Once Daily High-Dose Gentamicin to Prevent Infection in Open Fractures of the Tibial Shaft: A Preliminary Investigation

George V. Russell, Jr., MD, Chantaé King, Carmen G. May, RN, BSN, MSN, Albert W. Pearsall IV, MD

Disclosures

South Med J. 2001;94(12) 

In This Article

Discussion

Infection after open tibial shaft fractures has been reported in up to 50% of patients.[3,4,5,8,11] On the basis of several studies showing high levels of staphylococcal species as well as gram-negative species, treatment of high-energy open fractures has evolved to include cephalosporin and aminoglycoside antimicrobial prophylaxis.[6,8] Most institutions use 1 or 2 g of cefazolin as prophylaxis against gram-positive organisms; however, many institutional differences exist regarding the type, the dose, and dosing interval of aminoglycosides.[3,6,8,11]

Unlike b-lactam antibiotics, aminoglycoside antibiotics have concentration-dependent bactericidal activity. As the ratio of peak concentration to minimum inhibitory concentration increases, bactericidal activity of aminoglycosides increases.[12,13] Aminoglycosides also show persistent suppression of bacterial growth after antimicrobial exposure, commonly termed the postantibiotic effect. The precise mechanism is unknown; however, it has been postulated that aminoglycosides bind irreversibly to bacterial ribosomal subunits, inducing damage to bacteria.[13,14] Furthermore, evidence suggests that the postantibiotic effect is potentiated by increased antibiotic concentrations up to 10 times the minimum inhibitory concentration.[14,15]

Elevated serum trough levels are responsible for the nephrotoxic effects of aminoglycosides. Nephrotoxicity, the most common adverse effect seen with aminoglycoside usage, results from accumulation of drug in the renal cortex, causing proximal tubular necrosis.[15] It has been shown that short-term infusions of aminoglycosides (once daily dosing) result in significantly decreased levels of renal cortical accumulation.[16,17] Ototoxicity is another commonly cited complication associated with aminoglycoside use. In animal studies, uptake of aminoglycosides in inner ear tissues was greater with continuous infusion than with single injection.[18] However, the clearance rate of aminoglycosides is slow, and it is possible that the prolonged exposure time of the sensory hair cells makes the dosage less important in the etiology of ototoxicity as compared with nephrotoxicity.[18] These findings have been corroborated in clinical studies in which the incidence of ototoxicity was equivalent between once daily dosing versus multiple dosing of aminoglycosides.[19,20]

Clinical studies using large daily doses of aminoglycosides to treat established infections have shown good clinical responses without an increased complication profile. Koo et al,[21] in a randomized study evaluating elderly patients with various infections treated with once daily doses (4 mg/kg) of gentamicin or tobramycin compared with twice daily doses (2 mg/kg) of the same antibiotics, found no statistically significant difference in the clinical effectiveness between the two doses. Also, there was no difference in the incidence of nephrotoxicity between the two groups; however, in patients treated with once daily dosing, there was an increased incidence of nephrotoxicity in those patients whose initial peak serum concentration was greater than 12 mg/L.[21] Prins et al[19] compared once daily dosing of gentamicin (4 mg/kg) with thrice daily dosing (1.33 mg/kg) for various infections. The once daily regimen proved significantly less nephrotoxic (59% vs 24%), while preserving bacteriologic efficacy. Also, high-tone audiometry showed no significant differences in hearing between the two groups.[19]

While the use of once daily gentamicin has proven effective in the treatment of established infections, its use as a prophylactic agent in open fractures has been described infrequently. Sorger et al[9] used 6 mg/kg of gentamicin given either once daily or twice daily, combined with cefazolin, for upper and lower extremity Gustilo types II and III open fractures. They found a decreased incidence of infections in patients who received the once daily dose of gentamicin; however, this finding did not reach statistical significance. Two patients who received twice daily gentamicin had transient elevation of serum creatinine, which returned to normal after discontinuance of antibiotics. No patient showed signs of ototoxicity.

The use of high, once daily dosing of gentamicin has been shown effective in our series of type II and type III open tibial shaft fractures in the prophylaxis against infection. The one superficial pin tract infection in a patient with a type II open fracture responded rapidly to oral antibiotics and improved pin care. Deep infections were seen in two patients (12.5%), one in a type IIIA fracture and one in a type IIIC fracture. There were no deep infections in patients with type II open fractures.

Many factors contribute to infections after open tibial shaft fractures, but higher infection rates are more commonly associated with higher energy injuries.[1,3,11,22,23,24,25,26] Both of our patients who had deep infections sustained high-energy injuries. One patient with a type IIIC open fracture stabilized with an external fixator had a deep wound infection necessitating multiple surgical debridements and intravenous antibiotics. The infection was not unexpected, and the postoperative course was not unusual. Several authors have reported series of open tibial fractures treated with external fixators. Court-Brown et al[22] reported infection in 6 of 37 patients with type IIIA open fractures treated with an external fixator. Other studies of high-energy tibial shaft fractures stabilized with external fixators reported infection rates of 7% to 15%.[23,25]

Our other patient with a deep wound infection sustained a type IIIA open fracture resulting from a gunshot wound and stabilized with a reamed intramedullary nail. The role of reamed intramedullary nails in the treatment of open tibial shaft fractures is controversial; however, several recent studies have shown acceptable infection rates using reamed intramedullary nails for open fractures. Court-Brown et al[22] reported infection in 2 of 27 patients with type III open tibial shaft fractures treated with reamed intramedullary nails. Keating et al,[24] in a randomized study comparing reamed nailing with unreamed nailing, found a slightly higher infection rate in the reamed nail group (4%) than in the unreamed group (2%), though the difference did not reach statistical significance.

Our study has several limitations. It is a retrospective review of patients given prophylaxis with once daily high-dose gentamicin without a well-established enrollment protocol. During the period under review, patients were given once daily, twice daily, or thrice daily gentamicin as ordered by the different physicians who treated these patients. While this series consists of a fairly homogeneous patient population, multiple surgeons and multiple implants were used. Patient follow-up was also problematic but merely reflects our transient trauma patient population.

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