Sanjay G. Revankar

Melanized Fungi in Human Disease

SUMMARY Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections.

Primary Central Nervous System Phaeohyphomycosis: A Review of 101 Cases

Phaeohyphomycosis refers to infections caused by darkly pigmented fungi. These fungi rarely cause life-threatening disease. We reviewed 101 cases of culture-proven primary central nervous system phaeohyphomycosis reported in the English-language literature from 1966 to 2002. The most frequently isolated species was Cladophialophora bantiana. The next most frequent isolate was Ramichloridium mackenziei, seen exclusively in patients from the Middle East. More than one-half of the cases occurred in patients with no known underlying immunodeficiency. Mortality rates were high regardless of immune status. Therapy is not standardized, although the combination of amphotericin B, flucytosine, and itraconazole may improve survival rates. Newer azoles, such as voriconazole, also have a broad spectrum of activity against these fungi, although clinical experience is limited. Complete excision of brain lesions may provide better results than simple aspiration. An aggressive medical and surgical approach is warranted in treating these infections to optimize outcomes.

Genetic Diversity of Human Pathogenic Members of the Fusarium oxysporum Complex Inferred from Multilocus DNA Sequence Data and Amplified Fragment Length Polymorphism Analyses: Evidence for the Recent Dispersion of a Geographically Widespread Clonal Lineage and Nosocomial Origin

ABSTRACT Fusarium oxysporum is a phylogenetically diverse monophyletic complex of filamentous ascomycetous fungi that are responsible for localized and disseminated life-threatening opportunistic infections in immunocompetent and severely neutropenic patients, respectively. Although members of this complex were isolated from patients during a pseudoepidemic in San Antonio, Tex., and from patients and the water system in a Houston, Tex., hospital during the 1990s, little is known about their genetic relatedness and population structure. This study was conducted to investigate the global genetic diversity and population biology of a comprehensive set of clinically important members of the F. oxysporum complex, focusing on the 33 isolates from patients at the San Antonio hospital and on strains isolated in the United States from the water systems of geographically distant hospitals in Texas, Maryland, and Washington, which were suspected as reservoirs of nosocomial fusariosis. In all, 18 environmental isolates and 88 isolates from patients spanning four continents were genotyped. The major finding of this study, based on concordant results from phylogenetic analyses of multilocus DNA sequence data and amplified fragment length polymorphisms, is that a recently dispersed, geographically widespread clonal lineage is responsible for over 70% of all clinical isolates investigated, including all of those associated with the pseudoepidemic in San Antonio. Moreover, strains of the clonal lineage recovered from patients were conclusively shown to genetically match those isolated from the hospital water systems of three U.S. hospitals, providing support for the hypothesis that hospitals may serve as a reservoir for nosocomial fusarial infections.

A randomized trial of continuous or intermittent therapy with fluconazole for oropharyngeal candidiasis in HIV-infected patients: clinical outcomes and development of fluconazole resistance

PURPOSE The effects of continuous or intermittent therapy with fluconazole on the recurrence of and the development of fluconazole resistance are not known. PATIENTS AND METHODS We studied human immunodeficiency virus (HIV)-positive patients with CD4 cell count <350 x 10(6)/L and oropharyngeal candidiasis in a prospective, randomized study. After initial treatment, 20 patients (16 of whom completed 3 months of follow-up) received continuous fluconazole at 200 mg/day, and 48 patients (28 of whom completed follow-up) received intermittent therapy at the time of symptomatic relapses. Oral samples were obtained weekly during episodes of infection and quarterly as surveillance cultures. Development of resistance was defined as a fourfold rise in minimum inhibitory concentration (MIC) to at least 16 microg/mL from the initial culture in the same species, the emergence of new, resistant (MIC > or =16 microg/mL) species, or a significant increase in the proportion of resistant isolates. RESULTS During a mean follow-up of 11 months, median annual relapse rates were lower in patients on continuous therapy (0 episodes/year) than in patients on intermittent therapy (4.1 episodes/year; P <0.001). Sterile cultures were seen in 6 of 16 (38%) patients on continuous therapy compared with 3 of 28 (11%) on intermittent therapy (P = 0.04). Microbiological resistance developed in 9 of 16 (56%) patients on continuous treatment, compared with 13 of 28 (46%) on intermittent treatment (P = 0.75). However, despite isolates with increased MICs, 42 of 44 patients responded to fluconazole in doses up to 800 mg/day. CONCLUSIONS In patients with frequent recurrences, continuous suppressive therapy significantly reduced relapses and colonization. Resistance occurred with both continuous and intermittent therapy; however, therapeutic responses were excellent.

infected Cardiac Myxoma: Case Report and Literature Review

We present a case of a left atrial myxoma infected with Porphyromonas asaccharolytica in a 55-year-old man, successfully treated with surgical excision and a brief course of antibiotic therapy. Infected cardiac myxomas are extremely rare, with only 39 cases previously reported. They can be difficult to diagnose due to their protean clinical manifestations, which can often be seen in uninfected myxomas as well. We suggest that blood cultures and careful pathologic examination be performed in all cases of cardiac myxoma with constitutional symptoms. However, fever and elevated sedimentation rate are significantly more common in infected tumors. Organisms responsible are similar in distribution to those causing bacterial endocarditis. Emboli, though frequent, may not be more common in infected than uninfected myxomas. Case reports have become more common since the development of better diagnostic techniques. Echocardiography, especially by the transesophageal approach, is the diagnostic procedure of choice, and sensitivity approaches 100%. Surgical excision is curative and generally has low morbidity and mortality.

In vitro interaction of posaconazole with calcineurin inhibitors and sirolimus against zygomycetes

OBJECTIVES Zygomycosis is an uncommon but devastating disease with few therapeutic options. Calcineurin inhibitors and sirolimus (mTOR inhibitor), commonly used in transplant patients as immunosuppressives, have antifungal activity. They are known to demonstrate synergy with triazoles against certain fungi, though limited data exist about their activity against zygomycetes. Our aim was to study the in vitro interaction of posaconazole with calcineurin inhibitors and sirolimus against zygomycetes. METHODS Drug interactions were assessed with chequerboard dilution for posaconazole with calcineurin inhibitors and sirolimus according to the CLSI M38-A2 method for filamentous fungi. Twenty-eight clinical isolates were studied, including Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Mucor sp., Cunninghamella bertholletiae, Myocladus corymbifera and Apophysomyces elegans. Combinations of posaconazole with tacrolimus, cyclosporin A or sirolimus were used. Experiments were performed in duplicate. Mean fractional inhibitory concentration indices were calculated. RESULTS Posaconazole with calcineurin inhibitors demonstrated consistent synergy against C. bertholletiae, M. corymbifera and A. elegans, whereas synergy or no interaction was primarily observed against R. arrhizus, R. microsporus, R. pusillus and Mucor. Antagonism was seen with the combination of posaconazole and sirolimus. Strain variability was noted among the same species. CONCLUSIONS The clinical significance of these findings is unclear, but further studies are warranted given the potential for concomitant use of these agents in transplant patients treated for zygomycosis.

Clostridium Difficile Colonization in Hematopoietic Stem Cell Transplant Recipients: A Prospective Study of the Epidemiology and Outcomes Involving Toxigenic and Nontoxigenic Strains

Clostridium difficile is a leading cause of infectious diarrhea in hematopoietic stem cell transplant (HSCT) recipients. Asymptomatic colonization of the gastrointestinal tract occurs before development of C. difficile infection (CDI). This prospective study examines the rates, risk factors, and outcomes of colonization with toxigenic and nontoxigenic strains of C. difficile in HSCT patients. This 18-month study was conducted in the HSCT unit at the Karmanos Cancer Center and Wayne State University in Detroit. Stool samples from the patients who consented for the study were taken at admission and weekly until discharge. Anaerobic culture for C. difficile and identification of toxigenic strains by PCR were performed on the stool samples. Demographic information and clinical and laboratory data were collected. Of the 150 patients included in the study, 29% were colonized with C. difficile at admission; 12% with a toxigenic strain and 17% with a nontoxigenic strain. Over a 90-day follow-up, 12 of 44 (26%) patients colonized with any C. difficile strain at admission developed CDI compared with 13 of 106 (12%) of patients not colonized (odds ratio [OR], 2.70; 95% confidence interval [95% CI], 1.11 to 6.48; P = .025). Eleven of 18 (61%) patients colonized with the toxigenic strain and 1 of 26 (4%) of those colonized with nontoxigenic strain developed CDI (OR, 39.30; 95% CI, 4.30 to 359.0; P < .001) at a median of 12 days. On univariate and multivariate analyses, none of the traditional factors associated with high risk for C. difficile colonization or CDI were found to be significant. Recurrent CDI occurred in 28% of cases. Asymptomatic colonization with C. difficile at admission was high in our HSCT population. Colonization with toxigenic C. difficile was predictive of CDI, whereas colonization with a nontoxigenic C. difficile appeared protective. These findings may have implications for infection control strategies and for novel approaches for the prevention and preemptive treatment of CDI in the HSCT patient population.

Successful treatment of primary cutaneous Aspergillus ustus infection with surgical debridement and a combination of voriconazole and terbinafine

Aspergillus ustus infections are associated with a high mortality in immunocompromised hosts, and the mold has decreased susceptibility to most antifungal drugs, especially azoles. We report primary cutaneous A. ustus infection in a patient who failed itraconazole therapy and was switched to voriconazole (VRC). During VRC therapy, the MICs of VRC, amphotericin B (AMB), caspofungin (CFG), and terbinafine (TBF) were 4, 2, 64, and 0.13 microg/mL, respectively. Because the MIC to VRC was high, TBF was added to VRC for synergy based on anecdotal data from other mycoses. After treatment with VRC and TBF for 5 months, MICs of VRC, AMB, CFG, and TBF of A. ustus were 8, 1, 64, and 4 microg/mL respectively. Although the MICs of VRC and TBF increased during antifungal therapy, the patient responded well to the combination antifungal therapy with surgical debridement. With a successful outcome despite high MICs and with limited therapeutic options currently available, we investigated the in vitro activity of posaconazole (PCZ) and VRC individually and in combination with AMB, CFG, or TBF using the fractional inhibitory concentration index (FICI) method. Combination of VRC with TBF showed synergistic activity (FICI = 0.5). Therefore, combination of VRC and TBF with surgical debridement, when appropriate, may be a viable treatment option for refractory A. ustus infections.

Use of terbinafine in rare and refractory mycoses

Terbinafine is the only systemic allylamine antifungal currently available. Its mechanism of action is unique and sets it apart from other agents. Although it is primarily used for dermatophyte infections, such as onychomycosis and tinea pedis, terbinafine has broad in vitro activity against a variety of non-dermatophyte fungal pathogens, including Candida spp. and many molds. In addition, synergistic activity is noted with other antifungals, notably triazoles. Multiple case reports exist of its use for unusual and refractory fungal infections, but no systematic review is available. We review the current literature with regard to in vitro data and clinical experience with terbinafine in the treatment of rare and refractory mycoses.

Hyperammonemic Encephalopathy: A Rare Presentation of Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar carcinoma (FLC) is a rare malignant hepatocellular tumor of unknown etiology, arising almost exclusively from noninfected, noncirrhotic liver of young adults. FLC has traditionally been considered to have better survival than hepatocellular carcinoma; however, this notion might be highly erroneous. Patients with metastatic disease at presentation have a dismal prognosis with 5-year survival of only 15%. We describe a case of highly aggressive metastatic FLC that presented as hyperammonemic encephalopathy, which has never been previously reported in the literature.