Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic.

We report the presentation and management of 17 cases of Exophiala dermatitidis and Rhodotorula mucilaginosa bloodstream infections caused by a compounded parenteral medication at an oncology clinic. Twelve patients were asymptomatic. All central venous catheters were removed and antifungal therapy, primarily voriconazole, was administered to patients. Three patients died.

Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients.

BACKGROUND: Clostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described. METHODS: We performed a prospective, multicenter study of CDI within 365 days post-allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post-transplant and while hospitalized and contacted monthly up to 18 months post-transplantation. RESULTS: Six sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). One hundred and fifty CDI cases occurred within 1 year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs 90 days; P = .037). CDI was associated with significantly higher mortality from 31 to 180 days post-index date among the allogeneic HCT recipients (Hazard ratio [HR] = 1.80; P = .007). There was a trend towards increased mortality among lung transplant recipients from 120 to 180 days post-index date (HR = 4.7, P = .09). CONCLUSIONS: The epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post-transplant period.

Epidemiology of invasive mold infections in lung transplant recipients.

Invasive mold infections (IMIs) are a major source of morbidity and mortality among lung transplant recipients (LTRs), yet information regarding the epidemiology of IMI in this population is limited. From 2001 to 2006, multicenter prospective surveillance for IMIs among LTR was conducted by the Transplant-Associated Infection Surveillance Network. The epidemiology of IMI among all LTRs in the cohort is reported. Twelve percent (143/1173) of LTRs under surveillance at 15 US centers developed IMI infections. The 12-month cumulative incidence of IMIs was 5.5%; 3-month all-cause mortality was 21.7%. Aspergillus caused the majority (72.7%)of IMIs; non-Aspergillus infections (39, 27.3%) included Scedosporium (5, 3.5%), mucormycosis (3, 2.1%) and "unspecified" or "other" mold infections (31, 21.7%). Late-onset IMI was common: 52% occurred within 1 year posttransplant (median 11 months, range 0-162 months). IMIs are common late-onset complications with substantial mortality in LTRs. LTRs should be monitored for late-onset IMIs and prophylactic agents should be optimized based on likely pathogen.

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.

Safety and tolerability of voriconazole in patients with baseline renal insufficiency and candidemia.

Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.

Fatal Burkholderia gladioli infection misidentified as Empedobacter brevis in a lung transplant recipient with cystic fibrosis.

Data describing the risk of lung transplantation (LT), clinical features, and outcomes of patients with cystic fibrosis (CF) infected with Burkholderia gladioli are limited. Herein, we report a case of disseminated B. gladioli infection characterized by bacteremia, necrotizing pneumonia, lung abscess, and empyema in a lung transplant recipient with CF, highlight the importance of accurate microbiological identification, and review published outcomes of LT in CF patients infected with B. gladioli, which include cases of pneumonia, tracheobronchitis, bacteremia, and abscesses, and demonstrate an all-cause 1-year mortality of approximately 23%, often after combined medical and surgical treatment.

Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodeficiency virus (HIV)-infected and HIV-uninfected persons.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection for immunocompromised individuals. Robust data and clear guidelines are available for prophylaxis and treatment of human immunodeficiency virus (HIV)-related PCP (HIV-PCP), yet few data and no guidelines are available for non-HIV-related PCP (NH-PCP). We postulated that prevention and inpatient management of HIV-PCP differed from NH-PCP. METHODS: We performed a retrospective case review of all pathologically confirmed cases of PCP seen at the University of Alabama Medical Center from 1996 to 2008. Data on clinical presentation, hospital course, and outcome were collected using a standardized data collection instrument. Bivariate analysis compared prophylaxis, adjunctive corticosteroids, and clinical outcomes between patients with HIV-PCP and NH-PCP. RESULTS: Our analysis of the cohort included 97 cases of PCP; 65 HIV and 32 non-HIV cases. Non-HIV cases rarely received primary prophylaxis (4% vs. 38%, P = 0.01) and received appropriate antibiotics later in the course of hospitalization (5.2 days vs. 1.1 days, P < 0.005). Among transplant patients, NH-PCP was diagnosed a mean of 1066 days after transplantation and most patients were on low-dose corticosteroids (87%) at the time of disease onset. No significant differences in adjunctive corticosteroid use (69% vs. 77%, P = 0.39) and 90-day mortality (41% vs. 28%, P = 0.20) were detected. CONCLUSIONS: Patients who have undergone organ or stem cell transplant remain at risk for PCP for many years after transplantation. In our cohort, patients who developed NH-PCP were rarely given prophylaxis, and initiation of appropriate antibiotics was significantly delayed compared to cases of HIV-PCP. Medical providers should be aware of the ongoing risk for NH-PCP, even late after transplantation, and consider more aggressive approaches to both prophylaxis and earlier empirical therapy for PCP.

Multicenter Registry of Patients Receiving Systemic Mold-Active Triazoles for the Management of Invasive Fungal Infections.

INTRODUCTION: 'Real-world' data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs. METHODS: Data were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose. RESULTS: Overall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole). CONCLUSIONS: In this 'real-world' study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.

Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients.

OBJECTIVES: The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections. METHODS: A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography. RESULTS: Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively). CONCLUSION: High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.

Cryptococcal disease presenting as necrotizing cellulitis in transplant recipients.

Disseminated cryptococcosis uncommonly presents with skin lesions in immunocompromised hosts. Necrotizing fasciitis, necrotizing vasculitis, myositis, or necrotizing soft tissue infection are even more rare presentations. We report 3 cases of cryptococcal necrotizing soft tissue infection, 2 in renal transplant patients, and 1 in a heart transplant patient, and discuss similar cases from the literature. Cryptococcus neoformans should be considered in the differential diagnosis of cellulitis or necrotizing soft tissue infections in immunocompromised patients.

Outcomes of antifungal prophylaxis in high-risk liver transplant recipients.

Antifungal prophylaxis for liver transplant recipients (LTRs) is common among patients considered at high risk of infection, but optimal prophylaxis duration and drug has not been defined. This study aimed to assess the effects of 14 days of antifungal therapy prophylaxis in reducing proven invasive fungal infections (IFI) in high-risk subjects. Eligible subjects who met 2 or more risk criteria were randomized 1:1 to the treatment arms (liposomal amphotericin B or fluconazole) and were followed for 100 days post transplantation for evidence of IFI. The study was designed to enroll 300 subjects, but was closed early for insufficient enrollment. A total of 71 subjects were enrolled and randomized. Two-thirds of subjects completed 14 days of study therapy. Ten subjects developed proven or probable IFI with Candida species (9 subjects) and Cryptococcus neoformans (1 subject); rates were similar in the 2 treatment arms. Eleven subjects died, but no death was attributed to study drug or IFI. In summary, high-risk LTRs tolerated antifungal prophylaxis well, and rates of IFI were lower than previously reported in untreated high-risk LTRs.

Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease.

Cryptococcus neoformans is an uncommonly recognized cause of pneumonia in HIV-negative patients. Because of its propensity to disseminate to the meninges and other sites, a lumbar puncture is recommended for patients with pulmonary cryptococcosis, regardless of other risk factors. This study explored clinical and laboratory features to help predict which patients had pulmonary disease alone versus those who had pulmonary plus extrapulmonary disease. A retrospective chart review at 15 medical centers was performed from 1990 to 2000 of all HIV-negative patients who had pulmonary cryptococcosis. Demographic, clinical, radiographic, and laboratory features were evaluated to determine factors that differentiated those patients who had extrapulmonary disease. Among 166 patients who had pulmonary cryptococcosis, 122 had pulmonary infection only and 44 had pulmonary plus extrapulmonary (disseminated) disease. A negative serum cryptococcal antigen titer was more common in patients with pulmonary disease alone (p < 0.01). Multivariate analysis demonstrated that patients who had disseminated disease were more likely than those who only had pulmonary disease to have cirrhosis (p = 0.049), headache (p < 0.001), weight loss (p = 0.003), fever (p = 0.035), altered mental status (p < 0.001), and to be receiving high-dose corticosteroids (p = 0.008). In this large cohort of HIV-negative patients with pulmonary cryptococcosis, there were easily distinguished clinical and laboratory features among patients with pulmonary disease alone versus those with pulmonary plus extrapulmonary disease. These findings may be helpful in the evaluation of HIV-negative patients with pulmonary cryptococcosis with regard to the need for lumbar puncture or to search for disseminated disease.

Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.

BACKGROUND: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients. METHODS: Non-neutropenic patients with a positive blood culture for a species of candida and clinical evidence of infection were enrolled. Patients were randomly assigned, in a 2:1 ratio, either voriconazole (n=283) or amphotericin B followed by fluconazole (n=139). The primary efficacy analysis was based on clinical and mycological response 12 weeks after the end of treatment, assessed by an independent data-review committee unaware of treatment assignment. FINDINGS: Of 422 patients randomised, 370 were included in the modified intention-to-treat population. Voriconazole was non-inferior to amphotericin B/fluconazole in the primary efficacy analysis, with successful outcomes in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). At the last evaluable assessment, outcome was successful in 162 (65%) patients assigned voriconazole and 87 (71%) assigned amphotericin B/fluconazole (p=0.25). Voriconazole cleared blood cultures as quickly as amphotericin B/fluconazole (median time to negative blood culture, 2.0 days). Treatment discontinuations due to all-cause adverse events were more frequent in the voriconazole group, although most discontinuations were due to non-drug-related events and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/fluconazole group. INTERPRETATION: Voriconazole was as effective as the regimen of amphotericin B followed by fluconazole in the treatment of candidaemia in non-neutropenic patients, and with fewer toxic effects. RELEVANCE TO PRACTICE: There are several options for treatment of candidaemia in non-neutropenic patients, including amphotericin B, fluconazole, voriconazole, and echinocandins. Voriconazole can be given both as initial intravenous treatment and as an oral stepdown agent.

Blastomycosis in immunocompromised patients.

Among the endemic mycoses, blastomycosis has been least often associated with disorders of immune function, but the data presented herein suggest that blastomycosis may occur more commonly in immunocompromised patients than was previously recognized. We have observed a marked increased in the number of immunocompromised patients with blastomycosis over the last 15 years, increasing from about 3% of patients seen between 1956 and 1977 to almost 24% patients seen between 1978 and 1991. The disease appears to be much more aggressive in immunocompromised than in normal hosts. Almost 30% of the patients in our series died secondary to blastomycosis, with most deaths occurring within 5 weeks following the diagnosis. Furthermore, almost one third of those patients who died of other causes had evidence of persistent blastomycosis at death. Multiple organ and central nervous system involvement were relatively common in this series. For these reasons, early and aggressive therapy with amphotericin B is indicated for most immunocompromised patients with blastomycosis. Oral therapy with an azole compound should probably be reserved for patients who have responded to a primary course of amphotericin B but who require additional or long-term suppressive therapy. Until more data are available, the newer azoles should be used with caution as primary therapy in immunocompromised patients with blastomycosis, and considered only in patients with limited disease and a stable underlying condition. Caring for the immunocompromised patient poses many diagnostic and therapeutic challenges to the clinician, and among those patients who have been exposed to areas endemic for blastomycosis, B. dermatitidis must be regarded as a potentially important opportunistic pathogen.

Surveillance of cryptococcosis in Alabama, 1992-1994.

PURPOSE: Although cryptococcosis is a significant opportunistic infection among patients with human immunodeficiency virus (HIV), there is conflicting information on rates of cryptococcosis among HIV-positive and HIV-negative patients. Precise state-wide epidemiologic data for cryptococcosis are not available in Alabama. METHODS: We conducted an active laboratory and hospital medical record-based surveillance for cryptococcosis in Alabama from October 1, 1992 to September 30, 1994. A case of cryptococcosis was defined as a patient's initial episode of cryptococcal disease and based on either a positive culture for C. neoformans from any normally sterile site, a positive latex agglutination serologic test for cryptococcal antigen in CSF or serum, or histopathologic findings consistent with C. neoformans. RESULTS: Over the two year period, 153 cases were identified. The diagnosis was based on positive culture (37%), positive antigen (24%), positive autopsy culture (2%), and histopathologic findings (4%). Further, 33% of the total cases were diagnosed from combined positive culture, antigen, or histopathology. Of the total 153 cases, 55% were in HIV-positive patients and 44% were in HIV-negative individuals and one case (1%) had an unknown HIV status. The overall annual incidence rate of cryptococcosis was 1.89 cases per 100,000 population. The incidence was 1638.7 per 100,000 in the HIV-positive population and 0.84 per 100,000 in the HIV-negative population. CONCLUSION: The first Alabama statewide active surveillance system for cryptococcosis confirms previous observations that rates of cryptococcosis are consistently higher in HIV-infected individuals than in their HIV-negative counterparts. In Alabama, cryptococcosis occurs more commonly in urban residents and in men. Cryptococcosis in HIV-positive persons is more likely to occur in the 20 to 44 year age group, whereas cryptococcosis in HIV-negative persons is more likely to occur in those greater than 45 years old.

A randomized, double-blind trial of parenteral low dose versus high dose interferon-beta in combination with cryotherapy for treatment of condyloma acuminatum.

Forty-nine subjects were enrolled in a study comparing two dosages of parenterally administered interferon (IFN)-beta in combination with cryotherapy for the treatment of anogenital warts. Subjects were randomized to receive subcutaneous injections of either 2 x 10(6) or 4 x 10(6) IU/m2 of IFN-beta (Biogen) three times a week for a total of 6 weeks. Cryotherapy was administered concomitantly by aerosolization of liquid nitrogen at 10-day intervals. Systemic side- effects were modest in intensity and included fever, chills, myalgia, and headaches (flu-like symptoms). During the first 2 weeks of therapy, they were more common in the high dose group than in the low dose group (P = 0.02). Using survival analysis, there was no significant difference between the two groups in rates of resolution of warts present at baseline (P = 0.62). However, the rate of new lesion formation during the study was significantly lower in the high dose group (P = 0.04).

Trends in frequency and susceptibilities of Candida glabrata bloodstream isolates at a university hospital.

The frequency of isolation and antifungal susceptibility patterns to fluconazole and itraconazole were determined for 166 Candida glabrata isolates causing bloodstream infection at a single institution from 1995-2000. Findings demonstrated a trend of increasing resistance to itraconazole among the isolates, but no trend in resistance to fluconazole. The frequency of C. glabrata isolates among all blood culture isolates of Candida spp. causing bloodstream infection remained stable during the study period and ranged from 18-31%.

Comparative analysis of three antifungal susceptibility test methods against prospectively collected Candida species.

We performed antifungal susceptibility tests with cilofungin (LY121019), amphotericin B, and flucytosine against 38 strains of yeasts from patients with esophagitis or fungemia either before, during, or after treatment with cilofungin. Tests were performed using a macrobroth dilution method similar to that proposed by the National Committee for Clinical Laboratory Standards (M27-P) and two microbroth methods. For cilofungin and amphotericin B, minimum inhibitory concentrations from microbroth tests using Antibiotic Medium 3 (AM3) were systematically lower than results from the other two methods that utilized RPMI-1640 medium (RPMI). AM3 did not provide any greater degree of in vitro correlation with clinical results than did RPMI. We conclude that cilofungin and possibly other congeners of the echinocandin class of antifungal agents can effectively be studied using the proposed National Committee for Clinical Laboratory Standards method.

Itraconazole for the treatment of histoplasmosis and blastomycosis.

Itraconazole is a triazole compound with broad-spectrum antifungal activity which includes the pathogenic yeasts, certain Aspergillus species, and the endemic fungi such as Histoplasma capsulatum and Blastomycosis dermatitidis. Although prospective trials comparing itraconazole to other azoles and amphotericin B are unavailable, recently published data suggest that itraconazole is the drug of choice for patients with mild to moderate histoplasmosis and blastomycosis without central nervous system involvement. Among patients with the acquired immunodeficiency syndrome and histoplasmosis, itraconazole has emerged as an effective alternative to amphotericin B for induction therapy in selected patients, and has largely replaced amphotericin B for chronic maintenance therapy in these patients. For patients with severe or life-threatening histoplasmosis or blastomycosis and for patients with central nervous system involvement, amphotericin B remains the initial therapy of choice.