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Antibiotic Prophylaxis in Trauma: Penetrating Abdominal Injuries and Open Fractures E. Patchen Dellinger

From the Department of Surgery, University of Washington School of Medicine, Seattle, Washington

Infection is an important cause of late morbidity and mortality following traumatic injury. As part of a coordinated treatment effort for the injured patient, preventive antibiotic use can

Infection is an important cause of late morbidity and mortality following traumatic injury. The highest rate of early survival after injury is achieved when the cardiorespiratory status of a trauma victim is corrected and stabilized. Happily, this priority also minimizes late infectious complications. Nevertheless, infections frequently complicate injury, and antibiotics are commonly used in an effort to prevent such infections [1]. The experimental rationale for the use of antibiotics to prevent infections after surgery was established by the pioneering studies of Miles et a1. [2] and Burke [3] and was subsequently confirmed by the work of Alexander and Altemeier [4] and Edlich et a1. [5]. These investigators showed that the incidence and severity of infections in an animal model could be reduced by the administration of antibiotics during a finite interval following bacterial contamination of tissues. Protection was maximal with antibiotic administration before bacterial contamination of tissues. Prophylactic efficacy was reduced and ultimately disappeared altogether as the interval between contamination and antibiotic administration increased up to 3-6 hours (the exact effectdepending on the model used). The value of prophylaxis for elective and urgent operations in clinical practice has been validated by many prospective, randomized trials, which have recently been reviewed [6, 7]. Although these trials have clearly demonstrated the efficacy of early administration of preventive antibiotics, data on the ideal duration of administration are less clear. The initial studies in animals [3] involveda single dose of antibiotics given

Reprints and correspondence: Dr. E. Patchen Dellinger, Department of Surgery, RF-25, University ofWashington MedicalCenter,Seattle,Washington 98195. Reviews of Infectious Diseases 1991;13(SuppllO):S847-S7 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1305-0009$02.00

within 3 hours of contamination, and early clinical trials relied on a three-dose, 12-hour regimen [8, 9]. Published trials of successful antibiotic prophylaxis cite a range of durations from one dose to 14 days, with many courses given for ~8 hours [6-14]. When the duration of antibiotic administration has been the subject of a controlled trial, the shorter duration has consistently been as effective as the longer [15-20]. For patients who have undergone trauma, the purpose and the optimal duration of antibiotic use are less clear because there is no opportunity to administer the agent before initial bacterial contamination. Traditional teaching has held that antibiotics administered in this setting are in fact being used for early presumptive therapy and therefore are not prophylactic. The logical corollary has been that antibiotics should be administered to trauma patients over intervals of at least 3-5 days, with treatment extended when a patient has an elevated temperature or leukocytosis. However, while trauma patients are different from patients undergoing scheduled operations, they are also clearly different from patients with established infections. The line between prevention and treatment of infection is fine in this circumstance. In elective cases, where antibiotics can be administered before bacterial contamination, prevention is clearly being attempted. In a case of traumatic bacterial contamination where the patient is first seen ~24 hours after injury, established infection is present and antibiotics are being used in a therapeutic manner. Between these extremes, in the interval during which most trauma care is begun, lies a gray area where the goal of antibiotic administration is to prevent the development of an infection in a patient who has sustained a tissue injury with bacterial contamination but who is not yet infected. In addition, if antibiotics are administered between the time of injury and the beginning of a corrective operative procedure, the antibiotics clearly serve a prophylactic role in relation to the operative incision and to the tissues and anatomic planes that are first exposed in the course of

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reduce subsequent infectious complications. Available evidence supports the use of antibiotic(s) with activity against both aerobic and anaerobic enteric pathogens for patients with penetrating abdominal injuries and bowel penetration. Patients with open fractures benefit from the use of an antibiotic with activity against Staphylococcus aureus. Data on the ideal dose and duration of antibiotic administration in these situations are incomplete. It is likely that the best results will be obtained with early parenteral administration of large doses of the chosen antibiotic continuing for ~24 hours. For injuries other than penetrating abdominal wounds and open fractures, definitive information is not available.

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the procedure. Only two clinical settings have been studied in any depth with regard to the effect of antibiotics on the development of infection after traumatic injury: penetrating abdominal injuries and open fractures.

Penetrating Abdominal Injuries

does suggest that the way in which antibiotics are used in patients with penetrating abdominal injuries can change the subsequent development of trauma-related infections. The result desired in this situation is the same as that sought with prophylactic antibiotics in the traditional setting of scheduled operations. A report published in 1973 also demonstrated the influence of antibiotics on the development of postoperative infections in patients with intestinal injuries [24]. This paper described a prospective, randomized comparison of two groups of patients, one given kanamycin and cephalothin (a combination with excellent aerobic coverage but no anaerobic activity) and the other given kanamycin and clindamycin (a combination with excellent aerobic and anaerobic activity). Antibiotics were first given preoperatively. The rate of infection after surgery was lower for the group receiving clindamycin than for that receiving cephalothin (10% vs. 27 %; X2 with Yates's correction = 3.41; .05 < P < .1). The entire difference was due to an excess of anaerobic infections in the kanamycin/cephalothin group: infections involving anaerobic pathogens occurred in 11 (21 %) of the 52 patients in the kanamycin/cephalothin group but in only 1 (2 %) of the 48 patients in the kanamycin/clindamycin group (x 2 with Yates's correction = 6.885; P < .01). These two studies, which show significant differences in infection rates related to the timing of antibiotic administration on the one hand [21] and to the spectrum of antibiotic activity on the other [24], support the conclusion that antibiotic use can reduce the incidence of infectious complications following injury to the bowel. This conclusion and the high incidence of serious infections after intestinal injury haveeffectively precluded any placebo-controlled trials in this population of patients. Choice ofantibiotics. Table 1 lists 18 comparative studies published between 1973 and 1988 that prospectively examined the role of antibiotics in reducing infectious complications after surgery for penetrating abdominal injury. Most studies compared two or three different single antibiotics or antibiotic combinations, and none included a placebo arm. In most instances no significant difference between antibiotic regimens was found. Since many reports involved small numbers of patients and/or patients at low risk of infection, the potential for a type II error was relatively high and the chance of demonstrating a true difference was small. The differences that were shown most commonly resulted from an excess of infections in patients treated with an antibiotic regimen with poor activity against anaerobes. One example is the study just discussed [24], in which kanamycin/cephalothin was inferior to kanamycin/clindamycin; another is a study in which cefamandole was inferior to tobramycin/clindamycin or cefoxitin (regimens with greater activity against anaerobes) [33] in colon injuries. A third study [36] of three antibiotic regimens showed a significant difference that was primarily related to an extremely

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The earliest report to examine thoroughly the role of antibiotics for patients with penetrating abdominal injuries was published by Fullen and colleagues in 1972 [21]. These authors retrospectively examined 295 patients undergoing exploratory laparotomy for the treatment of penetrating abdominal injuries. The patients were divided into groups according to when they first received antibiotics: preoperatively (n = 116), intraoperatively (n = 98), or postoperatively (n = 81). Patients from all three groups were treated contemporaneously. The respective rates of infection for these groups were 7 %, 33%, and 30% (X2 with 2 degrees of freedom [dj] = 25.57; P < .0001). The benefit of preoperative antibiotics was evident for both incisional and deep infections. One must always hesitate to draw conclusions from a retrospective study; however, two factors make this report convincing. First, the differences are large and clinically meaningful, and the probability of a type I error is very small (P < .0001). Second, when the data were examined for a possible unequal distribution of risk factors, the advantage of preoperative antibiotics held and in some cases was strengthened. For instance, when only patients with colon injuries were examined, the respective rates of infection were 11% (2 of 18), 57% (13 of 23), and 70% (7 of 10) for the preoperative, intraoperative, and postoperative groups, respectively (X2 with 2 df = 12.15; P < .005). This finding was also valid after adjustment for the number of intraabdominal organs injured, the incidence of shock, and the need for blood transfusion, all of which are known to be additional risk factors for infection after penetrating abdominal injury [22, 23]. In a separate analysis the authors examined the patients from each group who developed a postoperative infection. The infected patients in the group first given antibiotics preoperatively were more severely injured, had more organs injured, and were more likely to have been in shock than were the infected patients who first received antibiotics intraoperatively or postoperatively. One can only speculate regarding the reason for the strikingly lower rate of infection among patients who first received antibiotics preoperatively. The interval from hospital admission to operative treatment (average, 1 hour 45 minutes) was the same for all three groups of patients. The intraoperative and postoperative groups thus had a longer interval between injury and antibiotic administration. Perhaps more important is the fact that patients in the preoperative group had antibiotics circulating at the time of surgery and before the abdominal wall tissue in the incision was potentially contaminated. Regardless of the exact reason for the difference, this study

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Antibiotic Prophylaxis in Trauma

either clindamycin or metronidazole has not resulted in the lowest rates of infection. However, the doses of aminoglycoside administered to these patients were most often quite low. (See below for a discussion of dose considerations.) The most common dose of tobramycin or gentamicin administered was 1.5 mg/kg every 8 hours (six studies); in only two studies was a higher dose administered (1.7 mg/kg every 8 hours), and in four a lower dose was given. The doses of amikacin given in these studies were also low. In general, it seems advisable in this setting to use an agent or agents active against both aerobic and anaerobic enteric bacteria. The following drugs have been employed in comparative studies and have not been found to be significantly different from one another, although most studies included only small numbers of patients and therefore were of low statistical power: an aminoglycoside combined with either clindamycin or metronidazole, cefoxitin, cefotaxime, moxalactam, carbenicillin, and ticarcillin/clavulanate. Duration ofantibioticadministration. The ideal duration of antibiotic administration for penetrating abdominal injuries has not been established. The reported range of durations is wide. Three trials have randomly and prospectively enrolled comparable patients to receive the same single antibiotic or antibiotic combination for different durations. Fabian and colleagues [26] compared 117 patients who received cefotaxime perioperatively only with 127 patients who received cefotaxime perioperatively and then every 6 hours for 24 hours postoperatively. The respective infection rates were 17% and 10% (P> .10). More than half of these patients did not have intestinal injuries. Our group [34] randomized patients with confirmed intestinal penetrating injuries to receive antibiotics for either 12 hours or 5 days. The first 56 patients received doxycycline and penicillin, whereas the last 58 received cefoxitin. The rates of infection were 16% and 17%, respectively (P> .90) for the 12-hour groups and the 5-day groups. Ericsson and associates [39] randomized patients to receive either 24 hours or 72 hours of prophylaxis with amikacin and clindamycin. Not all patients had intestinal injuries. The respective rates of infection were 19 % and 17%, respectively (P > .50). Table 1 includes two reports of studies using 12 mg/kg, 1 of 19 (5 %) (P < .025). Townsend and colleagues [47] also determined that in trauma patients the volume of distribution for aminoglycosides is higher than predicted and the serum levels correspondingly lower. They recommended an initial loading dose of 3 mg/kg for gentamicin and tobramycin. The importance of maintaining adequate levels of prophylactic antibiotic in serum [17], wound fluid [8], or target tissue [48] has also been demonstrated in several trials involving nontrauma patients undergoing elective surgical procedures. Standards for trials ofprophylaxis in penetrating abdominal injuries. Unfortunately, no standard criteria exist for the conduct of trials in patients with penetrating abdominal injuries. The following points should be considered minimal standards. (1) The numbers of patients with colon injuries, with other hollow gastrointestinal organ injuries (but without colon injury), and with no hollow gastrointestinal organ injury should be reported separately for each treatment arm. (2) The infection rates for each of these injury groups should be reported separately for each treatment arm. (3) It is preferable for a trial to concentrate on high-risk patients (i.e., those with colon injuries) and to direct its primary hypothesis and statistical testing to this group. (4) Comparative treatment arms should differ in only one respect, which it is the goal of the trial to compare. Thus, if doses are varied, the drugs and durations should be the same; if drugs are different, the doses and durations should be the same; and so on. (5) Risk factors known to influence the outcome of infection should be reported for each treatment arm. This information should include at least the interval from injury to antibiotic administration, the interval from injury to surgery, the number of organs injured, the presence or absence of colon injury, the patient's hypotension status, and one of the standard trauma indices, such as abdominal trauma index or injury severity

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crease in prospective studies comparing two antibiotics, and our group [49] found no difference in infection risk between internal fixation (hardware in the wound) and external fixation (no hardware in the wound). In the latter report, fractures that required either internal or external fixation were more severe than those that did not and occurred in patients who had more severe associated injuries and who required more transfusions. Both types of fixation (internal and external) were followed by higher rates of infection than those measured among patients whose fractures could be treated without fixation devices. Braun et al. [59] treated all fractures with internal fixation and noted a low rate of infection (5 %) among patients who received antibiotics. Chapman and Mahoney [56] asserted that internal fixation permits limb salvage in severe open tibial fractures that might otherwise require amputation. LaDuca et al. [61] and Tscherne and colleagues [62] recommended early fixation of open fractures. In one experimental study in dogs, massive bacterial contamination of a surgically created femoral cortical defect was used [64]. The wounds were inoculated with 5 x lOS Staphylococcusaureus organisms. None of six dogs given cephaloridine before bacterial contamination developed infection, whereas all eight dogs given cephaloridine beginning at intervals from 6 to 48 hours after contamination became infected. Cephaloridine was administered for 40 hours. In this model the wound was not subjected to debridement or irrigation, which are routine procedures in the clinical treatment of open fractures. The bacteria were inoculated into the marrow cavity and into the hematoma, and the inoculated sites were covered with the surgically created cortical fragment. This inoculum cannot be compared with those seen in the clinical setting of open fractures. Clinical papers reporting early cultures of the fracture wound [51, 52,58,63,65] have given no quantitative information and have failed to find a significant relation between initial cultures and subsequent clinical infections. The small number of animals studied and the uncertain relevance of the model to open fractures seen clinically limit the usefulness of this paper. The results are, however, consistent with those obtained in other animal models of surgical antibiotic prophylaxis [3-5]. Norden [66] reviewed the use of prophylactic antibiotics in orthopedics. He found convincing evidence that antibiotics administered before the incision reduce the risk of infection after operative fixation of closed hip fractures and after prosthetic hip replacement. Rates of infection in groups given antibiotics were 70%-80% lower than those in groups given placebo. In both of these procedures, the skin is intact and no wound contamination is possible until after the incision is made. Thus these procedures can provide the ideal circumstance for prophylaxis: the presence of significant antibiotic levels in blood and wound fluid before contamination. The reports covered in Norden's review show that prophylactic antibiotics can reduce the rate of infections following orthopedic procedures, including the operative fixation of closed

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number of patients examined. Investigators who have not seen a significant relation have all reported a trend consistent with higher rates of infection among patients with more severe grades of fracture [57, 58]. Open fractures of the tibia are associated with significantly higher rates of infection than are equivalent-grade fractures at other sites [49, 50, 52, 54, 56]. The importance of other factors is less well established. In a retrospective review of 1,104 open fractures treated between 1970 and 1981, Patzakis et al. [52] described a correlation between the development of infection and the length of the interval between injury and antibiotic administration, but the numbers provided did not support this assertion. With an interval of 3 hours, 49 (7.4 %) of 661 fractures became infected (x 2 = 2.93; P > .05). A more recent prospective study also failed to find an association, with 27 infections (13%) among 214 patients receiving antibiotics within 3 hours of injury and four infections (12%) among 34 patients receiving antibiotics 3-6 hours after injury (X2 < .0001; P> .95) [50]. Likewise, no significant correlation of the elapsed time from injury to initial debridement with the risk of infection has been shown [49, 52, 54]. Another aspect of open fractures has received scant attention in the available literature on the use of antibiotics for patients with this type of injury. An open fracture is in itself a severe injury and a sign that the patient's body has absorbed a large amount of kinetic energy from an object in the recent traumatic incident. The most common source of injury is the motor vehicle accident [49, 50, 53-55, 58-61], in which associated injuries, including other fractures and major nonorthopedic injuries, are common [49, 50, 61, 62]. A recent analysis found significant associations between each of the following and subsequent fracture infection: a global index of injury severity (injury severity score), the requirement for blood transfusion, the amount of blood transfused, and the presence of more than one fracture [49]. However, multivariate logistic regression identified local factors at the fracture site as more significant than any of the latter. Two principles of wound management compete with regard to an open fracture. Ideal bony healing at the fracture occurs with rigid fixation, which also prevents additional damage to surrounding soft tissues and allows greater mobility, thereby helping to avert pulmonary problems. On the other hand, internal fixation involves the introduction of a foreign body into a potentially contaminated wound and may further impair circulation to the fractured bone. There is no consensus on the relation of internal fixation to subsequent infection. Patzakis and colleagues [53] and Gustilo et al. [51] have stated that they try to avoid internal fixation because it increases the risk of infection. However, neither the retrospective review by the former group [53] nor a review by Clancy and Hansen [55] documented an increase in infection in the minority of patients who had internal fixation [53, 55]. Moreover, Benson et al. [63] and Johnson and associates [58] found no such in-

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biotics and 5.8% among 88 patients treated without antibiotics [62]. Unfortunately, the authors provided no details regarding the severity or location of fractures, the types of antibiotics used, the method of randomization employed, the dose or duration of antibiotics administered, or the types of infection developing. In addition, the differences cited are not statistically significant. Choice ofantibiotics. Three reports compared various antibiotics in patients with open fractures. In the first [63] patients were randomized to receive ~5 days of treatment with either cefazolin or clindamycin. Patients were also randomized to undergo primary or delayed closure of the fracture wound. Only 78 (17%) of 466 eligible patients were actually randomized. The fractures were not graded on the usual scale of 1-3 but were scored subjectively by the surgeon on a fourpoint rating system for degree of wound contamination. The wounds were also cultured at the time of debridement. Fortynine percent of the wounds yielded positive cultures, but these results had no relation to the surgeon's wound classification. Data on the relation of the surgeon's wound score to infection were not given. There was no difference between rates of infection following the use of cefazolin (3 of 41, or 7%) and those following the use of clindamycin (2 of 34, or 6%) or between rates among patients with primary closure (3 of 44, or 7%) and those with delayed closure (2 of 38, or 5%). Our group [50] reported a double-blind, prospectively randomized trial in which patients received either cefamandole or cefonicid. (See below for additional details.) In wellmatched groups, the rates of fracture-associated infection were 13% and 12% for patients who received cefamandole and cefonicid, respectively. The 80% confidence limit for the difference in outcome for the two antibiotic groups was from - 5 % to +7%. These results are not surprising in light of the similar in vitro spectra of the two antibiotics. Johnson et al. [58] randomized 46 patients with grade 2 or grade 3 fractures of the tibia to receive either cefazolin or cefotaxime. These authors reasoned that the added gramnegative activity of cefotaxime might prevent more infections than would cefazolin among patients with these high-risk fractures. (Several authors have noted the increased risk of gramnegativeinfections in fractures with relatively severe soft-tissue injury [49-52, 58]). Nevertheless, there was no significant difference between the rate of infection among patients who received cefazolin and that among patients who received cefotaxime (6 of 25, or 24%, vs. 4 of 21, or 19%; X2 with Yates's correction = .002). Because of the small number of patients studied, this result is not surprising. The authors oftwo reports [51, 52] examined retrospective series of more than 1,000 patients studied over intervals of 18 and 11 years, respectively, attempting to draw conclusions regarding the choice ofantibiotics for the prevention of infection after open fractures. The authors of the second report published a third [53] that examined the subset of tibia fractures within the larger series; the conclusions in the two reports

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fractures. They do not, however, elucidate this point with regard to open fractures, in 48 %-65 % of which bacterial contamination is present preoperatively [51, 52, 63, 65]. Controlled trials in open fractures. The first study comparing antibiotics with placebo for the prevention of infection in open fractures was performed by Patzakis and associates in 1974 [65]. These researchers reported a prospective, randomized study of 255 open fractures in 238 patients who were treated for 10 days with no antibiotic, penicillin and streptomycin, or cephalothin. The respective rates of infection were 14% (11 of79), 10% (nine of91), and 2% (two of 84) (X2 with 2 df = 7.137; P < .03). The study was not double-blinded. Unfortunately, since fractures were not graded according to severity, it is impossible to know how high-risk fractures were distributed among the groups. The overall infection rate of9% is low for this type of fracture. In addition, results were not reported for 72 patients who sustained 78 open fractures due to gunshot wounds, although all patients were randomized. Perhaps the significant difference noted for open fractures not due to gunshot wounds would not have been sustained if all randomized patients had been included in the report. More recently, Braun and colleagues [59] randomized 87 patients with 91 open fractures to receive either cloxacillin or placebo beginning as soon as possible after injury and continuing for 10 days. During the first 4 days, drugs were given intravenously (l g every 6 hours); during the last 6 days, they were given orally (1.5 g every 6 hours). All patients underwent internal fixation. More high-risk (grade 3) fractures were randomized to the antibiotic group than to the placebo group: 13 (30%) of 43 vs. 4 (9%) of 44 (P < .05). Nevertheless, the rate of infection was significantly lower in the antibiotic group: 2 (5%) of 43 vs. 12 (27%) of 44 (P < .01). The rate of infection among all 87 patients was 16%, although the proportion of fractures judged to be grade 3 (20 %) was lower than in many reported series of open fractures. This study, considered with the study by Patzakis et al. [65], lends credence to the belief that use of an agent effective against S. aureus can significantly reduce the rate of infection in open fracture wounds. Two other studies compared antibiotics with placebo. In the first report [57], both open fractures (n = 90) and closed fractures (n = 180) were randomized to treatment with placebo, benzylpenicillin, or dicloxacillin. The respective rates of infection were 15% (14 of 93), 10% (9 of 90) and 8% (7 of 87) (x 2 with 2 df = 2.268; P > .10). From the data presented, the infection rates for open fractures cannot be calculated separately within each treatment arm; thus, no conclusion can be drawn with regard to antibiotic efficacy in the infection of open fractures. In a review of the treatment of major fractures, Tscherne et al. [62] recommended 48 hours of antibiotic treatment for open fractures. Their randomized, prospective trial revealed infection rates of2.7% among 111patients treated with anti-

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Table 4. Incidence of fracture-associated infection, by duration of antibiotic administration and degree of soft-tissue injury. No. of infected fractures/total no. (% infected), by fracture grade

Antibiotic administration category 2 doses* 1d 3d 4-5 d All

3A

3B/3C

All

(14) (... ) (9) (14)

3/9 (33) 2/4 (50) 0/9 (...) 4/27 (15)

2/4 (50) 4/5 (80) 1/6 (17) 8/11 (73)

9/60 (15) 8/31 (26) 6170 (9) 19/102 (19)

13/118 (11)

9/49 (18)

15/26 (58)

42/263 (16)

2 0/19 2/10 2/20 1/21

(...) (20) (10) (5)

5170 (7)

4/28 0/12 3/35 6/43

NOTE. Data are adapted with permission from [49]. Copyright 1988, American Medical Association. * Administered 6 hours apart.

risk of infection (table 4; P> .1 by Bartholomew's test for order). The value for x2 with 3 difor the variation of the infection rate according to the grade of fracture is 40.159 (P < .0001 by Bartholomew's test for order). Study design. As in penetrating abdominal injuries, no commonly recognized criteria exist for the conduct of antibiotic trials in open fractures. The following points should be addressed in any trial: (1) Fractures should be graded according to the degree of soft-tissue injury, as previously described [51]. In addition, recent reports suggest that grade 3 fractures should be further subdivided as there are significant differences in the risk of infection within this category (table 4) [49,54]. (2) Infection rates should be reported separately by fracture grade for each treatment arm. (3) It is preferable to concentrate on high-risk patients, i.e., those with grade 3 fractures. (4) Other known risk factors should be reported separately by treatment arm. These include the location of the fracture in the tibia and the need for internal or external fixation. (5) Proper randomization techniques should be used, and treatment groups should be contemporaneous. (6) A double-blind design is preferred. (7) The duration of followup for infection should be recorded and ideally should be at least 6 months since deep infections may not be evident for long periods [50]. The number of randomized patients with full follow-up should be specified. Since patients treated for trauma are often transient, complete follow-upmay be difficult. (8) The incidence of severe infections involving bone should be reported separately from that of superficial infections. Fracture wound infections should be reported separately from other types of nosocomial infection, such as urinary tract infection and pneumonia. (9) Associated injuries in addition to the open fracture should be reported and discussed for each treatment arm since patients with open fractures characteristically have multiple other injuries as a result of the degree of trauma involved in the production of the open fracture [49, 50, 61, 62]. (10) The impact of the study's statistical power and/or the confidence intervals on the results should be reported as discussed for penetrating abdominal injuries.

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were the same. In each series, each of four antibiotic regimens was used for a certain period and then was replaced by the next. In each series, the infection rate improved over time, with the lowest rate reported for the most recently studied group and attributed to the most recently used antibiotic regimen, cefamandole plus tobramycin [53] or oxacillin plus ampicillin with or without kanamycin [51]. The problem with these reports is that they are retrospective and use noncontemporaneous historical comparisons. In addition, many of the fractures in the earlier periods were not graded, and no attempt was made to assess other changes in management that may have occurred over the long intervals covered. Duration of antibiotic administration. To address the necessary duration of antibiotic prophylaxis in open fractures, we conducted a multicenter study [50] in which 248 patients with open fractures were prospectively randomized to receive a single dose of cefonicid, one dose of cefonicid, daily for 5 days, or four doses of cefamandole daily for 5 days. The study was conducted in a strictly double-blind manner. Patients were stratified and randomized according to the worst open fracture present, and the distributions of fracture grades and other risk factors were equivalent among the groups. All patients were followed for 6 months. The rate of infection was 14 % for both the I-day group and the 5-day groups. The 80 % confidence limit for a difference between the I-day group and the 5-day groups was zero to 5.5 %. Forty-three percent of the patients had grade 3 fractures, and the remainder were equally divided between grades 1 and 2. The infection rates according to fracture grade were 4 % for grade 1, 6 % for grade 2, and 23 % for grade 3. In a subsequent report we examined risk factors for infection after open long-bone fractures in patients combined from two prospective studies [49]. This report identified the presence of a severe fracture, the need for a fixation device, and the location of the fracture in the tibia as the most significant predictors of subsequent infection of the fracture wound. There was no relation at all between the duration of antibiotic administration (6 hours, 24 hours, 3 days, or 5 days) and the

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Recommendations

Significant fluid shifts and volume resuscitation may also contribute to low antibiotic levels. The attainment of high levels of antibiotic in tissues during the early phase of treatment is probably more important than a long duration of administration [39]. One approach is to administer a second dose of antibiotic in the operating room to any patient who, after the initial dose, has required replacement of one-half or more of the blood volume in transfusions. Although this approach has not been studied, we know that this group of patients runs a greatly increased risk of trauma-related and nosocomial infection, independent of other risk factors [22, 23, 41). References

1. Dellinger EP. Antibiotics in trauma. In: Najarian JS, Delaney IP, eds. Trauma and critical care surgery. Chicago: Year Book Medical Publishers, 1986:107-12 2. Miles AA, Miles EM, Burke1. The value and duration of defence reactions of the skin to the primary lodgementof bacteria. Br I Exp Pathol 1957;38:79-96 3. BurkeJE The effective periodof preventive antibioticactionin experimental incisions and dermal lesions. Surgery 1961;50:161-8 4. Alexander JW, Altemeier WA. Penicillin prophylaxis of experimental staphylococcal wound infections. Surg Gynecol Obstet 1965;120: 243-54 5. Edlich RF, Smith QT, Edgerton MT. Resistance of the surgical wound to antimicrobial prophylaxisand its mechanisms of development.Am J Surg 1973;126:583-91 6. Hirschmann JV, Inui TS. Antimicrobial prophylaxis. A critique of recent trials. Rev Infect Dis 1980;2:1-23 7. Kaiser AB. Antimicrobial prophylaxis in surgery. N Engl J Med 1986;315:1129-38 8. PolkHC Jr, Lopez-Mayor IE Postoperative woundinfection: a prospective study of determinant factorsand prevention. Surgery 1969;66:97-103 9. Bernard HR, Cole WR. The prophylaxisof surgical infection. The effect of prophylactic antimicrobial drugs on the incidence of infection following potentially contaminated operations. Surgery 1964;56:151-7 10. Griffiths DA, Shorey BA, Simpson RA, Speller DCE, Williams NB. Single-dosepreoperativeantibioticprophylaxis in gastrointestinal surgery. Lancet 1976;2:325-8 11. Greenall MJ, Bakran A, Pickford IR, Bradley lA, Halsall A, Macfie J, Odell M, Cooke EM, Lincoln C, McMahon M1. A double-blind trial ofa singleintravenous doseof metronidazole as prophylaxis against woundinfection following appendicectomy. Br I Surg 1979;66:428-9 12. Jackson P, Ridley WI, Pattison NS. Single dose metronidazole prophylaxis in gynaecological surgery. N Z Med I 1979;89:243-5 13. Phelan IP, Pruyn Sc. Prophylactic antibiotics in cesarean section: a double-blindstudy of cefazolin. Am J ObstetGynecoll979;133:474-8 14. Donovan lA, Ellis 0, Gatheouse 0, Little G, Grimley R, Armistead S, Keighley RMB, Strachan CIL. One-dose antibiotic prophylaxis against wound infection after appendicectomy: a randomized trial of clindamycin, cefazolin sodium anda placebo. Br J Surg 1979;66:193-6 15. Mendelson I, Portnoy I, de Saint Victor JR, Gelfand MM. Effectof single and multidose cephradine prophylaxis on infectious morbidity of vaginal hysterectomy. Obstet Gynecol 1979;53:31-5 16. Strachan CJL, Black I, Powis SIA, Waterworth TA, Wise R, Wilkinson AR, Burdon OW, Severn M, Mitra B, Norcott H. Prophylactic use of cephazolin against wound sepsis after cholecystectomy. BMJ 1977;1:1254-6 17. Goldmann DA, Hopkins CC, Karchmer AW, Abel RM, McEnany T, Akins C, Buckley MI, Moellering RC Jr, Noel B. Cephalothin prophylaxis in cardiac valvesurgery.J Thorac Cardiovasc Surg 1977;73: 470-9

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For a penetrating or blunt abdominal injury in which disruption of the bowel is strongly suspected, one or more antibiotics with activity against both aerobic and anaerobic bowel flora should be administered as early as possible (e.g., during early resuscitation). If an exploratory laparotomy reveals no injury to the bowel and no other source of endogenous contamination, antibiotic prophylaxis can be discontinued after a single dose. If bowel injury is documented, antibiotic treatment should be continued for 12-24 hours. It is unlikely that administration beyond this point further reduces the final incidence of infection. Data regarding shorter periods of administration have not been published. Available data support the early use of adequate doses of antibiotics with activity against S. aureus in open fractures. Epidemiologic data have shown relatively frequent recovery of gram-negative rods from sites of infection complicating grade 3 fractures; some investigators therefore recommend the addition of an aminoglycoside or another agent with expanded activity against gram-negative rods for patients with these injuries [51, 52, 58], but available data do not permit a conclusion regarding the efficacyof this practice. Those fractures most likely to become infected are also most likely to pose problems in soft-tissue coverage of the fracture and in wound closure, and such problems put the wound at greater risk for colonization by nosocomial bacteria. In this setting prophylactic antibiotics historically have lacked efficacy. Further study is warranted and is in progress. The ideal duration of antibiotic administration for open fractures is unknown. Published reports describe courses lasting for 10 days [59], 7-10 days [51], 5 days [49, 50, 63], 3-5 days [49, 51, 53], 48 hours [58, 59], 24 hours [50], and 12 hours [49]. Epidemiologic principles suggest that the shortest effective duration is best, but available data do not conclusively define this duration. In the only reports specifically examining duration, courses lasting for 24 hours and 5 days were equally efficacious [49, 50]. Although there are traumatic injuries other than abdominal injuries and fractures that entail a high risk of infection, they have not been studied systematically. The existing data do permit a logical- though unprovell- approach to the prevention of infection in the patients involved. If a patient has sustained an injury with definite or potential contamination, it is reasonable to administer an antibiotic active against the pathogens historically associated with infection after that type of injury. If any antibiotic is used, it should be given as soon as possible, by the parenteral route, in a near-maximal dose, and for a duration of ~ 24 hours. After antibiotic administration the patient must be observed closely for infectious complications. These should be diagnosed and treated specifically- not empirically with broad-spectrum antibiotics. There is concern that patients with major bleeding may lose a significant quantity of antibiotic in the shed blood and thus have only low levels of antibiotic in serum and wound.

RID 1991;13 (Suppl 10)

RID 1991;13 (Suppl 10)

Antibiotic Prophylaxis in Trauma

41. Dawes LG, Aprahamian C, Condon RE, Malangoni MA. The risk of infection after colon injury. Surgery 1986;100:796-803 42. Weinstein L, Musher DM. Antibiotic-induced suprainfection. J Infect Dis 1969;119:662-5 43. Weinstein L, Goldfield M, Chang TW. Infections occurring during chemotherapy. N Engl J Med 1954;251:247-55 44. Maki DG, Schuna AA. A study of antimicrobial misuse in a university hospital. Am J Med Sci 1978;275 :271-82 45. Roberts NJ Jr, Douglas RG Jr. Gentamicin use and pseudomonas and serratia resistance. Effect of a surgical prophylaxis regimen. Antimicrob Agents Chemother 1978;13:214-20 46. Stone HH, Haney BB, Kolb LD, Geheber CE, Hooper CA. Prophylactic and preventive antibiotic therapy. Timing duration and economics. Ann Surg 1979;189:691-9 47. Townsend PL, Fink MP, Stein KL, Murphy SG. Aminoglycoside pharmacokinetics: dosage requirements and nephrotoxicity in trauma patients. Crit Care Med 1989;17:154-7 48. Platt R, Munoz A, Stella J, VanDevanter S, Koster JK. Antibiotic prophylaxis for cardiovascular surgery: efficacy with coronary artery bypass. Ann Intern Med 1984;101:770-4 49. Dellinger EP, Miller SD, Wertz MJ, Grypma M, Droppert B, Anderson . PA. Risk of infection after open fracture of the arm or leg. Arch Surg 1988;123:1320-7 50. Dellinger EP, Caplan ES, Weaver LD, Wertz MJ, Droppert BM, Hoyt N, Brumback R, Burgess A, Poka A, Benirschke SK, Lennard ES, Lou MA. Duration of preventive antibiotic administration for open extremity fractures. Arch Surg 1988;123:333-9 51. 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 1976;58-A:453-8 52. Patzakis MJ, Wilkins 1. Factors influencing infection rate in open fracture wounds. Clin Orthop 1989;243:36-40 53. Patzakis MJ, Wilkins J, Moore TM. Considerations in reducing the infection rate in open tibial fractures. Clin Orthop 1983;178:36-41 54. 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;24:742-6 55. Clancy GJ, Hansen ST Jr. Open fractures of the tibia: a review of one hundred and two cases. J Bone Joint Surg 1978;60-A:118-22 56. Chapman MW, Mahoney M. The role of early internal fixation in the management of open fractures. Clin Orthop 1979;138:120-31 57. Bergman BR. Antibiotic prophylaxisin open and closed fractures: a controlled trial. Acta Orthop Scand 1982;53:57-62 58. Johnson KD, Bone LB, Scheinberg R. Severe open tibial fractures: a study protocol. J Orthop Trauma 1988;2:175-80 59. Braun R, Enzler MA, Rittman WW. A double-blind clinical trial of prophylactic cloxacillin in open fractures. J Orthop Trauma 1987;1:12-7 60. Roth AI, Fry DE, Polk HJ Jr. Infectious morbidity in extremity fractures. J Trauma 1986;28:757-61 61. LaDuca IN, Bone LL, Seibel RW, Border JR. Primary open reduction and internal fixation of open fractures. J Trauma 1980;20:580-6 62. Tscherne H, Oestern HJ, Sturm 1. Osteosynthesis of major fractures in poly trauma. World J Surg 1983;7:80-7 63. Benson DR, RigginRS, LawrenceRM, HoeprichPD, HustonAC, Harrison JA. Treatment of open fractures: a prospective study. J Trauma 1983;23:25-30 64. Bowers WH, Wilson FC, Greene WB. Antibiotic prophylaxis in experimental bone infections. J Bone Joint Surg 1973;55-A:795-807 65. Patzakis MJ, Harvey P Jr, Ivler D. The role of antibiotics in the management of open fractures. J Bone Joint Surg 1974;56-A:532-41 66. Norden CWo A critical review of antibiotic prophylaxis in orthopedic surgery. Rev Infect Dis 1983;5:928-32

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18. Conte JE Jr, Cohen SN, Roe BB, Elashoff RM. Antibiotic prophylaxis and cardiac surgery. Ann Intern Med 1972;76:943-9 19. Pollard JP, Hughes SPF, Scott JE, Evans MJ, Benson MKD. Antibiotic prophylaxis in total hip replacement. BMJ 1979;1:707-9 20. DiPiro JT, Cheung RPF, Bowden TA Jr, Mansberger JA. Single dose systemic antibiotic prophylaxis of surgical wound infections. Am J Surg 1986;152:552-9 21. Fullen WD, HuntJ, Altemeier WA. Prophylactic antibiotics in penetrating wounds of the abdomen. J Trauma 1972;12:282-9 22. Nichols RL, Smith JW, Klein DB, Trunkey DD, Cooper RH, Adinolfi MF, Mills 1. Risk of infection after penetrating abdominal trauma. N Engl J Med 1984;311:1065-70 23. Dellinger EP, Oreskovich MR, Wertz MJ, Hamasaki V, Lennard ES. Risk of infection following laparotomy for penetrating abdominal injury. Arch Surg 1984;119:20-7 24. Thadepalli H, Gorbach SL, Broido PW, Norsen J, Nyhus L. Abdominal trauma, anaerobes, and antibiotics. Surg Gynecol Obstet 1973;137:270-6 25. O'Donnell V, MandaI AK, Lou MA, Thadepalli H. Evaluation of carbenicillin and a comparison of clindamycin and gentamicin combined therapy in penetrating abdominal trauma. Surg Gynecol Obstet 1978;147:525-8 26. Fabian TC, Hoefling SJ, Strom PR, Stone HH. Use of antibiotic prophylaxis in penetrating abdominal trauma. Clin Ther 1982;5(Suppl A):38-47 27. Crenshaw C, Glanges E, Webber C, McReynolds DB. A prospective random study of a single agent versus combination antibiotics as therapy in penetrating injuries of the abdomen. Surg Gynecol Obstet 1983;156:289-94 28. Moore FA, Moore EE, Mill MR. Preoperative antibiotics for abdominal gunshot wounds. Am J Surg 1983;146:762-5 29. Rowlands BJ, Ericsson CD. Comparative studies of antibiotic therapy after penetrating abdominal trauma. Am J Surg 1984;148:791-4 30. Gentry LO, Feliciano DV, Lea AS, Short DH, Mattox KL, Jordan GL Jr. Perioperative antibiotic therapy for penetrating injuries ofthe abdomen. Ann Surg 1984;200:561-6 31. Hofstetter SR, Pachter HL, Bailey AA, Coppa GF. A prospective comparison of two regimens of prophylactic antibiotics in abdominal trauma: cefoxitin vs. triple drug. J Trauma 1984;24:307-10 32. Fabian TC, Boldreghini S1. Antibiotics in penetrating abdominal trauma: comparison of ticarcillin plus clavulanic acid with gentamicin plus clindamycin. Am J Med 1985;79(Suppl 5B): 157-60 33. Jones RC, Thal ER, Johnson NA, Gollihar LN. Evaluation of antibiotic therapy following penetrating abdominal trauma. Ann Surg 1985;201:576-85 34. Dellinger EP, Wertz MJ, Lennard ES, Oreskovich MR. Efficacy of shortcourse antibiotic prophylaxis after penetrating intestinal injury: a prospective randomized trial. Arch Surg 1986;121:23-30 35. Heseltine PNR, Berne TV, Yellin AE, Gill MA, Appleman MD. The efficacy of cefoxitin vs. clindamycin/gentamicin in surgically treated stab wounds of the bowel. J Trauma 1986;26:241-5 36. Feliciano DV, Gentry LO, Bitondo CG, Burch JM, Mattox KL, Cruse PA, Jordan GL Jr. Single agent cephalosporin prophylaxis for penetrating abdominal trauma. Am J Surg 1986;152:674-81 37. Nelson RM, Benitez PR, Newell MA, Wilson RF. Single-antibiotic use for penetrating abdominal trauma. Arch Surg 1986;121:153-6 38. Rowlands BJ, Ericsson CD, Fischer RP. Penetrating abdomin.al trauma: the use of operative findings to determine length of antibiotic therapy. J Trauma 1987;27:250-5 39. Ericsson CD, Fischer RP, Rowlands BJ, Hunt C, Miller-Crotchett P, Reed L. Prophylactic antibiotics in trauma: the hazards of underdosing. J Trauma 1989;29:1356-61 40. Moore FA, Moore EE, Ammons LA, McCroskey BL. Presumptive antibiotics for penetrating abdominal wounds. Surg Gynecol Obstet 1989;169:99-103

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