum levels greater than 10 to 15 mcg/ml, and trough levels greater than 2 to 4 mcg/ml.

o     Streptomycin: Toxicity is associated with peak serumlevels greater than 50 mcg/ml.

o     The amounts of neomycin present in topical ointments, otic and ophthalmic preparations (3.5 to 5 mg/gm or ml) do not present a hazard even if the entire package contents were orally ingested (10 to 30 gm or ml).

·      Monitor renal function carefully. Laboratory abnormalities indicative of nephrotoxicity include proteinuria, granular casts, elevated urinary sodium, and increased fractional excretion of sodium. Elevation of serum creatinine occurs in the later stages.

Treatment

·      Acute overdoses of aminoglycoside antibiotics are almost invariably the result of dosage errors (especially in infants). Fortunately these overdoses are rarely life-threatening, and most patients can be successfully managed with supportive measures. Charcoal administration can be considered if the patient is seen within a short time following ingestion.

·      Maintain good urine output (3 to 6 ml/kg/hr) with intrave-nous fluids. This appears to be the treatment of choice for a single acute overdose of aminoglycosides.

·      Some cases of renal toxicity induced by aminoglycosides can be tackled by the administration of ticarcillin or carbeni-cillin which forms a complex with the aminoglycoside thereby inactivating its effects.

·      Peritoneal or haemodialysis is effective in eliminating aminoglycosides from the blood, the latter being prefer-able. In patients with compromised renal function and toxic levels of gentamicin or tobramycin, administration of ticarcillin to bind the aminoglycoside may be as effec-tive as hemodialysis. The complex has been shown to be excreted renally and decreases the aminoglycoside half-life to 12 hours in renal failure patients. Dose - 2 to 5 grams intravenously every 4 to 6 hours until serum aminoglyco-side levels are less than 0.2 mcg/ml.

·              In a guinea pig model of gentamicin ototoxicity, concurrent treatment with vitamin E 100 mg/kg day IM slowed the progression of high frequency hearing loss, and reduced the loss of outer hair cells in the cochlea of animals treated with intramuscular gentamicin 100 mg/kg daily for 14 days. It was postulated that vitamin E interfered with gentamicin-induced free radical formation.

·      Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta agonists, corti-costeroids or adrenaline. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, adrenaline, ECG monitoring, and IV fluids.