Once daily high-dose gentamicin to prevent infection in open fractures of the tibia shaft: A preliminary investigation. (*).

ABSTRACT

Background. Cephalosporin and aminoglycoside antibiotics are currently recommended for infection prophylaxis in high-energy open tibial shaft fractures. We evaluated cephalosporin in conjunction with once daily high-dose gentamicin as prophylaxis against infection in Gustilo types II and III open tibial shaft fractures.

Methods. Sixteen patients were identified in whom once daily gentamicin dosing was used as part of an antibiotic prophylaxis regimen in patients with types II and III open tibial shaft fractures. Cefazolin (1 g) and gentamicin (5 mg/kg) were given before operation. Antibiotic therapy was continued for 48 hours after definitive wound closure. Monitoring for gentamicin toxicity consisted of blood urea nitrogen (BUN) and creatinine levels, gentamicin trough levels, and a daily query for signs of prodromal ototoxicity.

Results. Average time to fracture union was 8 months. One superficial and two deep infections were observed. No patient showed signs of nephrotoxicity or ototoxicity.

Conclusions. Our investigation suggests that this dosing regimen might be safe as prophylaxis against infection in open tibial shaft fractures and that it warrants further study.

THE TIBIA is the most commonly fractured long bone, and many of these fractures are open. (1) The incidence of infection is noted to be 10 to 20 times higher in open tibial fractures than other open fractures. (2) Open tibial fractures are susceptible to infection due to several factors, including the high energy imparted to the leg, the poor blood supply of the tibia, and contamination of the fracture site at injury. (3) Several studies have shown that antibiotics significantly decrease the infection rate associated with open tibial shaft fractures. (2,4-6) It is generally agreed that a cephalosporin should be given in all open tibial shaft fractures. The addition of an aminoglycoside has been advocated for Gustilo types II and III open fractures (4,7) because of the higher incidence of gram-negative organisms contaminating these more severe open fractures. (2,4,8) Gentamicin is an aminoglycoside commonly used in prophylaxis against gram-negative colonization of open tibial fractures; however, institutional differences exist regarding the dose and dosing interval. A recent study has shown good results using a large daily dose of gentamicin in open fracture prophylaxis. (9) The purpose of this review was to investigate the efficacy of a 5 mg/kg daily dose of gentamicin in conjunction with a cephalosporin to prevent infection in operatively stabilized Gustilo types II and III open tibial shaft fractures.

MATERIALS AND METHODS

Between May 1, 1995, and May 31, 1999, 52 patients between the ages of 18 and 65 with an operatively treated Gustilo type II or III open tibial shaft fracture were identified using a prospectively gathered trauma registry. Three patients who had primary amputation and 2 who had delayed amputation were excluded from the study. Fifteen patients who received cefazolin only, 4 who received broad spectrum antibiotics, 2 who received twice daily gentamicin, and 2 others with incomplete antibiotic records were also excluded from the study. The remaining 24 patients received a cephalosporin and a once daily gentamicin dose of 5 mg/kg. Of these 24 patients, four were lost to follow-up, and four had follow-up for less than 3 months and were excluded from the study, leaving 16 patients for review (Table). There were 3 type II, 6 type IIIA, 5 type IIIB, and 2 type IIIC open fractures. There were 15 men and 1 woman, with an average age of 35 years (range, 28 to 65 years). The average Injury Severity Score (10 was 16 (rang e, 9 to 34). Fractures resulted from crushing injury in 2 patients, gunshot wound in 2, motorcycle accident in 3, pedestrian-car accident in 6, and motor vehicle accident in 3. Follow-up averaged 15 months (range, 3 to 42 months).

Patients were initially assessed and stabilized in the emergency room by the trauma surgery service, which then consulted orthopaedic surgery. A Betadine dampened sponge was placed over the open wound, and the lower extremity was splinted to minimize soft tissue damage. Attempts were made to obtain radiographs before splint application. Intravenous cefazolin (1 g) was administered on arrival to the emergency room. Gentamicin (5 mg/kg) was given if the patient had normal BUN and creatine levels, no history of either renal disease or granulocytopenia, and was not pregnant. After clearance by the trauma surgery service, patients were taken to the operating room for irrigation, debridement, and fracture stabilization.

Wound debridement was done in a meticulous fashion. The open wound was extended proximally and distally approximately 5 cm to facilitate visualization and wound debridement. After initial debridement, the wound was irrigated with 9,000 mL of pulsed lavage (Stryker, Kalamazoo, Mich). Inspection of the open wound was repeated after the irrigation, and debridement was continued as indicated by wound contamination. At completion of debridement, fractures were stabilized using a 4.5 mm plate, 2 reamed nails, 4 external fixators, and 9 unreamed nails. All but one patient, who had a primary wound closure, were returned to the operating room every 48 hours for repeat irrigation and debridement until the wound was clean, at which time the wound was closed. Additional wound closure techniques consisted of 9 delayed primary closures, 4 rotational tissue transfers, and 2 free tissue transfers. Intravenous administration of antibiotics was continued for 48 hours after the definitive wound closure, except in rotational an d free tissue transfers, for which antibiotics were continued until drains were removed.

Monitoring for gentamicin serum levels consisted of gentamicin trough determination 30 minutes before the third dose. For patients with an elevated gentamicin trough level, the dosage was decreased, and the trough measurement was repeated before the subsequent third dose. Gentamicin-associated nephrotoxicity was assessed by serologic monitoring of renal function consisting of BUN and creatinine levels examined every 2 days. Each patient who was responsive was queried about prodromal signs of ototoxicity (hearing loss, tinnitus, and dizziness). Audiograms were not obtained.

After discharge from the hospital, patients were examined 2 weeks postoperatively and every 4 to 6 weeks thereafter until fracture union. Further follow-up was arranged on an independent basis. Signs and symptoms of infection were carefully sought. Superficial infections were defined as infections superficial to bone not requiring surgical intervention. (3) Deep infections were defined as those that communicated with the site of the fracture, necessitating operative irrigation and debridement. (3) Serologic examinations of renal function were not done. Audiograms were not done, but patients were asked about possible prodromal signs of ototoxicity during return clinic examinations.

RESULTS

Fracture union was achieved in all patients an average of 8 months from the index procedure (range, 3 to 28 months). Seven patients required 9 subsequent procedures to obtain bony union, including 1 external fixator adjustment, 3 iliac crest bone grafting procedures, 2 nail dynamizations (removal of locking screws from the nail on one side of the fracture, thereby allowing francture compression), and 3 nail exchanges. Seven other procedures in 3 patients were required for soft tissue management or to control infections after initial wound closure. One patient who had a free tissue muscle transfer required an operative debridement for removal of the flap after it necrosed. The wound ultimately healed with dressing changes. Our 2 patients who had deep infections required 6 subsequent debridements and a nail removal to control the infections. No patient had either nephrotoxicity or ototoxicity (Table).

One patient treated with external fixator had a superficial pin tract infection. This infection was treated on an outpatient basis with oral antibiotics and vigilant pin care. Two patients had deep infections. One of these patients (No. 5, Table) sustained a type IIIA open fracture from multiple low-velocity gunshot wounds (Fig 1). This fracture was stabilized on the night of admission with a reamed intramedullary nail after irrigation and debridement (Fig 2). After 48 hours, irrigation and debridement were repeated, accompanied by delayed primary wound closure. Four months postoperatively, after one previous follow-up examination, fluctuation occurred at the most proximal gunshot wound. Local irrigation and debridement were done, and the patient was given oral antibiotics for a Staphylococcus aureus infection. At 6 months postoperatively, the patient returned with drainage from the abscess location with evidence of a nonunion. A reamed exchange nailing was done, and the patient was treated with intravenous cefazolin and oral ofloxacin for combined S aureus and Serratia marcescens infections. Three months after the exchange nail, the patient returned with a questionable fracture union and drainage from the proximal locking screw wounds, for which local irrigation and debridement were done in the office. Four months after exchange nailing, drainage occurred from the proximal locking screw sites. The patient had nail removal with reaming of the intramedullary canal and was again given oral ofloxacin. The patient was last seen in our hospital for an unrelated admission 17 months after injury. At that time, the patient's leg was healed, without evidence of further infection (Fig 3).

The other patient with a deep infection (No. 1, Table) sustained a type IIIC open fracture resulting from a crush injury. The patient was treated with immediate revascularization, irrigation and debridement, and bony stabilization with an external fixator. The patient required four additional debridements before a local gastrocnemius muscle transfer. Six weeks after wound closure, a deep infection due to S marcescens and Staphylococcus epidermidis developed. The patient required four subsequent debridements and a modification of antibiotic therapy to intravenous ceftriaxone and vancomycin to eradicate the infection. The fracture healed 12 months after injury.

DISCUSSION

Infection after open tibial shaft fractures has been reported in up to 50% of patients. (3-5,8,11) 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 [beta]-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 dosin g 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. Als o, 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. (1,3,11,22-26) 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.

CONCLUSIONS

Antimicrobial prophylaxis using once daily high-dose gentamicin in conjunction with cefazolin was found to be efficacious in our patients with high-energy open tibial shaft fractures. Once daily dosing of gentamicin permits higher serum peak concentrations and increased bactericidal action due to its concentration-dependent killing and the associated postantibiotic effect. (12-15) Once daily dosing of gentamicin leads to decreased renal accumulation of the drug, potentially decreasing the risk of nephrotoxicity. (16,17) No patient in this review had nephrotoxicity according to serologic monitoring of BUN and creatinine during hospitalization, and no patient showed any prodromal signs of ototoxicity.

We believe that in cases of open tibial shaft fractures, once daily high-dose gentamicin as prophylaxis against infection may be safely administered in patients who have a normal renal panel, are not pregnant, and have no renal disease, hearing loss, or granulocytopenia, without increased risk of nephrotoxicity or ototoxicity. On the basis of these results, we plan to initiate a prospective, multicenter study to further evaluate the role of once daily gentamicin for antimicrobial prophylaxis in open tibial shaft fractures.

(*.) Presented in part at the 17th Annual Meeting of the Southern Orthopaedic Association, Southampton, Bermuda, July 20, 2000.

References

(1.) Whittle AP, Russell TA, Taylor JC, et al: Treatment of open fractures of the tibial shaft with the use of interlocking nailing without reaming. J Bone Joint Surg Am 1992; 74:1162-1171

(2.) Patzakis MJ, Wilkins J, Moore TM: Considerations in reducing the infection rate in open tibial fractures. Clin Orthop 1983; 178:36-41

(3.) Caudle RJ, Stern PJ: Severe open fractures of the tibia. J Bone Joint Surg Am 1987; 69:801-807

(4.) Gustilo RB, Anderson JT: Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones. J Bone Joint Surg Am 1976; 58:453-458

(5.) Patzakis MJ, Harvey JP, Ivler D: The role of antibiotics in the management of open fractures. J Bone Joint Surg Am 1974; 56:532-541

(6.) Patzakis MJ, Wilkins J: Factors influencing infection rate in open fracture wounds. Clin Orthop 1989; 243:36-41

(7.) Gustilo RB, Mendoza RM, Williams DN: Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma 1984; 24:742-746

(8.) Gustilo RB, Merkow RL, Templeman D: Current concepts review: the management of open fractures. J Bone Joint Surg Am 1990; 72:299-304

(9.) Sorger JI, Kirk PG, Ruhnke CJ, et al: Once daily, high dose versus divided, low dose gentamicin for open fractures. Clin Orthop 1999; 366:197-204

(10.) Baker SP, O'Neill B, Haddon W Jr, et al: The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974; 14:187-196

(11.) Clancey GJ, Hansen ST: Open fractures of the tibia. J Bone Joint Surg Am 1978; 60:118-122

(12.) Moore RD, Lietman PS, Smith CR: Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155:93-99

(13.) Zhanel CG, Ariano RE: Once daily amonoglycosdide closing: maintained efficacy with reduced nephrotoxicity? Renal Fail 1992; 14:1-9

(14.) Vogelman BS, Craig WA: Postantibiotic effects. J Antimicrob Chemother 1985; 15S:37-46

(15.) Raz R, Adawi M, Romano S: Intravenous administration of gentamicin once daily versus thrice daily in adults. Eur J Clin Microbiol Infect Dis 1995; 14:88-91

(16.) DeBroe ME, Verbist L, Verpooten GA: Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man. J Antimicrob Chemother 1991; 27S:41-47

(17.) Verpooten GA, Giuliano RA, Verbist L, et al: Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther 1989; 45:22-27

(18.) Huy PTB, Bernards P, Schacht J: Kinetics of gentamicin uptake and release in the rat. comparison of inner ear tissues and fluids with other organs. J Clin Invest 1986; 77:1492-1500

(19.) Prins JM, Buller HR, Kuijper EJ, et al: Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341:335-339

(20.) Proctor L, Petty B, Lietman P, et al: A study of potential vestibulotoxic effects of once daily versus thrice daily administration of tobramycin. Laryngoscope 1987; 97:1443-1449

(21.) Koo J, Tight R, Rajkumar V, et al: Comparison of once-daily versus pharmacokinetic dosing of aminoglycosides in elderly patients. Am J Med 1996; 101:177-183

(22.) Court-Brown CM, Christie J, McQueen MM: Closed intrameclullary tibial nailing. its use in closed and type I open fractures. J Bone Joint Surg Br 1990; 72:605-611

(23.) Edwards CC, Simmons SC, Browner BD, et al: Severe open tibial fractures: results treating 202 injuries with external fixation. Clin Orthop 1988; 230:98-115

(24.) Keating JF, O'Brien PJ, Blachut PA, et al: Locking intra-medullary nailing with and without reaming for open fractures of the tibial shaft. J Bone Joint Surg Am 1997; 79:334- 341

(25.) Tornetta P, Bergman M, Watnik N, et al: Treatment of grade-IIIB open tibial fractures. a prospective randomised comparison of external fixation and non-reamed locked nailing. J Bone Joint Surg Br 1994; 76:13-19

(26.) Bone LB, Johnson KD: Treatment of tibial fractures by reaming and intramedullary nailing. J Bone Joint Surg Am 1986; 68:877-887

TABLE

Patient Data in 16 Cases of Open Fractures of the Tibial Shaft

         Gustilo
         Fracture                 Wound            Fracture
Patient    Type    Injury         Closure          Treatment

   1       IIIC    Crush          Rotation         External
                                  flap             fixator

   2       IIIA    Gunshot        Delayed primary  Unreamed
                                  closure          nailing
   3       IIIA    Pedestrian-    Delayed primary  Unreamed
                   auto           closure          nailing



   4        II     Motorcycle     Rotation         Unreamed
                   accident       flap             nailing
   5       IIIA    Gunshot        Delayed primary  Reamed
                                  closure          nailing


   6       IIIB    Pedestrian-    Delayed primary  Unreamed
                   auto           closure          nailing
   7       IIIA    Motorcycle     Delayed primary  Unreamed
                   accident       closure          nailing
   8        II     Motor vehicle  Delayed primary  Unreamed
                   accident       closure          nailing
   9       IIIC    Pedestrian-    Delayed primary  External
                   auto           closure          fixator
  10       IIIA    Motorcycle     Primary          Unreamed
                   accident       closure          nailing
  11       IIIB    Crush          Free flap        Reamed
                                                   nailing
  12        II     Motor vehicle  Delayed primary  Unreamed
                   accident       closure          nailing
  13       IIIB    Motor vehicle  Rotation         4.5 mm
                   accident       flap             plate
  14       IIIB    Pedestrian-    Free flap        External
                   auto                            fixator
  15       IIIB    Pedestrian-    Rotation         Unreamed
                   auto           flap             nailing
  16       IIIA    Pedestrian-    Delayed primary  External
                   auto           closure          fixator

                                         Union   Injury
         Wound                Follow-up  Time   Severity
Patient  Infection              (no)     (mo)    Score

   1     Staphylococcus          42       12        9
         epidermidis,
         Serratia marcescens
   2     None                    40        2       22

   3     None                    34       28       13




   4     None                    17       12        9

   5     Staphylococcus          17        9       13
         aureus,
         Serratia
         marcescens
   6     None                    15       15       10

   7     None                    12        4       27

   8     None                    12        4       13

   9     None                    11        4        9

  10     None                     9        8       22

  11     None                     8        7        9

  12     None                     7       3.5      34

  13     None                     5        4       13

  14     Pin tract                4        4        9
         infection
  15     None                    3.5      3.5      22

  16     None                     3        3       22



         Subsequent
Patient  Procedures

   1     Irrigation and
         debridement x 4

   2     None

   3     Iliac crest
         bone grafting
         Exchanged nail
         Posterolateral iliac
         crest bone grafting
   4     Dynamization
         Exchanged nail
   5     Irrigation and
         debridement x 2
         Exchanged nail
         Removed nail
   6     Dynamization

   7     None

   8     None

   9     None

  10     Iliac crest bone
         grafting
  11     Failed free flap
         with debridement
  12     None

  13     None

  14     Adjusted external
         fixator
  15     None

  16     None

RELATED ARTICLE: KEY POINTS

* Once daily high-dose gentamicin in combination with Cefazolin was found to be an effective infection prophylaxis in high-energy open tibial shaft fractures.

* No patient sustained either ototoxicity or nephrotoxicity from once-daily high-dose gentamicin.