Pulmonary Pseudallescheria boydii infection with cutaneous zygomycosis after near drowning.

Abstract: Pseudallescheria boydii is a ubiquitously occurring fungus. While rarely causing opportunistic infection in humans, it is the most common cause of fungal pneumonia in cases of near drowning, and is associated with high mortality. P boydii typically causes cutaneous mycetomas but may invade the lungs or brain. P boydii infections are difficult to treat due to amphotericin B resistance and frequent need for surgical resection. Zygomycetous infections, often referred to as "mucormycoses," usually occur in immunocompromised hosts, trauma or burn victims. Like P boydii, these organisms are found on decaying vegetation and in soil. Zygomycetous infections generally require debridement and prolonged amphotericin B. We report a case of P boydii pneumonia with a simultaneous brain lesion and cutaneous mucormycosis in a near drowning patient. The pneumonia responded to treatment with voriconazole and the brain lesion resolved without surgery. The cutaneous mucormycosis responded to surgery and amphotericin B. This is the first documented case of simultaneous invasive P boydii and cutaneous mucormycosis successfully treated with dual systemic antifungal therapy and resection.

Key Words: mucormycosis, near drowning, Pseudallescheria boydii, voriconazole, Zygomycetes

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Case Report

A 42-year-old male with underlying hepatitis C drove into a polluted Louisiana bayou in late May. Witnessed submersion time was 8 minutes. His initial Glascow Coma Score (GCS) was three. Tracheal suction showed mud and blood before intubation.

Physical examination revealed a slender male, sedated and intubated but responsive with a GCS of 12. The physical examination was unremarkable except for diffuse wheezing. Initial hypoxemia required a fractional inspiratory oxygen of 100%. His white blood cell count was 4,300/m[m.sup.2], while hemoglobin, hematocrit, and platelet counts were normal. Urine toxicology detected cocaine and cannabinoids.

The chest radiograph (Fig. 1) showed diffuse reticulonodular opacities. Intravenous steroids were administered for presumed asthma. The patient was extubated on hospital day 3, but became febrile. He was treated empirically with antibiotics and fluconazole. When the sputum culture yielded Pseudomonas aeruginosa, the antibiotic regimen was changed to ciprofloxacin and piperacillin/tazobactam. On day 8, a chest radiograph demonstrated new cavitary lesions throughout the lung fields (Fig. 2). A transthoracic echocardiogram was negative as were sputum cultures for acid-fast bacilli. New cutaneous nodules over the abdomen, left chest wall and left upper arm were observed soon thereafter (Fig. 3a). These were incised and the drainage sent for stains and cultures, which were nondiagnostic.

On day 10, consultation was obtained for persistent fevers. Repeated blood and urine cultures remained negative. Antibiotics were discontinued except ciprofloxacin. Continued fevers prompted adding amphotericin B to cover fungal pathogens.

Axial computed tomography (CT) confirmed multiple cavitary lesions throughout both lungs (Fig. 4a) but a transesophageal echocardiogram was negative for vegetations. The previously drained nodules did not heal and a punch biopsy revealed broad, aseptate hyphae consistent with a zygomycete (Fig. 5). Because the most common fungal etiology of near drowning pneumonia is P boydii, an organism resistant to amphotericin B, bronchoscopy was performed to assess for a common pulmonary and cutaneous pathogen. Sputum cultures finally yielded heavy growth of P boydii (Fig. 6). Itraconazole was initiated while compassionate-use voriconazole was requested. The known predilection of P boydii to invade the central nervous system (CNS) prompted brain magnetic resonance imaging (MRI), revealing an 0.8 cm lesion in the right parietal white matter (Fig. 7a). An MRI one week later revealed a 50% increase in the size of the lesion (Fig. 7b). Neurosurgical resection was unnecessary, as MRI revealed resolution of the lesion following several weeks of voriconazole. Follow-up CT scans documented improvement of pulmonary lesions several weeks into therapy (Fig. 4b). Fungal cultures from the cutaneous lesions repeatedly failed to yield the suspected zygomycete, but an antibody test performed by the Centers for Disease Control confirmed a Rhizomucor species.

The patient was discharged on day 68 on oral voriconazole. He declined further therapy with amphotericin B and was re-admitted two months later with recurrent lesions of the groin, thigh and gluteal region, which were successfully excised. He has remained well with regular follow-up after one year of voriconazole.

Discussion

Near drownings occur mainly in young individuals. The case-fatality rate for near drowning pneumonia approaches 60%. (1) These pneumonias are associated with many organisms (eg, Aeromonas, Burkholderia pseudomallei, Chromobacterium violaceum, and Pseudomonas species), and difficult to distinguish from noninfectious adult respiratory distress syndromes. Fungal etiologies for near drowning pneumonias are limited, with P boydii and Aspergillus the leading organisms. These fungi are difficult to differentiate with histopathology. They are narrow (2-5 mm diameter), have acuteangle branching, many septations, and parallel walls. Thus, culture results are necessary for diagnosis.

P boydii and its asexual form, Scedosporium apiospermum are ubiquitous saprophytes in polluted streams and decaying vegetation. (2) P boydii infections in normal hosts are rare, with most cases being related to trauma, T-cell immuno-deficiencies, surgery, prosthetic devices, or near drownings in polluted waters. (1) While P boydii often cause subcutaneous infections, it is also the most common fungal agent of near drowning pneumonia. Dissemination to the CNS and endophthalmitis are common sequelae. (4,5)

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Treatment of P boydii infection is challenging since the organism is resistant to amphotericin B. Not only is the in vitro minimum inhibitory concentration (MIC) greater than clinically achievable levels at 4.4 [micro]g/mL, but amphotericin B also has poor CNS penetration. (6) Miconazole, itraconazole, fluconazole, and ketoconazole have shown in vitro activity against P boydii, alone or in combination with amphotericin B. (7)

Historically, miconazole had the best in vitro activity against P boydii with an MIC of 0.36 [micro]g/mL. (7) However, it has poor CNS penetration and is no longer available in the United States due to toxicity. Itraconazole has been moderately successful, possessing an MIC of 1.1 [micro]g/mL for P boydii. (6) There are reports of successfully treated P boydii pneumonias, and some authors (7) have recommended itraconazole as first line treatment. Ketoconazole has also shown in vitro activity against P boydii with an MIC of 1 [micro]g/mL. (4) Itraconazole and ketoconazole have historically been successful adjuvant therapy for mycetomas and pneumonias. Unfortunately, these agents achieve poor levels in the CNS (ketoconazole <10%, itraconazole <1%). (4) Fluconazole has good CNS penetration but poor activity against P boydii (MIC 18 [micro]g/mL). (4)

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The antifungal agent showing the most promise for eradication of P boydii is voriconazole. This triazole derivative, recently approved for general use, has become the treatment of choice. Voriconazole achieves CNS levels of 50% of serum concentrations with an MIC of 0.44 [micro]g/mL against P boydii. (4,6) At this writing, there are 24 reported cases of P boydii infections involving a variety of organ systems treated with voriconazole, with successful response in 63%. (8)

Zygomycetes cause serious infections in immunocompromised humans. The term "mucor" is more readily recognized and "mucormycosis" is used to describe infections caused by this fungus. Zygomycetous fungi are found in decaying vegetation and soil. (1) The zygomycetes include Rhizopus, Absidia, Cunninghamella, Rhizomucor, Synchephalastrum, Saksenaea, Apophysomyces, and Mucor. The hyphae are broad (5-15 mm diameter), nonseptate, with irregular walls and 90[degrees] branches. Zygomycetes are difficult to culture from clinical specimens, as handling often includes a grinding step, damaging fragile hyphae.

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Clinically, mucormycosis is characterized by infarction and tissue necrosis from angioinvasion. Zygomycetes are seldom pathogenic in normal hosts. Most patients with mucormycosis have underlying diseases such as diabetes mellitus, metabolic acidosis, treatment with corticosteroids, organ transplantation, acquired immunodeficiency syndrome, intravenous drug use, or burns. (9)

Fortunately, pulmonary mucormycosis was excluded in our patient. Cutaneous mucormycosis can result from inoculation of the spores into the skin from trauma or burns. The lesions are painful, indurated, and ecthymic in appearance. Dissemination of cutaneous infection is rare. Other clinical presentations of mucormycosis include rhinocerebral, gastrointestinal, CNS, renal, or bone involvement. The definitive therapy is debridement and amphotericin B.

In our patient, skin biopsy at the indurated site suggested mucormycosis. With concomitant lung and cutaneous lesions, we were concerned about a disseminated infection and we sought a unifying diagnosis. Sputum and blood cultures did not aid our differential diagnoses early in the presentation, so empiric amphotericin B was initiated. Despite the evidence of broad aseptate hyphae from skin biopsies, the relative rarity of pulmonary mucormycosis led us to seek specific diagnosis with bronchoscopy.

Confirmation of pulmonary P boydii resulted in an important change in management. Voriconazole initiation ultimately led to resolution of brain and lung lesions (Fig. 4b). The concurrent mycetomas likely resulted from skin abrasions during the accident, and ultimately responded to wide excisions (Fig. 3b). Fourteen months later, the patient has returned to his usual state of health.

When systemic fungal infection is suspected, amphotericin B is usually initiated. As it is not susceptible to amphotericin B, early consideration of P boydii is important when addressing cavitary pulmonary lesions in near drowning victims. In this setting, CNS imaging is imperative to rule out brain lesions, even without focal neurologic changes. (10) Voriconazole appears superior to itraconazole because it has a lower MIC and better CNS penetration. Voriconazole is not active against mucormycoses, for which resection with amphotericin B is the mainstay of treatment. This case illustrates the importance of syndromic recognition and scientific rigor when pursuing the diagnosis of a dual fungal infection. The separate diagnoses were critical in determining management, and hence the final outcome and survival of our patient.

Laughter is a tranquilizer with no side effects.
--Arnold Glasgow

Acknowledgment

A special thanks to Dr. Alun Wang for his aid with photos of cultures and microscopic slides.

Accepted February 8, 2004.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0683

References

1. Ender PT, Dolan MJ. Pneumonia associated with near drowning. Clin Infect Dis 1997;25:896-907.

2. Ajello L. Soil as a natural reservoir for human pathogenic fungi. Science 1956;123:876-878.

3. Deleted in proof.

4. Nesky MA, McDougal EC, Peacock JE Jr. Pseudallescheria boydii brain abscess successfully treated with voriconazole and surgical drainage: case report and literature review of central nervous system pseudallescheriasis. Clin Infect Dis 2000;31:673-677.

5. Meadow WL, Tipple MA, Rippon JW. Endophthalmitis caused by Petriellidium boydii. Am J Dis Child 1981;135:378-380.

6. Espinel-Ingroff A. In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi. J Clin Microbiol 2001;39:954-958.

7. Walsh TJ, Peter J, McGough DA, et al. Activities of amphotericin B and antifungal azoles alone and in combination against Pseudallescheria boydii. Antimicrob Agents Chemother 1995;39:1361-1364.

8. Articles available at http://www.pdr.net/pdrnet/librarian/PFDefaultActionId/pdrcommon.ProductSearch. Accessed on November 24, 2003.

9. Butala A, Bhadresh S, Cho YT, et al. Isolated pulmonary mucormycosis in an apparently normal host: a case report. J Natl Med Assoc 1995;87:572-574.

10. Walsh TJ, Karp J, and Pizzo PA. Fungal Infections of the Respiratory Tract, in Kibbler CC, Mackenzie DWR, and Odds FC (eds): Principals and Practice of Clinical Mycology. West Sussex, England: John Wiley and Sons, Itd; 1999, ed 2, pp 235-259.

RELATED ARTICLE: Key Points

* P boydii is the most common fungal etiology of pneumonia associated with near drowning, and because of frequently associated brain lesions, neuroimaging should be performed in patients with this infection.

* Infections due to mucor are treated with surgical resection and amphotericin B.

* P boydii is resistant to amphotericin B.

* Voriconazole appears to be the current drug of choice for the treatment of P boydii infections.

* Syndromic recognition plays an important role in guiding the work-up for multiple infections in cases of near drowning.

Sun Chaney, MD, Ramprasad Gopalan, MD, and Ruth E. Berggren, MD

From the Department of Medicine, Louisiana State University Health Sciences Center and the Tulane University School of Medicine, New Orleans, LA.

Reprint requests to Dr. Sun Chaney, Louisiana State University Health Sciences Center, 1542 Tulane Ave., New Orleans, LA 70112. Email: [e-mail]