Drug Drug Interactions Cephalosporins

There are many reports of acute renal insufficiency from combined treatment with gentamicin (or another aminoglycoside) and one of the cephalosporins (174176). The potential nephrotoxic effect of the combinations seems to be related mainly to the nephrotoxic effect of the aminoglycosides. In contrast, there is some evidence, both experimental (177) and clinical (178), that ticarcillin may attenuate the renal toxicity of the aminoglycosides.

Cisplatin/carboplatin

The nephrotoxic and ototoxic effects of cisplatin and carboplatin can be potentiated by concurrent administration of aminoglycosides, as shown in animals (179).

Loop diuretics

Among the agents that promote the nephrotoxic effects of the aminoglycosides, the loop diuretics furosemide and etacrynic acid are often mentioned. However, this interaction is by no means clearly established (26). These agents are not nephrotoxic in themselves. This supposed interaction may only be a consequence of sodium and volume depletion. Other types of diuretics, such as mannitol, hydrochlorothiazide, and acetazola-mide, do not produce this interaction (26).

• A 60-year-old white woman developed ototoxicity after only 5 days of gentamicin therapy (500 mg, 6.8 mg/kg/ day) and one dose of furosemide 20 mg (180).

Loop diuretics greatly potentiate the cochleotoxic effects of aminoglycosides (181). In pigmented guinea-pigs the effects of high-dose topical (10 ml of a 100 mg/ml solution directly on to the round window) or single-dose systemic (100 mg/kg) gentamicin and intracardiac administration of the loop diuretic etacrynic acid (40 mg/kg) on cochlear function have been studied (182). Compound action potentials were elicited at 8 kHz. All animals that received etacrynic acid had an immediate and profound rise in hearing threshold, irrespective of the method of gentamicin administration. The maximum threshold shift occurred within 30 minutes. Animals that received topical gentamicin recovered after etacrynic acid treatment; by day 20 the mean threshold shift was 7 dB. This group did not differ statistically from animals that received etacry-nic acid alone. In contrast, animals that received systemic gentamicin initially recovered within 2 hours after etacry-nic acid, but subsequently deteriorated over the next 24 hours. The mean threshold shift was 70 dB at day 20. Animals that received topical gentamicin had a temporary shift that resolved within 24-48 hours; by day 20, the mean threshold shift was 7 dB. Animals treated with systemic gentamicin alone did not have hearing loss. This study suggests that the potentiating effect of etacry-nic acid on aminoglycoside ototoxicity is only after systematic and not topical aminoglycoside administration. This may be due to an etacrynic acid-induced increase in leakiness of the stria vascularis, thereby facilitating diffusion of aminoglycosides from the systemic circulation into the endolymphatic fluid.

Neuromuscular blocking drugs

The aminoglycosides have a curare-like action, which can be antagonized by calcium ions and acetylcholinesterase inhibitors (8). In patients who require general anesthesia, the effect of muscle relaxants, such as D-tubocurarine, pancuronium, and suxamethonium, can be potentiated by aminoglycosides (183).

Penicillins

There is an in vitro interaction between aminoglycoside antibiotics and carbenicillin or ticarcillin, leading to a significant loss of aminoglycoside antibacterial activity if these antibiotics are mixed in the same infusion bottle (184). The extent of inactivation depends on the penicillin concentration, the contact time, and the temperature. Azlocillin and mezlocillin inactivate aminoglycosides in a similar manner to that described for carbenicillin (185,186). Aminoglycosides should not be mixed with penicillins or cephalosporins in the same infusion bottle.

However, the clinical significance of the presence of both types of antibiotics in the patient is debatable. In patients who received a combination of gentamicin and carbenicillin the measured serum gentamicin concentrations were lower than the pharmacokinetically predicted values (187). This interaction may be especially important in patients with severe renal impairment, in whom long in vivo incubation of these drug combinations takes place before supplemental doses of the aminoglycoside drugs are given.

Vancomycin

Combined use of vancomycin and an aminoglycoside can increase the risk of toxicity (188-190).

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