M A J O R A R T I C L E
Invasive Mold Infections Following Combat-
Tyler Warkentien,1Carlos Rodriguez,1Bradley Lloyd,2Justin Wells,1Amy Weintrob,1,3James R. Dunne,1
Anuradha Ganesan,1,3Ping Li,3William Bradley,3Lakisha J. Gaskins,3Françoise Seillier-Moiseiwitsch,3
Clinton K. Murray,4Eugene V. Millar,3Bryan Keenan,1Kristopher Paolino,1Mark Fleming,1Duane R. Hospenthal,4
Glenn W. Wortmann,1Michael L. Landrum,3,4Mark G. Kortepeter,3and David R. Tribble3; for the Infectious Disease
Clinical Research Program Trauma Infectious Disease Outcomes Study Group
1Walter Reed National Military Medical Center, Bethesda, Maryland;2Landstuhl Regional Medical Center, Germany;3Infectious Disease Clinical
Research Program, Uniformed Services University of the Health Sciences, and4San Antonio Military Medical Center, Texas
extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, compli-
cation following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity.
Methods. The patient population includes US military personnel injured during combat from June 2009
through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence
by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the
Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and
pathologist review of histopathology specimens.
Results. A total of 37 cases were identified: proven (angioinvasion, n=20), probable (nonvascular tissue inva-
sion, n=4), and possible (positive fungal culture without histopathological evidence, n=13). In the last quarter
surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot
patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume
blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n=16; Aspergillus spp,
n=16; Fusarium spp, n=9), commonly with multiple mold species among infected wounds (28%). Clinical out-
comes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions
Conclusions. IFIs are an emerging trauma-related infection leading to significant morbidity. Early identifica-
tion, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by
aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending
mycology results) among patients with suspicious wounds.
Major advances in combat casualty care have led to increased survival of patients with complex
Invasive fungal wound infections (IFIs) of skin and
soft tissue occur in both immunocompromised and
immunocompetent hosts . Among immunocompe-
tent individuals, traumatic injury is the most common
risk factor for IFI, occurring in settings such as agri-
cultural, motor vehicle, and blunt crush injuries, as
well as during natural disasters as recently reported
among tornado victims [2–6]. Local invasive infection
often requires repeated and extensive surgical debride-
ment and systemic antifungal therapy complicated by
amputations (31%) and mortality (as high as 25%) .
Major advances in combat casualty care have led to
increased survival of patients with complex extremity
trauma [7–9]. Blast traumas, secondary to those
caused by improvised explosive devices, are among the
most severe injuries [7, 10]. Gross contamination of
these wounds with organic material may introduce
Received 8 May 2012; accepted 23 August 2012; electronically published 5
Correspondence: David R. Tribble, MD, DrPH, Director, General Infectious
Diseases, Infectious Disease Clinical Research Program, Preventive Medicine &
Biometrics Department, Uniformed Services University of the Health Sciences,
4301 Jones Bridge Rd, Bethesda, MD 20814-5119 (email@example.com).
Clinical Infectious Diseases2012;55(11):1441–9
Published by Oxford University Press on behalf of the Infectious Diseases Society of
Trauma-related Invasive Mold Infections • CID 2012:55 (1 December) • 1441
by guest on February 11, 2013
environmental filamentous fungi (molds), among other patho-
gens [2, 4]. This report describes IFI epidemiology, clinical
findings, and laboratory findings among American combat ca-
sualties in Afghanistan from June 2009 through December
MATERIALS AND METHODS
The population includes US military personnel who were
injured in combat in Afghanistan, then medically evacuated
through Landstuhl Regional Medical Center (LRMC) in
Germany and admitted to 1 of 3 US military hospitals: Walter
Reed Army Medical Center (WRAMC) in Washington, DC;
National Naval Medical Center (NNMC) in Bethesda, Mary-
land; and Brooke Army Medical Center in San Antonio,
IFI Case Definitions
Case definitions were adapted from the Mycosis Study
Group . Diagnostic criteria were as follows: (1) traumatic
wounds, (2) after ≥1 irrigation and debridement, (3) tissue
necrosis on ≥2 consecutive debridements, and (4) IFI evi-
dence. Cases were classified as either proven IFI (fungal
hyphae angioinvasion of viable tissue), probable IFI (viable
tissue invasion, but no angioinvasion), or possible IFI (mold
grown in culture but either histology not performed or no
fungal elements seen). Candida spp were specifically excluded
because their role in pathogenesis in wound infections is
The investigation was undertaken through the Trauma Infec-
tious Disease Outcomes Study (TIDOS) . Trauma history,
International Classification of Diseases (Ninth Revision) injury
codes, and surgical management history were obtained
through the US Department of Defense Joint Theater Trauma
Registry (JTTR) . IFI-specific data were collected through
a supplemental JTTR infectious disease module. All histopa-
thology specimens were reviewed by 2 surgical pathologists.
The study was approved by the institutional review board of
the Uniformed Services University of the Health Sciences.
Cases were identified through review of the TIDOS database
for all positive fungal wound cultures and histology during the
investigation period. To assure complete case capture, histopa-
thology and clinical microbiology reports were reviewed, as
were case records from infectious disease and trauma surgery
Clinical Outcomes and Statistical Analysis
IFI diagnosis date was the earliest specimen collection yielding
a positive result from either culture or pathology. Time to
clean wound was defined as the number of days from IFI diag-
nosis to first documented clean wound (operative report with
no evidence of infection and no subsequent histopathology or
culture evidence). High-level amputations were defined as hip
disarticulation or hemipelvectomy.
Fisher exact and χ2tests were used to test the association of
levels of categorical variables with IFI classes and clinical my-
cology groups. The Kruskal-Wallis test was implemented to
compare medians among these groupings.
Demographics and Injury Patterns
The investigation included the period from 1 June 2009
(TIDOS start date) through 31 December 2010. Trauma-
patient evacuations to LRMC from Afghanistan (n =2413) are
displayed in Figure 1 by calendar quarter against patients di-
agnosed with IFI (n= 37; proven, 20 patients [54.1%]; proba-
ble, 4 patients [10.8%]; possible, 13 patients [35.1%]). No IFI
cases were identified from Iraq during the study period. The
IFI rate gradually increased to the highest level of 3.5% in the
fourth quarter of 2010. The progressive increase was also ob-
served among trauma patient admissions (not restricted to Af-
ghanistan evacuations) to the LRMC intensive care unit
(ICU), reaching a high of 8% in the fourth quarter of 2010.
All cases were male enlisted personnel (25 Marines and 12
Army) with median age 23 years (interquartile range [IQR],
21–27). All injuries were secondary to explosive blasts, 34
(91.9%) were dismounted (ie, on foot patrol) at the time of
injury (more common in proven and probable groups), and
35 (94.6%) received initial care in a military facility in south-
ern Afghanistan (Helmand or Kandahar provinces; Table 1).
All had extremity injuries with 29 (78.4%) sustaining an am-
putation at time of injury or first surgery as exemplified in one
patient’s infected wound (Figure 2). Multiple limb amputa-
tions were common with 25 (67.6%) bilateral and 6 (16.2%)
involving three limbs. Other common findings included peri-
neal and genital wounds (67.6%), vascular repair (51.4%), and
penetrating abdominal trauma (32.4%).
Clinical Findings and Trauma Care
Characteristics of patients’ clinical findings and early trauma
care are detailed in Table 1 by IFI classification. Overall, most
patients presented with borderline hypotension and tachycar-
dia, with significant base deficit and required massive blood
transfusion, approximately 30 units on average of both packed
red blood cells and fresh frozen plasma, in the first 24 hours
(proven andprobablecases had highertransfusion
1442 • CID 2012:55 (1 December) • Warkentien et al
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requirement than did possible cases). The majority of patients
were febrile (temperature, >38°C) with leukocytosis (white
blood cell count, >10 × 109cells/L) within 1 week of IFI diag-
nosis irrespective of IFI classification.
IFI Wound Characteristics and Microbiology
Among the 37 patients, a total of 54 distinct wounds with IFI
were identified, 27 (50.0%) classified as proven, 8 (14.8%) as
probable, and 19 as (35.2%) possible (12 of which did not
have specimens sent for histopathology).These wounds were
characterized by myonecrosis (81%), liponecrosis (52%),
eschar (14%), purulence (43%), and fibrinous exudates (18%)
observed on surgical examination.
Among the wounds with pathological examination (n = 41),
hyphae were seen, from any staining technique, in 34 (82.9%)
wounds. Hyphal element staining was more commonly ob-
served with Gomori methenamine silver staining (72.4%) than
with periodic acid Schiff (PAS) staining (51.4%). Of critical
importance in specimens with aseptate hyphae, visuali-
zation with routine hematoxylin-eosin (H&E) staining was oc-
casionally the only method of identification (19.5%). Although
an intra-operative frozen section was not commonly obtained,
among the 15 wounds for which frozen sections were evaluat-
ed, there were 6 positive frozen sections (all also found posi-
tive for hyphae on standard histopathology) and 9 negative
frozen sections (6 later found to be positive on definitive
A total of 31 (83.8%) patients had at least 1 mold isolated
(Table 3). In 16 patients, a mold from the order Mucorales
was identified (multiple species isolated in some cases). Patho-
gens from the order Mucorales were isolated from 62.5%,
100%, and 38.5% of proven, probable, and possible cases, re-
spectively. Evidence of order Mucorales, from culture and/or
aseptate hyphae on histopathology, was observed in 25
(47.2%) infected wounds: 10 (40%) from culture and aseptate
morphology, 6 (24%) from culture only, and 9 (36%) from
pathology only. In addition, there were 16 patients with Asper-
gillus spp and 9 with Fusarium spp. Two or more mold
isolates, with one from Mucorales and another from a non-
Mucorales species, were recovered in 28.3% of infected
wounds. There were no statistically significant clinical differ-
ences based on fungal pathogen isolation. No mold isolates
were recovered from sites distant from the affected extremity
or blood with the exception of abdominal cavity involvement
contiguous with extensive perineal and hip invasive disease in
2 of the fatal cases as well as respiratory secretion cultures
(commonly sputum and tracheal aspirates) which were not
felt to represent invasive pulmonary disease.
All 54 wounds were also either colonized or infected with a
bacteria or yeast by the date of IFI diagnosis, with the most
Medical Center (LRMC), from June 2009 through December 2010. An average of 324 patients (range, 95–509 patients) per quarter admitted to LRMC
with an average of 5 patients (range, 0–12 patients) with invasive fungal infection per quarter. Abbreviation: IFI, invasive fungal infection.
Number and percentage of patients with diagnoses of invasive fungal wound infections based on dates of admission to Landstuhl Regional
Trauma-related Invasive Mold Infections • CID 2012:55 (1 December) • 1443
by guest on February 11, 2013
Table 1. Injury and Clinical Characteristics by Invasive Fungal Infection Classification
Characteristics Proven or Probable (n=24)Possible (n=13)P
Injury circumstances and severity
First medical facility location (Afghanistan province), No. (%)
Dismounted (foot patrol) at time of injury, No. (%)
Injury severity score, median (IQR)
First documented shock index, median (IQR)
Median heart rate, beats/min (IQR)
Median systolic blood pressure, mm Hg (IQR)
Median blood gas, base deficit (IQR)
Median blood gas, pH (IQR)
Injury management and comorbidity
Lower extremity amputation, No. (%)
All blood products, all care levels, median (IQR)
Blood products in theater, U (IQR)
Packed red blood cells
Fresh frozen plasma
Admitted to ICU at US hospital transfer, No. (%)
Admission SOFA, median (IQR)
Landstuhl Regional Medical Center
Selected clinical and laboratory findings within 5 days of IFI diagnosis
Fever (temperature of >38°C), No. (%)
Median maximum oral temperature, °C (IQR)
Elevated WBC count (>10×109cells/L), No. (%)
Median maximum WBC, 109cells/L (IQR)
−9 (−13.5 to −5)
−7 (−9 to −5)
Abbreviations: ICU, intensive care unit; IFI, invasive fungal infection; IQR, interquartile range; SOFA, Sequential Organ Failure Assessment score ; WBC,
white blood cell.
and medical therapy (B). High-level lower extremity amputation with necrotic fibrinous material documented on histopathology with aseptate mold
angioinvasion (initial presentation). Wound appearance after serial debridements, hemipelvectomy, and antifungal therapy (8 days later).
Intraoperative findings of wound following explosive blast injury subsequently infected with invasive mold (A) and after successful surgical
1444 • CID 2012:55 (1 December) • Warkentien et al
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commonly identified organisms being Enterococcus faecium
(n =11; 20.4%) and Acinetobacter calcoaceticus-baumannii
complex (n = 9; 17%). Candida albicans grew in cultures from
5 wounds (9.3%).
IFI-specific Management and Outcomes
The overall median duration from the time of injury to IFI
diagnosis was 10 days (IQR, 7–14 days). The time from IFI
diagnosis to discharge from the US facility was 57.5 days
(IQR, 35–68 days). The median number of surgeries at the IFI
wound site after medical evacuation from the operational
theater was 11 surgeries (IQR, 7–16 surgeries) consisting of
frequent debridements and amputation revisions. Time from
IFI diagnosis to clean wounds, documented in 20 cases, was a
median of 21 days (IQR, 18–35 days). Ten patients (27%) ulti-
mately required a high-level lower extremity amputation.
Thirty-three patients (89.2%) received antifungal therapy,
most commonly lipid formulations of amphotericin B (LFAB)
in 91% of patients, voriconazole in 85% of patients, and
posaconazole in 49% of patients. Eight (21.6%) patients re-
ceived monotherapy, whereas the most common combination
therapy (≥3 days of overlap) was LFAB plus a triazole (vorico-
nazole or posaconazole) in 65% of patients. Overall, patients
with possible cases received less total antifungal therapy than
did patients with proven or probable cases as reflected by
overall receipt (69% vs 100%), shorter treatment duration, and
less common combination therapy (46% vs 79%). The 4 pa-
tients who did not receive antifungal therapy were all classified
as having possible IFI, with 1 diagnosis of IFI on the day of
death. The other 3 patients underwent frequent debridements
(range, 8–11 debridements) leading to infection resolution.
Several topical agents were used, including 0.025% sodium hy-
pochlorite solution (modified Dakin solution) applied through
a negative pressure therapy device in 12 (32.4%) patients, am-
photericin B beads in 3 (8.1%) patients, and amphotericin
peritoneal irrigation in 1 patient. The median time between
the IFI diagnosis date (when specimen yielding first positive
result was collected) and antifungal therapy initiation was 4
Invasive Fungal Infection Timelines, Antifungal Agent Management, and Outcomes by Invasive Fungal Infection
FindingsProven or Probable (n=24) Possible (n=13)P
Median IFI-related timeline, days (IQR)
Injury to first IFI diagnosis
IFI diagnosis to first antifungal drug
Total duration of antifungal treatments
Systemic antifungal agents, No. (%); median d (IQR)a
Common regimens, No. (%)
Death, No. (%)
Median hospital duration after injury, days (IQR)
Median duration of ICU stay (LRMC and US; IQR)
Patients with amputations after Afghanistan evacuation, No. (%)
High-level amputation, No. (%)c
Median No. of amputation revision procedures (IQR)
22 (91.7); 22 (13–30)
20 (83.3); 11.5 (5–22)
13 (54.2); 16 (5–29)
9 (37.5); 6 (4–14)
8 (61.5); 18 (5–21.5)
8 (61.5); 14.5 (3.5–23)
3 (23.1); 16 (6–42)
5 (38.5); 13 (10–14)
Abbreviations: ICU, intensive care unit; IFI, invasive fungal infection; IQR, interquartile range; LFAB, lipid formulations of amphotericin B; LRMC, Landstuhl
Regional Medical Center.
aAntifungal agent combination use: LFAB and triazole (proven or probable cases, 15 patients; possible cases, 3 patients); LFAB, triazole, and caspofungin
(proven or probable cases, 3 patients; possible cases, 2 patients); LFAB and voriconazole (proven or probable cases, 1 patient; possible cases, 0 patients);
triazole and micafungin (proven or probable cases, 0 patients; possible cases, 1 patient).
bIncludes caspofungin and micafungin.
cTotal hip disarticulation or hemipelvectomy.
Trauma-related Invasive Mold Infections • CID 2012:55 (1 December) • 1445
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days (IQR, 1.5–7 days). The median duration of antifungal
therapy was 26.5 days (IQR, 14.5–42.5 days).
There were no significant differences for duration of hospi-
talization, ICU stay, new amputations, or revised amputations
by IFI classification (Table 2). Five patients with IFI died. IFI
contributed to death in 3 (8.1%) of these cases. In each of
these 3 cases, new-onset necrotic wounds presented 8–12 days
after injury with widespread progression of necrosis despite
intensified debridements over a period of 2–7 days. In each of
these fatal cases the necrosis extended beyond affected extrem-
ities into truncal areas as well as through the abdominal wall
with involvement of intra-abdominal tissues. All fatal cases
were in the proven group except 1 possible case (no tissue
specimen sent for histopathology). Three patients who died
with positive cultures near time of death were all from the
group with Mucorales infection. One patient tested positive
for an Alternaria species at the infected wound site 1 week
prior to patient death; however, wound culture was negative
with documented angioinvasion the day prior to death (pri-
marily attributed to severe head injury and not IFI). The fifth
patient had aseptate angioinvasive fungal elements observed
but no culture obtained (Table 3).
To our knowledge, this is the largest case series of trauma-
related IFI described to date. Invasive fungal infections have
emerged as an important cause of morbidity and mortality
among US military personnel who have suffered combat-
related traumatic injuries. The most common features among
these patients are lower extremity amputation with perineal or
pelvic injury and receipt of massive blood transfusions follow-
ing blast injuries incurred while on foot patrol in southern
Afghanistan. This profile is consistent with a previous British
military report in the “green zone” of Helmand province in
Afghanistan . This region, with large agricultural areas,
may have a more dense concentration of environmental molds
than more arid regions of Afghanistan or in Iraq; however, the
primary risk may be more related to the mechanism of injury
in an individual on foot patrol than to a regional endemic
threat given the ubiquitous nature of these molds. The increas-
ing number of IFI cases follows the upward trend in lower ex-
tremity amputations among injured personnel returning from
Previous case reports of US combat-related IFI describe
wound infections with rare mold species [15–17], one of
which was a fatal case included in this investigation .
Cases have also been reported from a military burn center
noting higher numbers of attributable deaths related to inva-
sive mold infection in combat-related compared with civilian
burn patients at the center . In addition, there were 6 pa-
tients with IFI, all injured in Iraq, from March 2002 through
July 2008 among US military personnel sustaining traumatic
war wounds who wer hospitalized at WRAMC, yielding
estimates of 0.4 cases per 1000 admissions, much lower than
observed during this investigation .
Blast extremity wounds typically undergo meticulous low-
pressure irrigation and debridement within 1–2 hours of
injury and are commonly dressed using vacuum-assisted
wound closure. Serial debridement occurs approximately every
48 hours with wound closure often first considered after
injury day 8 if evidence of wound contraction and healthy
wound closure are as follows, in order of preference: delayed
primary closure, split thickness skin graft, rotational flap, and
free flap. The average injury severity score (ISS) from one case
series of mucormycosis after traumatic injury was 24 (range,
9–41), similar to the average ISS observed in this series .
The high fatality rate exceeds observed mortality among
wound infections secondary to bacterial infections , al-
though causes of death in this series were multifactorial in
nature and 2 deaths were not related to IFI diagnosis. IFI case
fatality is lowest among trauma-associated etiologies that typi-
cally occur in previously immunocompetent individuals;
tissue. Techniques of
Diagnoses of Invasive Fungal Infections Following Combat-
related Traumatic Injury, 2009–2010
Fungal Species Isolated From Wounds in Patients With
Pathogen No. (%) of Patients
Not otherwise specified
Other molds and moldlike organisms
Frequencies based on 31 patients (83.8%) with wound cultures testing
positive for mold species; proportions based on 69 mold cultures with
1446 • CID 2012:55 (1 December) • Warkentien et al
by guest on February 11, 2013
however, mortality of 25% exceeded our observed rate despite
the more extensive trauma in our series . A recent large
series of cutaneous mucormycosis among persons injured in
the tornado that struck Joplin, Missouri, in 2011 reported an
even higher fatality rate of 38.5% . The 13 confirmed case
patients in the Joplin series had a higher median age with a
wide range (as high as 76 years) and diabetes in 2 cases but
none were immunocompromised.
All but 1 patient in this series were transfused with
≥10 units of blood in theater (a commonly used threshold de-
lineating massive transfusion requirement)  with an initial
24-hour requirement almost 3 times this threshold. The
receipt of blood products can have immunosuppressive effects
and thereby increase the risk for infection [22, 23]. An addi-
tional consideration pertaining to IFI is the iron burden that is
received with blood transfusions, given that these molds are
known to utilize iron as a nutrition source, which may be
further exacerbated with acidosis during the immediate post-
trauma period . Iron burden was not assessed in these
In recent years, rates of IFI have increased, most commonly
among immunocompromised patients with mucormycosis .
Mucor spp, Saksenaea vasiformis, and Apophysomyces elegans
were the most common species isolated from the order Mucor-
ales in this case series. The invasive potential of S. vasiformis
and A. elegans observed in this series is consistent with previous
reports and a recent review [15, 25, 26]. Of note, there were no
isolates of Rhizopus spp, the most common identified mucor-
mycosis etiology; although this is primarily due to the predomi-
nance of immunocompromised hosts among cases . Other
environmental molds such as Aspergillus spp, Fusarium spp,
and Scedosporium spp have been reported to cause wound in-
fections and were isolated in this series [2, 4, 27]. Only the Mu-
corales group and Aspergillus spp were observed in proven
cases as solitary pathogens. It is likely that many of the diverse
mold species isolated, particularly given the common finding of
multiple isolates per wound, represent wound contamination.
A favorable prognosis is dependent upon early identifica-
tion and aggressive surgical debridement combined with
antifungal treatment [3, 4]. IFI diagnosis relies on histopatho-
logical confirmation of tissue invasion, with fungal culture
providing species identification . Mold cultures often
require several days to grow and may be insensitive (20% of
wounds in this series had negative cultures) ; therefore,
surgical tissue samples for histopathology are essential for ac-
curate diagnosis particularly since fungal colonization alone is
not indicative of an invasive infection [29, 30]. Standard H&E
staining is reported to be insensitive, prompting recommenda-
tions for special staining ; however, in this series more
wounds with hyphae were identified with H&E staining than
with PAS staining, particularly aseptate hyphae. Real-time
frozen sections demonstrated poor negative predictive value,
limiting clinical utility, although the number of cases exam-
ined was small and no prospective evaluation was undertaken.
Calcofluor white, a fluorescent stain used for rapid detection
of fungal elements in the microbiology laboratory [31–33],
was positive in only 49% of 33 mold culture positive speci-
mens at one of the hospitals. The 4-day average “delay”
between IFI diagnosis and start of antifungal therapy reflects
the time required for tissue specimen collection, laboratory
work-up, reporting results, and starting therapy. This delay
was most evident among cases reliant upon microbiological
findings to fulfill IFI criteria, highlighting the need for im-
proved rapid and sensitive diagnostic methods, as well as use
of empiric antifungal therapy pending laboratory results.
Encouraging reports applying rapid diagnostic molecular
methods warrant further investigation [34, 35].
Debridement of necrotic material is paramount, as the
thrombosed blood vessels from the IFI results in poor tissue
penetration of antifungal agents [1, 36]. Frequent debridement
is necessary (potentially daily); one series had an average of
10 surgeries, comparable with the average number in this
series . The majority (89%) of the patients in this series
received antifungal therapy, with those managed with surgery
alone classified as possible IFI. No well-controlled studies are
available on which to base antifungal therapy in trauma-
associated IFI. A lipid polyene, amphotericin B (LFAB), at a
dose of 5 mg/kg per day, is the preferred agent for mucormy-
cosis without controlled trial evidence for added benefit when
combined with other antifungal agents . Voriconazole is
not active against mucormycosis, but it is primary therapy for
invasive aspergillosis including molds such as Aspergillus
terreus which are resistant to amphotericin B . Empiric
regimens should include LFAB and voriconazole pending
results of serial wound cultures and histopathology findings to
better target treatment on probable pathogens rather than
transient colonizing species.
Topical therapy was commonly used, including specific an-
tifungal agents or, more commonly, the disinfectant sodium
hypochlorite (0.025% Dakin solution instilled in wound
vacuum device) . Anecdotally, Dakin solution was felt to
be effective, leading to common use in the latter half of the
investigation period; however, no outcome difference was ap-
parent. Potential adjunctive therapy options for invasive mucor-
mycosis have been reported including hyperbaric oxygen ,
with encouraging results from case series but no controlled
studies, and deferasirox iron chelation, recently reported to have
higher mortality among patients receiving adjunctive treatment
in a small randomized placebo-controlled trial .
In summary, IFI is an increasingly important cause of mor-
bidity and mortality among US military personnel who suffer
combat-related traumatic injury. Awareness of the common
Trauma-related Invasive Mold Infections • CID 2012:55 (1 December) • 1447
by guest on February 11, 2013
features (blast injury while on foot patrol, extensive lower ex-
tremity traumatic amputations with associated perineal injury,
and massive blood transfusion) in the setting of necrotic
wounds requires aggressive and extensive surgical debride-
ment and empiric systemic antifungal therapy. In addition, cli-
nicians should also recognize that the median time from
injury to diagnosis is 10 days (IQR, 7–14 days). Increased
awareness and early diagnostic efforts utilizing tissue histopa-
thology and clinical mycology may shorten this interval,
lessening the requirement for extensive debridement and ulti-
mately minimizing long-term disability due to high-level am-
putations. Future strategies for IFI prevention, diagnosis, and
treatment require preclinical and clinical research efforts to
support ongoing refinement of clinical practice guidance.
Research Program (IDCRP) Trauma Infectious Diseases Outcomes Study
team of clinical investigators, clinical coordinators, microbiology techni-
cians, data managers, clinical site managers, and administrative support
personnel to ensure the success of this project. We also wish to
thank John Bennett, National Institute of Allergy and Infectious Diseases,
National Institutes of Health (NIH), for his critical review of the
The content of this publication is the sole responsibility of the authors
and does not necessarily reflect the views or policies of the NIH or the
Department of Health and Human Services, the Department of Defense
(DoD), or the Departments of the Army, Navy, or Air Force. Mention
of trade names, commercial products, or organizations does not imply
endorsement by the US Government.
This work was supported by the IDCRP, a DoD program executed
through the Uniformed Services University of the Health Sciences. This
project (IDCRP-024) has been funded by the National Institute of Allergy
and Infectious Diseases, NIH, under Inter-Agency Agreement Y1-AI-5072
and the Department of the Navy under the Wounded, Ill, and Injured
Program. D. R. T. had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
Potential conflicts of interest.
All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
We are indebted to the Infectious Disease Clinical
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