Gentamicin

Observational studies

In 17 patients with suspected postoperative endophthalmitis who were given intravitreal vancomycin 0.2 mg and gentamicin 0.05 mg, there were adequate intravitreal vancomycin and gentamicin concentrations for over a week; there were no adverse reactions [ ].

Intratympanic gentamicin has been used to treat vertigo associated with Ménière’s disease, as it offers some advantages over traditional surgical treatment. In a 2-year follow-up of 15 patients with Ménière’s disease, gentamicin solution 0.5 ml (20 mg/ml) injected intratympanically once a week minimized the risk of hearing loss in the treated ear, allowing complete control of vertigo in eight patients after two doses and in 14 patients after four doses [ ].

In an open, randomized, controlled trial, once-daily and thrice-daily gentamicin were compared in 173 children aged 1 month to 12 years; there was no nephrotoxicity or ototoxicity [ ]. Daily doses of gentamicin in both groups were 7.5 mg/kg (under 5 years old), 6.0 mg/kg (5–10 years old), and 4.5 mg/kg (over 10 years old).

Respiratory

Acute respiratory failure with near-fatal bronchoconstriction has been reported in an adult with bronchiectasis and chronic P. aeruginosa airways colonization immediately after the first inhalation of a commercially available gentamicin solution [ ].

Nervous system

Intraventricular gentamicin can cause aseptic meningitis [ ].

Sensory systems

Psychiatric

There have been several case reports of acute toxic psychoses attributed to gentamicin [ ].

Mineral balance

In a retrospective analysis of 1624 neonates, serum calcium concentrations were measured during gentamicin therapy [ ]. There was hypocalcemia (less than 2.0 mmol/l) in 15% and 23% were still hypocalcemic when a second measurement was made, although 30% were given oral calcium. The authors suggested that calcium concentrations should be monitored when gentamicin is given for more than 4 days in neonates.

Gentamicin-induced magnesium depletion is most likely to occur in older patients when large doses are used over long periods of time [ ]. Under these circumstances, serum concentrations and urinary electrolyte losses should be monitored.

In a prospective study in 659 neonates who received gentamicin for more than 4 days, the incidence of hypocalcemia was five times higher after the dosage was changed from 2.5 mg/kg bd to 4 mg/kg/day [ ].

Liver

Increases in alkaline phosphatase after gentamicin have been described [ ].

Urinary tract

The mechanisms of adverse reactions to aminoglycosides, mainly gentamicin-induced glomerular nephrotoxicity, have been reviewed in detail [ ].

In a retrospective review of 24 patients with cystic fibrosis, an aminoglycoside had been prescribed at onset of acute renal insufficiency in 88%, and 76% of these had been given gentamicin [ ]. A renal biopsy showed tubular necrosis in six of seven patients. There was complete recovery in 92%.

A full course of gentamicin therapy causes nephrotoxicity in 1–55% of patients. Two types of gentamicin-induced nephrotoxicity are recognized: (1) a gradual reduction in creatinine clearance, occurring after about 2 weeks, in about 5–10% of patients receiving the drug in full doses, the reduction being rapidly reversible in most cases as soon as gentamicin is withdrawn; (2) acute renal insufficiency due to tubular necrosis, usually associated with oliguria lasting 10–12 days, followed by a diuretic phase; this type of nephrotoxicity occurs far less often than the first type.

The following order of relative nephrotoxicity has been found in many animal experiments: neomycin > gentamicin > tobramycin > amikacin > netilmicin [ , ]. However, in humans, conclusive data regarding the relative toxicity of the various aminoglycosides are still lacking. An analysis of 24 controlled trials showed the following average rates for nephrotoxicity: gentamicin 11%; tobramycin 11.5%; amikacin 8.5%; and netilmicin 2.8% [ ]. In contrast to this survey, direct comparison in similar patient groups showed no significant differences between the various agents in most trials [ ]. In fact, the relative advantage of lower nephrotoxicity rates observed with netilmicin in some studies may be limited to administration of low doses. One prospective trial showed a significant advantage of tobramycin over gentamicin [ ]. However, these findings could subsequently not be confirmed [ ]. The risk of gentamicin nephrotoxicity is increased in biliary obstruction [ ].

In a few cases, gentamicin nephrotoxicity was associated with a Fanconi syndrome, with raised serum enzymes activities in the urine. Among these, muramidase seemed to be especially useful in checking for proximal tubular dysfunction [ ].

Gentamicin is of considerable value in the management of sepsis in immunosuppressed patients and renal transplant recipients. Although it has been suggested that gentamicin should be avoided in such patients because of potential renal toxicity in the allograft [ , ], experienced physicians have felt that gentamicin may be given, provided the dosage schedule is adapted to the degree of allograft function and that blood concentrations are monitored.

After a full course of gentamicin 1–55% of patients have nephrotoxicity. The increased serum creatinine concentration peaks on day 6 of therapy and is reversible in most cases within 30 days. Nephrotoxicity appears to be more common among patients with pre-existing renal impairment, longer treatment duration (over 7 days), repeated courses of aminoglycosides, and after the co-administration of other nephrotoxic drugs (for example amphotericin, cisplatin, daunorubicin, furosemide, and vancomycin). Animal studies have suggested that hydrocortisone, angiotensin converting enzyme inhibitors, and hypercalcemia can also increase aminoglycoside nephrotoxicity, whereas acetazolamide, bicarbonate, ceftriaxone, lithium, magnesium, melatonin, piperacillin, polyaspartic acid, pyridoxal-5′-phosphate, and a high protein diet may be protective [ , ].

In 87 patients with intertrochanteric hip fractures, preoperative antibiotic prophylaxis (gentamicin 240 mg and dicloxacillin 2 g) had no significant effect on wound infections; however, there were 16 reversible cases of nephrotoxicity and one irreversible case among patients who received antibiotic prophylaxis, compared with only four cases of reversible kidney damage among 76 patients who did not receive antibiotics [ ].

• Acute renal insufficiency occurred in an 83-year-old woman after two-stage revision of an infected knee prosthesis with gentamicin-impregnated beads and block spacers [ ]. The combined use of beads and a cement block spacer, both gentamicin impregnated, may have caused this severe complication.

• A 43-year-old black woman with a 13-year history of lupus developed severe acute tubular necrosis secondary to gentamicin [ ].

Since serum creatinine does not accurately reflect renal function in patients with spinal cord injury, dosage regimens of gentamicin should be individualized, based on age, sex, weight, height, the level of spinal cord injury, and renal function [ ].

In animals melatonin [ , ] and l-carnitine [ ] protected the kidneys against oxidative damage and the nephrotoxic effect of gentamicin.

Nephrocalcinosis occurred in 16 of 101 babies born at less than 32 weeks gestation [ ]. Multivariate analysis showed that the strongest predictors of nephrocalcinosis were duration of ventilation, toxic gentamicin/vancomycin concentrations, low fluid intake, and male sex.

In a retrospective review of 744 patients who were dose-individualized with gentamicin once daily, in those patients in whom nephrotoxicity was predicted from a change in gentamicin clearance, this change occurred on average 3 days before the change in creatinine clearance [ ].

Agents that can augment aminoglycoside-induced nephrotoxicity (for example calcium channel blockers and nephrotoxic agents such as ciclosporin) should not be combined with these antibiotics. However, antioxidant drugs, especially the natural antioxidants, seem to have the most potential for clinical use. Of these natural antioxidants, melatonin seems to be the most promising in abating nephrotoxicity [ ].

Four women presented with a Bartter-like syndrome, with hypokalemia, metabolic alkalosis, hypomagnesemia, hypermagnesiuria, hypocalcemia, and hypercalciuria, after receiving gentamicin 1.2–2.6 g [ ]. The syndrome lasted for 2–6 weeks after withdrawal of gentamicin.

Aminoglycoside-induced renal tubular dysfunction can be divided into a Fanconi-like syndrome and a Bartter-like syndrome. Rarely they can occur together.

• A 66-year-old Chinese man developed a Fanconi-like syndrome, a Bartter-like syndrome, distal renal tubular acidosis, acute renal failure, and deafness after receiving a large dose of gentamicin, which was considered the major susceptibility factor [ ]. The dose of gentamicin was 4.9 mg/kg/day, higher than the calculated dose of 3.75 mg/kg/day based on estimated creatinine clearance. Impaired mitochondria and ATP generation might participate in the mechanism of renal tubular dysfunction due to aminoglycosides.

• A 53-year-old man who received intermittent intravenous gentamicin (320–560 mg/day) for a total of 4 months to a total cumulative dose of 9.4 g developed Fanconi syndrome, with profound hypophosphatemia, hypocalcemia, hyperphosphaturia, and aminoaciduria [ ]. The electrolyte disturbances persisted until gentamicin was withdrawn and recurred after rechallenge.

Acute tubular necrosis occurred in an adolescent with cystic fibrosis receiving intravenous gentamicin and ceftazidime [ ].

Skin

Erythema multiforme developed in a 4-year-old girl after treatment with topical aural gentamicin sulfate (0.3%) plus hydrocortisone acetate (1%) prescribed for otorrhea [ ].