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Antifungal wound penetration of amphotericin and voriconazole in combat-related injuries: case report.

Akers KS, Rowan MP, Niece KL, Graybill JC, Mende K, Chung KK, Murray CK - BMC Infect. Dis. (2015)

Bottom Line: Survivors of combat trauma can have long and challenging recoveries, which may be complicated by infection.Invasive fungal infections are a rare but serious complication with limited treatment options.In addition, considerable between-patient and within-patient variability was observed in antifungal pharmacokinetic parameters.

View Article: PubMed Central - PubMed

Affiliation: United States Army Institute of Surgical Research, 3698 Chambers Pass, JBSA Fort Sam Houston, TX, 78234, USA. kevin.s.akers.mil@mail.mil.

ABSTRACT

Background: Survivors of combat trauma can have long and challenging recoveries, which may be complicated by infection. Invasive fungal infections are a rare but serious complication with limited treatment options. Currently, aggressive surgical debridement is the standard of care, with antifungal agents used adjunctively with uncertain efficacy. Anecdotal evidence suggests that antifungal agents may be ineffective in the absence of surgical debridement, and studies have yet to correlate antifungal concentrations in plasma and wounds.

Case presentation: Here we report the systemic pharmacokinetics and wound effluent antifungal concentrations of five wounds from two male patients, aged 28 and 30 years old who sustained combat-related blast injuries in southern Afghanistan, with proven or possible invasive fungal infection. Our data demonstrate that while voriconazole sufficiently penetrated the wound resulting in detectable effluent levels, free amphotericin B (unbound to plasma) was not present in wound effluent despite sufficient concentrations in circulating plasma. In addition, considerable between-patient and within-patient variability was observed in antifungal pharmacokinetic parameters.

Conclusion: These data highlight the need for further studies evaluating wound penetration of commonly used antifungals and the role for therapeutic drug monitoring in providing optimal care for critically ill and injured war fighters.

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Related in: MedlinePlus

Amphotericin B concentrations in plasma and wound effluent in two patients with 5 wounds. Abd, abdomen; LLQ, left lower quadrant.
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Fig1: Amphotericin B concentrations in plasma and wound effluent in two patients with 5 wounds. Abd, abdomen; LLQ, left lower quadrant.

Mentions: A 30 year-old male suffered a complex blast injury as a result of a dismounted improvised explosive device blast in southern Afghanistan, resulting in polytrauma including bilateral above-the-knee amputations, perineal/gluteal avulsion and 20% total body surface area burns to the posterior thighs and back. Initial resuscitation and damage control surgery was performed in Afghanistan, followed by medical evacuation on post-injury day 3 to Landstuhl Regional Medical Center (LRMC) in Germany. At LRMC, tissue samples of the lower extremity amputation sites and gluteal wounds were collected as part of clinical care for early detection of invasive fungal infection in accordance with the LRMC “blast protocol” [8], demonstrating angioinvasive non-septate branching hyphae diagnostic of a proven invasive fungal infection by a Mucorales mold [9]. Repeated surgical debridements performed at the discretion of the clinical care team with tissue fungal cultures (post-injury days 3 to 7) resulted in recovery of Aspergillus flavus, A. terreus, Fusarium sp. and an unidentified Mucorales mold. Following transfer to Brooke Army Medical Center, subsequent tissue fungal cultures from debridements recovered Saksenea erythrospora on 10 different occasions between post-injury days 12 and 46, with non-septate branching hyphae observed but not cultured on 5 additional soft tissue specimens collected on 3 separate days. Additionally, Fusarium sp. was recovered on post-injury day 59. Plasma and effluent sampling was performed on post-injury day 18 (Patient 1, Table 1, antifungal treatment day 15) following a once-daily dose of L-AmB (5 mg/kg IV), with effluent recovered from two abdominal NPWT sites (midline and left lower quadrant, Figure 1). While the plasma peak and trough concentrations were 25.5 μg/mL and 6.1 μg/mL, respectively (Table 1), total amphotericin B in the wound effluent was 0.2-0.3 μg/mL and free amphotericin B levels were undetectable by our assay (Table 2). At the time of sampling, NPWT with periodic instillation of Dakin’s solution was employed to provide local antifungal therapy to the subject’s bilateral lower extremity amputation sites, precluding effluent collection at these locations. Patient 1 survived to hospital discharge on post-injury day 193.Figure 1


Antifungal wound penetration of amphotericin and voriconazole in combat-related injuries: case report.

Akers KS, Rowan MP, Niece KL, Graybill JC, Mende K, Chung KK, Murray CK - BMC Infect. Dis. (2015)

Amphotericin B concentrations in plasma and wound effluent in two patients with 5 wounds. Abd, abdomen; LLQ, left lower quadrant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4403850&req=5

Fig1: Amphotericin B concentrations in plasma and wound effluent in two patients with 5 wounds. Abd, abdomen; LLQ, left lower quadrant.
Mentions: A 30 year-old male suffered a complex blast injury as a result of a dismounted improvised explosive device blast in southern Afghanistan, resulting in polytrauma including bilateral above-the-knee amputations, perineal/gluteal avulsion and 20% total body surface area burns to the posterior thighs and back. Initial resuscitation and damage control surgery was performed in Afghanistan, followed by medical evacuation on post-injury day 3 to Landstuhl Regional Medical Center (LRMC) in Germany. At LRMC, tissue samples of the lower extremity amputation sites and gluteal wounds were collected as part of clinical care for early detection of invasive fungal infection in accordance with the LRMC “blast protocol” [8], demonstrating angioinvasive non-septate branching hyphae diagnostic of a proven invasive fungal infection by a Mucorales mold [9]. Repeated surgical debridements performed at the discretion of the clinical care team with tissue fungal cultures (post-injury days 3 to 7) resulted in recovery of Aspergillus flavus, A. terreus, Fusarium sp. and an unidentified Mucorales mold. Following transfer to Brooke Army Medical Center, subsequent tissue fungal cultures from debridements recovered Saksenea erythrospora on 10 different occasions between post-injury days 12 and 46, with non-septate branching hyphae observed but not cultured on 5 additional soft tissue specimens collected on 3 separate days. Additionally, Fusarium sp. was recovered on post-injury day 59. Plasma and effluent sampling was performed on post-injury day 18 (Patient 1, Table 1, antifungal treatment day 15) following a once-daily dose of L-AmB (5 mg/kg IV), with effluent recovered from two abdominal NPWT sites (midline and left lower quadrant, Figure 1). While the plasma peak and trough concentrations were 25.5 μg/mL and 6.1 μg/mL, respectively (Table 1), total amphotericin B in the wound effluent was 0.2-0.3 μg/mL and free amphotericin B levels were undetectable by our assay (Table 2). At the time of sampling, NPWT with periodic instillation of Dakin’s solution was employed to provide local antifungal therapy to the subject’s bilateral lower extremity amputation sites, precluding effluent collection at these locations. Patient 1 survived to hospital discharge on post-injury day 193.Figure 1

Bottom Line: Survivors of combat trauma can have long and challenging recoveries, which may be complicated by infection.Invasive fungal infections are a rare but serious complication with limited treatment options.In addition, considerable between-patient and within-patient variability was observed in antifungal pharmacokinetic parameters.

View Article: PubMed Central - PubMed

Affiliation: United States Army Institute of Surgical Research, 3698 Chambers Pass, JBSA Fort Sam Houston, TX, 78234, USA. kevin.s.akers.mil@mail.mil.

ABSTRACT

Background: Survivors of combat trauma can have long and challenging recoveries, which may be complicated by infection. Invasive fungal infections are a rare but serious complication with limited treatment options. Currently, aggressive surgical debridement is the standard of care, with antifungal agents used adjunctively with uncertain efficacy. Anecdotal evidence suggests that antifungal agents may be ineffective in the absence of surgical debridement, and studies have yet to correlate antifungal concentrations in plasma and wounds.

Case presentation: Here we report the systemic pharmacokinetics and wound effluent antifungal concentrations of five wounds from two male patients, aged 28 and 30 years old who sustained combat-related blast injuries in southern Afghanistan, with proven or possible invasive fungal infection. Our data demonstrate that while voriconazole sufficiently penetrated the wound resulting in detectable effluent levels, free amphotericin B (unbound to plasma) was not present in wound effluent despite sufficient concentrations in circulating plasma. In addition, considerable between-patient and within-patient variability was observed in antifungal pharmacokinetic parameters.

Conclusion: These data highlight the need for further studies evaluating wound penetration of commonly used antifungals and the role for therapeutic drug monitoring in providing optimal care for critically ill and injured war fighters.

Show MeSH
Related in: MedlinePlus