Case Report of an Uncommon Dermatologic Manifestation of Disseminated Stenotrophomonas Maltophilia Infection in a Patient With Aplastic Anemia

Case Report

Ecthyma gangrenosum (EG) is a cutaneous infection frequently associated with disseminated Gram-negative bacteremia. Most reports of ecthyma gangrenosum occur in patients who are critically ill, immunocompromised, and have disseminated Pseudomonas aeruginosa infection with bacteremia. ¹ Skin lesions associated with EG are characterized as hemorrhagic vesicles or pustules that evolve into necrotic ulcers with an erythematous border and usually affect the axillary and anogenital area, sometimes involving the arms, legs, trunk, and face. The appearance of EG is due to bacterial infiltration into the arteries and veins in the skin and subcutaneous tissue causing cellular damage and ischemic necrosis. EG has also been reported in cases associated with invasive Gram-positive bacteria as well as fungal infections.

EG from Stenotrophomonas maltophilia bacteremia is a rare manifestation, with only 12 patient case reports found in a literature search and 1 case series on skin manifestation of S. maltophilia. In the case series, there were 6 cases identified as metastatic cellulitis. ² The diagnosis of EG is often overlooked resulting in delays in appropriate treatment. We describe a case of EG associated with S. maltophilia bacteremia in a patient with aplastic anemia and prolonged neutropenia secondary to antithymocyte globulin therapy, cyclosporine, and methylprednisolone administration. This case highlights significant challenges associated with managing disseminated S. maltophilia infection in an immunocompromised host. These difficulties impacted treatment selection, progressing to bone marrow transplantation, and achieving culture clearance. To our knowledge, this is the first case report in a patient with aplastic anemia undergoing triple therapy who developed this condition and we hope to offer valuable insights that may help guide treatment decisions for this specific patient population.

Case Presentation

In early February 2024, a 41-year-old male presented to outside hospital (OSH) A with hematuria, initial vitals on presentation was significant for BP: 96/63 mmHg and HR: 91 bpm. Patient also had significant laboratory findings for pancytopenia; notably, leukopenia with white blood cell counts (WBC): 500 cells/µL, anemia with hemoglobin (Hgb): 7.1 g/dL, thrombocytopenia with a platelet count (Plt): 21,000 cells/mm³, and neutropenia with absolute neutrophil count (ANC): 0 cells/mm³. He subsequently underwent a bone marrow biopsy and was diagnosed with aplastic anemia. His course was complicated by S. maltophilia bacteremia, with persistent positive cultures lasting less than 72 hours for which the patient was started on dual therapy with oral minocycline 100 mg every 12 hours and sulfamethoxazole-trimethoprim (TMP-SMX) 800-160 mg, 2 tablets every 8 hours. Subsequent workup also showed evidence of numerous inflammatory pulmonary nodules with additional smaller ground glass opacities which were initially concerning for fungal etiology, although all subsequent work-up for invasive fungal infection remained negative. The patient completed only 3 days of antibiotics prior to leaving the hospital against medical advice.

Four weeks after the initial presentation, the patient was admitted to OSH B with epistaxis. On admission, patient’s vitals were stable and laboratory finding was significant for pancytopenia; with WBC: 230 cells/µL, Hgb: 6.7 g/dL, Plt: 4000 cells/mm³, ANC: 100 cells/mm³. Although his 2 sets of blood cultures remained negative, he was restarted on intravenously (IV) minocycline 100 mg every 12 hours and TMP-SMX IV at 5 mg/kg every 12 hours for 2 weeks. On day 2 of admission, patient remains febrile, so cefepime 2g q8h and vancomycin 15 mg/kg q12h was added for neutropenic fever and patient was also started on posaconzole and acyclovir for fungal and HSV prophylaxis. Ultimately patient was transferred to the authors’ institution for management of aplastic anemia. Upon transfer to author’s institution, patient’s vitals were significant for Temp: 38.8°C and BP: 107/65 mmHg and HR 97 bpm. Significant laboratory findings included WBC: 240 cells/µL, Hgb: 7.1 g/dL, Plt: 17,000 cells/mm³, ANC: 100 cells/mm³. Patient remained on empiric antibiotic treatment for neutropenic fever with cefepime and vancomycin and was on antifungal and HSV prophylaxis.

The hematology and oncology service was consulted and patient was initiated on triple therapy with antithymocyte globulin (ATG), cyclosporine, and eltrombopag. Following ATG 40 mg/kg daily for 4 days, the patient developed diffuse monomorphic erythematous papules on the face, trunk, and all four extremities (Figure 1). Infectious Disease and dermatology were consulted and diagnostic workup included testing for disseminated fungal infection (aspergillus, candidiasis, cryptococcus, coccidioidomycosis, histoplasmosis, Blastomyces), disseminated bacterial infection, HSV or VZV, and additional differential included folliculitis/steroid acne, urticaria or serum sickness secondary to receiving antithymocyte globulin therapy, or arthropod bites. Biopsies of the lesions were performed. Patient was transitioned from prophylaxis dosing of acyclovir for HSV and posaconazole for fungal infection to treatment dose of acyclovir 10 mg/kg IV every 8 hours for disseminated herpes simplex virus/varicella zoster virus (HSV/VZV) infection and isavuconazonium sulfate 372 mg PO every 8 hour for 6 doses follow by maintenance dose of 372 mg PO daily for management of disseminated fungal infection. . He had also been started on empiric vancomycin and cefepime due to concern for a multiloculated fluid collection in the right calf, thought to be a chronic hematoma that was possibly superinfected. Later, an HSV and VZV PCR swab from a skin lesion was negative and acyclovir was discontinued.OPEN IN VIEWER

Two days later blood cultures, sputum, and skin biopsy cultures again grew out S. maltophilia. Dermatopathology from the skin biopsy revealed clusters of bacterial organisms emanating from the vascular lumina into the dermis. The results from blood culture, skin biopsy culture, and pathology confirms diagnosis of disseminated S. maltophilia infection with dissemination to skin. Antimicrobial susceptibility testing demonstrated resistance to TMP-SMX and levofloxacin and the patient was started on cefiderocol 2g IV every 6 hours and oral minocycline 200 mg every 12 hours in consultation with infectious diseases specialists. His course was further complicated by persistent febrile neutropenia. Follow-up blood cultures confirmed clearance of S. maltophilia at the time, but instead grew out vancomycin-resistant Enterococcus faecium. Clinically patient continued to have diffuse erythematous painful papules more diffuse on the face, trunk, and upper and lower extremities with new lesions on bilateral palms and soles. (Figure 2). Blood cultures remained positive for E. faecium for 8 days, despite therapy with linezolid 600 mg oral every 12 hours which was concerning for an endovascular focus. Patient at this time was transitioned to daptomycin 10 mg/kg IV every 24 hours. A transthoracic echocardiogram did not reveal any valvular vegetations, but he was deemed a poor candidate for a transesophageal echocardiogram due to his immunocompromised state.OPEN IN VIEWER

Outcome and Follow-up

The patient was continued on cefiderocol and oral minocycline for treatment of S. maltophilia for a combined 5-week treatment duration at which point the skin lesions no longer appeared infected (Figure 3). The patient was transitioned back to levofloxacin for neutropenic prophylaxis and remained on oral minocycline to prevent a relapse of S. maltophilia infection. However, 10 days after discontinuation of cefiderocol, the patient again grew out S. maltophilia in blood culture, sensitive to cefiderocol and minocycline. The patient was reinitiated on cefiderocol and continued on oral minocycline. Three weeks later, the patient was discharged to home hospice care after extensive discussion with palliative care and psychiatry to focus on quality of life over ongoing treatment, due to poor bone marrow response to treatment and ongoing infectious complications. After discharge, attempts were made by phone to reach out to the patient for follow up but patient was not reachable and was lost to follow-up (Figure 4).OPEN IN VIEWER

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Figure 4.

Timeline of immunosuppression and targeted antimicrobial therapies once admitted to author’s institution excluding antiviral/antifungal prophylaxis

Discussion

S. maltophilia is an opportunistic multi-drug resistant organism that typically affects immunocompromised hosts. S. maltophilia is associated with the production of antimicrobial resistance enzymes including metallo-B-lactamases that make most beta-lactam antimicrobials ineffective against this organism. Further resistance is garnered to fluoroquinolones and TMP-SMX via multi-drug efflux pumps. ³

IDSA 2024 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections recommends an initial approach for the treatment of Stenotrophomonas infections with the combination of two antimicrobials either with two of the following: TMP-SMX, levofloxacin, cefiderocol, or minocycline; or with the combination of ceftazidime-avibactam and aztreonam. A standard-of-care antibiotic regimen for S. maltophilia infection is not evident due to lack of clinical trials comparing the effectiveness of commonly used agents for S. maltophilia. ⁴

S. maltophilia is frequently associated with polymicrobial infections with rates ranging from 33-70%. One of the organisms identified as a common co-infecting bacterium in these polymicrobial infections is Enterococcus sp., which is notable because our patient also had vancomycin-resistant E. faecium bacteremia. Notably, S. maltophilia is known for its production of a biofilm which can occur in the lungs creating a friendly environment for organism growth. ⁵ During this admission, the patient was found to have pulmonary nodules that were unchanged by effective therapy for S. maltophilia although his sputum also grew out the organism.

Empiric treatment of EG typically involves antimicrobials with anti-pseudomonal activity as EG is most often described in disseminated Pseudomonas aeruginosa infections. Debridement of the lesion is recommended based on the depth and extent of cutaneous infection. Prompt diagnosis and recognition of EG is vital as EG most often occurs in critically ill, immunocompromised patients. ⁶

We conducted a systematic PubMed search on August 2024 for previously published cases of EG and cellulitis caused by S. maltophilia. To isolate only cases involving systematic dissemination, we excluded instances of primary cellulitis where no disseminated disease was present, as verified by positive blood culture for S. maltophilia. The results of our review are summarized in Table 1. All prior patient cases had diagnosis of either hematologic malignancy or aplastic anemia. From the literature review, common risk factors for S. maltophilia infection include prolonged hospitalization, extended periods of neutropenia, and exposure to broad-spectrum antimicrobials which provide a selective pressure that favors growth of S. maltophilia. A total of 8 out of 18 patient cases had poor outcomes and expired due to treatment failure and prolonged neutropenia. Skin lesions in these cases were often characterized as erythematous, painful nodules, and sometimes as hemorrhagic, necrotic, gangrenous, or vesicular. A majority of the S. maltophilia organisms were sensitive to TMP-SMX and treatment choices varied from TMP-SMX, levofloxacin, tigecycline, or colistin, minocycline, moxalactam, and ceftazidime. For cases that mention the duration of antimicrobial therapy, the most common treatment duration was 14 days.

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Table 1.

A Literature Review of Cases Reported as EG or Metastatic Cellulitis Associated With S. maltophilia

Reference	Patient information	Acquisition	Predisposing factors	Physical findings	Source of positive culture	Treatment	Outcome
Bin Abdulhak et al. (2009) 7	47 YOF	Nosocomial	Relapsed AML on induction chemotherapy	Left arm pain and swelling with overlying erythema and tenderness	Skin biopsy and blood culture	TMP-SMX for 14 days	Swelling and erythema resolved after 2 weeks of therapy.
Bottone EJ et al. (1986) 8	66 YOF	Nosocomial	Relapsed AML on chemotherapy	Warm, raised indurated lesions on inner aspect of both thighs. Legions enlarged over 2 days with dusky violaceous center surrounded by erythema	Blood culture and aspirate of skin lesion	Moxalactam of unknown duration	Skin lesion resolved and had clearance of bacteremia.
Burns RL et al. (1997) 9	57 YOM	Nosocomial	ALL treated with chemotherapy and steroids and was on consolidation chemotherapy	Erythematous, tender nodules on bilateral lower extremities	Skin biopsy, venous catheter culture, and blood culture	TMP-SMX and ciprofloxacin for 21 days	Skin lesions resolved, but patient expired from candidemia.
Das DK et al. (2016) 10	9-month-old M	Unknown	ALL and completed induction chemotherapy	A small indurated papulovesicle on nose that evolved into a necrotic ulcer with central black eschar and surrounding erythema	Blood and skin lesion culture	Colistin based on sensitivities for 14 days	Lesion healed completely after 2 weeks of therapy and patient was discharged 21 days after admission.
Moser et al. (1997) 11	44 YOF	Nosocomial	Relapsed ALL and started on induction chemotherapy	Tender, erythematous lesion found on bilateral lower extremities, back and chest.	Blood culture and skin biopsy	TMP-SMX and ceftazidime	Lesions resolved after 12 days of treatment.
	65 YOF	Nosocomial	AML on induction chemotherapy	Tender, red, not well demarcated subcutaneous lesion on thigh, chest, and back	Blood culture	Ceftazidime	Recovered after 10 days of treatment.
Muder RR et al. (1987) 12	48 YOF	Nosocomial	Relapsed ALL on reinduction chemotherapy	Circular, raised, erythematous lesion on lower extremities and tender to palpation	Blood culture and skin biopsy	TMP-SMX, and moxalactam for 14 days	Patient’s skin lesions resolved.
Sakhnini E et al. (2002) 13	29 YOF	Nosocomial	Aplastic anemia on high dose IVIG and steroids	Pain in right shoulder and in the chest wall along the catheter tract. Found with gangrene of skin and soft tissue of the chest wall.	Blood culture, chest wall tissue culture, and mitral valve vegetation culture	Post-mortem diagnosis	Patients expired
Sarkar S et al. (2024) 14	14 YOF	Nosocomial	Mixed T-cell myeloid leukemia refractory to treatment	Right necrotic, erythematous heel wound	Tracheostomy culture, heel wound culture and blood culture	TMP-SMX, ceftazidime, and minocycline	Patient expired on day of 12 of hospitalization
Son YM et al. (2009) 15	47 YOM	Nosocomial	AML underwent allogenic bone marrow transplant	Edematous, erythematous, and necrotic plaques with bullae formation around lip that developed into necrotic, hemorrhagic vesicles	Blood culture, and skin biopsy	Post-mortem diagnosis	Patient expired
Takagi I et al. (2023) 16	45 YOF	Nosocomial	B cell ALL underwent cord blood transplantation with myeloablative conditioning regimen. Patient was also on cyclosporine and methotrexate and hydrocortisone.	Painful blister on right lateral malleolus. Symptoms migrated to right dorsum of the foot and left wrist joint within a few days.	Blood culture and blister puncture culture	TMP-SMX and levofloxacin patient was on treatment for 14 days	Patient expired
Teo WY et al. (2006) 17	8 YOF	Nosocomial	Relapsed AML after chemotherapy and re-induced with a course of FLAG-Ida chemotherapy.	Painful, erythematous lesion on the limbs. Lesions were nodular and tender without central necrosis noted.	Blood culture and skin biopsy	TMP-SMX for 7 days	Lesions gradually resolved after a week of TMP-SMX therapy.
Vartivarian SE et al. (1994) 2	6 patients median age 38, 2 male and 4 female	Unknown	ALL (4 patients)	Hard, nonfluctuant, tender skin, or subcutaneous nodules characterized by warmth and violaceous erythema of overlying skin. Black central necrosis or ulcerations developed in some nodules and cellulitic areas. Skin lesions involved extremities, scalp, back, and abdomen.	Blood cultures, skin biopsy	TMP-SMX	2 patients responded to treatment when they recovered from myelosuppression. The other 4 expired due to persistent neutropenia (median 10 days) post onset of skin lesions.
			AML (1 patient)
			CLL (1 patient)

There is a lack of clinical data guiding selection and duration of antibiotic therapy for management of ecthyma gangrenosum in general and in particular with the organism described. Of the case reports that have been published, two articles demonstrated a treatment duration of 2 weeks of which the patient had resolution of their infection. In the other case reports published, no duration of therapy had been determined, either due to post-mortem identification of the organism or transition to comfort care. Our patient suffered a recurrence of bacteremia when effective dual therapy was discontinued despite continuation of minocycline monotherapy. Possible reasons for recurrence of bacteremia include patient’s immunosuppression, incomplete source control, as patient had a thigh abscess that was not drained and pulmonary nodules that were unchanged even after months of antibiotic therapy, and lack of highly effective antimicrobial agent targeting Stenotrophomonas maltophilia infections. The ideal duration of therapy was, further, not able to be determined due to the patient’s discharge to home hospice care following a prolonged hospital admission. Patient’s persistent immunosuppression from aplastic anemia was the most complicating factor in achieving clinical cure. This patient’s clinical course further supports the need for prolonged courses in patients with persistent neutropenia, the importance of managing infection source, and monitoring for recurrence.

Conclusions

Stenotrophomonas maltophilia is a multi-drug resistant, Gram-negative organism associated with nosocomial settings that can be pathogenic in an immunocompromised host. Here, we present a rare case of ecthyma gangrenosum secondary to S. maltophilia in a patient with neutropenia who had received antithymocyte globulin as a component of triple therapy for aplastic anemia 1 week prior to the development of the skin manifestations depicted in this report.