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 Head & Neck

Epidemiology

CNS penetrating trauma can result in high mortality. In the pre-antibiotic era, Cushing described a 60% mortality, usually from sepsis complications, but reduced this to 30% with rapid surgical debridement and wound care, suggesting possible survival even where antibiotics resources are limited, such as in developing countries.^[21] Modern trauma care and antibiotics have reduced mortality to 4% in HE injuries.^[22] In the antibiotic era, CNS infections include meningitis, cerebritis, subdural empyema/abscess and osteomyelitis, the former two often related to bullets and shrapnel, and the latter two to retained fragments and VLE injuries, respectively.^[14] Scalp wound dehiscence is associated with 90% of intracranial infections.^[23] Infections occur in 0–3% of LE weapons injuries,^[14] 1–3% of HE injuries during the Vietnam era, and recently increased to 10–14% in the Balkans conflict^[24] and 9% in Iraq, increasing further (26%) when a cerebrospinal fluid (CSF) leak is present.^[22] Bacterial epidemiology of infections is poorly described, but several studies of HE weapons indicate wound infections of the scalp are predominated by coagulase-negative Staphylococcus spp., while intracranial infections are predominated by meningitis caused by Staphylococcus aureus and Gram-negative pathogens.^[24]Acinetobacter baumannii appears to be emerging among Gram-negatives, causing 13–32% of infections in recent conflicts.^[22,25] Anaerobic and actinomycetes infection is possible when the injury occurs through the mouth (e.g., attempted suicide)^[14] or with soil contamination.^[26] Rarely, LE injury infections are caused by rapidly growing mycobacteria species.^[27]

The maxillofacial region contains bacteria-rich skin and mucosal linings, but no large muscular masses. Hence, risk of cavitation, necrosis and subsequent infection is lower than penetrating trauma to other regions.^[28] Ocular injury and infection is complex, common and beyond the scope of this article. Facial injury can be extensive but rarely life threatening; airway, hemostasis and shock management transcend early treatment for infection.^[29] Oral mucosa integrity prevents bacterial contamination of deep maxillofacial structures, hence penetrating injury increases infection risk.^[28] HE injury mortality was as high as 40% in both World War II and Mogadishu, but can drop to 2% with rapid surgical management as occurred in Vietnam.^[28] LE weapon injuries cause a 2% mortality^[30] increasing to 32% in falling bullet injury from celebratory firearms discharged into the air.^[31] LE injury maxillofacial infection rate is 10–14%^[32,33] with HE rates historically 7–42%, but more recently 10–11% in the Balkan and Iran–Iraq wars.^[28] Unfortunately, reports of bacterial epidemiology consist of two poorly described studies. During the Vietnam War, preoperative cultures isolated Pseudomonas and Klebsiella spp. in 100% of patients. S. aureus, E. coli and fungi (probably Candida spp.) also occurred, but infection prevalence was not described.^[34] Maxillofacial infections in the Lebanon war consisted of the same pathogens, plus Proteus mirabilis, Bacteroides fragilis, Peptococcus and Peptostreptococcus, but the frequency of each was not described.^[35]

Perioperative Prophylaxis

Perioperative prophylaxis is paramount in CNS injury given the high mortality and sepsis rates in the pre-antibiotic era.^[21] Antibiotics should be started as soon as possible.^[14] HE injuries successfully utilized perioperative chloramphenicol, ampicillin with gentamicin, cloxacillin with chloramphenicol, or gentamicin with ceftriaxone, and metronidazole.^[24] In LE injuries, the data is less robust but a cephalosporin with or without gentamicin has been studied for 4–10 days.^[14] For VLE injury, penicillin with chloramphenicol, clindamycin with ceftriaxone, or flucloxacillin, with cefuroxime and metronidazole, have been used successfully.^[14] Published reports detail duration of prophylaxis for VLE injury as 6–14 days postoperatively.^[14] Two recent guidelines recommend antibiotic prophylaxis against pathogens previously described in the literature.^[14,24] This includes Staphylococcus spp. and Gram-negative bacilli, plus occasionally adding anaerobic coverage. One group advocated for all (HE, LE, VLE) penetrating intracranial injuries, one of two suggested prophylactic regimens should be recommended: either intravenous amoxicillin/clavulanate 1200 mg every 8 h, or intravenous cefuroxime as a 1500-mg loading dose, followed by 750 mg every 8 h with intravenous metronidazole 500 mg every 8 h (or 1 g every 12 h per rectum or 400 mg every 8 h by mouth).^[14] However, no alternative was provided for β-lactam allergy and amoxicillin/clavulanate is not available intravenously in the USA. A second guideline for HE injury advocated: cefazolin 1000 mg every 8 h with additional gentamicin and penicillin if gross contamination is present or ceftriaxone 2 g every 24 h with the same augmentation for gross contamination. For β-lactam allergy, vancomycin 1 g every 12 h with ciprofloxacin 400 mg every 8–12 h was recommended.^[24]

For maxillofacial trauma, there are no clinical studies of perioperative antibiotics for LE trauma; VLE injury through both oral mucosa and facial skin have experienced infection reduction from 27 to 7% with a short course of perioperative penicillin.^[36] In HE injury, perioperative cephalosporins, continued for at least 3 days postoperatively in maxillofacial fractures, have been described^[35] as has perioperative ampicillin or penicillin prophylaxis for mandibular fracture augmented with postoperative cephalothin and gentamicin for bone grafting procedures.^[37] Perioperative antibiotics for maxillofacial fracture have reduced infection rates from 42 to 8% compared with surgery alone and are therefore recommended.^[38] However, recent analysis of four clinical trials revealed compound mandibular fractures derived the most benefit, and benefit did not extend beyond 48 h of therapy.^[39] A recent review of antibiotics for facial trauma recommends limiting prophylaxis to those who are immunocompromised, have gross wound contamination, open fractures, joint involvement or require delayed wound closure; or to those patients at high risk for endocarditis or having LE/HE injuries.^[36] In VLE antibiotics are required only in compound fractures of the mandible and penetrating injury of the mouth through the face.^[36] A 2007 guideline for HE injuries recommends cefazolin 2 g every 8 h for 24 h postoperatively with alternatives of clindamycin 600 mg every 8 h or ceftriaxone 1 g every 12 h, but conceded there was only moderate evidence to support these guidelines.^[28]

Levels of evidence for use of antibiotic prophylaxis and empiric therapy are adapted from previous guidelines^[40] and can be found in Table 1. In summary, for CNS injury (Table 2) based on consensus statements derived from case reports (BIII level of evidence), we recommend cefazolin or ceftriaxone prophylaxis continued for no more than 5 days (BII level of evidence) with consideration of addition of gentamicin or penicillin if the wound is grossly contaminated. For the patient with β-lactam allergy we recommend vancomycin plus ciprofloxacin. For maxillofacial injury (Table 3), based on prospective randomized and meta-analysis trials of patients with mandibular fracture or contaminated head and neck surgery (BI level of evidence), we recommend cefazolin or clindamycin prophylaxis continued no longer than 24 h (AI level of evidence).

Antibiotic Therapy for Infection

Antibiotic therapy for the CNS should ultimately be guided by culture and antimicrobial susceptibility results of the CSF or debrided tissue.^[14,24] CSF should be obtained as soon as infection is suspected and a Gram stain performed.^[41] Since microbiologic identification can exceed 72 h, empiric therapy should be instituted immediately after cultures are obtained.^[41] Initial therapy should be directed against previously discussed organisms including methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa. Guidelines recommend vancomycin with one of three additional therapies: ceftazidime, cefepime or meropenem.^[41] Meropenem is preferred over the cephalosporins if A. baumannii is a common nosocomial pathogen in the trauma institution, because of superior activity against this pathogen.^[42] Meropenem is favored over imipenem owing to lower seizure potential at high doses, but imipenem has been used successfully.^[43] Doripenem has a low seizure potential in animal studies, and favorable MICs to most pathogens that cause traumatic CNS infection, but has not been evaluated for meningitis treatment.^[43] For carbapenem-resistant Acinetobacter infection, colistin 10 mg intrathecally has been found to be effective.^[41] Therapy for maxillofacial and neck infections should similarly be guided by culture results. Optimum therapy duration remains unclear; guidelines suggest 10–14 days, or for 2–3 days after the wound is closed and no signs of infection are present, but lack strong evidence.^[28] However, if osteomyelitis is present, particularly of the mandible, 6 weeks of therapy is required.^[28] Penetrating neck injuries below the level of the arytenoid cartilage are more predisposed to infection and require surgical drainage in addition to antibiotics to prevent infection.^[44] There are no guidelines for VLE or LE injury, but recent guidelines for empiric therapy in HE injury recommend ampicillin/sulbactam 2 g every 6 h, or clindamycin 600 mg every 8 h with moxifloxacin 400 mg daily for β-lactam allergy.^[28] Alternative suggestions include piperacillin/tazobactam or cefoxitin if specific allergies to preferred agents exist.^[28]

In summary, for empiric treatment of infections of the CNS following surgery and prophylactic antibiotics for trauma (Table 2) based on consensus statements and case reports, we recommend vancomycin combined with either an antipseudomonal third-generation cephalosporin or alternatively a carbapenem with treatment for 21 days (BIII level of evidence). For maxillofacial injury (Table 3), based on consensus statements, we recommend ampicillin/sulbactam or clindamycin plus moxifloxacin for β-lactam allergy with treatment for 10–14 days up to 6 weeks if osteomyelitis is found (BIII level of evidence).

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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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