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 Extremities

Epidemiology

Soft-tissue Injuries In every war from World War I to Somalia, orthopedic injuries have accounted for the majority (65%) of the total injuries sustained from HE penetrating trauma.^[80] Similar numbers continue to be seen in the 39,570 wounded in current conflicts.^{[81–83,202]} A 5-year retrospective review of 1281 HE injuries from current conflicts (2001–2005) revealed 3575 extremity wounds. Injuries afflicted upper and lower extremities equally (51 vs 49%) comprising both soft-tissue wounds (53%) and fractures (26%). Fragmentation weapons (IED 36%, grenade/rocket-propelled grenade 16%) predominated over gunshot injuries (16%).^[84] Polytrauma was also common, with 1.6 different anatomic regions per injury reported at the start of the Iraq war.^[85]

Historical references indicate that Gram-positive and anaerobic bacteria represent the predominant flora at the time of wounding.^[86–88] In the pre-antibiotic era, morbidity was highly attributable to gas gangrene and mortality to Streptococcal sepsis, in large part, due to delays in surgical debridement.^[88] Vietnam era wounds revealed a combination of Gram-positive and -negative organisms at the time of injury with Gram negatives beginning to predominate.^[89] Currently, predominantly coagulase-negative Staphylococci are cultured from open wounds at the time of injury,^[90] but 5 days after injury, 47% of wounds have polymicrobial infection with Acinetobacter spp. representing 36% of isolates followed by E. coli (20%) and P. aeruginosa (19%), whereas coagulase-negative Staphylococcus has dropped to 3% of infections.^[51] Resistant bacteria complicating HE/LE injuries from combat are emerging, but the source(s) (inoculation upon injury, antibiotic choice, pre-existing colonization prior to injury, or nosocomial transmission during evacuation) remain unclear.^[91] Some would suggest that all injuries, LE and HE, in times of war can be treated empirically with antibiotics, whereas LE civilian gunshot wounds require less aggressive management owing to the significantly higher wound contamination on the battlefield.^[92]

Osteomyelitis Fractures associated with penetrating trauma are classified as: type 1 fracture with laceration less than 1 cm, minimal contamination or soft-tissue damage; type 2 fracture with lacerations greater than 1 cm with moderate soft-tissue damage; and type III HE typically with bone loss. The incidence of osteomyelitis after open fracture is reported to be 2–16%, depending significantly on the grade of trauma and the type of treatment administered.^[93] Osteomyelitis in penetrating trauma can result from multiple sources including hematogenous spread from bacteremia, contiguous spread from infected soft tissues, direct inoculation and vascular insufficiency.^[94] The presence of an orthopedic device further increases the risk for recurrence of osteomyelitis.^[95] Pathogens described include S. aureus, Enterobacter spp., K. pneumonia, P. aeruginosa and A. baumannii with the majority of recurrences caused by Staphylococcus.^[96,97]

Orthopedic Hardware Infection Orthopedic hardware is defined as intra-medullary nails, external fixation pins, plates and screws. Infections associated with hardware placed for traumatic orthopedic injuries are often related to organisms growing in biofilms. Whether early, delayed or late infections, most hardware infections are caused by S. aureus acquired during penetrating trauma.^[98] Mody et al., however, noted polymicrobial etiology with S. aureus and A. baumannii representing the most common causative organisms in patients requiring early external fixation for damage control followed by delayed intra-medullary nail placement.^[99]

Perioperative Prophylaxis

Soft-tissue Injuries All traumatic wounds become contaminated. Infection occurs based upon the bacterial load and host defenses to eradicate the inoculum.^[100] Expert opinion endorses prophylactic antimicrobials at the time of injury as the standard of care, although the best agent and duration remains less well defined.^[89,101] Penicillin is recommended by the International Committee of the Red Cross for amputations, compound fractures and major soft-tissue wounds for 5 days, or until delayed primary closure. For absent delayed primary closure, in the case of repeat debridement, the recommendation is to stop antibiotics unless infection is apparent. Metronidazole is suggested for infections developing after 72 h or from land mines.^[102] The environment where injury occurred may impact prophylactic antibiotic selection. For example, Acinetobacter spp. infection following gunshot injuries to extremities were rarely encountered in Australia, but increased substantially with imported casualties from the East Timor conflict.^[103] Furthermore, the site of injury also impacts outcomes, with the pretibial soft-tissue areas found to have higher morbidity than the same injury to the thigh.^[104] Currently, most literature relates to open fractures secondary to gunshot wounds. In HE cases, guidelines recommend first-generation cephalosporins for 24–72 h perioperatively in Type I and II fractures.^[89] Additional Gram-negative therapies are discouraged, even for Type III fractures.^[105] In summary (see Table 6), based upon consensus opinion (BIII level of evidence),^[89,106] we recommend penicillin or cefazolin (or clindamycin for the β-lactam allergic patient) for prophylaxis for a period of up to 5 days (BII level of evidence).

Osteomyelitis Antibiotics have clear benefit in prophylaxis of open fractures. A Cochrane review of seven trials containing over 900 patients revealed a relative risk of 0.41 when patients received antibiotics compared with placebo.^[107] In general, rising rates of penicillin-resistant bacteria have led to the recommendation to use cephalosporin prophylaxis in HE gunshot bony injuries in an attempt to limit chronic infection, or osteomyelitis.^[108] While there is some controversy, most authors recommend no prophylaxis for LE injuries as studies using prophylaxis and those using none show similar rates of infection of approximately 2–4%.^[108] Most experts would recommend prophylaxis for those injuries that are grossly contaminated or when there is articular involvement.

Historically, cephalosporins plus gentamicin were given intravenously for LE gunshot wounds considered high risk due to gross contamination or intra-articular involvement.^[108] Others opted for short courses of oral fluoroquinolones in lower risk LE injuries.^[108] Data from 1996 actually found no difference in long-term infection rates between the two antimicrobial approaches, although they studied only extra-articular bony injuries.^[95] One trial showed cephalosporins alone appear to be as effective as when combined with additional Gram-negative coverage.^[109] A prospective trial of duration showed that 1–5 days appears to be prophylactic, reducing infection rates to 12–13% in all groups.^[110]

Local therapy might also provide benefit in HE injuries. Cohort studies suggest local therapy with antibiotic-impregnated polymerized polymethacrylate (PMMA) beads placed directly at and around the fracture site is superior to intravenous prophylaxis alone, especially in the setting of a contaminated open fracture following trauma.^[111] Infection rates fell from 12 to 4%; however, this study was not randomized, and the control arm was only one quarter the size of the local therapy arm and patients in the local therapy arm often had their wounds closed sooner than the conventional arm. A second prospective study of conventional intravenous versus local therapy showed 8 versus 5% infection rates, but failed to achieve significance owing to a limited number of subjects.^[112] Local therapy has also been delivered by bead pouch method where a membrane is placed over a locally applied therapy.^[113] One study describes this method results in a 5.5% osteomyelitis rate in Grade III open fractures.^[113] A retrospective study comparing bead pouch to standard intravenous therapy resulted in 4 versus 16% infection rate.^[114] Data supports achieving adequate bone concentrations using gentamicin and tobramycin-impregnated cement. However, successful in vivo cement studies use concomitant systemic therapy to which the organism is sensitive, making the benefit of the supplementary beads unclear.^[115,116] Generally, the combination of debridement, fixation for fracture, soft-tissue coverage and parenteral antimicrobials is used to manage open contaminated fractures to stave off future infection.^[109] Without a target pathogen, prophylaxis should be directed against the commonly seen staphylococci with an agent such as cefazolin or clindamycin in β-lactam allergy. In summary, for prophylaxis to prevent osteomyelitis (Table 6) based on a Cochrane review, retrospective studies and consensus opinion (BII level of evidence), we recommend cefazolin or vancomycin for the patient with β-lactam allergy for HE injury or LE injury with articular involvement or contamination. Addition of local therapy via antibiotic beads should also be considered especially in Grade III fractures (BII level of evidence). Based on a prospective study,^[110] duration of therapy should be for 1–5 days (AI level of evidence.

Orthopedic Hardware Infection As with osteomyelitis prevention, there is some data to suggest using antibiotic-impregnated PMMA cement locally at the site of fracture in an attempt to prevent infection.^[111,117] For empiric therapy only, the best data available reduced infection using aminoglycoside or vancomycin-impregnated PMMA beads.^[118–121] Caution is advised, however, that not every antibiotic elutes from cements in a similarly predictable fashion, and true systemic effects are difficult to assess as most studies employ beads in conjunction with systemic intravenous therapy.^{[115,121,122]} In summary, for orthopedic hardware infections, based upon consensus opinion and small prospective and retrospective studies,^[99,109] we recommend cefazolin (vancomycin for β-lactam allergy) for early prophylaxis for open wounds requiring placement of orthopedic hardware (BII level of evidence). Addition of local therapy via antibiotic beads should also be considered, especially in Grade III fractures (BII level of evidence). Based on a prospective study,^[110] duration of therapy should be for 1–5 days (AI level of evidence).

Antibiotic Therapy for Infection

Soft-tissue Injuries Given the varied times of presentation postinjury and emerging antimicrobial resistance, antimicrobial therapy should be directed at pathogens identified on culture. Fluoroquinolones, such as levofloxacin and moxifloxacin, have been shown to have comparable activity to cephalexin against sensitive staphylococcal organisms; however, concerns about fluoroquinolone-induced tendinopathy or the tendency for staphylococci to rapidly develop resistance limit use.^[123] Vancomycin remains the therapy of choice for Gram-positive organisms pending antimicrobial susceptibility results. Daptomycin and linezolid are potential alternatives to vancomycin for MRSA treatment; linezolid can be transitioned to oral therapy easily. Given recent findings,^[51] strong consideration should be given to using carbapenems (meropenem and imipenem) if Acinetobacter spp. infection is possible. Carbapenems offer additional coverage against Gram-positive and -negative aerobes and anaerobes. When isolated, P. aeruginosa is also often multidrug resistant, therefore empiric antipseudomonal cephalosporins or carbapenems should be considered until sensitivity data is available. In the event of clinical decline on carbapenem therapy, strong consideration should be given to using colistin or polymyxin B. Tigecycline, a tetracycline analog, may also have a role in treating soft-tissue infections from multidrug-resistant Acinetobacter spp., other extended-spectrum β-lactamase Enterobacteriaceae and MRSA. However, given significant nausea associated with its use and recent concerns regarding potentially increased mortality in certain clinical settings, other agents are preferred as empiric therapy. Broad-spectrum empiric therapy should always be narrowed as soon as susceptibility data is available, provided source control is achieved; duration of therapy for penetrating soft-tissue injury is typically 7–14 days^[123] or sooner if the wound is closed/healed. In summary, for empiric therapy of trauma associated soft-tissue infection (Table 6), based upon consensus opinion (BIII level of evidence), we recommend vancomycin, daptomycin or linezolid for empiric Gram-positive coverage. Ceftazidime, cefepime or meropenem are recommended for Gram-negative infections, especially in settings of prolonged hospitalizations, with a duration of treatment for 7–14 days (BIII).

Osteomyelitis Early management of orthopedic wounds improves outcomes. Normal bone is rather resistant to infection; osteomyelitis therefore, results from an unusually high inoculation of organisms and is made worse with bone necrosis – two conditions commonly seen following penetrating trauma. Therapy should be directed against identified pathogens, for example, a semi-synthetic anti-staphylococcal penicillin or cefazolin for methicillin-sensitive S. aureus, and vancomycin or linezolid for MRSA. Penicillin G and vancomycin are recommended for penicillin-sensitive streptococci, with additional gentamicin if enterococci or resistant streptococci are isolated. Ceftriaxone or fluoroquinolones are recommended for Enterobacteriaceae and advanced-generation cephalosporins (e.g., cefepime and ceftazidime) or fluoroquinolones for P. aeruginosa. The combination of rifampin and a quinolone, for 3–6 months, eradicated hardware-associated Staphylococcus osteomyelitis in more than 80% of cases.^[124,125] Available data does not yet support the use of daptomycin for resistant staphylococci or enterococci.^[126] As stated previously, resistant Gram-negative bacteria are not typically the first organisms cultured from wounds at the time of injury. However, a study of deep wound cultures obtained from HE orthopedic injuries on average 7 days following injury found predominantly Gram-negative organisms in 27 of 35 patients;^[96] of the 27, 24 received 6 or more weeks of Gram-negative-directed antibiotics for osteomyelitis and 13 developed subsequent Gram-positive infections after completion of therapy. Another retrospective review found similar results in recurrent infection in those with an initial diagnosis of HE injury associated osteomyelitis.^[97] A recent paper reported an unusually high occurrence of Acinetobacter spp. osteomyelitis in HE injury. All infections responded to susceptibility directed therapy with a carbapenem (imipenem) and aminoglycoside (amikacin), meropenem monotherapy, ceftazidime or gentamicin, and ampicillin/sulbactam.^[127] Another case report of HE injury with subsequent osteomyelitis due to Acinetobacter was treated successfully with tigecycline.^[128] However, tigecycline use remains uncertain for osteomyelitis given unclear dosing for adequate bone concentrations.

Duration of therapy is generally recommended to be 4–6 weeks, although possibly shortened in conjunction with surgical debridement. A total of 90% of patients with osteomyelitis received 4 weeks of therapy with 78% receiving greater than 6 weeks in one study,^[97] although total duration ranged from 10 to 150 days. As discussed above in prophylactic therapy, the role of antibiotic-impregnated (cement) adjuvant therapy remains unclear in the treatment of osteomyelitis. In summary, based on all available literature (Table 6), we recommend vancomycin for a period of 4–6 weeks for MRSA osteomyelitis (BII level of evidence). Penicillin can be used with susceptible organisms. Cefepime, ceftazidime or meropenem should be used for Gram-negative osteomyelitis, although would narrow the spectrum with available culture results (BII level of evidence).

Orthopedic Hardware Infection Removal of hardware demonstrates the best outcomes. If hardware is retained, prolonged courses of pathogen-directed antimicrobial suppression are often used until there is evidence of bone healing. If recurrence occurs, definitive therapy would be removal of any foreign material. A recent study reported retention of delayed intramedullary nail placement as more common in uninfected patients (74%) versus infected patients (57%).^[99] Quinolones, while shown to have high bone concentrations, may have clinical limitations in prolonged use, such as tendinopathies.^[129] Rifampin (± quinolone) has been shown to effect outcomes in the setting of fracture-fixation devices^[98] involving Gram-positive organisms. In summary (see Table 6), based upon a small retrospective review^[99] and consensus opinion,^[89] removal of hardware in conjunction with vancomycin are indicated for MRSA hardware-associated infections (BII). We recommend 4–6 weeks, although this can be prolonged with retained hardware (BII). A carbapenem or susceptible advanced-generation cephalosporin (ceftazidime and cefepime) is recommended for Gram-negative hardware-associated infections (BII 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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