Prophylaxis and Treatment of Infections Associated with Penetrating Traumatic Injury

Kyle Petersen; Paige Waterman

Expert Rev Anti Infect Ther. 2011;9(1):81-96.

Infections of the Abdomen & Pelvis

Epidemiology

In the pre-antibiotic era, mortality from penetrating colonic injury was as high as 60–75%.^[63,64] However, the colon is not solely responsible for intra-abdominal postoperative infections in penetrating trauma patients. Studies have shown both gastric and pancreatic injuries increase infection rates.^[50] The highest risks for infection include peritoneal contamination with colon contents, advanced age, hemorrhagic shock/transfusion requirement and concomitant stomach injury,^[65] with both VLE and LE injuries having similar infection rates.^[16] Laparotomy is generally recommended with surgical repair for source control and concomitant antibiotics if perforated viscus is found at surgery.^[16] However, LE penetrating trauma to the liver has been managed without laparotomy with subsequent low infection rate (5%) if CT imaging was performed showing no bowel involvement.^[66] This management style requires careful serial examination to rule out missed hollow-viscus injury. Of note, whether or not perioperative antibiotics are required for liver injury without bowel involvement is unclear because this study does not mention antibiotics. The flora of the GI tract comprises aerobic and facultative Gram-positive cocci (e.g., streptococci) in the upper gut, transitioning in the distal small bowel and colon to anaerobes (e.g., B. fragilis), and aerobic and facultative Gram-negative bacilli (e.g., E. coli).^[50]P. aeruginosa IAI may emerge after prolonged antibiotic treatment.^[67] IAIs complicating penetrating trauma of the abdomen include intra-abdominal abscess, suppurative peritonitis, superficial wound infection and necrotizing fasciitis of the abdominal wall, while sepsis remains a major cause of morbidity and mortality.^[68] A recent 6-year retrospective review of LE penetrating trauma with hollow viscus injury yields interesting epidemiological results regarding the causative microbial flora of traumatic abdominal infections.^[69] Of the 14% of injuries reviewed developing an infection, 80% involved penetrating trauma, 75% had a colonic injury and 25% had a small bowel or stomach injury. E. coli predominated (55% of isolates), followed by Enterobacter cloacae (26%), Klebsiella spp. (17%) and Proteus mirabilis (4%). E. coli and Bacteroides spp. predominated in colon injury and Enterobacter and Klebsiella in stomach/small bowel injury.^[69] The second most common pathogen encountered overall was Enterococcus, and yeast was isolated in 20% of infections. Organisms remained most susceptible to cephalosporins, fluoroquinolones and carbapenems and there were no trends of increasing resistance over time, but Enterobacteriaceae were highly resistant to ampicillin/sulbactam, resulting in almost 50% of patients receiving inadequate empiric therapy.^[69]

Perioperative Prophylaxis

Perioperative antibiotic therapy is the mainstay of penetrating traumatic injury to prevent subsequent IAI. A recent evidence-based study of perioperative antibiotics concluded there were no randomized placebo-controlled clinical trials to support this practice concluding, however, that all recommendations are based purely on expert opinion and arguing for a necessary clinical trial on this subject.^[70] A trial comparing preoperative, intraoperative and postoperative antibiotic therapy for penetrating abdominal injury demonstrated a 7, 33 and 30% incidence in infections, respectively.^[71] A more impressive result occurred in the subgroup analysis of colonic injuries where infections numbered 11, 57 and 70% for each group. This trial proved the superiority of preoperative antibiotics over later administration times.^[71] A subsequent study emphasized the importance of anaerobic coverage in preventing infection. Clindamycin therapy significantly reduced infection rates to 11 versus 27% for a first-generation cephalosporin.^[72] Following these two trials, investigators abandoned the practice of placebo arms in trials arguing that it was unethical. To date, no study has been able to demonstrate the advantage of continuing perioperative antibiotics for over 24 h if primary intestinal repair has occurred within 12 h of injury. A guidelines group in the year 2000 reviewed 39 publications for evidence of optimum antibiotic regimen and dosing duration.^[16] They concluded, based on two studies,^[73,74] that there was adequate evidence for one preoperative dose of broad-spectrum antibiotics, with discontinuation if no hollow viscus injury is found at laparotomy, versus continuing for 24 h if an injury is identified but found no evidence for determining appropriate duration in the setting of hemorrhagic shock where antibiotic delivery is impaired. More recently, investigators found no increase in complications from stopping antibiotics under 24 h versus prolonged use in a prospective study of over 90 patients, even in severe injury when the abdomen is left open.^[75] Furthermore, over 24 h of antibiotics leads to increased bacteria with antibiotic resistance and death from these drug-resistant pathogens.^[76] Recent guidelines recommend cefoxitin 2 g every 6 h or moxifloxacin 400 mg daily monotherapy, or alternatively levofloxacin 750 mg or ciprofloxacin 400 mg combined with metronidazole 500 mg every 8 h as primary perioperative prophylaxis.^[50] Additional regimens also thought to be effective if your local antibiogram has high rates of resistance to primary agents include single-agent ticarcillin/clavulanate, ertapenem, moxifloxacin or tigecycline, or combinations of metronidazole with either cefazolin, cefuroxime, ceftriaxone or cefotaxime,^[77] again limiting to 24 h postoperatively. In summary, based on all available literature (Table 5), we recommend cefoxitin or moxifloxacin monotherapy, or alternatively ciprofloxacin combined with metronidazole, as perioperative agents of choice with an AI level of evidence. Antibiotics should be started prior to surgery, and based on several prospective randomized trials (AI level of evidence) continued for no more than 24 h.

Antibiotic Therapy for Infection

The optimum antibiotic therapy for IAI following trauma remains unclear. However, incorrect empiric therapy results in higher mortality.^[78] Recent guidelines have been published advocating empiric single-agent ticarcillin/clavulanate, cefoxitin, ertapenem, moxifloxacin or tigecycline, plus combinations of metronidazole with either cefazolin, cefuroxime, ceftriaxone, cefotaxime, levofloxacin or ciprofloxacin as first-line therapy for IAI, and limiting treatment to 4–7 days.^[77] Guidelines specifically recommend against the use of empiric ampicillin/sulbactam, clindamycin, cefotetan, fluoroquinolone-based regimens when hospital antibiograms indicate less than 90% E. coli susceptibility, and against empiric coverage for enterococcus or yeast in moderate IAI.^[77] The guidelines do not mention penetrating trauma except for perioperative prophylaxis, and penetrating trauma is often excluded entirely from the studies that form the basis for this guidance. For HE injury, a recent guideline suggested infections developing after 48 h, or with accompanying sepsis, are highly likely to be nosocomial based on previous studies^[67] and recommended therapy based on hospital antibiogram. They suggested a number of regimens suitable for nosocomial infection including piperacillin/tazobactam, carbapenems, advanced-generation cephalosporin (ceftazidime or cefepime) with metronidazole, or aztreonam with metronidazole.^[50] For infections less then 48 h old or with no sepsis they recommended fluoroquinolone (ciprofloxacin or levofloxacin) with metronidazole, third-generation cephalosporin (cefotaxime or ceftriaxone) with metronidazole, ticarcillin/clavulanic acid or moxifloxacin monotherapy. Tigecycline might also be a useful agent in this setting, and has activity against Acinetobacter spp. as well,^[79] although it has been recently associated with an increase in mortality in certain populations.^[201] In summary (see Table 5), based on our opinion and two recent consensus statements (BIII level of evidence)^[50,77] we recommend ticarcillin/clavulanate, cefoxitin, ertapenem or moxifloxacin if injury is under 48 h old or mild/moderate and a carbapenem or piperacillin/tazobactam if over 48 h old or severe.

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Table 1. Strength of recommendation and quality of evidence.
Assessment	Type of evidence
*Strength of recommendation*
Grade A	Good evidence to support a recommendation for use
Grade B	Moderate evidence to support a recommendation for use
Grade C	Poor evidence to support a recommendation
*Quality of evidence*
Level I	Evidence from at least one properly designed, randomized controlled trial
Level II	Evidence from at least one well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from >one center); from multiple time series; or from dramatic results of uncontrolled experiments
Level III	Evidence from opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees

Table 2. Epidemiology and recommended prophylaxis and empiric treatment for CNS infection following penetrating trauma.
Seminal papers (type)	Pathogens described	Prophylactic antibiotic of choice (level of evidence)	Duration of prophylaxis (level of evidence)	Empiric treatment of choice^† (level of evidence)	Duration of treatment (level of evidence)
No controlled trials of prophylaxis or therapy exist	Scalp wound: Coagulase-negative Staphylococcus Meningitis: Coagulase-negative Staphylococcus Staphylococcus aureus Gram-negative facultative aerobes Anaerobes^‡ Rapidly growing mycobacteria^§	Cefazolin 1 g iv. q 8 h or ceftriaxone 2 g q 24 h^¶ Penicillin allergic: Vancomycin 15 mg/kg divided q 6 h plus ciprofloxacin 400 mg iv. q 12 h (BIII)	5 days (BII)	Vancomycin 15 mg/kg divided q 6 h plus cefepime or ceftazidime or meropenem 2g q 8 h^# (BIII)	21 days (BIII)

^†Empiric antimicrobials should be 'de-escalated' to target susceptibility of pathogens isolated from culture as soon as possible.
^‡If oral injury or soil contamination occurs.
^§Rarely found.
^¶Consider adding gentamicin and penicillin prophylaxis if wound grossly contaminated.
^#Consider ciprofloxacin for β-lactam allergy.
iv.: Intravenously; q: Every.

Table 3. Epidemiology and recommended prophylaxis and empiric treatment for maxillofacial infection following penetrating trauma.
Seminal papers (type)	Pathogens described	Prophylactic antibiotic of choice(level of evidence)	Duration of prophylaxis (level of evidence)	Empiric treatment of choice^† (level of evidence)	Duration of treatment (level of evidence)	Ref.
Chole and Yee (prospective randomized trial) Andreasen et al. (meta-analysis)	Pseudomonas spp. Staphylococcus aureus Escherichia coli and Klebsiella spp. Candida spp. Proteus mirabilis Bacteroides fragilis Peptococcus Peptostreptococcus	Cefazolin 2 g iv. q 8 h Or Clindamycin 900 mg iv. q 8 h^‡ (BI)	24 h (AI)	Ampicillin/sulbactam 2 g iv. q 6 h Or Clindamycin 600 mg iv. q 8 h plus moxifloxacin 400 mg every day^‡ (BIII)	10–14 days or 2–3 days after wound closed 6 weeks for mandibular osteomyelitis (BIII)	[38] [39]

^†Empiric antimicrobials should be 'de-escalated' to target susceptibility of pathogens isolated from culture as soon as possible.
^‡Consider clindamycin regimen for β-lactam allergy.
iv.: Intraveniously; q: Every.

Table 4. Epidemiology and recommended prophylaxis and empiric treatment for thoracic infections following penetrating trauma.
Seminal papers (type)	Pathogens described	Prophylactic antibiotic of choice (level of evidence)	Duration of prophylaxis (level of evidence)	Empiric treatment of choice^† (level of evidence)	Duration of treatment (level of evidence)	Ref.
Maxwell et al. (prospective, randomized) Sanabria et al. (meta-analysis)	Empyema with tube thoracostomy: Coagulase-negative Staphylococcus Delayed onset (>48 h after admission): Coagulase-negative Staphylococcus MRSA Gram-negative facultative aerobes Anaerobes Abdominal contamination: Enterococcus spp. Candida spp.	Cefazolin 1 g iv. q 8 h (BII)^‡	24 h (BII)	Vancomycin 15 mg/kg divided q 6 h plus cefepime or ceftazidime or meropenem 2 g q 8 h^‡ (BIII)	21 days (BIII)^§	[60] [59]

^†Empiric antimicrobials should be 'de-escalated' to target susceptibility of pathogens isolated from culture as soon as possible.
^‡Aminoglycosides should be avoided.
^§Could be shortened if adequate drainage achieved earlier.
iv.: Intravenously; MRSA: Methicillin-resistant Staphylococcus aureus; q: Every.

Table 5. Epidemiology and recommended prophylaxis and empiric treatment for abdominal infection following penetrating trauma.
Seminal papers (type)	Pathogens described	Prophylactic antibiotic of choice (level of evidence)	Duration of prophylaxis (level of evidence)	Empiric treatment of choice^† (level of evidence)	Duration of treatment (level of evidence)	Ref.
Fullen et al. (retrospective cohort) Fabian et al. (prospective randomized) Griswold et al. (prospective randomized) Velmahos et al. (prospective observational) Brand et al. (Cochrane review)	Escherichia coli Enterobacter cloacae Klebsiella spp. Proteus mirabilis Bacteroides spp.	Cefoxitin 2 g iv. q 6 h Or Moxifloxacin 400 mg iv. daily or ciprofloxacin 400 mg iv. q 24 h Plus Metronidazole 500 mg q 8 h^‡ (AI)	24 h (AI)	Moderate injury: Ticarcillin/clavulanate 3.1 g q 4–6 h or cefoxitin 2 g iv. q 6 h or ertapenem 1 g iv. q 24 h or moxifloxacin 400 mg iv. q 24 h^‡ Severe injury:carbapenem or piperacillin/tazobactam 4.5 g iv. q 6 h (AII)	4–7 days (BIII)	[71] [73] [74] [76] [70]

^†Several other regimens possible [58].
^‡Empiric antimicrobials should be 'de-escalated' to target susceptibility of pathogens isolated from culture as soon as possible.
iv.: Intravenously; q: Every.

Table 6. Epidemiology and recommended prophylaxis and empiric treatment for extremity infections following penetrating trauma.
Seminal papers (type)	Pathogens described	Prophylactic antibiotic of choice (level of evidence)	Duration of prophylaxis (level of evidence)	Empiric treatment of choice^† (level of evidence)	Duration of treatment (level of evidence)	Ref.
Johnson et al. (retrospective review) Mody et al. (retrospective review) Ostermann et al. (retrospective cohort) Gosselin et al. (Cochrane review) Dellinger et al. (prospective randomized) Patzakis et al. (prospective, randomized)	Soft tissue: Coagulase-negative Staphylococcus Streptococcus spp. Acinetobacter spp.^‡ Escherichia coli ^‡ Pseudomonas aeruginosa ^‡ Osteomyelitis: Staphylococcus aureus (often MRSA) Orthopedic hardware: S. aureus (often MRSA) Acinetobacter spp.	Penicillin 2–4 mu q 4 h or cefazolin 1 g iv. q 8 h^§ β-lactam allergy: Clindamycin 900 mg iv. q 6 h (BII) Local: Consider cefazolin or tobramycin beads especially in Grade III fractures (BII)	1–5 days (AI)	Gram positive: Vancomycin 15 mg/kg divided q 6 h or Daptomycin 4–6 mg/kg iv. q 24 h or linezolid 600 mg q 24 h^¶# Gram negative: Cefepime 2 g q 8 h or ceftazidime 2 g q 12 h or carbapenem (BIII)	Soft tissue: 7–14 days (BII) Osteomyelitis: 4–6 weeks (BII) Hardware: 4–6 weeks (BII)^††	[96] [99] [111] [107] [110] [109]

Empiric antimicrobials should be de-escalated to target susceptibility of pathogens isolated from culture as soon as possible.
^†Seen after 5 days of initial injury.
^‡Metronidazole added when infections develop after 72 h.
^¶Linezolid toxicity limits utility when used for >2 weeks duration.
^#Rifampin (± quinolone) may improve outcomes.
^††Duration depends upon removal of hardware.
iv.: Intravenously; MRSA: Methicillin-resistant Staphylococcus aureus; mu: Million units; q: Every.

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