Infectious Diseases

Several newly identified biomarkers can help distinguish invasive aspergillosis from aspergillus colonization in lung transplant recipients, according to data from a new study presented at the annual meeting of the International Society for Heart and Lung Transplantation.

Aspergillus, a common environmental mold, can cause potentially serious infection or asymptomatic colonization in patients who have significant lung disease or are immunosuppressed, said Aaron Mishkin, MD, associate professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia, who was not involved in the study.

“Determining if the aspergillus that is present is a colonizing organism vs disease is challenging clinically,” Mishkin said. Clinicians currently rely on criteria including a compatible patient, imaging findings, and a laboratory-based diagnostic such as tissue from a biopsy, cultures, polymerase chain reaction (PCR), or fungal antigen detection, said Mishkin. “Fungal antigen detection has variable specificity and sensitivity,” he noted. New biomarkers that look for an immune response could help differentiate between colonization and infection by assessing an immune-mediated inflammatory response, the hallmark of infection, he said.

To tease out potential biomarkers associated with invasive aspergillosis, Christine Ng, MS, a researcher at the University Health Network, Toronto, Ontario, Canada, and colleagues performed RNA sequencing on samples from 14 control lung transplant patients, 34 with aspergillus colonization, and seven with invasive aspergillosis. They identified potential candidate genes in 15 control samples, 17 aspergillus colonization samples, and 15 invasive aspergillosis samples.

Overall, signaling pathway analysis showed robust immune response, T-cell immunity, and leukocyte immunity in patients with invasive aspergillosis. By contrast, patients with aspergillus colonization showed enriched cellular responses (response to stimuli, epithelium development).

In a real-time quantitative PCR analysis, the researchers validated three biomarkers specific to invasive aspergillosis (IRF7, ZBP1, CYP27B1). Biomarkers AKR1C2, FGF10, and VGLL3 demonstrated specificity for aspergillus colonization. Additionally, biomarkers PTGER3, LPAR3, and COL14A1 were significant when aspergillus colonization was compared to controls but not in comparisons between invasive aspergillosis and aspergillus colonization. 

The study findings were limited by the small sample size, and larger studies are needed before they can be implemented in clinical practice, the researchers wrote. However, the results suggest that the new biomarkers reveal distinct host immune patterns and may improve differentiation of aspergillosis from colonization in lung transplant recipients, they concluded.

Clinical Implications and Next Steps

RNA testing can help differentiate colonization vs infection, Mishkin said. “Colonization is not typically treated, whereas infection would be treated with an anti-fungal and, in the case of a transplant recipient, a reduction in immunosuppression,” he said. “In lung transplantation, a delicate equilibrium must be maintained between achieving optimal immunosuppression and minimizing or treating infection. Any tools that can aid in this decision-making have the potential to enhance patient outcomes,” he added.

The current study was limited by the use of data only from a single center, and the broader applicability to additional populations, broader geographic areas, and a larger number of organisms remains unknown, Mishkin said. “This type of assay does have the possibility of applicability to a larger number of fungal and even bacterial species,” he noted.

A version of this article first appeared on Medscape.com.

Several newly identified biomarkers can help distinguish invasive aspergillosis from aspergillus colonization in lung transplant recipients, according to data from a new study presented at the annual meeting of the International Society for Heart and Lung Transplantation.

Aspergillus, a common environmental mold, can cause potentially serious infection or asymptomatic colonization in patients who have significant lung disease or are immunosuppressed, said Aaron Mishkin, MD, associate professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia, who was not involved in the study.

“Determining if the aspergillus that is present is a colonizing organism vs disease is challenging clinically,” Mishkin said. Clinicians currently rely on criteria including a compatible patient, imaging findings, and a laboratory-based diagnostic such as tissue from a biopsy, cultures, polymerase chain reaction (PCR), or fungal antigen detection, said Mishkin. “Fungal antigen detection has variable specificity and sensitivity,” he noted. New biomarkers that look for an immune response could help differentiate between colonization and infection by assessing an immune-mediated inflammatory response, the hallmark of infection, he said.

To tease out potential biomarkers associated with invasive aspergillosis, Christine Ng, MS, a researcher at the University Health Network, Toronto, Ontario, Canada, and colleagues performed RNA sequencing on samples from 14 control lung transplant patients, 34 with aspergillus colonization, and seven with invasive aspergillosis. They identified potential candidate genes in 15 control samples, 17 aspergillus colonization samples, and 15 invasive aspergillosis samples.

Overall, signaling pathway analysis showed robust immune response, T-cell immunity, and leukocyte immunity in patients with invasive aspergillosis. By contrast, patients with aspergillus colonization showed enriched cellular responses (response to stimuli, epithelium development).

In a real-time quantitative PCR analysis, the researchers validated three biomarkers specific to invasive aspergillosis (IRF7, ZBP1, CYP27B1). Biomarkers AKR1C2, FGF10, and VGLL3 demonstrated specificity for aspergillus colonization. Additionally, biomarkers PTGER3, LPAR3, and COL14A1 were significant when aspergillus colonization was compared to controls but not in comparisons between invasive aspergillosis and aspergillus colonization. 

The study findings were limited by the small sample size, and larger studies are needed before they can be implemented in clinical practice, the researchers wrote. However, the results suggest that the new biomarkers reveal distinct host immune patterns and may improve differentiation of aspergillosis from colonization in lung transplant recipients, they concluded.

Clinical Implications and Next Steps

RNA testing can help differentiate colonization vs infection, Mishkin said. “Colonization is not typically treated, whereas infection would be treated with an anti-fungal and, in the case of a transplant recipient, a reduction in immunosuppression,” he said. “In lung transplantation, a delicate equilibrium must be maintained between achieving optimal immunosuppression and minimizing or treating infection. Any tools that can aid in this decision-making have the potential to enhance patient outcomes,” he added.

The current study was limited by the use of data only from a single center, and the broader applicability to additional populations, broader geographic areas, and a larger number of organisms remains unknown, Mishkin said. “This type of assay does have the possibility of applicability to a larger number of fungal and even bacterial species,” he noted.

A version of this article first appeared on Medscape.com.

Several newly identified biomarkers can help distinguish invasive aspergillosis from aspergillus colonization in lung transplant recipients, according to data from a new study presented at the annual meeting of the International Society for Heart and Lung Transplantation.

Aspergillus, a common environmental mold, can cause potentially serious infection or asymptomatic colonization in patients who have significant lung disease or are immunosuppressed, said Aaron Mishkin, MD, associate professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia, who was not involved in the study.

“Determining if the aspergillus that is present is a colonizing organism vs disease is challenging clinically,” Mishkin said. Clinicians currently rely on criteria including a compatible patient, imaging findings, and a laboratory-based diagnostic such as tissue from a biopsy, cultures, polymerase chain reaction (PCR), or fungal antigen detection, said Mishkin. “Fungal antigen detection has variable specificity and sensitivity,” he noted. New biomarkers that look for an immune response could help differentiate between colonization and infection by assessing an immune-mediated inflammatory response, the hallmark of infection, he said.

To tease out potential biomarkers associated with invasive aspergillosis, Christine Ng, MS, a researcher at the University Health Network, Toronto, Ontario, Canada, and colleagues performed RNA sequencing on samples from 14 control lung transplant patients, 34 with aspergillus colonization, and seven with invasive aspergillosis. They identified potential candidate genes in 15 control samples, 17 aspergillus colonization samples, and 15 invasive aspergillosis samples.

Overall, signaling pathway analysis showed robust immune response, T-cell immunity, and leukocyte immunity in patients with invasive aspergillosis. By contrast, patients with aspergillus colonization showed enriched cellular responses (response to stimuli, epithelium development).

In a real-time quantitative PCR analysis, the researchers validated three biomarkers specific to invasive aspergillosis (IRF7, ZBP1, CYP27B1). Biomarkers AKR1C2, FGF10, and VGLL3 demonstrated specificity for aspergillus colonization. Additionally, biomarkers PTGER3, LPAR3, and COL14A1 were significant when aspergillus colonization was compared to controls but not in comparisons between invasive aspergillosis and aspergillus colonization. 

The study findings were limited by the small sample size, and larger studies are needed before they can be implemented in clinical practice, the researchers wrote. However, the results suggest that the new biomarkers reveal distinct host immune patterns and may improve differentiation of aspergillosis from colonization in lung transplant recipients, they concluded.

Clinical Implications and Next Steps

RNA testing can help differentiate colonization vs infection, Mishkin said. “Colonization is not typically treated, whereas infection would be treated with an anti-fungal and, in the case of a transplant recipient, a reduction in immunosuppression,” he said. “In lung transplantation, a delicate equilibrium must be maintained between achieving optimal immunosuppression and minimizing or treating infection. Any tools that can aid in this decision-making have the potential to enhance patient outcomes,” he added.

The current study was limited by the use of data only from a single center, and the broader applicability to additional populations, broader geographic areas, and a larger number of organisms remains unknown, Mishkin said. “This type of assay does have the possibility of applicability to a larger number of fungal and even bacterial species,” he noted.

A version of this article first appeared on Medscape.com.

Chromoblastomycosis is a neglected tropical implantation mycosis caused by dematiaceous fungi that leads to substantial morbidity. This condition is diagnosed microscopically by visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).¹ The main causative fungi varies by geographic region, but most commonly is caused by Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa.^2-4 Standardized treatment guidelines have not been established, but itraconazole typically is considered first-line regardless of causative fungi.⁵ Terbinafine, other azoles, and topical immunomodulators, either as monotherapy or in combination, may be appropriate alternative or adjunctive options for refractory disease, although supporting data are limited.^6-9

Complications from chromoblastomycosis are common, particularly in long-standing, severe, or refractory disease. An analysis using billing codes in the United States found 14% (35/255) of hospitalized patients with chromoblastomycosis had lymphedema.¹⁰ In Mexico, 63% (32/51) of patients with chromoblastomycosis developed secondary bacterial infections.¹¹ Skin fibrosis and ankylosis also can occur and cause mobility issues and decreased quality of life. An infrequent but potentially life-threatening complication¹² is the development of squamous cell carcinoma (SCC) associated with chronic lesions, representing a preventable end-stage complication of delayed diagnosis and treatment (Figure).

In this review, we summarize reported epidemiology and clinical risk factors for SCC complicating chromoblastomycosis. We also discuss plausible inflammatory mechanisms of malignant transformation and propose pragmatic clinical and public health interventions, including decentralized microscopy-based diagnosis, timely antifungal access, and biopsy-triggered surveillance of chronically inflamed lesions, to reduce preventable morbidity.

Epidemiology and Risk Factors

The epidemiology of SCC developing from chromoblastomycosis is not well understood due to gaps in national and global surveillance. Some studies have found that 2% to 13% of patients with chromoblastomycosis developed SCC.^4,11,13-15 Based on case reports and case series, a symptom duration of more than 10 years appears to be the most substantial risk factor for the development of SCC rather than host immune status.^16-18 Severity, specifically the size of the injury, and vegetating lesions also have been suggested as risk factors for the development of SCC.¹⁶ Additionally, the appearance of new lesions (mainly ulcers not related to secondary infection) that appear during the healing phase should raise the suspicion of SCC and warrant a biopsy for evaluation.¹⁶

Pathophysiology

The exact mechanism of malignant transformation has not been elucidated, but histopathologic features suggest substantial epidermal proliferation. In some cases, this leads to pseudoepitheliomatous hyperplasia, a nonmalignant hyperproliferative state that is an important differential HPV to leishmaniasis and lupus vulgaris.¹⁹ The chronic inflammation from long-standing chromoblastomycosis likely contributes to the further malignant transformation to SCC.

Polymorphonuclear cells and activated macrophages seen in chronic inflammation can promote the release of enzymes and free radicals that has led to malignant transformation in vitro but has not been investigated specifically in chromoblastomycosis.¹⁶ Additionally, chronic inflammation and metabolic products of phagocytosis often are accompanied by excessive production of reactive oxygen and nitrogen species, which can damage DNA, lipoproteins, and cell membranes. Other potential contributors include the expression of cyclooxygenase 2 and release of arachidonic acid metabolites (eg, prostaglandins, leukotrienes), which can damage the cell and promote carcinogenesis. It is not clear whether similar mechanisms account for the development of SCCs in other chronic skin inflammations or infections such as cutaneous tuberculosis or Marjolin ulcers.²⁰

Clinical and Public Health Interventions

Squamous cell carcinoma arising in the setting of chromoblastomycosis warrants prompt oncologic evaluation and definitive surgical management, which may require extensive surgical excision and, in advanced disease, amputation.^14,17,18 Advanced malignant tumors can be difficult to manage and can result in death.^21,22 Additionally, clinicians should maintain a low threshold for biopsy in long-standing chromoblastomycosis, particularly when lesions demonstrate new ulceration, rapid growth, bleeding, pain, malodor, or failure to improve with appropriate antifungal therapy.¹⁶ Recurrent or new lesions after amputation may indicate persistent or recurrent infection and may require continued antifungal management alongside cancer care.¹⁶

Squamous cell carcinoma arising from chromoblastomycosis results after substantial diagnostic delays, allowing chronic inflammation to transform infection into malignancy. Separating benign inflammation-associated epidermal proliferation from transformation to SCC requires histopathologic skill. An assay based on increased expression of chromosome 15 open reading frame 48 (C15orf48), an immune regulatory protein, has been developed to aid in this distinction; however, it is not widely available.²³

Raising awareness of chromoblastomycosis among clinicians and communities, particularly in rural areas where the disease is more common, is critical to improve health care–seeking behaviors and expedite access to care pathways.² Furthermore, access and training on microscopy to diagnose chromoblastomycosis in decentralized areas can facilitate earlier diagnosis in primary health care settings rather than waiting for diagnosis in tertiary care settings, at which point disease usually is advanced. Global implementation of existing programs that use microscopy (eg, malaria in rural areas) can be partnered with frontline health worker cross-training on chromoblastomycosis diagnosis to improve appropriate identification of disease.²⁴ Finally, improving access to affordable antifungals, particularly itraconazole, is necessary along with further research into novel therapeutic strategies. Approaches that utilize local manufacturing and pooled procurement could help expand treatment availability in parallel with diagnostic improvement initiatives.²⁵

Final Thoughts

Squamous cell carcinoma resulting from chromoblastomycosis is a devastating complication, often leading to limb amputation. The true prevalence is unknown, but it occurs more commonly in long-standing disease without appropriate therapy. The appearance of new lesions or ulcers after initial improvement should increase suspicion and lead to biopsy and careful pathologic evaluation. Prevention of SCC requires increased clinical awareness, early diagnosis, and timely initiation of antifungal treatment. Enhanced surveillance among individuals with chromoblastomycosis would help to better understand its prevalence, associated risk factors, and impact on quality of life.

Chromoblastomycosis is a neglected tropical implantation mycosis caused by dematiaceous fungi that leads to substantial morbidity. This condition is diagnosed microscopically by visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).¹ The main causative fungi varies by geographic region, but most commonly is caused by Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa.^2-4 Standardized treatment guidelines have not been established, but itraconazole typically is considered first-line regardless of causative fungi.⁵ Terbinafine, other azoles, and topical immunomodulators, either as monotherapy or in combination, may be appropriate alternative or adjunctive options for refractory disease, although supporting data are limited.^6-9

Complications from chromoblastomycosis are common, particularly in long-standing, severe, or refractory disease. An analysis using billing codes in the United States found 14% (35/255) of hospitalized patients with chromoblastomycosis had lymphedema.¹⁰ In Mexico, 63% (32/51) of patients with chromoblastomycosis developed secondary bacterial infections.¹¹ Skin fibrosis and ankylosis also can occur and cause mobility issues and decreased quality of life. An infrequent but potentially life-threatening complication¹² is the development of squamous cell carcinoma (SCC) associated with chronic lesions, representing a preventable end-stage complication of delayed diagnosis and treatment (Figure).

In this review, we summarize reported epidemiology and clinical risk factors for SCC complicating chromoblastomycosis. We also discuss plausible inflammatory mechanisms of malignant transformation and propose pragmatic clinical and public health interventions, including decentralized microscopy-based diagnosis, timely antifungal access, and biopsy-triggered surveillance of chronically inflamed lesions, to reduce preventable morbidity.

Epidemiology and Risk Factors

The epidemiology of SCC developing from chromoblastomycosis is not well understood due to gaps in national and global surveillance. Some studies have found that 2% to 13% of patients with chromoblastomycosis developed SCC.^4,11,13-15 Based on case reports and case series, a symptom duration of more than 10 years appears to be the most substantial risk factor for the development of SCC rather than host immune status.^16-18 Severity, specifically the size of the injury, and vegetating lesions also have been suggested as risk factors for the development of SCC.¹⁶ Additionally, the appearance of new lesions (mainly ulcers not related to secondary infection) that appear during the healing phase should raise the suspicion of SCC and warrant a biopsy for evaluation.¹⁶

Pathophysiology

The exact mechanism of malignant transformation has not been elucidated, but histopathologic features suggest substantial epidermal proliferation. In some cases, this leads to pseudoepitheliomatous hyperplasia, a nonmalignant hyperproliferative state that is an important differential HPV to leishmaniasis and lupus vulgaris.¹⁹ The chronic inflammation from long-standing chromoblastomycosis likely contributes to the further malignant transformation to SCC.

Polymorphonuclear cells and activated macrophages seen in chronic inflammation can promote the release of enzymes and free radicals that has led to malignant transformation in vitro but has not been investigated specifically in chromoblastomycosis.¹⁶ Additionally, chronic inflammation and metabolic products of phagocytosis often are accompanied by excessive production of reactive oxygen and nitrogen species, which can damage DNA, lipoproteins, and cell membranes. Other potential contributors include the expression of cyclooxygenase 2 and release of arachidonic acid metabolites (eg, prostaglandins, leukotrienes), which can damage the cell and promote carcinogenesis. It is not clear whether similar mechanisms account for the development of SCCs in other chronic skin inflammations or infections such as cutaneous tuberculosis or Marjolin ulcers.²⁰

Clinical and Public Health Interventions

Squamous cell carcinoma arising in the setting of chromoblastomycosis warrants prompt oncologic evaluation and definitive surgical management, which may require extensive surgical excision and, in advanced disease, amputation.^14,17,18 Advanced malignant tumors can be difficult to manage and can result in death.^21,22 Additionally, clinicians should maintain a low threshold for biopsy in long-standing chromoblastomycosis, particularly when lesions demonstrate new ulceration, rapid growth, bleeding, pain, malodor, or failure to improve with appropriate antifungal therapy.¹⁶ Recurrent or new lesions after amputation may indicate persistent or recurrent infection and may require continued antifungal management alongside cancer care.¹⁶

Squamous cell carcinoma arising from chromoblastomycosis results after substantial diagnostic delays, allowing chronic inflammation to transform infection into malignancy. Separating benign inflammation-associated epidermal proliferation from transformation to SCC requires histopathologic skill. An assay based on increased expression of chromosome 15 open reading frame 48 (C15orf48), an immune regulatory protein, has been developed to aid in this distinction; however, it is not widely available.²³

Raising awareness of chromoblastomycosis among clinicians and communities, particularly in rural areas where the disease is more common, is critical to improve health care–seeking behaviors and expedite access to care pathways.² Furthermore, access and training on microscopy to diagnose chromoblastomycosis in decentralized areas can facilitate earlier diagnosis in primary health care settings rather than waiting for diagnosis in tertiary care settings, at which point disease usually is advanced. Global implementation of existing programs that use microscopy (eg, malaria in rural areas) can be partnered with frontline health worker cross-training on chromoblastomycosis diagnosis to improve appropriate identification of disease.²⁴ Finally, improving access to affordable antifungals, particularly itraconazole, is necessary along with further research into novel therapeutic strategies. Approaches that utilize local manufacturing and pooled procurement could help expand treatment availability in parallel with diagnostic improvement initiatives.²⁵

Final Thoughts

Squamous cell carcinoma resulting from chromoblastomycosis is a devastating complication, often leading to limb amputation. The true prevalence is unknown, but it occurs more commonly in long-standing disease without appropriate therapy. The appearance of new lesions or ulcers after initial improvement should increase suspicion and lead to biopsy and careful pathologic evaluation. Prevention of SCC requires increased clinical awareness, early diagnosis, and timely initiation of antifungal treatment. Enhanced surveillance among individuals with chromoblastomycosis would help to better understand its prevalence, associated risk factors, and impact on quality of life.

Chromoblastomycosis is a neglected tropical implantation mycosis caused by dematiaceous fungi that leads to substantial morbidity. This condition is diagnosed microscopically by visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).¹ The main causative fungi varies by geographic region, but most commonly is caused by Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa.^2-4 Standardized treatment guidelines have not been established, but itraconazole typically is considered first-line regardless of causative fungi.⁵ Terbinafine, other azoles, and topical immunomodulators, either as monotherapy or in combination, may be appropriate alternative or adjunctive options for refractory disease, although supporting data are limited.^6-9

Complications from chromoblastomycosis are common, particularly in long-standing, severe, or refractory disease. An analysis using billing codes in the United States found 14% (35/255) of hospitalized patients with chromoblastomycosis had lymphedema.¹⁰ In Mexico, 63% (32/51) of patients with chromoblastomycosis developed secondary bacterial infections.¹¹ Skin fibrosis and ankylosis also can occur and cause mobility issues and decreased quality of life. An infrequent but potentially life-threatening complication¹² is the development of squamous cell carcinoma (SCC) associated with chronic lesions, representing a preventable end-stage complication of delayed diagnosis and treatment (Figure).

In this review, we summarize reported epidemiology and clinical risk factors for SCC complicating chromoblastomycosis. We also discuss plausible inflammatory mechanisms of malignant transformation and propose pragmatic clinical and public health interventions, including decentralized microscopy-based diagnosis, timely antifungal access, and biopsy-triggered surveillance of chronically inflamed lesions, to reduce preventable morbidity.

Epidemiology and Risk Factors

The epidemiology of SCC developing from chromoblastomycosis is not well understood due to gaps in national and global surveillance. Some studies have found that 2% to 13% of patients with chromoblastomycosis developed SCC.^4,11,13-15 Based on case reports and case series, a symptom duration of more than 10 years appears to be the most substantial risk factor for the development of SCC rather than host immune status.^16-18 Severity, specifically the size of the injury, and vegetating lesions also have been suggested as risk factors for the development of SCC.¹⁶ Additionally, the appearance of new lesions (mainly ulcers not related to secondary infection) that appear during the healing phase should raise the suspicion of SCC and warrant a biopsy for evaluation.¹⁶

Pathophysiology

The exact mechanism of malignant transformation has not been elucidated, but histopathologic features suggest substantial epidermal proliferation. In some cases, this leads to pseudoepitheliomatous hyperplasia, a nonmalignant hyperproliferative state that is an important differential HPV to leishmaniasis and lupus vulgaris.¹⁹ The chronic inflammation from long-standing chromoblastomycosis likely contributes to the further malignant transformation to SCC.

Polymorphonuclear cells and activated macrophages seen in chronic inflammation can promote the release of enzymes and free radicals that has led to malignant transformation in vitro but has not been investigated specifically in chromoblastomycosis.¹⁶ Additionally, chronic inflammation and metabolic products of phagocytosis often are accompanied by excessive production of reactive oxygen and nitrogen species, which can damage DNA, lipoproteins, and cell membranes. Other potential contributors include the expression of cyclooxygenase 2 and release of arachidonic acid metabolites (eg, prostaglandins, leukotrienes), which can damage the cell and promote carcinogenesis. It is not clear whether similar mechanisms account for the development of SCCs in other chronic skin inflammations or infections such as cutaneous tuberculosis or Marjolin ulcers.²⁰

Clinical and Public Health Interventions

Squamous cell carcinoma arising in the setting of chromoblastomycosis warrants prompt oncologic evaluation and definitive surgical management, which may require extensive surgical excision and, in advanced disease, amputation.^14,17,18 Advanced malignant tumors can be difficult to manage and can result in death.^21,22 Additionally, clinicians should maintain a low threshold for biopsy in long-standing chromoblastomycosis, particularly when lesions demonstrate new ulceration, rapid growth, bleeding, pain, malodor, or failure to improve with appropriate antifungal therapy.¹⁶ Recurrent or new lesions after amputation may indicate persistent or recurrent infection and may require continued antifungal management alongside cancer care.¹⁶

Squamous cell carcinoma arising from chromoblastomycosis results after substantial diagnostic delays, allowing chronic inflammation to transform infection into malignancy. Separating benign inflammation-associated epidermal proliferation from transformation to SCC requires histopathologic skill. An assay based on increased expression of chromosome 15 open reading frame 48 (C15orf48), an immune regulatory protein, has been developed to aid in this distinction; however, it is not widely available.²³

Raising awareness of chromoblastomycosis among clinicians and communities, particularly in rural areas where the disease is more common, is critical to improve health care–seeking behaviors and expedite access to care pathways.² Furthermore, access and training on microscopy to diagnose chromoblastomycosis in decentralized areas can facilitate earlier diagnosis in primary health care settings rather than waiting for diagnosis in tertiary care settings, at which point disease usually is advanced. Global implementation of existing programs that use microscopy (eg, malaria in rural areas) can be partnered with frontline health worker cross-training on chromoblastomycosis diagnosis to improve appropriate identification of disease.²⁴ Finally, improving access to affordable antifungals, particularly itraconazole, is necessary along with further research into novel therapeutic strategies. Approaches that utilize local manufacturing and pooled procurement could help expand treatment availability in parallel with diagnostic improvement initiatives.²⁵

Final Thoughts

Squamous cell carcinoma resulting from chromoblastomycosis is a devastating complication, often leading to limb amputation. The true prevalence is unknown, but it occurs more commonly in long-standing disease without appropriate therapy. The appearance of new lesions or ulcers after initial improvement should increase suspicion and lead to biopsy and careful pathologic evaluation. Prevention of SCC requires increased clinical awareness, early diagnosis, and timely initiation of antifungal treatment. Enhanced surveillance among individuals with chromoblastomycosis would help to better understand its prevalence, associated risk factors, and impact on quality of life.

Quality measures for primary care in the US Department of Veterans Affairs (VA) remained stable when telehealth was mixed with in-person visits, but influenza vaccination fell among patients who relied on online visits the most, a retrospective cohort study finds.

Analysis of the medical records for 744,599 veterans from federal fiscal years 2022 and 2023 revealed that patients aged 19-65 years who relied on telehealth for at least half of their primary care visits were less likely to receive an influenza vaccine (37.9%) compared with those seen only in person (50.0%, P < .001). The study was lead by researchers at VA Puget Sound and published in JAMA Network Open. 

There was also an influenza vaccination gap in patients aged ≥ 66 years: 62.8% in patients who received some care via telehealth telehealth vs 71.5% seen only in person, respectively (P < .001). 

“Our study showed that primary care quality at the VA is quite high,” Jonathan Staloff, MD, MSc, a family medicine physician with VA Puget Sound told Federal Practitioner. “And we found that for almost all quality measures, having a low proportion of care via telehealth was associated with the same quality as in-person care.”

As Staloff explained, “telehealth in primary care, as well as in general, has emerged as an additional means of preserving access to care for veterans. Evidence suggests that veterans have a high degree of satisfaction with telehealth but it’s mixed as it relates to quality outcome differences between those who receive any via telehealth vs none.”

For the study, Staloff said, “we wanted to see if there was a dose-response relationship between telehealth utilization and care quality and if certain hybrid models could help optimize quality of care. To our knowledge, this study was the first national evaluation to investigate primary care telehealth and care quality in this way.”

Reassuring Findings About Low Telehealth Use

For the study, researchers tracked a national sample of patient data from the Veterans Health Administration (VHA) Support Service Center Capital Assets Databases, Primary Care Management Module, and VHA Corporate Data Warehouse (mean age, 65 years; 86% male; 63% White, 22% Black, 10% Hispanic). 

The study defined categories of primary-care telehealth use as no telehealth, low telehealth (> 0.0% to < 28.6%), intermediate telehealth (28.6% to < 50.0%), and high telehealth (> 50.0%).

Highest Telehealth Use Raises Red Flags

The differences in influenza vaccine rates between the no-telehealth and high-telehealth groups held up in an adjusted analysis.

The study found small but statistically significant worsening of several quality measures in the high-telehealth use vs no-telehealth use cohorts: hypertension control, statin therapy and adherence, and annual screening for depression, alcohol use, and tobacco use.

The study cites limitations such as reliance on patients with ≥ 3 or more evaluation-and- management visits and lack of information about influenza vaccines delivered outside the VA. 

In a statement, VA Telehealth Services said it is “encouraged” the study demonstrates “equivalence in many clinical measures among veterans using telehealth. This study reinforces the potential of telehealth to provide high-quality health care to veterans.”

The organization added that it’s “committed to better understanding potential gaps highlighted in this study,” and “it is critical that research databases capture care rendered outside VA … and whether care was offered during a telehealth visit.”

Batching In-Person Services May Be Helpful

As for messages from the study for clinicians, Staloff said there are some preventive care measures that may be more difficult to deliver through telehealth.

“Clinicians should consider batching these in-person services for patients that have a high reliance on telehealth when they have an opportunity to see these patients in-person,” Staloff said. “Health systems may need new workflows to optimize hybrid care, particularly for those that receive most of their care via telehealth.”

Outside Perspective: ‘Access is Not the Same as Quality’

After reviewing the study findings, Ilana Graetz, PhD, a professor who studies health policy at the Emory University Rollins School of Public Health, praised the research design and said the results overall are “more reassuring than alarming.” However, she did caution that there could potentially be ways these patients differ that could not be categorized by the data.

“Patients with higher telehealth use may differ from those with lower telehealth use in important ways not fully captured in the data — barriers to in-person care, the complexity of the visit, patient preferences, or care received outside the system,” Graetz said.

As for the influenza vaccine, Graetz said patients need to be physically present: “Patients seen mostly by telehealth will have fewer opportunities to receive any preventive care that can only be delivered in person.”

Graetz said the study is timely given ongoing debates over COVID-19 pandemic-era telehealth flexibilities.

“The findings suggest that telehealth can function well as part of a hybrid primary care model,” she said, “but health systems still need to ensure that preventive services, chronic disease management, and follow-up care are not lost in the shift to virtual care.”

VHA Primary Care Analytics Team supported the study with funding from the VHA Office of Primary Care. Staloff has no disclosures. One coauthor disclosed a relationship with the US Department of Veterans Affairs. 

Graetz disclosed relationships the Donaghue Foundation, Pfizer, PRIME Education, and the National Institutes of Health. 

Quality measures for primary care in the US Department of Veterans Affairs (VA) remained stable when telehealth was mixed with in-person visits, but influenza vaccination fell among patients who relied on online visits the most, a retrospective cohort study finds.

Analysis of the medical records for 744,599 veterans from federal fiscal years 2022 and 2023 revealed that patients aged 19-65 years who relied on telehealth for at least half of their primary care visits were less likely to receive an influenza vaccine (37.9%) compared with those seen only in person (50.0%, P < .001). The study was lead by researchers at VA Puget Sound and published in JAMA Network Open. 

There was also an influenza vaccination gap in patients aged ≥ 66 years: 62.8% in patients who received some care via telehealth telehealth vs 71.5% seen only in person, respectively (P < .001). 

“Our study showed that primary care quality at the VA is quite high,” Jonathan Staloff, MD, MSc, a family medicine physician with VA Puget Sound told Federal Practitioner. “And we found that for almost all quality measures, having a low proportion of care via telehealth was associated with the same quality as in-person care.”

As Staloff explained, “telehealth in primary care, as well as in general, has emerged as an additional means of preserving access to care for veterans. Evidence suggests that veterans have a high degree of satisfaction with telehealth but it’s mixed as it relates to quality outcome differences between those who receive any via telehealth vs none.”

For the study, Staloff said, “we wanted to see if there was a dose-response relationship between telehealth utilization and care quality and if certain hybrid models could help optimize quality of care. To our knowledge, this study was the first national evaluation to investigate primary care telehealth and care quality in this way.”

Reassuring Findings About Low Telehealth Use

For the study, researchers tracked a national sample of patient data from the Veterans Health Administration (VHA) Support Service Center Capital Assets Databases, Primary Care Management Module, and VHA Corporate Data Warehouse (mean age, 65 years; 86% male; 63% White, 22% Black, 10% Hispanic). 

The study defined categories of primary-care telehealth use as no telehealth, low telehealth (> 0.0% to < 28.6%), intermediate telehealth (28.6% to < 50.0%), and high telehealth (> 50.0%).

Highest Telehealth Use Raises Red Flags

The differences in influenza vaccine rates between the no-telehealth and high-telehealth groups held up in an adjusted analysis.

The study found small but statistically significant worsening of several quality measures in the high-telehealth use vs no-telehealth use cohorts: hypertension control, statin therapy and adherence, and annual screening for depression, alcohol use, and tobacco use.

The study cites limitations such as reliance on patients with ≥ 3 or more evaluation-and- management visits and lack of information about influenza vaccines delivered outside the VA. 

In a statement, VA Telehealth Services said it is “encouraged” the study demonstrates “equivalence in many clinical measures among veterans using telehealth. This study reinforces the potential of telehealth to provide high-quality health care to veterans.”

The organization added that it’s “committed to better understanding potential gaps highlighted in this study,” and “it is critical that research databases capture care rendered outside VA … and whether care was offered during a telehealth visit.”

Batching In-Person Services May Be Helpful

As for messages from the study for clinicians, Staloff said there are some preventive care measures that may be more difficult to deliver through telehealth.

“Clinicians should consider batching these in-person services for patients that have a high reliance on telehealth when they have an opportunity to see these patients in-person,” Staloff said. “Health systems may need new workflows to optimize hybrid care, particularly for those that receive most of their care via telehealth.”

Outside Perspective: ‘Access is Not the Same as Quality’

After reviewing the study findings, Ilana Graetz, PhD, a professor who studies health policy at the Emory University Rollins School of Public Health, praised the research design and said the results overall are “more reassuring than alarming.” However, she did caution that there could potentially be ways these patients differ that could not be categorized by the data.

“Patients with higher telehealth use may differ from those with lower telehealth use in important ways not fully captured in the data — barriers to in-person care, the complexity of the visit, patient preferences, or care received outside the system,” Graetz said.

As for the influenza vaccine, Graetz said patients need to be physically present: “Patients seen mostly by telehealth will have fewer opportunities to receive any preventive care that can only be delivered in person.”

Graetz said the study is timely given ongoing debates over COVID-19 pandemic-era telehealth flexibilities.

“The findings suggest that telehealth can function well as part of a hybrid primary care model,” she said, “but health systems still need to ensure that preventive services, chronic disease management, and follow-up care are not lost in the shift to virtual care.”

VHA Primary Care Analytics Team supported the study with funding from the VHA Office of Primary Care. Staloff has no disclosures. One coauthor disclosed a relationship with the US Department of Veterans Affairs. 

Graetz disclosed relationships the Donaghue Foundation, Pfizer, PRIME Education, and the National Institutes of Health. 

Quality measures for primary care in the US Department of Veterans Affairs (VA) remained stable when telehealth was mixed with in-person visits, but influenza vaccination fell among patients who relied on online visits the most, a retrospective cohort study finds.

Analysis of the medical records for 744,599 veterans from federal fiscal years 2022 and 2023 revealed that patients aged 19-65 years who relied on telehealth for at least half of their primary care visits were less likely to receive an influenza vaccine (37.9%) compared with those seen only in person (50.0%, P < .001). The study was lead by researchers at VA Puget Sound and published in JAMA Network Open. 

There was also an influenza vaccination gap in patients aged ≥ 66 years: 62.8% in patients who received some care via telehealth telehealth vs 71.5% seen only in person, respectively (P < .001). 

“Our study showed that primary care quality at the VA is quite high,” Jonathan Staloff, MD, MSc, a family medicine physician with VA Puget Sound told Federal Practitioner. “And we found that for almost all quality measures, having a low proportion of care via telehealth was associated with the same quality as in-person care.”

As Staloff explained, “telehealth in primary care, as well as in general, has emerged as an additional means of preserving access to care for veterans. Evidence suggests that veterans have a high degree of satisfaction with telehealth but it’s mixed as it relates to quality outcome differences between those who receive any via telehealth vs none.”

For the study, Staloff said, “we wanted to see if there was a dose-response relationship between telehealth utilization and care quality and if certain hybrid models could help optimize quality of care. To our knowledge, this study was the first national evaluation to investigate primary care telehealth and care quality in this way.”

Reassuring Findings About Low Telehealth Use

For the study, researchers tracked a national sample of patient data from the Veterans Health Administration (VHA) Support Service Center Capital Assets Databases, Primary Care Management Module, and VHA Corporate Data Warehouse (mean age, 65 years; 86% male; 63% White, 22% Black, 10% Hispanic). 

The study defined categories of primary-care telehealth use as no telehealth, low telehealth (> 0.0% to < 28.6%), intermediate telehealth (28.6% to < 50.0%), and high telehealth (> 50.0%).

Highest Telehealth Use Raises Red Flags

The differences in influenza vaccine rates between the no-telehealth and high-telehealth groups held up in an adjusted analysis.

The study found small but statistically significant worsening of several quality measures in the high-telehealth use vs no-telehealth use cohorts: hypertension control, statin therapy and adherence, and annual screening for depression, alcohol use, and tobacco use.

The study cites limitations such as reliance on patients with ≥ 3 or more evaluation-and- management visits and lack of information about influenza vaccines delivered outside the VA. 

In a statement, VA Telehealth Services said it is “encouraged” the study demonstrates “equivalence in many clinical measures among veterans using telehealth. This study reinforces the potential of telehealth to provide high-quality health care to veterans.”

The organization added that it’s “committed to better understanding potential gaps highlighted in this study,” and “it is critical that research databases capture care rendered outside VA … and whether care was offered during a telehealth visit.”

Batching In-Person Services May Be Helpful

As for messages from the study for clinicians, Staloff said there are some preventive care measures that may be more difficult to deliver through telehealth.

“Clinicians should consider batching these in-person services for patients that have a high reliance on telehealth when they have an opportunity to see these patients in-person,” Staloff said. “Health systems may need new workflows to optimize hybrid care, particularly for those that receive most of their care via telehealth.”

Outside Perspective: ‘Access is Not the Same as Quality’

After reviewing the study findings, Ilana Graetz, PhD, a professor who studies health policy at the Emory University Rollins School of Public Health, praised the research design and said the results overall are “more reassuring than alarming.” However, she did caution that there could potentially be ways these patients differ that could not be categorized by the data.

“Patients with higher telehealth use may differ from those with lower telehealth use in important ways not fully captured in the data — barriers to in-person care, the complexity of the visit, patient preferences, or care received outside the system,” Graetz said.

As for the influenza vaccine, Graetz said patients need to be physically present: “Patients seen mostly by telehealth will have fewer opportunities to receive any preventive care that can only be delivered in person.”

Graetz said the study is timely given ongoing debates over COVID-19 pandemic-era telehealth flexibilities.

“The findings suggest that telehealth can function well as part of a hybrid primary care model,” she said, “but health systems still need to ensure that preventive services, chronic disease management, and follow-up care are not lost in the shift to virtual care.”

VHA Primary Care Analytics Team supported the study with funding from the VHA Office of Primary Care. Staloff has no disclosures. One coauthor disclosed a relationship with the US Department of Veterans Affairs. 

Graetz disclosed relationships the Donaghue Foundation, Pfizer, PRIME Education, and the National Institutes of Health. 

Infectious diseases historically have posed major challenges to the operations and health of military forces. In recent conflicts, nonbattle injuries including infections have caused more evacuations than combat trauma.¹ Deployment to endemic regions, poor sanitation, and trauma increase susceptibility to both common and rare infections, many of which have cutaneous manifestations.

Surveillance programs such as the Armed Forces Health Surveillance Division serve a critical role in monitoring outbreaks among deployed personnel.² Cutaneous manifestations of systemic disease often serve as early clinical indicators, especially in settings with limited diagnostic resources. This review describes rarely encountered infectious agents for which US military personnel are at increased risk and outlines management strategies for clinicians practicing in austere environments.

EPIDEMIOLOGIC RISK FACTORS IN MILITARY POPULATIONS

United States military personnel face an elevated risk for infectious diseases when deployed in tropical and subtropical regions where endemic pathogens are prevalent. Exposure to soil, water, and insect vectors facilitates transmission. Direct exposure during combat or training combined with high-density housing, combat-related trauma, and constraints on hygiene access during operations increases infection risk.³

REGION-SPECIFIC PATHOGENS

Middle East

Leishmania species—Leishmania, a protozoa transmitted via sand fly bites, has caused multiple documented outbreaks among US troops in Iraq and Afghanistan, with a reported incidence of 14%.⁴ Leishmaniasis can present as 3 main clinical variants: cutaneous, visceral, and mucocutaneous. Cutaneous leishmaniasis typically manifests as painless ulcers covered with hemorrhagic crusts on exposed regions of the body. While typically self-limited, lesions frequently result in irreversible scarring. Many Leishmania species respond well to antimonials such as sodium stibogluconate. Preventive measures include wearing protective clothing and sleeping inside insecticide-treated bed nets.⁵

Coxiella burnetii—Coxiella burnetii transmits through inhalation of aerosolized particles originating from the urine, feces, birth products, or milk of infected bovine. In 2003, a small number of cases were identified in US service members exposed to livestock while serving in Iraq.⁶ Outbreaks also occurred during World War II, but it is unclear whether they were caused by naturally occurring C burnetii or biowarfare.⁷ Though primarily a systemic illness with severe pneumonia, Q fever may manifest with an associated purpuric or morbilliform rash.⁸ Doxycycline is recommended both for treatment and empiric coverage.⁶

Acinetobacter baumannii—This multidrug-resistant organism is known to infect combat wounds and is associated with nosocomial outbreaks in military hospitals. Studies suggest environmental contamination and health care transmission contribute substantially to outbreaks in military hospitals.⁹ Cutaneous manifestations can include cellulitis with a peau d’orange appearance or necrotizing fasciitis; however, pneumonia and bacteremia have been reported. Prompt culture and antibiotic initiation with debridement are essential for treatment.¹⁰ Antibiotic stewardship and strict infection control are critical to prevent outbreaks and limit resistance.⁹

Africa

Plasmodium species—Malaria remains a life-threatening disease found in tropical and subtropical areas around the world. Despite preventive measures, 30 cases among US service members were reported in 2024.¹¹ Cutaneous findings include purpura fulminans, petechiae, acral necrosis, or reticulated erythema.¹² Service members stationed in endemic areas should take prophylactic antimalarials. Symptoms include fevers, headaches, and malaise, with possible rapid deterioration.¹³

Mycobacterium ulcerans—Mycobacterium ulcerans causes extensive necrotic ulcers—commonly known as Buruli ulcers—which generally begin as a nodule, plaque, papule, or edematous lesion, eventually progressing to extensive ulceration. Despite no documented cases of US personnel contracting Buruli ulcers, those stationed in endemic regions remain at risk. Environmental reservoirs of M ulcerans are unknown, but its DNA has been isolated from water sources.^14,15 These ulcers take months to heal, making wound management and antimycobacterial therapy essential. Primary preventive measures include avoidance of swimming in rivers or agricultural work in endemic areas.¹⁴

Mpox Virus—During the 2022 mpox outbreak, male service members who engaged in sexual activity with other men were at the highest risk, with 88.8% of infected service members reporting this practice.¹⁶ While the virus is endemic to Africa, 89.0% of cases were reported from service members stationed in the United States.¹⁷ Typical infection results in fever, headache, lymphadenopathy, and myalgias, followed by a facial rash that spreads over the body, palms, and soles. Safe-sex practices help prevent transmission, and there is a vaccine available for high-risk patients.¹⁶

Southeast Asia

Leptospira species—Leptospira is an aerobic spirochete found in tropical regions worldwide. Transmission occurs when water contaminated with urine from infected animals exposes humans to the organism. Infection manifests as a mild febrile illness, though approximately 10% of patients develop Weil syndrome, consisting of conjunctival suffusion, jaundice, and acute kidney injury. Treatment and prophylaxis include doxycycline, but severe disease warrants intravenous antibiotics.^17,18 A 2014 outbreak among Marines in Japan highlighted poor prophylactic compliance as a key risk factor.¹⁹ Proper education for those at risk is essential to prevent future outbreaks.

Mycobacterium leprae—Leprosy is an acid-fast mycobacterium that remains endemic in the Pacific Islands and Southeast Asia. Case reports of US service members diagnosed with leprosy exist, though only in patients who emigrated from endemic areas.²⁰ This disease has a spectrum of manifestations depending on the immune response, with tuberculoid leprosy showing a ­cell-mediated (T helper 1) response and lepromatous leprosy having more of a humoral (T helper 2) response.²¹ It manifests with hypopigmented anesthetic macules and peripheral neuropathy. Diagnosis is made by skin biopsy, which shows perineural lymphohistiocytic inflammation and non-necrotizing granulomas.²⁰ The infection typically is curable with a multidrug regimen.²¹

Strongyloides stercoralis—This nematode causes infection by transdermal penetration of bare feet. They then migrate to the lungs where the patient coughs and swallows the nematode into the gastrointestinal tract. Strongyloides stercoralis autoinfect by penetrating the intestinal wall, resulting in chronic digestive, respiratory, and cutaneous symptoms. Worldwide prevalence of S stercoralis infection is estimated to be 10% to 40%, with foreign-born US military members at increased risk compared to the general military population.^22,23 Larva currens may manifest with a pruritic erythematous plaque at the site of penetration that progresses to an intensely pruritic, creeping dermatitis as the nematode migrates under the skin. Avoidance of barefoot soil exposure and treatment with ivermectin are effective preventive and therapeutic measures.²³

South America

Ancylostoma braziliense—Found throughout the subtropical world, this hookworm primarily infects dogs and cats and is found in their stool. Larva currens has a similar manifestation and life cycle to cutaneous larva migrans, but autoinfection does not occur. Transmission occurs similarly to S stercoralis and responds well to oral albendazole or ivermectin; however, the infection is self-limited.²⁴ Military cases have been reported,²⁵ though overall morbidity remains poorly characterized.

Dengue Virus—An arbovirus transmitted by Aedes mosquitoes, dengue remains a major military threat. Service members in the Vietnam War experienced an attack rate as high as 80%.^26,27 Infection often manifests with retro-orbital pain and a morbilliform rash that occurs 2 to 5 days after fever, though severe cases may progress to hemorrhagic dengue with skin petechiae or ecchymosis.²⁸ Immediate intervention is essential in symptomatic patients to prevent life-threatening progression. There are no dengue vaccines approved by the US Food and Drug Administration for adults, thus military personnel in endemic areas remain at risk.²⁷

Trypanosoma cruzi—Chagas disease is transmitted when a reduviid infected with T cruzi bites and defecates on the patient’s skin. A skin nodule (chagoma) or painless eyelid edema (Romaña sign) may appear at the site of parasite entry. Chronic disease may result in dilated cardiomyopathy.²⁹ Several cases of Chagas disease have been reported in South American military operations, including an outbreak in 9 Columbian military personnel.³⁰ Cases in the southwestern United States have recently emerged, emphasizing the need for increased awareness.³¹ Proper insect repellent helps to ward off reduviid bugs. Nifurtimox and benznidazole are the only drugs with proven efficacy against T cruzi.²⁹

Continental United States of America

Coccidioides immitis—The first reported case of coccidiomycosis was described in 1892 in a service member with debilitating masses and ulcers.³² Endemic to arid regions of the western United States, coccidioidomycosis affects military trainees at rates up to 32% annually in high-risk settings.³³ Primary infection occurs in the lungs and may spread hematologically. The fungi prefer dry desert soils, which may aerosolize during military maneuvers. Coccidioidomycosis occasionally causes erythema nodosum, and diffuse infection shows verrucous plaques, ulcers, or abscesses. Dust avoidance and mask wearing are advised for those in endemic regions. Ketoconazole and amphotericin B are the only treatments approved by the US Food and Drug Administration.³² When starting immunosuppressive drugs, clinicians should inquire if patients have previously been stationed in Coccidioides-endemic areas, such as Fort Irwin, California, to avoid reactivation of the fungi.³³

Francisella tularensis—Acquired via ticks or contact with wild animals, tularemia causes an ulceroglandular disease with regional lymphadenopathy. Inoculation requires as few as 10 to 25 organisms; thus it is considered a Category A agent for bioterror.³⁴ Natural outbreaks have occurred during war times, most recently during the civil wars in Bosnia and Kosovo.³⁵ Patients may present with a painful ulcer that enlarges to form a plaque with raised borders. Personnel in wooded areas should use tick precautions and handle wild animals cautiously. Treatment includes gentamicin for severe disease, with tetracyclines effective in mild cases.³⁴

PREVENTION AND MANAGEMENT STRATEGIES IN AUSTERE SETTINGS

For health care professionals practicing in military settings, austere environments can provide a challenge for diagnosis of neglected diseases. Despite a lack of advanced diagnostic tools, practical options can be applied to the diagnostic process; for example, teledermatology is utilized for treatment of service members deployed to remote environments.³⁶

Management of uncommon infectious diseases in military personnel often requires treatments outside those practiced in domestic clinics. Field management may indicate prompt empiric therapy while balancing the risks of overtreatment against those of missed diagnoses³⁷; however, medical evacuation to a higher level of care may be indicated in patients with severe presentations to expedite diagnosis and treatment.³⁸

Prevention remains the primary goal to avoid local outbreaks. Long-sleeved uniforms, DEET (N, ­N-diethyl-meta-toluamide)–based repellents, permethrin-impregnated clothing, and bed nets are effective for vector protection. Prophylactic medications and vaccinations often are provided when personnel are deployed to endemic locations.³⁹

Onsite entomology teams also can provide surveillance of the local insect populations. They may contribute to vector control through insecticide application and environmental modification. The Armed Forces Health Surveillance Division and the Global Emerging Infections Surveillance Program monitor infectious threats in real time to locate any potential outbreaks, guiding operational responses.⁴⁰

FINAL THOUGHTS

Dermatologic signs often provide early evidence of infection in military personnel. With increasing antimicrobial resistance and the emergence of new pathogens, it is imperative for clinicians treating members of the military to recognize cutaneous signs, employ efficient diagnostic strategies, and encourage proactive prevention. A collaborative approach spanning dermatology, infectious disease, and public health is essential to protect the modern service member.

Infectious diseases historically have posed major challenges to the operations and health of military forces. In recent conflicts, nonbattle injuries including infections have caused more evacuations than combat trauma.¹ Deployment to endemic regions, poor sanitation, and trauma increase susceptibility to both common and rare infections, many of which have cutaneous manifestations.

Surveillance programs such as the Armed Forces Health Surveillance Division serve a critical role in monitoring outbreaks among deployed personnel.² Cutaneous manifestations of systemic disease often serve as early clinical indicators, especially in settings with limited diagnostic resources. This review describes rarely encountered infectious agents for which US military personnel are at increased risk and outlines management strategies for clinicians practicing in austere environments.

EPIDEMIOLOGIC RISK FACTORS IN MILITARY POPULATIONS

United States military personnel face an elevated risk for infectious diseases when deployed in tropical and subtropical regions where endemic pathogens are prevalent. Exposure to soil, water, and insect vectors facilitates transmission. Direct exposure during combat or training combined with high-density housing, combat-related trauma, and constraints on hygiene access during operations increases infection risk.³

REGION-SPECIFIC PATHOGENS

Middle East

Leishmania species—Leishmania, a protozoa transmitted via sand fly bites, has caused multiple documented outbreaks among US troops in Iraq and Afghanistan, with a reported incidence of 14%.⁴ Leishmaniasis can present as 3 main clinical variants: cutaneous, visceral, and mucocutaneous. Cutaneous leishmaniasis typically manifests as painless ulcers covered with hemorrhagic crusts on exposed regions of the body. While typically self-limited, lesions frequently result in irreversible scarring. Many Leishmania species respond well to antimonials such as sodium stibogluconate. Preventive measures include wearing protective clothing and sleeping inside insecticide-treated bed nets.⁵

Coxiella burnetii—Coxiella burnetii transmits through inhalation of aerosolized particles originating from the urine, feces, birth products, or milk of infected bovine. In 2003, a small number of cases were identified in US service members exposed to livestock while serving in Iraq.⁶ Outbreaks also occurred during World War II, but it is unclear whether they were caused by naturally occurring C burnetii or biowarfare.⁷ Though primarily a systemic illness with severe pneumonia, Q fever may manifest with an associated purpuric or morbilliform rash.⁸ Doxycycline is recommended both for treatment and empiric coverage.⁶

Acinetobacter baumannii—This multidrug-resistant organism is known to infect combat wounds and is associated with nosocomial outbreaks in military hospitals. Studies suggest environmental contamination and health care transmission contribute substantially to outbreaks in military hospitals.⁹ Cutaneous manifestations can include cellulitis with a peau d’orange appearance or necrotizing fasciitis; however, pneumonia and bacteremia have been reported. Prompt culture and antibiotic initiation with debridement are essential for treatment.¹⁰ Antibiotic stewardship and strict infection control are critical to prevent outbreaks and limit resistance.⁹

Africa

Plasmodium species—Malaria remains a life-threatening disease found in tropical and subtropical areas around the world. Despite preventive measures, 30 cases among US service members were reported in 2024.¹¹ Cutaneous findings include purpura fulminans, petechiae, acral necrosis, or reticulated erythema.¹² Service members stationed in endemic areas should take prophylactic antimalarials. Symptoms include fevers, headaches, and malaise, with possible rapid deterioration.¹³

Mycobacterium ulcerans—Mycobacterium ulcerans causes extensive necrotic ulcers—commonly known as Buruli ulcers—which generally begin as a nodule, plaque, papule, or edematous lesion, eventually progressing to extensive ulceration. Despite no documented cases of US personnel contracting Buruli ulcers, those stationed in endemic regions remain at risk. Environmental reservoirs of M ulcerans are unknown, but its DNA has been isolated from water sources.^14,15 These ulcers take months to heal, making wound management and antimycobacterial therapy essential. Primary preventive measures include avoidance of swimming in rivers or agricultural work in endemic areas.¹⁴

Mpox Virus—During the 2022 mpox outbreak, male service members who engaged in sexual activity with other men were at the highest risk, with 88.8% of infected service members reporting this practice.¹⁶ While the virus is endemic to Africa, 89.0% of cases were reported from service members stationed in the United States.¹⁷ Typical infection results in fever, headache, lymphadenopathy, and myalgias, followed by a facial rash that spreads over the body, palms, and soles. Safe-sex practices help prevent transmission, and there is a vaccine available for high-risk patients.¹⁶

Southeast Asia

Leptospira species—Leptospira is an aerobic spirochete found in tropical regions worldwide. Transmission occurs when water contaminated with urine from infected animals exposes humans to the organism. Infection manifests as a mild febrile illness, though approximately 10% of patients develop Weil syndrome, consisting of conjunctival suffusion, jaundice, and acute kidney injury. Treatment and prophylaxis include doxycycline, but severe disease warrants intravenous antibiotics.^17,18 A 2014 outbreak among Marines in Japan highlighted poor prophylactic compliance as a key risk factor.¹⁹ Proper education for those at risk is essential to prevent future outbreaks.

Mycobacterium leprae—Leprosy is an acid-fast mycobacterium that remains endemic in the Pacific Islands and Southeast Asia. Case reports of US service members diagnosed with leprosy exist, though only in patients who emigrated from endemic areas.²⁰ This disease has a spectrum of manifestations depending on the immune response, with tuberculoid leprosy showing a ­cell-mediated (T helper 1) response and lepromatous leprosy having more of a humoral (T helper 2) response.²¹ It manifests with hypopigmented anesthetic macules and peripheral neuropathy. Diagnosis is made by skin biopsy, which shows perineural lymphohistiocytic inflammation and non-necrotizing granulomas.²⁰ The infection typically is curable with a multidrug regimen.²¹

Strongyloides stercoralis—This nematode causes infection by transdermal penetration of bare feet. They then migrate to the lungs where the patient coughs and swallows the nematode into the gastrointestinal tract. Strongyloides stercoralis autoinfect by penetrating the intestinal wall, resulting in chronic digestive, respiratory, and cutaneous symptoms. Worldwide prevalence of S stercoralis infection is estimated to be 10% to 40%, with foreign-born US military members at increased risk compared to the general military population.^22,23 Larva currens may manifest with a pruritic erythematous plaque at the site of penetration that progresses to an intensely pruritic, creeping dermatitis as the nematode migrates under the skin. Avoidance of barefoot soil exposure and treatment with ivermectin are effective preventive and therapeutic measures.²³

South America

Ancylostoma braziliense—Found throughout the subtropical world, this hookworm primarily infects dogs and cats and is found in their stool. Larva currens has a similar manifestation and life cycle to cutaneous larva migrans, but autoinfection does not occur. Transmission occurs similarly to S stercoralis and responds well to oral albendazole or ivermectin; however, the infection is self-limited.²⁴ Military cases have been reported,²⁵ though overall morbidity remains poorly characterized.

Dengue Virus—An arbovirus transmitted by Aedes mosquitoes, dengue remains a major military threat. Service members in the Vietnam War experienced an attack rate as high as 80%.^26,27 Infection often manifests with retro-orbital pain and a morbilliform rash that occurs 2 to 5 days after fever, though severe cases may progress to hemorrhagic dengue with skin petechiae or ecchymosis.²⁸ Immediate intervention is essential in symptomatic patients to prevent life-threatening progression. There are no dengue vaccines approved by the US Food and Drug Administration for adults, thus military personnel in endemic areas remain at risk.²⁷

Trypanosoma cruzi—Chagas disease is transmitted when a reduviid infected with T cruzi bites and defecates on the patient’s skin. A skin nodule (chagoma) or painless eyelid edema (Romaña sign) may appear at the site of parasite entry. Chronic disease may result in dilated cardiomyopathy.²⁹ Several cases of Chagas disease have been reported in South American military operations, including an outbreak in 9 Columbian military personnel.³⁰ Cases in the southwestern United States have recently emerged, emphasizing the need for increased awareness.³¹ Proper insect repellent helps to ward off reduviid bugs. Nifurtimox and benznidazole are the only drugs with proven efficacy against T cruzi.²⁹

Continental United States of America

Coccidioides immitis—The first reported case of coccidiomycosis was described in 1892 in a service member with debilitating masses and ulcers.³² Endemic to arid regions of the western United States, coccidioidomycosis affects military trainees at rates up to 32% annually in high-risk settings.³³ Primary infection occurs in the lungs and may spread hematologically. The fungi prefer dry desert soils, which may aerosolize during military maneuvers. Coccidioidomycosis occasionally causes erythema nodosum, and diffuse infection shows verrucous plaques, ulcers, or abscesses. Dust avoidance and mask wearing are advised for those in endemic regions. Ketoconazole and amphotericin B are the only treatments approved by the US Food and Drug Administration.³² When starting immunosuppressive drugs, clinicians should inquire if patients have previously been stationed in Coccidioides-endemic areas, such as Fort Irwin, California, to avoid reactivation of the fungi.³³

Francisella tularensis—Acquired via ticks or contact with wild animals, tularemia causes an ulceroglandular disease with regional lymphadenopathy. Inoculation requires as few as 10 to 25 organisms; thus it is considered a Category A agent for bioterror.³⁴ Natural outbreaks have occurred during war times, most recently during the civil wars in Bosnia and Kosovo.³⁵ Patients may present with a painful ulcer that enlarges to form a plaque with raised borders. Personnel in wooded areas should use tick precautions and handle wild animals cautiously. Treatment includes gentamicin for severe disease, with tetracyclines effective in mild cases.³⁴

PREVENTION AND MANAGEMENT STRATEGIES IN AUSTERE SETTINGS

For health care professionals practicing in military settings, austere environments can provide a challenge for diagnosis of neglected diseases. Despite a lack of advanced diagnostic tools, practical options can be applied to the diagnostic process; for example, teledermatology is utilized for treatment of service members deployed to remote environments.³⁶

Management of uncommon infectious diseases in military personnel often requires treatments outside those practiced in domestic clinics. Field management may indicate prompt empiric therapy while balancing the risks of overtreatment against those of missed diagnoses³⁷; however, medical evacuation to a higher level of care may be indicated in patients with severe presentations to expedite diagnosis and treatment.³⁸

Prevention remains the primary goal to avoid local outbreaks. Long-sleeved uniforms, DEET (N, ­N-diethyl-meta-toluamide)–based repellents, permethrin-impregnated clothing, and bed nets are effective for vector protection. Prophylactic medications and vaccinations often are provided when personnel are deployed to endemic locations.³⁹

Onsite entomology teams also can provide surveillance of the local insect populations. They may contribute to vector control through insecticide application and environmental modification. The Armed Forces Health Surveillance Division and the Global Emerging Infections Surveillance Program monitor infectious threats in real time to locate any potential outbreaks, guiding operational responses.⁴⁰

FINAL THOUGHTS

Dermatologic signs often provide early evidence of infection in military personnel. With increasing antimicrobial resistance and the emergence of new pathogens, it is imperative for clinicians treating members of the military to recognize cutaneous signs, employ efficient diagnostic strategies, and encourage proactive prevention. A collaborative approach spanning dermatology, infectious disease, and public health is essential to protect the modern service member.

Infectious diseases historically have posed major challenges to the operations and health of military forces. In recent conflicts, nonbattle injuries including infections have caused more evacuations than combat trauma.¹ Deployment to endemic regions, poor sanitation, and trauma increase susceptibility to both common and rare infections, many of which have cutaneous manifestations.

Surveillance programs such as the Armed Forces Health Surveillance Division serve a critical role in monitoring outbreaks among deployed personnel.² Cutaneous manifestations of systemic disease often serve as early clinical indicators, especially in settings with limited diagnostic resources. This review describes rarely encountered infectious agents for which US military personnel are at increased risk and outlines management strategies for clinicians practicing in austere environments.

EPIDEMIOLOGIC RISK FACTORS IN MILITARY POPULATIONS

United States military personnel face an elevated risk for infectious diseases when deployed in tropical and subtropical regions where endemic pathogens are prevalent. Exposure to soil, water, and insect vectors facilitates transmission. Direct exposure during combat or training combined with high-density housing, combat-related trauma, and constraints on hygiene access during operations increases infection risk.³

REGION-SPECIFIC PATHOGENS

Middle East

Leishmania species—Leishmania, a protozoa transmitted via sand fly bites, has caused multiple documented outbreaks among US troops in Iraq and Afghanistan, with a reported incidence of 14%.⁴ Leishmaniasis can present as 3 main clinical variants: cutaneous, visceral, and mucocutaneous. Cutaneous leishmaniasis typically manifests as painless ulcers covered with hemorrhagic crusts on exposed regions of the body. While typically self-limited, lesions frequently result in irreversible scarring. Many Leishmania species respond well to antimonials such as sodium stibogluconate. Preventive measures include wearing protective clothing and sleeping inside insecticide-treated bed nets.⁵

Coxiella burnetii—Coxiella burnetii transmits through inhalation of aerosolized particles originating from the urine, feces, birth products, or milk of infected bovine. In 2003, a small number of cases were identified in US service members exposed to livestock while serving in Iraq.⁶ Outbreaks also occurred during World War II, but it is unclear whether they were caused by naturally occurring C burnetii or biowarfare.⁷ Though primarily a systemic illness with severe pneumonia, Q fever may manifest with an associated purpuric or morbilliform rash.⁸ Doxycycline is recommended both for treatment and empiric coverage.⁶

Acinetobacter baumannii—This multidrug-resistant organism is known to infect combat wounds and is associated with nosocomial outbreaks in military hospitals. Studies suggest environmental contamination and health care transmission contribute substantially to outbreaks in military hospitals.⁹ Cutaneous manifestations can include cellulitis with a peau d’orange appearance or necrotizing fasciitis; however, pneumonia and bacteremia have been reported. Prompt culture and antibiotic initiation with debridement are essential for treatment.¹⁰ Antibiotic stewardship and strict infection control are critical to prevent outbreaks and limit resistance.⁹

Africa

Plasmodium species—Malaria remains a life-threatening disease found in tropical and subtropical areas around the world. Despite preventive measures, 30 cases among US service members were reported in 2024.¹¹ Cutaneous findings include purpura fulminans, petechiae, acral necrosis, or reticulated erythema.¹² Service members stationed in endemic areas should take prophylactic antimalarials. Symptoms include fevers, headaches, and malaise, with possible rapid deterioration.¹³

Mycobacterium ulcerans—Mycobacterium ulcerans causes extensive necrotic ulcers—commonly known as Buruli ulcers—which generally begin as a nodule, plaque, papule, or edematous lesion, eventually progressing to extensive ulceration. Despite no documented cases of US personnel contracting Buruli ulcers, those stationed in endemic regions remain at risk. Environmental reservoirs of M ulcerans are unknown, but its DNA has been isolated from water sources.^14,15 These ulcers take months to heal, making wound management and antimycobacterial therapy essential. Primary preventive measures include avoidance of swimming in rivers or agricultural work in endemic areas.¹⁴

Mpox Virus—During the 2022 mpox outbreak, male service members who engaged in sexual activity with other men were at the highest risk, with 88.8% of infected service members reporting this practice.¹⁶ While the virus is endemic to Africa, 89.0% of cases were reported from service members stationed in the United States.¹⁷ Typical infection results in fever, headache, lymphadenopathy, and myalgias, followed by a facial rash that spreads over the body, palms, and soles. Safe-sex practices help prevent transmission, and there is a vaccine available for high-risk patients.¹⁶

Southeast Asia

Leptospira species—Leptospira is an aerobic spirochete found in tropical regions worldwide. Transmission occurs when water contaminated with urine from infected animals exposes humans to the organism. Infection manifests as a mild febrile illness, though approximately 10% of patients develop Weil syndrome, consisting of conjunctival suffusion, jaundice, and acute kidney injury. Treatment and prophylaxis include doxycycline, but severe disease warrants intravenous antibiotics.^17,18 A 2014 outbreak among Marines in Japan highlighted poor prophylactic compliance as a key risk factor.¹⁹ Proper education for those at risk is essential to prevent future outbreaks.

Mycobacterium leprae—Leprosy is an acid-fast mycobacterium that remains endemic in the Pacific Islands and Southeast Asia. Case reports of US service members diagnosed with leprosy exist, though only in patients who emigrated from endemic areas.²⁰ This disease has a spectrum of manifestations depending on the immune response, with tuberculoid leprosy showing a ­cell-mediated (T helper 1) response and lepromatous leprosy having more of a humoral (T helper 2) response.²¹ It manifests with hypopigmented anesthetic macules and peripheral neuropathy. Diagnosis is made by skin biopsy, which shows perineural lymphohistiocytic inflammation and non-necrotizing granulomas.²⁰ The infection typically is curable with a multidrug regimen.²¹

Strongyloides stercoralis—This nematode causes infection by transdermal penetration of bare feet. They then migrate to the lungs where the patient coughs and swallows the nematode into the gastrointestinal tract. Strongyloides stercoralis autoinfect by penetrating the intestinal wall, resulting in chronic digestive, respiratory, and cutaneous symptoms. Worldwide prevalence of S stercoralis infection is estimated to be 10% to 40%, with foreign-born US military members at increased risk compared to the general military population.^22,23 Larva currens may manifest with a pruritic erythematous plaque at the site of penetration that progresses to an intensely pruritic, creeping dermatitis as the nematode migrates under the skin. Avoidance of barefoot soil exposure and treatment with ivermectin are effective preventive and therapeutic measures.²³

South America

Ancylostoma braziliense—Found throughout the subtropical world, this hookworm primarily infects dogs and cats and is found in their stool. Larva currens has a similar manifestation and life cycle to cutaneous larva migrans, but autoinfection does not occur. Transmission occurs similarly to S stercoralis and responds well to oral albendazole or ivermectin; however, the infection is self-limited.²⁴ Military cases have been reported,²⁵ though overall morbidity remains poorly characterized.

Dengue Virus—An arbovirus transmitted by Aedes mosquitoes, dengue remains a major military threat. Service members in the Vietnam War experienced an attack rate as high as 80%.^26,27 Infection often manifests with retro-orbital pain and a morbilliform rash that occurs 2 to 5 days after fever, though severe cases may progress to hemorrhagic dengue with skin petechiae or ecchymosis.²⁸ Immediate intervention is essential in symptomatic patients to prevent life-threatening progression. There are no dengue vaccines approved by the US Food and Drug Administration for adults, thus military personnel in endemic areas remain at risk.²⁷

Trypanosoma cruzi—Chagas disease is transmitted when a reduviid infected with T cruzi bites and defecates on the patient’s skin. A skin nodule (chagoma) or painless eyelid edema (Romaña sign) may appear at the site of parasite entry. Chronic disease may result in dilated cardiomyopathy.²⁹ Several cases of Chagas disease have been reported in South American military operations, including an outbreak in 9 Columbian military personnel.³⁰ Cases in the southwestern United States have recently emerged, emphasizing the need for increased awareness.³¹ Proper insect repellent helps to ward off reduviid bugs. Nifurtimox and benznidazole are the only drugs with proven efficacy against T cruzi.²⁹

Continental United States of America

Coccidioides immitis—The first reported case of coccidiomycosis was described in 1892 in a service member with debilitating masses and ulcers.³² Endemic to arid regions of the western United States, coccidioidomycosis affects military trainees at rates up to 32% annually in high-risk settings.³³ Primary infection occurs in the lungs and may spread hematologically. The fungi prefer dry desert soils, which may aerosolize during military maneuvers. Coccidioidomycosis occasionally causes erythema nodosum, and diffuse infection shows verrucous plaques, ulcers, or abscesses. Dust avoidance and mask wearing are advised for those in endemic regions. Ketoconazole and amphotericin B are the only treatments approved by the US Food and Drug Administration.³² When starting immunosuppressive drugs, clinicians should inquire if patients have previously been stationed in Coccidioides-endemic areas, such as Fort Irwin, California, to avoid reactivation of the fungi.³³

Francisella tularensis—Acquired via ticks or contact with wild animals, tularemia causes an ulceroglandular disease with regional lymphadenopathy. Inoculation requires as few as 10 to 25 organisms; thus it is considered a Category A agent for bioterror.³⁴ Natural outbreaks have occurred during war times, most recently during the civil wars in Bosnia and Kosovo.³⁵ Patients may present with a painful ulcer that enlarges to form a plaque with raised borders. Personnel in wooded areas should use tick precautions and handle wild animals cautiously. Treatment includes gentamicin for severe disease, with tetracyclines effective in mild cases.³⁴

PREVENTION AND MANAGEMENT STRATEGIES IN AUSTERE SETTINGS

For health care professionals practicing in military settings, austere environments can provide a challenge for diagnosis of neglected diseases. Despite a lack of advanced diagnostic tools, practical options can be applied to the diagnostic process; for example, teledermatology is utilized for treatment of service members deployed to remote environments.³⁶

Management of uncommon infectious diseases in military personnel often requires treatments outside those practiced in domestic clinics. Field management may indicate prompt empiric therapy while balancing the risks of overtreatment against those of missed diagnoses³⁷; however, medical evacuation to a higher level of care may be indicated in patients with severe presentations to expedite diagnosis and treatment.³⁸

Prevention remains the primary goal to avoid local outbreaks. Long-sleeved uniforms, DEET (N, ­N-diethyl-meta-toluamide)–based repellents, permethrin-impregnated clothing, and bed nets are effective for vector protection. Prophylactic medications and vaccinations often are provided when personnel are deployed to endemic locations.³⁹

Onsite entomology teams also can provide surveillance of the local insect populations. They may contribute to vector control through insecticide application and environmental modification. The Armed Forces Health Surveillance Division and the Global Emerging Infections Surveillance Program monitor infectious threats in real time to locate any potential outbreaks, guiding operational responses.⁴⁰

FINAL THOUGHTS

Dermatologic signs often provide early evidence of infection in military personnel. With increasing antimicrobial resistance and the emergence of new pathogens, it is imperative for clinicians treating members of the military to recognize cutaneous signs, employ efficient diagnostic strategies, and encourage proactive prevention. A collaborative approach spanning dermatology, infectious disease, and public health is essential to protect the modern service member.

Self-reported penicillin allergies are common, with a prevalence of about 10% of patients, according to the Centers for Disease Control and Prevention (CDC).¹ However, only about 1% of patients have a true immunoglobulin E (IgE)-mediated allergy. This issue is often further complicated by inaccurate classification of nonallergic adverse effects as an allergy, resulting in incomplete allergy documentation in the electronic health record (EHR). The cross-reactivity rate with cephalosporins (Β-lactam antibiotics) in patients reporting a penicillin allergy is < 1%, which suggests that many patients with reported penicillin allergies can safely receive them.² Despite this, patients with self-reported penicillin allergies often receive non–Β-lactam antibiotic agents, which may be associated with an increased risk of adverse drug reactions (ADRs), increased health care costs, and inferior clinical outcomes.³

Several strategies are recommended to assess patients with self-reported penicillin allergies. According to the CDC, evaluating a patient who reports a penicillin or other Β-lactam antibiotic allergy involves 3 steps: (1) obtaining a thorough medical history, including previous exposures to penicillin or other Β-lactam antibiotic; (2) performing a skin test using the penicillin major and minor determinants; and (3) among those who have a negative penicillin skin test, performing an observed oral challenge with 250 mg amoxicillin before proceeding directly to treatment with the indicated Β-lactam therapy.⁴

Most existing clinical guidance for assessing patients with self-reported penicillin allergies stems from site-specific policies and primarily focuses on oral amoxicillin challenges or penicillin skin testing (PST). However, performing these tests may not be feasible at all facilities due to time constraints and lack of allergists. Therefore, alternative strategies are necessary, such as conducting detailed patient interviews. Few studies have evaluated switching to Β-lactam agents following a penicillin allergy interview alone. However, with thorough patient histories and detailed interviews, patients with reported penicillin allergies can safely use Β-lactam antibiotics.⁵ Implementing this procedure provides a cost-savings opportunity by not having to administer additional antibiotics for testing in addition to improving antibiotic stewardship.

The Memphis Veterans Affairs Medical Center (MVAMC) created the Allergy to Β-Lactam Evaluation (ABLE) process to clarify and remove penicillin allergies. The process involves conducting a thorough chart review and patient interview followed by completion of a note template that provides recommendations about patient allergies and Β-lactam prescribing. Mitchell et al found that the pharmacist-led process to be beneficial for addressing Β-lactam allergy clearance.⁶ As a result, the ABLE process was implemented at several other US Department of Veterans Affairs (VA) medical centers (VAMCs). Using the ABLE template, the purpose of this study was to evaluate the impact of a pharmacist-led penicillin allergy initiative on penicillin allergy delabeling with an interview process alone.

Methods

Prior to ABLE process implementation, there were no standardized procedures for documenting allergy histories. ABLE was implemented at the Robley Rex VAMC (RRVAMC) in November 2022. During the interview phase, patients were initially identified during admission via TheraDoc as having either a penicillin allergy or ADR. The infectious disease pharmacist or pharmacy resident interviewed patients with documented penicillin allergies or ADRs using a standardized questionnaire (eAppendix 1). Not all identified patients could be interviewed. Patients currently receiving an antibiotic were prioritized for interviews. Patients were excluded if they declined or were unable to be interviewed, although a patient’s caregiver(s) could be interviewed in person or via telephone, if the patient was not available.

Following the interview, pharmacists used guidance from the ABLE process in addition to a detailed EHR review to determine whether the patient was eligible for an allergy update or removal and/or switch to a Β-lactam antibiotic (Figure). If eligible for modification, the interviewing pharmacist made the necessary changes. A templated process note with patient-specific recommendations was entered into the Computerized Patient Record System (CPRS) and the primary care team attending physician was added as an additional signer to be alerted in the system note (eAppendix 2).

This single-center, retrospective cohort study involved review of CPRS notes and clinical interviews in the interviewed group. Hospitalized patients at the RRVAMC aged ≥ 18 years with a documented penicillin allergy or ADR were included. The historical control group consisted of patients admitted between October 31, 2019, and October 31, 2022, and the intervention group consisted of patients admitted between November 1, 2022, and March 1, 2023. Patients in the historical control group were matched 1:1 to the intervention group for penicillin allergy severity (allergy [IgE-mediated], unknown, adverse effect, severe cutaneous or other non–IgE-mediated reaction) and whether they received a noncarbapenem non–Β-lactam antibiotic.

The primary outcome was the number of patient allergies/ADRs removed or changed on patient profiles regardless of whether their antibiotic regimen was changed. This outcome was further assessed by evaluating the number of patient allergies or ADRs removed or changed on patient profiles with or without a change in antibiotic regimen. Primary outcomes were analyzed using χ² and/ or Fisher exact tests, as appropriate to determine statistically significant differences between the interviewed group and the historical control.

Results

Seventy patients were included: 35 patients in the interviewed group and 35 patients in the historical control group, respectively. Both groups had a mean age of 72 years and predominantly included White male patients (Table 1). Following the interview, the allergy profile was modified for 6 patients (17%) in the interview group vs 0 patients in the control group (P = .03) (Table 2). The primary outcome was analyzed separately regardless of an antibiotic regimen change. There was not a statistically significant difference between groups when assessing patients for change in therapy (P > .99). All 6 patients with an allergy profile modification had no change in antibiotic regimen.

Discussion

This study suggests the ABLE process may be a valuable tool for adjusting penicillin allergies or ADRs within patient EHRs. In the interview group, allergies were modified in 6 (17%) patients while no patients in the control group had allergy modifications. Of the 6 allergy profile modifications, 4 allergy labels were changed from an allergy to an ADR. These patients were cleared to receive future Β-lactam antibiotics after clinicians recognized the lack of a true IgE-mediated allergic reaction. In addition, 2 of the modified allergy profiles removed the allergy designation. Although this represents a small subset of interviewed patients, it illustrates the clinical effectiveness of an interview process alone to remove penicillin allergy designations.

Previous research has assessed the impact of pharmacist intervention on penicillin allergy clarification. Mitchell et al implemented a pharmacist-driven Β-lactam allergy assessment and penicillin allergy clinic (PAC) at the MVAMC with the goal of evaluating its impact on allergy clearance. In their study, clinical pharmacy specialists evaluated patients with Β-lactam allergies, and those deemed eligible were later seen in the PAC. Among the 246 patients evaluated using the Β-lactam allergy assessment alone and who were not seen in the PAC, 25% had their penicillin allergy removed following a detailed assessment.⁶

Song et al evaluated the effectiveness and feasibility of a pharmacist-driven penicillin allergy delabeling pilot program without skin testing or oral challenges. Patients with penicillin allergies were interviewed by a pharmacy resident using a standardized checklist. Among the 66 patients interviewed, 12 (18%) met the criteria for delabeling and consented to removal of their allergy.⁷ The delabeling rates in these 2 studies are similar to the 17% rate of allergy modification in our study, although this study is the only one to compare results to a historical control group.

Harper et al evaluated the impact of a penicillin allergy assessment, including penicillin skin testing and oral amoxicillin challenges, on delabeling penicillin allergies. Pharmacists completed a penicillin allergy assessment and performed penicillin skin testing and/or oral amoxicillin challenges for eligible patients. Of 35 patients, 31 (89%) had their penicillin allergies delabeled in the EHR.⁸ The rate of penicillin allergy delabeling in Harper et al was likely higher than that seen in our study due to the use of oral challenge and skin testing. Regardless, a detailed penicillin allergy interview alone was effective at RRVAMC, resulting in a significant rate of allergy removal or change. This supports the use of detailed penicillin allergy assessments in settings where penicillin skin testing or oral challenges may not be feasible.

Mann et al demonstrated the effectiveness of penicillin allergy assessments in switching eligible patients to Β-lactam antibiotics. Their single-center, prospective study assessed the impact of a pharmacist-driven detailed penicillin allergy interview initiative. Interviews that evaluated potential changes to allergy profiles were conducted with 175 patients. Of these patients, 135 (77.1%) were on antimicrobial therapy and 42 (31.1%) patients receiving therapy met criteria to switch to a noncarbapenem Β-lactam antibiotic. Thirty-one patients (73.8%) switched with no signs or symptoms of intolerance demonstrating that an interview can be a valuable tool for antibiotic optimization, specifically in patients with penicillin allergy.⁹ No patients in our study switched antibiotic therapy, likely because only a small number of patients were eligible for transition to a noncarbapenem Β-lactam antibiotic. In the Mann et al study, non–Β-lactam antibiotics, such as fluoroquinolones and carbapenems, accounted for > 75% of the antibiotics used.

Limitations

The sample size of this study was small and its duration was short. There is a risk for selection bias as not all identified patients were able to be interviewed while admitted, but patients on antibiotics were prioritized as they were most likely to directly benefit during their current admission from a modification of their allergy. Most patients in the study were White and male, which may limit the generalizability of the results. Additionally, recommendations regarding antibiotic changes were primarily communicated to the treatment team based on a templated note in CPRS alone. Therefore, implementation of these recommendations largely relied upon nonverbal communication. Direct pharmacist-physician communication could have led to a larger impact on antimicrobial therapy changes. The interviewer’s participation in daily rounds with time allotted to discuss this topic can be considered in the future to improve these processes.

Conclusions

This study found that the ABLE process identified patients for penicillin allergy delabeling. With the high prevalence of inaccurate penicillin allergy documentation, this tool offers VA health care systems a way to empower pharmacists in allergy clarification, leading to improvements in antibiotic stewardship. Although the sample size was small, the ABLE process may provide a framework for VA clinicians. Future research has the potential to demonstrate the practicality and effectiveness this pharmacist-led penicillin allergy interview process can offer clinicians.

Self-reported penicillin allergies are common, with a prevalence of about 10% of patients, according to the Centers for Disease Control and Prevention (CDC).¹ However, only about 1% of patients have a true immunoglobulin E (IgE)-mediated allergy. This issue is often further complicated by inaccurate classification of nonallergic adverse effects as an allergy, resulting in incomplete allergy documentation in the electronic health record (EHR). The cross-reactivity rate with cephalosporins (Β-lactam antibiotics) in patients reporting a penicillin allergy is < 1%, which suggests that many patients with reported penicillin allergies can safely receive them.² Despite this, patients with self-reported penicillin allergies often receive non–Β-lactam antibiotic agents, which may be associated with an increased risk of adverse drug reactions (ADRs), increased health care costs, and inferior clinical outcomes.³

Several strategies are recommended to assess patients with self-reported penicillin allergies. According to the CDC, evaluating a patient who reports a penicillin or other Β-lactam antibiotic allergy involves 3 steps: (1) obtaining a thorough medical history, including previous exposures to penicillin or other Β-lactam antibiotic; (2) performing a skin test using the penicillin major and minor determinants; and (3) among those who have a negative penicillin skin test, performing an observed oral challenge with 250 mg amoxicillin before proceeding directly to treatment with the indicated Β-lactam therapy.⁴

Most existing clinical guidance for assessing patients with self-reported penicillin allergies stems from site-specific policies and primarily focuses on oral amoxicillin challenges or penicillin skin testing (PST). However, performing these tests may not be feasible at all facilities due to time constraints and lack of allergists. Therefore, alternative strategies are necessary, such as conducting detailed patient interviews. Few studies have evaluated switching to Β-lactam agents following a penicillin allergy interview alone. However, with thorough patient histories and detailed interviews, patients with reported penicillin allergies can safely use Β-lactam antibiotics.⁵ Implementing this procedure provides a cost-savings opportunity by not having to administer additional antibiotics for testing in addition to improving antibiotic stewardship.

The Memphis Veterans Affairs Medical Center (MVAMC) created the Allergy to Β-Lactam Evaluation (ABLE) process to clarify and remove penicillin allergies. The process involves conducting a thorough chart review and patient interview followed by completion of a note template that provides recommendations about patient allergies and Β-lactam prescribing. Mitchell et al found that the pharmacist-led process to be beneficial for addressing Β-lactam allergy clearance.⁶ As a result, the ABLE process was implemented at several other US Department of Veterans Affairs (VA) medical centers (VAMCs). Using the ABLE template, the purpose of this study was to evaluate the impact of a pharmacist-led penicillin allergy initiative on penicillin allergy delabeling with an interview process alone.

Methods

Prior to ABLE process implementation, there were no standardized procedures for documenting allergy histories. ABLE was implemented at the Robley Rex VAMC (RRVAMC) in November 2022. During the interview phase, patients were initially identified during admission via TheraDoc as having either a penicillin allergy or ADR. The infectious disease pharmacist or pharmacy resident interviewed patients with documented penicillin allergies or ADRs using a standardized questionnaire (eAppendix 1). Not all identified patients could be interviewed. Patients currently receiving an antibiotic were prioritized for interviews. Patients were excluded if they declined or were unable to be interviewed, although a patient’s caregiver(s) could be interviewed in person or via telephone, if the patient was not available.

Following the interview, pharmacists used guidance from the ABLE process in addition to a detailed EHR review to determine whether the patient was eligible for an allergy update or removal and/or switch to a Β-lactam antibiotic (Figure). If eligible for modification, the interviewing pharmacist made the necessary changes. A templated process note with patient-specific recommendations was entered into the Computerized Patient Record System (CPRS) and the primary care team attending physician was added as an additional signer to be alerted in the system note (eAppendix 2).

This single-center, retrospective cohort study involved review of CPRS notes and clinical interviews in the interviewed group. Hospitalized patients at the RRVAMC aged ≥ 18 years with a documented penicillin allergy or ADR were included. The historical control group consisted of patients admitted between October 31, 2019, and October 31, 2022, and the intervention group consisted of patients admitted between November 1, 2022, and March 1, 2023. Patients in the historical control group were matched 1:1 to the intervention group for penicillin allergy severity (allergy [IgE-mediated], unknown, adverse effect, severe cutaneous or other non–IgE-mediated reaction) and whether they received a noncarbapenem non–Β-lactam antibiotic.

The primary outcome was the number of patient allergies/ADRs removed or changed on patient profiles regardless of whether their antibiotic regimen was changed. This outcome was further assessed by evaluating the number of patient allergies or ADRs removed or changed on patient profiles with or without a change in antibiotic regimen. Primary outcomes were analyzed using χ² and/ or Fisher exact tests, as appropriate to determine statistically significant differences between the interviewed group and the historical control.

Results

Seventy patients were included: 35 patients in the interviewed group and 35 patients in the historical control group, respectively. Both groups had a mean age of 72 years and predominantly included White male patients (Table 1). Following the interview, the allergy profile was modified for 6 patients (17%) in the interview group vs 0 patients in the control group (P = .03) (Table 2). The primary outcome was analyzed separately regardless of an antibiotic regimen change. There was not a statistically significant difference between groups when assessing patients for change in therapy (P > .99). All 6 patients with an allergy profile modification had no change in antibiotic regimen.

Discussion

This study suggests the ABLE process may be a valuable tool for adjusting penicillin allergies or ADRs within patient EHRs. In the interview group, allergies were modified in 6 (17%) patients while no patients in the control group had allergy modifications. Of the 6 allergy profile modifications, 4 allergy labels were changed from an allergy to an ADR. These patients were cleared to receive future Β-lactam antibiotics after clinicians recognized the lack of a true IgE-mediated allergic reaction. In addition, 2 of the modified allergy profiles removed the allergy designation. Although this represents a small subset of interviewed patients, it illustrates the clinical effectiveness of an interview process alone to remove penicillin allergy designations.

Previous research has assessed the impact of pharmacist intervention on penicillin allergy clarification. Mitchell et al implemented a pharmacist-driven Β-lactam allergy assessment and penicillin allergy clinic (PAC) at the MVAMC with the goal of evaluating its impact on allergy clearance. In their study, clinical pharmacy specialists evaluated patients with Β-lactam allergies, and those deemed eligible were later seen in the PAC. Among the 246 patients evaluated using the Β-lactam allergy assessment alone and who were not seen in the PAC, 25% had their penicillin allergy removed following a detailed assessment.⁶

Song et al evaluated the effectiveness and feasibility of a pharmacist-driven penicillin allergy delabeling pilot program without skin testing or oral challenges. Patients with penicillin allergies were interviewed by a pharmacy resident using a standardized checklist. Among the 66 patients interviewed, 12 (18%) met the criteria for delabeling and consented to removal of their allergy.⁷ The delabeling rates in these 2 studies are similar to the 17% rate of allergy modification in our study, although this study is the only one to compare results to a historical control group.

Harper et al evaluated the impact of a penicillin allergy assessment, including penicillin skin testing and oral amoxicillin challenges, on delabeling penicillin allergies. Pharmacists completed a penicillin allergy assessment and performed penicillin skin testing and/or oral amoxicillin challenges for eligible patients. Of 35 patients, 31 (89%) had their penicillin allergies delabeled in the EHR.⁸ The rate of penicillin allergy delabeling in Harper et al was likely higher than that seen in our study due to the use of oral challenge and skin testing. Regardless, a detailed penicillin allergy interview alone was effective at RRVAMC, resulting in a significant rate of allergy removal or change. This supports the use of detailed penicillin allergy assessments in settings where penicillin skin testing or oral challenges may not be feasible.

Mann et al demonstrated the effectiveness of penicillin allergy assessments in switching eligible patients to Β-lactam antibiotics. Their single-center, prospective study assessed the impact of a pharmacist-driven detailed penicillin allergy interview initiative. Interviews that evaluated potential changes to allergy profiles were conducted with 175 patients. Of these patients, 135 (77.1%) were on antimicrobial therapy and 42 (31.1%) patients receiving therapy met criteria to switch to a noncarbapenem Β-lactam antibiotic. Thirty-one patients (73.8%) switched with no signs or symptoms of intolerance demonstrating that an interview can be a valuable tool for antibiotic optimization, specifically in patients with penicillin allergy.⁹ No patients in our study switched antibiotic therapy, likely because only a small number of patients were eligible for transition to a noncarbapenem Β-lactam antibiotic. In the Mann et al study, non–Β-lactam antibiotics, such as fluoroquinolones and carbapenems, accounted for > 75% of the antibiotics used.

Limitations

The sample size of this study was small and its duration was short. There is a risk for selection bias as not all identified patients were able to be interviewed while admitted, but patients on antibiotics were prioritized as they were most likely to directly benefit during their current admission from a modification of their allergy. Most patients in the study were White and male, which may limit the generalizability of the results. Additionally, recommendations regarding antibiotic changes were primarily communicated to the treatment team based on a templated note in CPRS alone. Therefore, implementation of these recommendations largely relied upon nonverbal communication. Direct pharmacist-physician communication could have led to a larger impact on antimicrobial therapy changes. The interviewer’s participation in daily rounds with time allotted to discuss this topic can be considered in the future to improve these processes.

Conclusions

This study found that the ABLE process identified patients for penicillin allergy delabeling. With the high prevalence of inaccurate penicillin allergy documentation, this tool offers VA health care systems a way to empower pharmacists in allergy clarification, leading to improvements in antibiotic stewardship. Although the sample size was small, the ABLE process may provide a framework for VA clinicians. Future research has the potential to demonstrate the practicality and effectiveness this pharmacist-led penicillin allergy interview process can offer clinicians.

Self-reported penicillin allergies are common, with a prevalence of about 10% of patients, according to the Centers for Disease Control and Prevention (CDC).¹ However, only about 1% of patients have a true immunoglobulin E (IgE)-mediated allergy. This issue is often further complicated by inaccurate classification of nonallergic adverse effects as an allergy, resulting in incomplete allergy documentation in the electronic health record (EHR). The cross-reactivity rate with cephalosporins (Β-lactam antibiotics) in patients reporting a penicillin allergy is < 1%, which suggests that many patients with reported penicillin allergies can safely receive them.² Despite this, patients with self-reported penicillin allergies often receive non–Β-lactam antibiotic agents, which may be associated with an increased risk of adverse drug reactions (ADRs), increased health care costs, and inferior clinical outcomes.³

Several strategies are recommended to assess patients with self-reported penicillin allergies. According to the CDC, evaluating a patient who reports a penicillin or other Β-lactam antibiotic allergy involves 3 steps: (1) obtaining a thorough medical history, including previous exposures to penicillin or other Β-lactam antibiotic; (2) performing a skin test using the penicillin major and minor determinants; and (3) among those who have a negative penicillin skin test, performing an observed oral challenge with 250 mg amoxicillin before proceeding directly to treatment with the indicated Β-lactam therapy.⁴

Most existing clinical guidance for assessing patients with self-reported penicillin allergies stems from site-specific policies and primarily focuses on oral amoxicillin challenges or penicillin skin testing (PST). However, performing these tests may not be feasible at all facilities due to time constraints and lack of allergists. Therefore, alternative strategies are necessary, such as conducting detailed patient interviews. Few studies have evaluated switching to Β-lactam agents following a penicillin allergy interview alone. However, with thorough patient histories and detailed interviews, patients with reported penicillin allergies can safely use Β-lactam antibiotics.⁵ Implementing this procedure provides a cost-savings opportunity by not having to administer additional antibiotics for testing in addition to improving antibiotic stewardship.

The Memphis Veterans Affairs Medical Center (MVAMC) created the Allergy to Β-Lactam Evaluation (ABLE) process to clarify and remove penicillin allergies. The process involves conducting a thorough chart review and patient interview followed by completion of a note template that provides recommendations about patient allergies and Β-lactam prescribing. Mitchell et al found that the pharmacist-led process to be beneficial for addressing Β-lactam allergy clearance.⁶ As a result, the ABLE process was implemented at several other US Department of Veterans Affairs (VA) medical centers (VAMCs). Using the ABLE template, the purpose of this study was to evaluate the impact of a pharmacist-led penicillin allergy initiative on penicillin allergy delabeling with an interview process alone.

Methods

Prior to ABLE process implementation, there were no standardized procedures for documenting allergy histories. ABLE was implemented at the Robley Rex VAMC (RRVAMC) in November 2022. During the interview phase, patients were initially identified during admission via TheraDoc as having either a penicillin allergy or ADR. The infectious disease pharmacist or pharmacy resident interviewed patients with documented penicillin allergies or ADRs using a standardized questionnaire (eAppendix 1). Not all identified patients could be interviewed. Patients currently receiving an antibiotic were prioritized for interviews. Patients were excluded if they declined or were unable to be interviewed, although a patient’s caregiver(s) could be interviewed in person or via telephone, if the patient was not available.

Following the interview, pharmacists used guidance from the ABLE process in addition to a detailed EHR review to determine whether the patient was eligible for an allergy update or removal and/or switch to a Β-lactam antibiotic (Figure). If eligible for modification, the interviewing pharmacist made the necessary changes. A templated process note with patient-specific recommendations was entered into the Computerized Patient Record System (CPRS) and the primary care team attending physician was added as an additional signer to be alerted in the system note (eAppendix 2).

This single-center, retrospective cohort study involved review of CPRS notes and clinical interviews in the interviewed group. Hospitalized patients at the RRVAMC aged ≥ 18 years with a documented penicillin allergy or ADR were included. The historical control group consisted of patients admitted between October 31, 2019, and October 31, 2022, and the intervention group consisted of patients admitted between November 1, 2022, and March 1, 2023. Patients in the historical control group were matched 1:1 to the intervention group for penicillin allergy severity (allergy [IgE-mediated], unknown, adverse effect, severe cutaneous or other non–IgE-mediated reaction) and whether they received a noncarbapenem non–Β-lactam antibiotic.

The primary outcome was the number of patient allergies/ADRs removed or changed on patient profiles regardless of whether their antibiotic regimen was changed. This outcome was further assessed by evaluating the number of patient allergies or ADRs removed or changed on patient profiles with or without a change in antibiotic regimen. Primary outcomes were analyzed using χ² and/ or Fisher exact tests, as appropriate to determine statistically significant differences between the interviewed group and the historical control.

Results

Seventy patients were included: 35 patients in the interviewed group and 35 patients in the historical control group, respectively. Both groups had a mean age of 72 years and predominantly included White male patients (Table 1). Following the interview, the allergy profile was modified for 6 patients (17%) in the interview group vs 0 patients in the control group (P = .03) (Table 2). The primary outcome was analyzed separately regardless of an antibiotic regimen change. There was not a statistically significant difference between groups when assessing patients for change in therapy (P > .99). All 6 patients with an allergy profile modification had no change in antibiotic regimen.

Discussion

This study suggests the ABLE process may be a valuable tool for adjusting penicillin allergies or ADRs within patient EHRs. In the interview group, allergies were modified in 6 (17%) patients while no patients in the control group had allergy modifications. Of the 6 allergy profile modifications, 4 allergy labels were changed from an allergy to an ADR. These patients were cleared to receive future Β-lactam antibiotics after clinicians recognized the lack of a true IgE-mediated allergic reaction. In addition, 2 of the modified allergy profiles removed the allergy designation. Although this represents a small subset of interviewed patients, it illustrates the clinical effectiveness of an interview process alone to remove penicillin allergy designations.

Previous research has assessed the impact of pharmacist intervention on penicillin allergy clarification. Mitchell et al implemented a pharmacist-driven Β-lactam allergy assessment and penicillin allergy clinic (PAC) at the MVAMC with the goal of evaluating its impact on allergy clearance. In their study, clinical pharmacy specialists evaluated patients with Β-lactam allergies, and those deemed eligible were later seen in the PAC. Among the 246 patients evaluated using the Β-lactam allergy assessment alone and who were not seen in the PAC, 25% had their penicillin allergy removed following a detailed assessment.⁶

Song et al evaluated the effectiveness and feasibility of a pharmacist-driven penicillin allergy delabeling pilot program without skin testing or oral challenges. Patients with penicillin allergies were interviewed by a pharmacy resident using a standardized checklist. Among the 66 patients interviewed, 12 (18%) met the criteria for delabeling and consented to removal of their allergy.⁷ The delabeling rates in these 2 studies are similar to the 17% rate of allergy modification in our study, although this study is the only one to compare results to a historical control group.

Harper et al evaluated the impact of a penicillin allergy assessment, including penicillin skin testing and oral amoxicillin challenges, on delabeling penicillin allergies. Pharmacists completed a penicillin allergy assessment and performed penicillin skin testing and/or oral amoxicillin challenges for eligible patients. Of 35 patients, 31 (89%) had their penicillin allergies delabeled in the EHR.⁸ The rate of penicillin allergy delabeling in Harper et al was likely higher than that seen in our study due to the use of oral challenge and skin testing. Regardless, a detailed penicillin allergy interview alone was effective at RRVAMC, resulting in a significant rate of allergy removal or change. This supports the use of detailed penicillin allergy assessments in settings where penicillin skin testing or oral challenges may not be feasible.

Mann et al demonstrated the effectiveness of penicillin allergy assessments in switching eligible patients to Β-lactam antibiotics. Their single-center, prospective study assessed the impact of a pharmacist-driven detailed penicillin allergy interview initiative. Interviews that evaluated potential changes to allergy profiles were conducted with 175 patients. Of these patients, 135 (77.1%) were on antimicrobial therapy and 42 (31.1%) patients receiving therapy met criteria to switch to a noncarbapenem Β-lactam antibiotic. Thirty-one patients (73.8%) switched with no signs or symptoms of intolerance demonstrating that an interview can be a valuable tool for antibiotic optimization, specifically in patients with penicillin allergy.⁹ No patients in our study switched antibiotic therapy, likely because only a small number of patients were eligible for transition to a noncarbapenem Β-lactam antibiotic. In the Mann et al study, non–Β-lactam antibiotics, such as fluoroquinolones and carbapenems, accounted for > 75% of the antibiotics used.

Limitations

The sample size of this study was small and its duration was short. There is a risk for selection bias as not all identified patients were able to be interviewed while admitted, but patients on antibiotics were prioritized as they were most likely to directly benefit during their current admission from a modification of their allergy. Most patients in the study were White and male, which may limit the generalizability of the results. Additionally, recommendations regarding antibiotic changes were primarily communicated to the treatment team based on a templated note in CPRS alone. Therefore, implementation of these recommendations largely relied upon nonverbal communication. Direct pharmacist-physician communication could have led to a larger impact on antimicrobial therapy changes. The interviewer’s participation in daily rounds with time allotted to discuss this topic can be considered in the future to improve these processes.

Conclusions

This study found that the ABLE process identified patients for penicillin allergy delabeling. With the high prevalence of inaccurate penicillin allergy documentation, this tool offers VA health care systems a way to empower pharmacists in allergy clarification, leading to improvements in antibiotic stewardship. Although the sample size was small, the ABLE process may provide a framework for VA clinicians. Future research has the potential to demonstrate the practicality and effectiveness this pharmacist-led penicillin allergy interview process can offer clinicians.

Given its safety profile and bactericidal activity against the predominant organisms causing surgical site infections (SSIs), cefazolin remains the most popular choice for surgical prophylaxis.¹ Cefazolin offers protection against the pathogens most likely to contaminate the surgical site while minimizing inappropriate methicillin- resistant Staphylococcus aureus coverage that occurs with alternatives such as vancomycin and clindamycin. Documented allergies to Β-lactam antibiotics have historically forced clinicians to avoid the use of cephalosporins due to the potential risk of cross-reactivity. True type 1 (immunoglobin E [IgE]-mediated) cross-allergic reactions between penicillin and cephalosporins are rare, and previously reported data indicate cross-reactivity as a result of antibody recognition is more closely related to the side-chain identity rather than the Β-lactam ring.^2,3

About 10% of US patients report having a penicillin allergy; however, < 1% of the population has a true IgE-mediated allergic reaction.⁴ Previous research that has challenged penicillin allergies with cefazolin for surgical prophylaxis has reported minimal rates of allergic reactions.^2-5

In previous trials, patients with a history of delayed skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), were excluded. Additionally, patients with an allergy to cefazolin including those with urticaria, angioedema, bronchospasm, or anaphylaxis, were excluded from perioperative retrial of cefazolin. Grant et al found that cefazolin can be safely given to patients with IgE-mediated reactions to penicillin and other cephalosporins due to a structurally different side chain.³

In January 2023, the Veteran Health Indiana (VHI) pharmacy team in conjunction with surgery, infectious disease, and anesthesiology, implemented a screening tool as an amendment to perioperative antibiotic guidance to help determine which patients with a documented penicillin allergy could be candidates for perioperative cefazolin. The implemented screening tool (Allergy Clarification for Cefazolin Evidence-Based Prescribing Tool) has been described by Lam et al, who reported that an increased proportion of patients with documented penicillin allergy received cefazolin without more adverse drug reactions (ADRs).⁵ Patients with a Β-lactam allergy were eligible to receive cefazolin unless the ADR was SJS, TEN, or DRESS, or the offending agent was cefazolin and the patient experienced urticaria, angioedema, bronchospasm, or anaphylaxis. If the reaction was not from cefazolin or was unknown, patients were eligible to receive cefazolin (Figure).

To date, minimal data exist to evaluate the incidence of ADRs when cefazolin is given perioperatively to patients with a previously documented penicillin allergy. The purpose of this study was to evaluate the incidence of allergic ADRs in patients who had a documented penicillin allergy and received periprocedural antibiotics.

Methods

This single-center, retrospective chart review used the US Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) to identify patients with a documented penicillin allergy who underwent an operation and received periprocedural antibiotics between February 1, 2023, and January 31, 2024. This study was reviewed and approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.

Patients were enrolled if they were aged ≥ 18 years, had a documented penicillin allergy, underwent a surgical intervention, and received perioperative antibiotics during the study period. Patients were excluded if they had a documented penicillin allergy resulting in severe delayed skin reactions (ie, SJS, TEN, or DRESS). These criteria produced 197 surgical procedures. Data were collected for each surgical procedure, so patients could be included more than once. Patient history of allergic reaction to penicillin was obtained through CPRS.

The primary endpoint was the percentage of allergic ADRs in patients with penicillin allergies receiving cefazolin perioperatively. Secondary outcomes included the appropriateness of the antibiotic regimen in congruence with American System of Health Pharmacists (ASHP) recommendations, incidence of SSIs within 30 days of the procedure, incidence of ADRs in those with a history of anaphylaxis vs nonanaphylaxis allergy, incidence of allergic reaction requiring pharmacologic and nonpharmacologic interventions, and incidence of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or an increase in serum creatinine to ≥ 1.5 times baseline.

Demographic data included sex, age, race, preoperative serum creatinine, and postoperative serum creatinine. Anaphylaxis was defined as an acute onset of illness (within minutes to several hours) with involvement of skin, mucosal tissue, or both involving either respiratory compromise or reduced blood pressures. Allergic reactions were defined as facial, tongue, throat, airway, lip, mouth, periorbital, or eye swelling, urticaria, angioedema, dyspnea, anaphylaxis, or a positive penicillin skin test. Additionally, data collected included the description and severity of postprophylactic antibiotic reaction, antibiotic choice, interventions required for the allergic reaction, SSI occurrence, date of SSI, operating specialty, and postoperative change in renal function.

Descriptive statistics, including mean, SD, and percentages were reported for baseline characteristics of the study population. Percentages were used to demonstrate the differences in primary and secondary outcomes for each study group. Fisher exact tests were used for incidence of ADRs in patients with penicillin allergy who received cefazolin and reported incidence of SSIs.

Results

A total of 197 surgical procedures in patients with a documented penicillin allergy were included; 127 procedures used cefazolin perioperatively, 3 procedures used cefazolin plus gentamicin, and 67 procedures used other antibiotics. Most patients were White (n = 160; 81.2%), male (n = 158; 80.2%), and had a mean age of 64.9 years. Urology was the most common surgical specialty (n = 59; 29.9%) (Table 1). Of the 16 patients with documented penicillin anaphylaxis reaction, 8 received cefazolin and 8 received a different antibiotic. A total of 181 patients reported a nonanaphylaxis allergy. One hundred fifty-one patients (68.6%) reported a reaction history of hives, rash, or swelling (Table 2). Patients could report ≥ 1 reaction. The most prevalent antibiotics used were cefazolin, which was used by 130 patients (61.3%), and clindamycin which was used by 33 patients (15.6%) (Table 3). Patients could receive ≥ 1 antibiotic.

For the primary outcome, the incidence of allergic reactions in patients allergic to penicillin, there was no incidence of allergic reactions in either the cefazolin or other group. Given the absence of reactions, no interventions were required.

There were no ADRs in those with history of anaphylaxis or nonanaphylaxis allergy. In the cefazolin group, 126 of 127 surgical procedure regimens (99.2%) were congruent with ASHP recommendations, all 3 surgical procedures regimens in the cefazolin plus gentamicin group were congruent with ASHP recommendations, and 58 of 67 surgical procedure regimens (86.6%) in the other antibiotic group were congruent with ASHP recommendations. None of the 127 patients in the cefazolin group or of the 3 patients in the cefazolin plus gentamicin group reported an SSI, and 3 of 67 patients (4.5%) had an SSI in the other antibiotic group. One procedure that resulted in SSI was not congruent with ASHP recommendations. Twenty-four patients had 2 serum creatinine levels drawn within 48 hours of surgery. One of 12 patients (8.3%) and 0 of 12 patients had an AKI in the cefazolin and other antibiotic group, respectively (Table 4).

Discussion

Implementation of a screening tool at VHI allowed patients with documented penicillin allergy, including anaphylaxis, to receive cefazolin perioperatively. Broad spectrum antibiotics such as vancomycin, clindamycin, and fluoroquinolones are frequently used in patients allergic to penicillin, which can increase health care costs, risk of toxicity, and antimicrobial resistance.⁴ There was no incidence of allergic reactions noted in patients allergic to penicillin who received cefazolin. When comparing the incidence of observed allergic reactions to received perioperative antibiotics in the cefazolin group to previously published literature, no difference in allergy rates (P = .09) was found.³ Most antibiotics administered were congruent with ASHP guideline recommendations, and most patients eligible for cefazolin received it perioperatively.

Similar to this study, Goodman et al concluded that cefazolin appears to be a safe regimen in patients with documented penicillin anaphylactic reaction for surgical prophylaxis with only 1 (0.2%) potential allergic reaction.⁶ Patients who received cefazolin perioperatively had a statistically significant decrease in SSI rates. There were no clinically or statistically significant differences found between the proportion of allergic reactions or ADRs when compared to alternative antibiotics. Lessard et al concluded that a pharmacist-led interdisciplinary collaborative practice agreement increased cefazolin use in patients allergic to penicillin, including those with urticaria and anaphylaxis, with no reported ADRs.⁷ This study further demonstrated the safety of cefazolin use in patients with anaphylaxis to penicillin.

Limitations

This study’s single-center, retrospective design, patient population, and small sample size limit the generalizability of its results. The data collected are dependent on documentation in the chart. No ADRs were reported from the antibiotics patients received perioperatively. When considering safety data, information such as serum creatinine were available only in CPRS and some patients did not receive a postprocedure serum creatinine level. Additionally, this study did not investigate whether there was an increase in preferred preoperative antimicrobial prophylaxis after implementation of this protocol.

Conclusions

The results of this study support the use of cefazolin perioperatively in patients allergic to penicillin, including those with a history of anaphylaxis. Additional research should be conducted to validate data given the low incidence of ADRs. The primary outcome did not reach statistical significance, but the results may be clinically significant from a stewardship and safety perspective. VHI continues to use the screening tool described in this article.

Given its safety profile and bactericidal activity against the predominant organisms causing surgical site infections (SSIs), cefazolin remains the most popular choice for surgical prophylaxis.¹ Cefazolin offers protection against the pathogens most likely to contaminate the surgical site while minimizing inappropriate methicillin- resistant Staphylococcus aureus coverage that occurs with alternatives such as vancomycin and clindamycin. Documented allergies to Β-lactam antibiotics have historically forced clinicians to avoid the use of cephalosporins due to the potential risk of cross-reactivity. True type 1 (immunoglobin E [IgE]-mediated) cross-allergic reactions between penicillin and cephalosporins are rare, and previously reported data indicate cross-reactivity as a result of antibody recognition is more closely related to the side-chain identity rather than the Β-lactam ring.^2,3

About 10% of US patients report having a penicillin allergy; however, < 1% of the population has a true IgE-mediated allergic reaction.⁴ Previous research that has challenged penicillin allergies with cefazolin for surgical prophylaxis has reported minimal rates of allergic reactions.^2-5

In previous trials, patients with a history of delayed skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), were excluded. Additionally, patients with an allergy to cefazolin including those with urticaria, angioedema, bronchospasm, or anaphylaxis, were excluded from perioperative retrial of cefazolin. Grant et al found that cefazolin can be safely given to patients with IgE-mediated reactions to penicillin and other cephalosporins due to a structurally different side chain.³

In January 2023, the Veteran Health Indiana (VHI) pharmacy team in conjunction with surgery, infectious disease, and anesthesiology, implemented a screening tool as an amendment to perioperative antibiotic guidance to help determine which patients with a documented penicillin allergy could be candidates for perioperative cefazolin. The implemented screening tool (Allergy Clarification for Cefazolin Evidence-Based Prescribing Tool) has been described by Lam et al, who reported that an increased proportion of patients with documented penicillin allergy received cefazolin without more adverse drug reactions (ADRs).⁵ Patients with a Β-lactam allergy were eligible to receive cefazolin unless the ADR was SJS, TEN, or DRESS, or the offending agent was cefazolin and the patient experienced urticaria, angioedema, bronchospasm, or anaphylaxis. If the reaction was not from cefazolin or was unknown, patients were eligible to receive cefazolin (Figure).

To date, minimal data exist to evaluate the incidence of ADRs when cefazolin is given perioperatively to patients with a previously documented penicillin allergy. The purpose of this study was to evaluate the incidence of allergic ADRs in patients who had a documented penicillin allergy and received periprocedural antibiotics.

Methods

This single-center, retrospective chart review used the US Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) to identify patients with a documented penicillin allergy who underwent an operation and received periprocedural antibiotics between February 1, 2023, and January 31, 2024. This study was reviewed and approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.

Patients were enrolled if they were aged ≥ 18 years, had a documented penicillin allergy, underwent a surgical intervention, and received perioperative antibiotics during the study period. Patients were excluded if they had a documented penicillin allergy resulting in severe delayed skin reactions (ie, SJS, TEN, or DRESS). These criteria produced 197 surgical procedures. Data were collected for each surgical procedure, so patients could be included more than once. Patient history of allergic reaction to penicillin was obtained through CPRS.

The primary endpoint was the percentage of allergic ADRs in patients with penicillin allergies receiving cefazolin perioperatively. Secondary outcomes included the appropriateness of the antibiotic regimen in congruence with American System of Health Pharmacists (ASHP) recommendations, incidence of SSIs within 30 days of the procedure, incidence of ADRs in those with a history of anaphylaxis vs nonanaphylaxis allergy, incidence of allergic reaction requiring pharmacologic and nonpharmacologic interventions, and incidence of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or an increase in serum creatinine to ≥ 1.5 times baseline.

Demographic data included sex, age, race, preoperative serum creatinine, and postoperative serum creatinine. Anaphylaxis was defined as an acute onset of illness (within minutes to several hours) with involvement of skin, mucosal tissue, or both involving either respiratory compromise or reduced blood pressures. Allergic reactions were defined as facial, tongue, throat, airway, lip, mouth, periorbital, or eye swelling, urticaria, angioedema, dyspnea, anaphylaxis, or a positive penicillin skin test. Additionally, data collected included the description and severity of postprophylactic antibiotic reaction, antibiotic choice, interventions required for the allergic reaction, SSI occurrence, date of SSI, operating specialty, and postoperative change in renal function.

Descriptive statistics, including mean, SD, and percentages were reported for baseline characteristics of the study population. Percentages were used to demonstrate the differences in primary and secondary outcomes for each study group. Fisher exact tests were used for incidence of ADRs in patients with penicillin allergy who received cefazolin and reported incidence of SSIs.

Results

A total of 197 surgical procedures in patients with a documented penicillin allergy were included; 127 procedures used cefazolin perioperatively, 3 procedures used cefazolin plus gentamicin, and 67 procedures used other antibiotics. Most patients were White (n = 160; 81.2%), male (n = 158; 80.2%), and had a mean age of 64.9 years. Urology was the most common surgical specialty (n = 59; 29.9%) (Table 1). Of the 16 patients with documented penicillin anaphylaxis reaction, 8 received cefazolin and 8 received a different antibiotic. A total of 181 patients reported a nonanaphylaxis allergy. One hundred fifty-one patients (68.6%) reported a reaction history of hives, rash, or swelling (Table 2). Patients could report ≥ 1 reaction. The most prevalent antibiotics used were cefazolin, which was used by 130 patients (61.3%), and clindamycin which was used by 33 patients (15.6%) (Table 3). Patients could receive ≥ 1 antibiotic.

For the primary outcome, the incidence of allergic reactions in patients allergic to penicillin, there was no incidence of allergic reactions in either the cefazolin or other group. Given the absence of reactions, no interventions were required.

There were no ADRs in those with history of anaphylaxis or nonanaphylaxis allergy. In the cefazolin group, 126 of 127 surgical procedure regimens (99.2%) were congruent with ASHP recommendations, all 3 surgical procedures regimens in the cefazolin plus gentamicin group were congruent with ASHP recommendations, and 58 of 67 surgical procedure regimens (86.6%) in the other antibiotic group were congruent with ASHP recommendations. None of the 127 patients in the cefazolin group or of the 3 patients in the cefazolin plus gentamicin group reported an SSI, and 3 of 67 patients (4.5%) had an SSI in the other antibiotic group. One procedure that resulted in SSI was not congruent with ASHP recommendations. Twenty-four patients had 2 serum creatinine levels drawn within 48 hours of surgery. One of 12 patients (8.3%) and 0 of 12 patients had an AKI in the cefazolin and other antibiotic group, respectively (Table 4).

Discussion

Implementation of a screening tool at VHI allowed patients with documented penicillin allergy, including anaphylaxis, to receive cefazolin perioperatively. Broad spectrum antibiotics such as vancomycin, clindamycin, and fluoroquinolones are frequently used in patients allergic to penicillin, which can increase health care costs, risk of toxicity, and antimicrobial resistance.⁴ There was no incidence of allergic reactions noted in patients allergic to penicillin who received cefazolin. When comparing the incidence of observed allergic reactions to received perioperative antibiotics in the cefazolin group to previously published literature, no difference in allergy rates (P = .09) was found.³ Most antibiotics administered were congruent with ASHP guideline recommendations, and most patients eligible for cefazolin received it perioperatively.

Similar to this study, Goodman et al concluded that cefazolin appears to be a safe regimen in patients with documented penicillin anaphylactic reaction for surgical prophylaxis with only 1 (0.2%) potential allergic reaction.⁶ Patients who received cefazolin perioperatively had a statistically significant decrease in SSI rates. There were no clinically or statistically significant differences found between the proportion of allergic reactions or ADRs when compared to alternative antibiotics. Lessard et al concluded that a pharmacist-led interdisciplinary collaborative practice agreement increased cefazolin use in patients allergic to penicillin, including those with urticaria and anaphylaxis, with no reported ADRs.⁷ This study further demonstrated the safety of cefazolin use in patients with anaphylaxis to penicillin.

Limitations

This study’s single-center, retrospective design, patient population, and small sample size limit the generalizability of its results. The data collected are dependent on documentation in the chart. No ADRs were reported from the antibiotics patients received perioperatively. When considering safety data, information such as serum creatinine were available only in CPRS and some patients did not receive a postprocedure serum creatinine level. Additionally, this study did not investigate whether there was an increase in preferred preoperative antimicrobial prophylaxis after implementation of this protocol.

Conclusions

The results of this study support the use of cefazolin perioperatively in patients allergic to penicillin, including those with a history of anaphylaxis. Additional research should be conducted to validate data given the low incidence of ADRs. The primary outcome did not reach statistical significance, but the results may be clinically significant from a stewardship and safety perspective. VHI continues to use the screening tool described in this article.

Given its safety profile and bactericidal activity against the predominant organisms causing surgical site infections (SSIs), cefazolin remains the most popular choice for surgical prophylaxis.¹ Cefazolin offers protection against the pathogens most likely to contaminate the surgical site while minimizing inappropriate methicillin- resistant Staphylococcus aureus coverage that occurs with alternatives such as vancomycin and clindamycin. Documented allergies to Β-lactam antibiotics have historically forced clinicians to avoid the use of cephalosporins due to the potential risk of cross-reactivity. True type 1 (immunoglobin E [IgE]-mediated) cross-allergic reactions between penicillin and cephalosporins are rare, and previously reported data indicate cross-reactivity as a result of antibody recognition is more closely related to the side-chain identity rather than the Β-lactam ring.^2,3

About 10% of US patients report having a penicillin allergy; however, < 1% of the population has a true IgE-mediated allergic reaction.⁴ Previous research that has challenged penicillin allergies with cefazolin for surgical prophylaxis has reported minimal rates of allergic reactions.^2-5

In previous trials, patients with a history of delayed skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), were excluded. Additionally, patients with an allergy to cefazolin including those with urticaria, angioedema, bronchospasm, or anaphylaxis, were excluded from perioperative retrial of cefazolin. Grant et al found that cefazolin can be safely given to patients with IgE-mediated reactions to penicillin and other cephalosporins due to a structurally different side chain.³

In January 2023, the Veteran Health Indiana (VHI) pharmacy team in conjunction with surgery, infectious disease, and anesthesiology, implemented a screening tool as an amendment to perioperative antibiotic guidance to help determine which patients with a documented penicillin allergy could be candidates for perioperative cefazolin. The implemented screening tool (Allergy Clarification for Cefazolin Evidence-Based Prescribing Tool) has been described by Lam et al, who reported that an increased proportion of patients with documented penicillin allergy received cefazolin without more adverse drug reactions (ADRs).⁵ Patients with a Β-lactam allergy were eligible to receive cefazolin unless the ADR was SJS, TEN, or DRESS, or the offending agent was cefazolin and the patient experienced urticaria, angioedema, bronchospasm, or anaphylaxis. If the reaction was not from cefazolin or was unknown, patients were eligible to receive cefazolin (Figure).

To date, minimal data exist to evaluate the incidence of ADRs when cefazolin is given perioperatively to patients with a previously documented penicillin allergy. The purpose of this study was to evaluate the incidence of allergic ADRs in patients who had a documented penicillin allergy and received periprocedural antibiotics.

Methods

This single-center, retrospective chart review used the US Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) to identify patients with a documented penicillin allergy who underwent an operation and received periprocedural antibiotics between February 1, 2023, and January 31, 2024. This study was reviewed and approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.

Patients were enrolled if they were aged ≥ 18 years, had a documented penicillin allergy, underwent a surgical intervention, and received perioperative antibiotics during the study period. Patients were excluded if they had a documented penicillin allergy resulting in severe delayed skin reactions (ie, SJS, TEN, or DRESS). These criteria produced 197 surgical procedures. Data were collected for each surgical procedure, so patients could be included more than once. Patient history of allergic reaction to penicillin was obtained through CPRS.

The primary endpoint was the percentage of allergic ADRs in patients with penicillin allergies receiving cefazolin perioperatively. Secondary outcomes included the appropriateness of the antibiotic regimen in congruence with American System of Health Pharmacists (ASHP) recommendations, incidence of SSIs within 30 days of the procedure, incidence of ADRs in those with a history of anaphylaxis vs nonanaphylaxis allergy, incidence of allergic reaction requiring pharmacologic and nonpharmacologic interventions, and incidence of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or an increase in serum creatinine to ≥ 1.5 times baseline.

Demographic data included sex, age, race, preoperative serum creatinine, and postoperative serum creatinine. Anaphylaxis was defined as an acute onset of illness (within minutes to several hours) with involvement of skin, mucosal tissue, or both involving either respiratory compromise or reduced blood pressures. Allergic reactions were defined as facial, tongue, throat, airway, lip, mouth, periorbital, or eye swelling, urticaria, angioedema, dyspnea, anaphylaxis, or a positive penicillin skin test. Additionally, data collected included the description and severity of postprophylactic antibiotic reaction, antibiotic choice, interventions required for the allergic reaction, SSI occurrence, date of SSI, operating specialty, and postoperative change in renal function.

Descriptive statistics, including mean, SD, and percentages were reported for baseline characteristics of the study population. Percentages were used to demonstrate the differences in primary and secondary outcomes for each study group. Fisher exact tests were used for incidence of ADRs in patients with penicillin allergy who received cefazolin and reported incidence of SSIs.

Results

A total of 197 surgical procedures in patients with a documented penicillin allergy were included; 127 procedures used cefazolin perioperatively, 3 procedures used cefazolin plus gentamicin, and 67 procedures used other antibiotics. Most patients were White (n = 160; 81.2%), male (n = 158; 80.2%), and had a mean age of 64.9 years. Urology was the most common surgical specialty (n = 59; 29.9%) (Table 1). Of the 16 patients with documented penicillin anaphylaxis reaction, 8 received cefazolin and 8 received a different antibiotic. A total of 181 patients reported a nonanaphylaxis allergy. One hundred fifty-one patients (68.6%) reported a reaction history of hives, rash, or swelling (Table 2). Patients could report ≥ 1 reaction. The most prevalent antibiotics used were cefazolin, which was used by 130 patients (61.3%), and clindamycin which was used by 33 patients (15.6%) (Table 3). Patients could receive ≥ 1 antibiotic.

For the primary outcome, the incidence of allergic reactions in patients allergic to penicillin, there was no incidence of allergic reactions in either the cefazolin or other group. Given the absence of reactions, no interventions were required.

There were no ADRs in those with history of anaphylaxis or nonanaphylaxis allergy. In the cefazolin group, 126 of 127 surgical procedure regimens (99.2%) were congruent with ASHP recommendations, all 3 surgical procedures regimens in the cefazolin plus gentamicin group were congruent with ASHP recommendations, and 58 of 67 surgical procedure regimens (86.6%) in the other antibiotic group were congruent with ASHP recommendations. None of the 127 patients in the cefazolin group or of the 3 patients in the cefazolin plus gentamicin group reported an SSI, and 3 of 67 patients (4.5%) had an SSI in the other antibiotic group. One procedure that resulted in SSI was not congruent with ASHP recommendations. Twenty-four patients had 2 serum creatinine levels drawn within 48 hours of surgery. One of 12 patients (8.3%) and 0 of 12 patients had an AKI in the cefazolin and other antibiotic group, respectively (Table 4).

Discussion

Implementation of a screening tool at VHI allowed patients with documented penicillin allergy, including anaphylaxis, to receive cefazolin perioperatively. Broad spectrum antibiotics such as vancomycin, clindamycin, and fluoroquinolones are frequently used in patients allergic to penicillin, which can increase health care costs, risk of toxicity, and antimicrobial resistance.⁴ There was no incidence of allergic reactions noted in patients allergic to penicillin who received cefazolin. When comparing the incidence of observed allergic reactions to received perioperative antibiotics in the cefazolin group to previously published literature, no difference in allergy rates (P = .09) was found.³ Most antibiotics administered were congruent with ASHP guideline recommendations, and most patients eligible for cefazolin received it perioperatively.

Similar to this study, Goodman et al concluded that cefazolin appears to be a safe regimen in patients with documented penicillin anaphylactic reaction for surgical prophylaxis with only 1 (0.2%) potential allergic reaction.⁶ Patients who received cefazolin perioperatively had a statistically significant decrease in SSI rates. There were no clinically or statistically significant differences found between the proportion of allergic reactions or ADRs when compared to alternative antibiotics. Lessard et al concluded that a pharmacist-led interdisciplinary collaborative practice agreement increased cefazolin use in patients allergic to penicillin, including those with urticaria and anaphylaxis, with no reported ADRs.⁷ This study further demonstrated the safety of cefazolin use in patients with anaphylaxis to penicillin.

Limitations

This study’s single-center, retrospective design, patient population, and small sample size limit the generalizability of its results. The data collected are dependent on documentation in the chart. No ADRs were reported from the antibiotics patients received perioperatively. When considering safety data, information such as serum creatinine were available only in CPRS and some patients did not receive a postprocedure serum creatinine level. Additionally, this study did not investigate whether there was an increase in preferred preoperative antimicrobial prophylaxis after implementation of this protocol.

Conclusions

The results of this study support the use of cefazolin perioperatively in patients allergic to penicillin, including those with a history of anaphylaxis. Additional research should be conducted to validate data given the low incidence of ADRs. The primary outcome did not reach statistical significance, but the results may be clinically significant from a stewardship and safety perspective. VHI continues to use the screening tool described in this article.

THE DIAGNOSIS: Cutaneous Leishmaniasis

The biopsy results revealed amastigotes at the periphery of parasitized histiocytes, consistent with a diagnosis of cutaneous leishmaniasis. Polymerase chain reaction analysis revealed Leishmania guyanensis species complex, which includes both L guyanensis and Leishmania panamensis. In this case of disseminated cutaneous leishmaniasis (Figure 1), our patient received a prolonged course of systemic therapy with oral miltefosine 50 mg 3 times daily. At the most recent follow-up appointment, she showed ongoing resolution of ulcerations, subcutaneous plaques, and lymphadenopathy on the trunk and face, but development of subcutaneous nodules continued on the arms and legs. At the next follow-up, physical examination revealed that the lesions slowly started to fade.

Leishmania species are parasites transmitted by bites of female sand flies, which belong to the genera Phlebotomus (Old World, Eastern Hemisphere) and Lutzomyia (New World, Western Hemisphere) genera.¹ Leishmania species have a complex life cycle, propagating within human macrophages, ultimately leading to cutaneous, mucocutaneous, and visceral disease manifestations.² Cutaneous leishmaniasis manifests classically as scattered, painless, slow-healing ulcers.³ A biopsy taken from the edge of a cutaneous ulcer for hematoxylin and eosin processing is recommended for initial diagnosis, and subsequent polymerase chain reaction of the sample is required for speciation, which guides therapeutic options.^4,5 Classic hematoxylin and eosin and Giemsa stain findings include amastigotes lining the edges of parasitized histiocytes (Figure 2).

Systemic treatment options include sodium stibogluconate, amphotericin B, pentamidine, paromomycin, miltefosine, and azole antifungals.^2,5 Geography often plays a critical role in selecting treatment options due to resistance rates of individual Leishmania species; for example, paromomycin compounds are more effective for cutaneous disease caused by Leishmania major than Leishmania tropica. Miltefosine is not effective for treating Leishmania braziliensis which can be acquired outside Guatemala, and higher doses of amphotericin B are recommended for visceral disease from East Africa.^2,5 In patients with cutaneous leishmaniasis caused by L guyanensis, miltefosine remains a first-line option due to its oral formulation and long half-life within organisms, though there is a risk for teratogenicity.² Amphotericin B remains the most effective treatment for visceral leishmaniasis and can be used off label to treat mucocutaneous disease or when cutaneous disease is refractory to other treatment options.³

Given the potential of L guyanensis to progress to mucocutaneous disease, monitoring for mucosal involvement should be performed at regular intervals for 6 months to 1 year.² Treatment may be considered efficacious if no new skin lesions occur after 4 to 6 weeks of therapy; existing skin lesions should be re-epithelializing and reduced by 50% in size, with most cutaneous disease adequately controlled after 3 months of therapy.²

THE DIAGNOSIS: Cutaneous Leishmaniasis

The biopsy results revealed amastigotes at the periphery of parasitized histiocytes, consistent with a diagnosis of cutaneous leishmaniasis. Polymerase chain reaction analysis revealed Leishmania guyanensis species complex, which includes both L guyanensis and Leishmania panamensis. In this case of disseminated cutaneous leishmaniasis (Figure 1), our patient received a prolonged course of systemic therapy with oral miltefosine 50 mg 3 times daily. At the most recent follow-up appointment, she showed ongoing resolution of ulcerations, subcutaneous plaques, and lymphadenopathy on the trunk and face, but development of subcutaneous nodules continued on the arms and legs. At the next follow-up, physical examination revealed that the lesions slowly started to fade.

Leishmania species are parasites transmitted by bites of female sand flies, which belong to the genera Phlebotomus (Old World, Eastern Hemisphere) and Lutzomyia (New World, Western Hemisphere) genera.¹ Leishmania species have a complex life cycle, propagating within human macrophages, ultimately leading to cutaneous, mucocutaneous, and visceral disease manifestations.² Cutaneous leishmaniasis manifests classically as scattered, painless, slow-healing ulcers.³ A biopsy taken from the edge of a cutaneous ulcer for hematoxylin and eosin processing is recommended for initial diagnosis, and subsequent polymerase chain reaction of the sample is required for speciation, which guides therapeutic options.^4,5 Classic hematoxylin and eosin and Giemsa stain findings include amastigotes lining the edges of parasitized histiocytes (Figure 2).

Systemic treatment options include sodium stibogluconate, amphotericin B, pentamidine, paromomycin, miltefosine, and azole antifungals.^2,5 Geography often plays a critical role in selecting treatment options due to resistance rates of individual Leishmania species; for example, paromomycin compounds are more effective for cutaneous disease caused by Leishmania major than Leishmania tropica. Miltefosine is not effective for treating Leishmania braziliensis which can be acquired outside Guatemala, and higher doses of amphotericin B are recommended for visceral disease from East Africa.^2,5 In patients with cutaneous leishmaniasis caused by L guyanensis, miltefosine remains a first-line option due to its oral formulation and long half-life within organisms, though there is a risk for teratogenicity.² Amphotericin B remains the most effective treatment for visceral leishmaniasis and can be used off label to treat mucocutaneous disease or when cutaneous disease is refractory to other treatment options.³

Given the potential of L guyanensis to progress to mucocutaneous disease, monitoring for mucosal involvement should be performed at regular intervals for 6 months to 1 year.² Treatment may be considered efficacious if no new skin lesions occur after 4 to 6 weeks of therapy; existing skin lesions should be re-epithelializing and reduced by 50% in size, with most cutaneous disease adequately controlled after 3 months of therapy.²

THE DIAGNOSIS: Cutaneous Leishmaniasis

The biopsy results revealed amastigotes at the periphery of parasitized histiocytes, consistent with a diagnosis of cutaneous leishmaniasis. Polymerase chain reaction analysis revealed Leishmania guyanensis species complex, which includes both L guyanensis and Leishmania panamensis. In this case of disseminated cutaneous leishmaniasis (Figure 1), our patient received a prolonged course of systemic therapy with oral miltefosine 50 mg 3 times daily. At the most recent follow-up appointment, she showed ongoing resolution of ulcerations, subcutaneous plaques, and lymphadenopathy on the trunk and face, but development of subcutaneous nodules continued on the arms and legs. At the next follow-up, physical examination revealed that the lesions slowly started to fade.

Leishmania species are parasites transmitted by bites of female sand flies, which belong to the genera Phlebotomus (Old World, Eastern Hemisphere) and Lutzomyia (New World, Western Hemisphere) genera.¹ Leishmania species have a complex life cycle, propagating within human macrophages, ultimately leading to cutaneous, mucocutaneous, and visceral disease manifestations.² Cutaneous leishmaniasis manifests classically as scattered, painless, slow-healing ulcers.³ A biopsy taken from the edge of a cutaneous ulcer for hematoxylin and eosin processing is recommended for initial diagnosis, and subsequent polymerase chain reaction of the sample is required for speciation, which guides therapeutic options.^4,5 Classic hematoxylin and eosin and Giemsa stain findings include amastigotes lining the edges of parasitized histiocytes (Figure 2).

Systemic treatment options include sodium stibogluconate, amphotericin B, pentamidine, paromomycin, miltefosine, and azole antifungals.^2,5 Geography often plays a critical role in selecting treatment options due to resistance rates of individual Leishmania species; for example, paromomycin compounds are more effective for cutaneous disease caused by Leishmania major than Leishmania tropica. Miltefosine is not effective for treating Leishmania braziliensis which can be acquired outside Guatemala, and higher doses of amphotericin B are recommended for visceral disease from East Africa.^2,5 In patients with cutaneous leishmaniasis caused by L guyanensis, miltefosine remains a first-line option due to its oral formulation and long half-life within organisms, though there is a risk for teratogenicity.² Amphotericin B remains the most effective treatment for visceral leishmaniasis and can be used off label to treat mucocutaneous disease or when cutaneous disease is refractory to other treatment options.³

Given the potential of L guyanensis to progress to mucocutaneous disease, monitoring for mucosal involvement should be performed at regular intervals for 6 months to 1 year.² Treatment may be considered efficacious if no new skin lesions occur after 4 to 6 weeks of therapy; existing skin lesions should be re-epithelializing and reduced by 50% in size, with most cutaneous disease adequately controlled after 3 months of therapy.²

France has authorized Ricimed, the first antibody-based treatment specifically indicated for acute ricin intoxication, providing clinicians with a targeted option beyond supportive care for exposure to one of the most lethal naturally occurring toxins.

Fabentech is a French biopharmaceutical company specializing in medical countermeasures against biological threats and infectious diseases.

The polyclonal antibody technology used in the development of Ricimed has received marketing authorization in France as a treatment for ricin poisoning. Ricin is a highly toxic natural substance that can cause death within hours to a few days of exposure.

Supported by the Ministry of Armed Forces and Veterans Affairs (Directorate General of Armaments [DGA] and Armed Forces Health Service) in France, Ricimed is the first approved antidote for ricin poisoning, a condition for which treatment was previously limited to supportive measures alone.

Historical Incident

One incident, in particular, remains etched in espionage history. On September 7, 1978 in London during the Cold War, Bulgarian dissident writer Georgi Markov, living in exile, was struck by the umbrella of a passer-by while waiting at a bus stop. He felt a slight sting. Four days later, he died in the hospital due to a sudden and unexplained illness. An autopsy revealed that he had been poisoned by a tiny metal pellet implanted at the tip of an umbrella containing ricin, a lethal toxin. The legend of the “Bulgarian umbrella,” later invoked in other assassination attempts, was born.

Since then, although Markov remains the only known individual to have been killed by ricin poisoning, this theoretically extremely toxic substance, which can be manufactured relatively easily from castor beans, a widely available plant, has continued to fascinate authors of thrillers and spy novels.

Numerous works of fiction depict characters who succumb to ricin poisoning. The toxin is notably portrayed as a favored weapon of the main character in the hit television series Breaking Bad.

However, ricin is not confined to the realm of science fiction. For several years, authorities in various countries have feared that extremist groups could carry out attacks using ricin. The threat has been taken particularly seriously since 2018, when a clandestine ricin laboratory operated by members of the Islamic State was dismantled in Germany. Since then, several similar attack plots have been thwarted.

This context triggered a race among major powers to develop an effective antidote as quickly as possible. In this effort, Fabentech has risen to a challenge.

“Having demonstrated its ability to target and then neutralize ricin before it causes irreparable damage, Ricimed is a treatment that works based on polyclonal antibodies and compensates for the absence of a vaccine or specific treatment,” Fabentech said in a press release.

The polyclonal antibody technology used by Fabentech offers potential for the development of antidotes against bioterrorist attacks and for the treatment of many infectious diseases.

Ricimed contributed to the deployment of a European health shield against intentional biological threats in France.

Military Backing

Speaking to Le Figaro, France’s oldest national newspaper, Fabentech CEO Sébastien Iva explained that ricin disrupts the body by halting cell function, while noting several other drug candidates in development at the firm.

Typically, the lungs sustain fatal damage. Our treatment interrupts this toxic process. In animals administered the antidote, we observed pulmonary function recovery, allowing survival.

Given that the possibility of terrorist attacks using ricin is considered a national security issue, Fabentech benefited from the support by the Ministry of the Armed Forces and the DGA and lasted nearly a decade of research and development work.

The granting of marketing authorisation was also supported by the French Armed Forces and welcomed by the French Minister of the Armed Forces, Catherine Vautrin, who previously served as France’s Minister of Labour, Health, and Solidarity.

“Supporting the development of companies in France capable of manufacturing antidotes against certain biological agents helps guarantee the operational superiority of our armed forces. Developing and producing such drugs when they do not yet exist on the market is also serving the nation and the public interest,” she said.

Although the threat posed by ricin remains hypothetical, Fabentech reports a strong interest from potential clients, with many countries seeking protection against possible bioterrorist attacks.

The DGA had already placed an order for several doses of Ricimed for deployment in France. For optimal effectiveness, the antidote must be administered within 6 hours of poisoning. Iva confirmed that multiple countries had already expressed interest in acquiring the antidote.

This story was translated from JIM, part of the Medscape Professional Network.

A version of this article first appeared on Medscape.com.

France has authorized Ricimed, the first antibody-based treatment specifically indicated for acute ricin intoxication, providing clinicians with a targeted option beyond supportive care for exposure to one of the most lethal naturally occurring toxins.

Fabentech is a French biopharmaceutical company specializing in medical countermeasures against biological threats and infectious diseases.

The polyclonal antibody technology used in the development of Ricimed has received marketing authorization in France as a treatment for ricin poisoning. Ricin is a highly toxic natural substance that can cause death within hours to a few days of exposure.

Supported by the Ministry of Armed Forces and Veterans Affairs (Directorate General of Armaments [DGA] and Armed Forces Health Service) in France, Ricimed is the first approved antidote for ricin poisoning, a condition for which treatment was previously limited to supportive measures alone.

Historical Incident

One incident, in particular, remains etched in espionage history. On September 7, 1978 in London during the Cold War, Bulgarian dissident writer Georgi Markov, living in exile, was struck by the umbrella of a passer-by while waiting at a bus stop. He felt a slight sting. Four days later, he died in the hospital due to a sudden and unexplained illness. An autopsy revealed that he had been poisoned by a tiny metal pellet implanted at the tip of an umbrella containing ricin, a lethal toxin. The legend of the “Bulgarian umbrella,” later invoked in other assassination attempts, was born.

Since then, although Markov remains the only known individual to have been killed by ricin poisoning, this theoretically extremely toxic substance, which can be manufactured relatively easily from castor beans, a widely available plant, has continued to fascinate authors of thrillers and spy novels.

Numerous works of fiction depict characters who succumb to ricin poisoning. The toxin is notably portrayed as a favored weapon of the main character in the hit television series Breaking Bad.

However, ricin is not confined to the realm of science fiction. For several years, authorities in various countries have feared that extremist groups could carry out attacks using ricin. The threat has been taken particularly seriously since 2018, when a clandestine ricin laboratory operated by members of the Islamic State was dismantled in Germany. Since then, several similar attack plots have been thwarted.

This context triggered a race among major powers to develop an effective antidote as quickly as possible. In this effort, Fabentech has risen to a challenge.

“Having demonstrated its ability to target and then neutralize ricin before it causes irreparable damage, Ricimed is a treatment that works based on polyclonal antibodies and compensates for the absence of a vaccine or specific treatment,” Fabentech said in a press release.

The polyclonal antibody technology used by Fabentech offers potential for the development of antidotes against bioterrorist attacks and for the treatment of many infectious diseases.

Ricimed contributed to the deployment of a European health shield against intentional biological threats in France.

Military Backing

Speaking to Le Figaro, France’s oldest national newspaper, Fabentech CEO Sébastien Iva explained that ricin disrupts the body by halting cell function, while noting several other drug candidates in development at the firm.

Typically, the lungs sustain fatal damage. Our treatment interrupts this toxic process. In animals administered the antidote, we observed pulmonary function recovery, allowing survival.

Given that the possibility of terrorist attacks using ricin is considered a national security issue, Fabentech benefited from the support by the Ministry of the Armed Forces and the DGA and lasted nearly a decade of research and development work.

The granting of marketing authorisation was also supported by the French Armed Forces and welcomed by the French Minister of the Armed Forces, Catherine Vautrin, who previously served as France’s Minister of Labour, Health, and Solidarity.

“Supporting the development of companies in France capable of manufacturing antidotes against certain biological agents helps guarantee the operational superiority of our armed forces. Developing and producing such drugs when they do not yet exist on the market is also serving the nation and the public interest,” she said.

Although the threat posed by ricin remains hypothetical, Fabentech reports a strong interest from potential clients, with many countries seeking protection against possible bioterrorist attacks.

The DGA had already placed an order for several doses of Ricimed for deployment in France. For optimal effectiveness, the antidote must be administered within 6 hours of poisoning. Iva confirmed that multiple countries had already expressed interest in acquiring the antidote.

This story was translated from JIM, part of the Medscape Professional Network.

A version of this article first appeared on Medscape.com.

France has authorized Ricimed, the first antibody-based treatment specifically indicated for acute ricin intoxication, providing clinicians with a targeted option beyond supportive care for exposure to one of the most lethal naturally occurring toxins.

Fabentech is a French biopharmaceutical company specializing in medical countermeasures against biological threats and infectious diseases.

The polyclonal antibody technology used in the development of Ricimed has received marketing authorization in France as a treatment for ricin poisoning. Ricin is a highly toxic natural substance that can cause death within hours to a few days of exposure.

Supported by the Ministry of Armed Forces and Veterans Affairs (Directorate General of Armaments [DGA] and Armed Forces Health Service) in France, Ricimed is the first approved antidote for ricin poisoning, a condition for which treatment was previously limited to supportive measures alone.

Historical Incident

One incident, in particular, remains etched in espionage history. On September 7, 1978 in London during the Cold War, Bulgarian dissident writer Georgi Markov, living in exile, was struck by the umbrella of a passer-by while waiting at a bus stop. He felt a slight sting. Four days later, he died in the hospital due to a sudden and unexplained illness. An autopsy revealed that he had been poisoned by a tiny metal pellet implanted at the tip of an umbrella containing ricin, a lethal toxin. The legend of the “Bulgarian umbrella,” later invoked in other assassination attempts, was born.

Since then, although Markov remains the only known individual to have been killed by ricin poisoning, this theoretically extremely toxic substance, which can be manufactured relatively easily from castor beans, a widely available plant, has continued to fascinate authors of thrillers and spy novels.

Numerous works of fiction depict characters who succumb to ricin poisoning. The toxin is notably portrayed as a favored weapon of the main character in the hit television series Breaking Bad.

However, ricin is not confined to the realm of science fiction. For several years, authorities in various countries have feared that extremist groups could carry out attacks using ricin. The threat has been taken particularly seriously since 2018, when a clandestine ricin laboratory operated by members of the Islamic State was dismantled in Germany. Since then, several similar attack plots have been thwarted.

This context triggered a race among major powers to develop an effective antidote as quickly as possible. In this effort, Fabentech has risen to a challenge.

“Having demonstrated its ability to target and then neutralize ricin before it causes irreparable damage, Ricimed is a treatment that works based on polyclonal antibodies and compensates for the absence of a vaccine or specific treatment,” Fabentech said in a press release.

The polyclonal antibody technology used by Fabentech offers potential for the development of antidotes against bioterrorist attacks and for the treatment of many infectious diseases.

Ricimed contributed to the deployment of a European health shield against intentional biological threats in France.

Military Backing

Speaking to Le Figaro, France’s oldest national newspaper, Fabentech CEO Sébastien Iva explained that ricin disrupts the body by halting cell function, while noting several other drug candidates in development at the firm.

Typically, the lungs sustain fatal damage. Our treatment interrupts this toxic process. In animals administered the antidote, we observed pulmonary function recovery, allowing survival.

Given that the possibility of terrorist attacks using ricin is considered a national security issue, Fabentech benefited from the support by the Ministry of the Armed Forces and the DGA and lasted nearly a decade of research and development work.

The granting of marketing authorisation was also supported by the French Armed Forces and welcomed by the French Minister of the Armed Forces, Catherine Vautrin, who previously served as France’s Minister of Labour, Health, and Solidarity.

“Supporting the development of companies in France capable of manufacturing antidotes against certain biological agents helps guarantee the operational superiority of our armed forces. Developing and producing such drugs when they do not yet exist on the market is also serving the nation and the public interest,” she said.

Although the threat posed by ricin remains hypothetical, Fabentech reports a strong interest from potential clients, with many countries seeking protection against possible bioterrorist attacks.

The DGA had already placed an order for several doses of Ricimed for deployment in France. For optimal effectiveness, the antidote must be administered within 6 hours of poisoning. Iva confirmed that multiple countries had already expressed interest in acquiring the antidote.

This story was translated from JIM, part of the Medscape Professional Network.

A version of this article first appeared on Medscape.com.