Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort.

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

Strain-dependent variation in 18S ribosomal DNA Copy numbers in Aspergillus fumigatus.

Enumerating Aspergillus fumigatus CFU can be challenging since CFU determination by plate count can be difficult. CFU determination by quantitative real-time PCR (qPCR), however, is becoming increasingly common and usually relies on detecting one of the subunits of the multicopy rRNA genes. This study was undertaken to determine if ribosomal DNA (rDNA) copy number was constant or variable among different A. fumigatus isolates. FKS1 was used as a single-copy control gene and was validated against single-copy (pyrG and ARG4) and multicopy (arsC) controls. The copy numbers of the 18S rDNA subunit were then determined for a variety of isolates and were found to vary with the strain, from 38 to 91 copies per genome. Investigation of the stability of the 18S rDNA copy number after exposure to a number of different environmental and growth conditions revealed that the copy number was stable, varying less than one copy across all conditions, including in isolates recovered from an animal model. These results suggest that while the ribosomal genes are excellent targets for enumeration by qPCR, the copy number should be determined prior to using them as targets for quantitative analysis.

Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis.

We describe herein 98 hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA) (refractory in 83) who received micafungin either alone (8 patients) or in combination with other licensed antifungal therapies (OLAT) (90 patients). Of the 8 monotherapy patients, 4 were failing OLAT, received de novo micafungin, or were intolerant to prior OLAT (2 patients each). Of the 90 patients treated with combination, 7 had de novo IA and 83 had refractory infection. Most patients (81) had pulmonary IA, 42 (43%) had graft-versus-host disease (GVHD), and 26 (27%) were neutropenic (absolute neutrophil count <500 cells/mm(3)) at onset of treatment. Successful response was seen in 25/98 (26%); an additional 12 patients achieved stable disease. Response was seen in 2/9 (22%) in de novo treatment, 21/87 (24%) in refractory patients, and 2/2 (100%) in toxicity failure patients. Additionally, response was seen in 22 of the 90 (24%) patients treated with combination therapy, and in 3 of 8 (38%) patients who were treated with micafungin alone. No significant differences in responses were found based on type of HSCT, GVHD status, site of IA, or Aspergillus species, and no significant toxicity was seen. Micafungin was well tolerated, even at high doses, and is a reasonable option for treatment of IA in this high-risk patient population.

Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.

During the past several decades, there has been a steady increase in the frequency of opportunistic invasive fungal infections (IFIs) in immunocompromised patients. However, there is substantial controversy concerning optimal diagnostic criteria for these IFIs. Therefore, members of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group formed a consensus committee to develop standard definitions for IFIs for clinical research. On the basis of a review of literature and an international consensus, a set of research-oriented definitions for the IFIs most often seen and studied in immunocompromised patients with cancer is proposed. Three levels of probability are proposed: "proven," "probable," and "possible." The definitions are intended for use in the context of clinical and/or epidemiological research, not for clinical decision making.

Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group.

A review of representative cases of invasive aspergillosis was conducted to describe current treatment practices and outcomes. Eighty-nine physicians experienced with aspergillosis completed case forms on 595 patients with proven or probable invasive aspergillosis diagnosed using modifications of the Mycoses Study Group criteria. Pulmonary disease was present in 56%, with disseminated infection in 19%. The major risk factors for aspergillosis were bone marrow transplantation (32%) and hematologic malignancy (29%), but patients had a variety of underlying conditions including solid organ transplants (9%), AIDS (8%), and pulmonary diseases (9%). Overall, high antifungal failure rates occurred (36%), and complete antifungal responses were noted in only 27%. Treatment practices revealed that amphotericin B alone (187 patients) was used in most severely immunosuppressed patients while itraconazole alone (58 patients) or sequential amphotericin B followed by itraconazole (93 patients) was used in patients who were less immunosuppressed than patients receiving amphotericin B alone. Response rate for patients receiving amphotericin B alone was poor, with complete responses noted in only 25% and death due to or with aspergillosis in 65%. In contrast, patients receiving itraconazole alone or following amphotericin B had death due to or with Aspergillus in 26% and 36%, respectively. These results confirm that mortality from invasive aspergillosis in severely immunosuppressed patients remains high even with standard amphotericin B. Improved responses were seen in the less immunosuppressed patients receiving sequential amphotericin B followed by itraconazole and those receiving itraconazole alone. New approaches and new therapies are needed to improve the outcome of invasive aspergillosis in high-risk patients.

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.

Hospital epidemiologic surveillance for invasive aspergillosis: patient demographics and the utility of antigen detection.

OBJECTIVE: To monitor the epidemiology of invasive aspergillosis at a university hospital during a period of hospital construction. To compare the efficacy of active epidemiologic surveillance for invasive aspergillosis using Aspergillus cultures with the efficacy of surveillance using Aspergillus antigen detection. DESIGN: A prospective surveillance study. SETTING: An 850-bed, tertiary-care, university-based hospital. PATIENTS: A convenience sample of 153 patients with Aspergillus antigen testing and culture. RESULTS: 24 cases were identified over a 12-month period; 7 were nosocomial, and 17 were community-acquired. Cases occurred primarily in patients with hematologic malignancy, but also occurred in patients with solid tumor, steroid treatment, cardiac transplant, and acquired immunodeficiency syndrome. Culture techniques identified only 14 (58%) of 24 cases, whereas Aspergillus antigen was positive in 19 (79%) of 24 cases tested. Epidemiological surveillance using either antigen or culture positivity detected 22 (92%) of 24 cases. In addition, antigen detection was 98% specific for the detection of aspergillosis, as compared to 91% for culture and 88% for antigen and culture combined. CONCLUSIONS: Hospital surveillance for aspergillosis should include determination of whether cases are nosocomial or community-acquired, because many may be the latter. Patients at risk for aspergillosis include patients without hematologic malignancies. Enhanced case detection occurred with active surveillance of patients considered to be at risk using both fungal serology and traditional microbiological techniques. Antigen detection was more sensitive and specific for the detection of invasive aspergillosis and may improve epidemiological surveillance for aspergillosis.

Bacteriuria in pregnancy.

The urinary tract undergoes profound physiologic and anatomic changes during pregnancy that facilitate the development of symptomatic urinary tract infections in women with bacteriuria. While the adverse effects of asymptomatic bacteriuria on maternal and fetal health continue to be debated, it is clear that asymptomatic bacteriuria is the major risk factor for developing symptomatic urinary tract infection and that symptomatic infections are associated with significant maternal and fetal risks. Because the majority of symptomatic urinary tract infections develop in women with bacteriuria earlier in pregnancy, treatment of bacteriuria is undertaken to prevent symptomatic infections. All women should be screened at the first antenatal visit, which is reliably and inexpensively done with a dipstick culture. Short-course therapy is as effective as prolonged therapy and should be followed with a repeat culture to document clearing of the bacteriuria. Failure to eliminate bacteriuria with repeated therapy or recurrence with the same organism is indicative of renal parenchymal infection or a structural abnormality. All women with persistent bacteriuria or recurrent infection should have follow-up cultures and a complete urologic evaluation after delivery.

Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era.

Profound physiologic and anatomic changes of the urinary tract during pregnancy contribute to the increased risk for symptomatic urinary tract infection in women with bacteriuria. Asymptomatic bacteriuria is the major risk factor for developing symptomatic UTIs during pregnancy and may be associated with adverse effects on maternal and fetal health. Because most symptomatic UTIs develop in women with bacteriuria earlier in pregnancy, treatment of bacteriuria is undertaken to prevent symptomatic infections. All pregnant women should be screened at the first antenatal visit, which is reliably and inexpensively done with a dipstick culture. Short-course therapy should be given to women with bacteriuria and clearance of bacteriuria should be documented after therapy is complete. Failure to eliminate bacteriuria with repeated therapy or recurrence with the same organism is indicative of renal parenchymal infection or a structural abnormality. All women with persistent bacteriuria or recurrent infection should have follow-up cultures and a urologic evaluation after delivery.

Epidemiology, natural history, and management of urinary tract infections in pregnancy.

The urinary tract undergoes profound physiologic and anatomic changes during pregnancy that facilitate the development of symptomatic UTIs in women with bacteriuria. Although the adverse effects of asymptomatic bacteriuria on maternal and fetal health continue to be debated, it is clear that asymptomatic bacteriuria is the major risk factor for developing symptomatic UTI and that symptomatic infections are associated with significant maternal and fetal risks. Because the majority of symptomatic UTIs develop in women with bacteriuria earlier in pregnancy, treatment of bacteriuria is undertaken to prevent symptomatic infections. All women should be screened at the first antenatal visit, which is reliably and inexpensively done with a dipstick culture. Short-course therapy is as effective as prolonged therapy and should be followed with a repeat culture to document clearing of the bacteriuria. Failure to eliminate bacteriuria with repeated therapy or recurrence with the same organism is indicative of renal parenchymal infection or a structural abnormality. All women with persistent bacteriuria or recurrent infection should have follow-up cultures and a complete urologic evaluation after delivery.

Clinical presentation as a guide to therapy for travelers' diarrhea.

To better define the role of antimicrobial therapy among U.S. travelers in Mexico, clinical and nonculture laboratory parameters were compared for 56 patients with shigellosis and 204 others with diarrhea of other causes. The presence of fever, stool mucus and blood, and fecal leukocytes were significantly more common among patients with shigellosis (p less than 0.001) who also tended not to present with mild diarrhea (p less than 0.05). However, clinical and laboratory parameters were either too insensitive or too nonspecific to be useful in identifying most cases of shigellosis or in excluding the likelihood of its presence. Patients with mild clinical presentations, regardless of etiology, experienced resolution of disease sooner than those with moderate to severe presentations (p less than 0.01), but withholding therapy from patients with mild presentations resulted in 48% of these patients remaining ill at the end of 48 hours. Based on these findings, the authors advise empiric use of antimicrobial agents in travelers with diarrhea associated with fever, bloody stools, or fecal leukocytes, and for all travelers with moderate and severe diarrhea. If therapy is withheld from patients with initially mild presentations, a proportion might still require therapy, possibly an antimicrobial agent, for optimal control of symptoms.

Role of newer azoles in surgical patients.

Fungal infection has become an important cause of morbidity and mortality in critically ill surgical patients. Surgical patients at highest risk for invasive mycoses include those undergoing extensive abdominal surgery, those with underlying malignancy or other immunosuppressive conditions, and patients undergoing transplantation. Nosocomial candidemia remains a major complication for patients in surgical intensive units; however, the epidemiology of invasive fungal infection continues to change with molds and yeasts other than Candida albicans emerging as important causes of infection especially in immunosuppressed patients. This changing epidemiology has resulted in the need for an expanded armamentarium of antifungal therapies. One effective approach has been the utilization of higher doses of well-tolerated azoles, such as fluconazole, particularly against yeasts with dose-dependent susceptibility. Alternatively, the presumptive use of therapeutic doses of fluconazole may be indicated in intensive care unit patients with persistent leukocytosis and fever in whom a source of fever cannot be identified, particularly if the patient is extensively colonized at mucosal sites with yeast. New azoles with an expanded spectrum of activity are in development. These include agents include voriconazole, which has activity against resistant yeasts and molds and is in phase III clinical trials, posaconazole (Sch 56592) and ravuconazole (BMS-207147)--both of which are less advanced in clinical development, but which also offer an expanded spectrum of activity. Other new azoles with expanded activity are still in the early phases of development. In this review, strategies for optimizing use of the clinically available new azoles and the potential for new agents are discussed.

The epidemiology of pseudallescheriasis complicating transplantation: Nosocomial and community-acquired infection.

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.

The role of antifungal susceptibility testing in the management of patients with invasive mycoses.

The availability of standardized antifungal susceptibility testing methodologies as well as the definition of interpretative breakpoints have made possible the establishment of useful correlations between in vitro testing data and clinical results with antifungal drugs such as fluconazole and itraconazole in patients with oropharyngeal candidiasis. The results obtained in these studies, however, can not be extrapolated to other organisms or clinical syndromes. Although there has been some recent progress, the interpretations of in vitro and in vivo results obtained in patients suffering cryptococcosis or invasive candidiasis needs to be further defined in order to establish meaningful clinical-laboratory correlations. Furthermore, the method needs to be fully standardized in case of filamentous fungi. It can be anticipated that the development, standardization and validation of in vitro antifungal susceptibility testing will guide clinicians in the management of patients with invasive mycoses.

Comparison of DNA-based typing methods to assess genetic diversity and relatedness among Candida albicans clinical isolates.

Three serial isolates of Candida albicans were obtained from each of five HIV infected patients with recurrent oropharyngeal candidiasis from the same geographical area. Isolates from one patient remained susceptible to fluconazole whereas serial isolates from the other four patients showed decreasing susceptibilities to the drug. Strain identity was investigated by pulse-field gel electrophoretic (PFGE) separation of chromosomes, restriction fragment length polymorphism (RFLP) of chromosomal DNA, Southern blot analysis with the moderately repetitive probe Ca3 of the materials present in the RFLP gels after transfer to nylon membranes, and random amplification of polymorphic DNA (RAPD). All techniques were able to group isolates obtained from the same patient. Techniques resulting in more complex banding profiles exhibited increased discriminatory power allowing detection of strain variants. Methods resulting in less complex banding patterns, especially Southern hybridization of SfiI digested chromosomal DNA with the moderately repetitive probe Ca3, were more helpful to determine isogenicity among isolates obtained from the same patient. The combination of results from methods with high discriminatory power (to maximize detection of strain variants) and methods resulting in less complex banding patterns (to allow determination of isogenic isolates) should facilitate the delineation of the epidemiology of C. albicans infection.

Cell wall proteinaceous components in isolates of Candida albicans and non-albicans species from HIV-infected patients with oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC) remains a common opportunistic infection in HIV-infected patients. Candida albicans is the most frequent causative agent of OPC. However, non-albicans spp. are being increasingly isolated. Candidal cell wall proteins and mannoproteins play important roles in the biology and patogenesis of candidiasis. In the present study, we have analyzed the proteinaceous components associated with cell wall extracts from C. albicans, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii and Candida rugosa obtained from HIV-infected patients with recurrent OPC. Cell wall proteinaceous components were extracted with beta-mercaptoethanol and analyzed using electrophoresis, immunoblotting (with antisera generated against C. albicans cell wall components, and with serum samples and oral saline rinses from patients with OPC), and lectin-blotting (concanavalin A) techniques. Numerous molecular species were solubilized from the various isolates. Major qualitative and quantitative differences in the polypeptidic and antigenic profiles associated with the cell wall extracts from the different Candida spp. were discernible. Some of the antibody preparations generated against C. albicans cell wall components were able to recognize homologous materials present in the extracts from non-albicans spp. Information on cell wall antigens of Candida species may be important in the therapy and prevention of HIV-related OPC.

Candida dubliniensis in radiation-induced oropharyngeal candidiasis.

Candida dubliniensis is a recently described species that has been shown to cause oropharyngeal candidiasis in patients with HIV. We present a detailed evaluation of a patient undergoing head and neck radiation for oral cancer who developed oropharyngeal candidiasis from a mixed infection of C dubliniensis and Candida albicans. To our knowledge, this is the first described case of C dubliniensis contributing to oropharyngeal candidiasis in this patient population.

Assuring safe travel for today's elderly.

The increased availability of time and resources has made travel attractive to many elderly patients. Both healthy and chronically ill geriatric patients can travel safely and without medical complications in many circumstances. Many of these patients, however, have special health needs that call for specific advice from practitioners. Patients with medical problems, such as chronic obstructive pulmonary disease, cardiovascular disease, thrombotic disease, sinus conditions, or diabetes, should be aware of possible complications involved in travel. In addition, medical advice regarding vaccinations, traveler's diarrhea, jet lag, and malaria prophylaxis should be tailored to this population. Such a prescribed regimen may make travel safe and feasible for many geriatric patients.

The epidemiology of non-albicans Candida in oropharyngeal candidiasis in HIV patients.

Oropharyngeal candidiasis (OPC) is the most common fungal infection in patients with HIV infection. Fluconazole has been proven to be very effective in treating this infection, but decreased susceptibility of Candida to this drug has emerged. Certain non-albicans species such as C. glabrata and C. krusei are commonly less susceptible to fluconazole than C. albicans and are being isolated with increased frequency in HIV patients. The purpose of this study was to determine if the presence of non-albicans Candida with OPC in HIV patients had an impact on clinical presentation. This study shows that late-stage HIV patients have a high prevalence of Candida with decreased susceptibility to fluconazole, especially non-albicans species. OPC episodes with non-albicans isolates were more likely to require higher doses of fluconazole to achieve clinical cure. Also, the presence of non-albicans Candida was more frequently associated with severe symptoms.