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1.  Acute Cryptococcal Immune Reconstitution Inflammatory Syndrome in a Patient on Natalizumab 
Open Forum Infectious Diseases  2016;3(1):ofw038.
Presented is the first case of acute immune reconstitution inflammatory syndrome (IRIS)-associated cryptococcal meningoencephalitis in a patient on natalizumab for multiple sclerosis. The patient developed acute cerebral edema after initiation of amphotericin B. We propose several mechanisms that explain the acuity of IRIS in this specific patient population and suggest possible therapies.
PMCID: PMC4800467  PMID: 27006962
Cryptococcus; fungal; IRIS; meningitis; natalizumab
2.  Aspergillus Polymerase Chain Reaction: Systematic Review of Evidence for Clinical Use in Comparison With Antigen Testing 
There is sufficient evidence that is at least equivalent to that used to include galactomannan enzyme immunoassay and β-d-glucan testing for polymerase chain reaction to be included in the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group definitions.
Background. Aspergillus polymerase chain reaction (PCR) was excluded from the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions of invasive fungal disease because of limited standardization and validation. The definitions are being revised.
Methods. A systematic literature review was performed to identify analytical and clinical information available on inclusion of galactomannan enzyme immunoassay (GM-EIA) (2002) and β-d-glucan (2008), providing a minimal threshold when considering PCR. Categorical parameters and statistical performance were compared.
Results. When incorporated, GM-EIA and β-d-glucan sensitivities and specificities for diagnosing invasive aspergillosis were 81.6% and 91.6%, and 76.9% and 89.4%, respectively. Aspergillus PCR has similar sensitivity and specificity (76.8%–88.0% and 75.0%–94.5%, respectively) and comparable utility. Methodological recommendations and commercial PCR assays assist standardization. Although all tests have limitations, currently, PCR is the only test with independent quality control.
Conclusions. We propose that there is sufficient evidence that is at least equivalent to that used to include GM-EIA and β-d-glucan testing, and that PCR is now mature enough for inclusion in the EORTC/MSG definitions.
PMCID: PMC4583581  PMID: 26113653
Aspergillus; PCR; galactomannan; β-d-glucan; aspergillosis
3.  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 (LTR) yet information regarding the epidemiology of IMI in this population are limited. From 2001–2006, multicenter prospective surveillance for IMIs among LTR was conducted by the Transplant-Associated Infection Surveillance Network. The epidemiology of IMI among all LTR in the cohort is reported. Twelve percent (143/1173) of LTRs under surveillance at 15 U.S. centers developed IMI infections. The 12-month cumulative incidence of IMIs was 5.5%; 3-month all-cause mortality was 21.7%. s caused the majority (70%)of IMIs; non-infections (39; 27%) included: (5), mucormycosis (3), and “unspecified” or “other” mold infections (31). Late-onset IMI was common: 52% occurred within one year post-transplant (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.
PMCID: PMC4158712  PMID: 24726020
lung transplant; mold; infection; epidemiology
5.  Invasive Non-Aspergillus Mold Infections in Transplant Recipients, United States, 2001–2006 
Emerging Infectious Diseases  2011;17(10):1855-1864.
PMCID: PMC3311117  PMID: 22000355
Mucorales; Fusarium; Scedosporium; mucormycosis; non-Aspergillus; fungi; organ transplant; epidemiology; invasive mold infections; zygomycosis; fusariosis; surveillance; United States; research
6.  Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial 
Hospitalized patients are at increased risk for candidemia and invasive candidiasis (C/IC). Improved therapeutic regimens with enhanced clinical and pharmacoeconomic outcomes utilizing existing antifungal agents are still needed.
An open-label, non-comparative study evaluated an intravenous (IV) to oral step-down strategy. Patients with C/IC were treated with IV anidulafungin and after 5 days of IV therapy had the option to step-down to oral azole therapy (fluconazole or voriconazole) if they met prespecified criteria. The primary endpoint was the global response rate (clinical + microbiological) at end of treatment (EOT) in the modified intent-to-treat (MITT) population (at least one dose of anidulafungin plus positive Candida within 96 hours of study entry). Secondary endpoints included efficacy at other time points and in predefined patient subpopulations. Patients who stepped down early (≤ 7 days’ anidulafungin) were identified as the "early switch" subpopulation.
In total, 282 patients were enrolled, of whom 250 were included in the MITT population. The MITT global response rate at EOT was 83.7% (95% confidence interval, 78.7–88.8). Global response rates at all time points were generally similar in the early switch subpopulation compared with the MITT population. Global response rates were also similar across multiple Candida species, including C. albicans, C. glabrata, and C. parapsilosis. The most common treatment-related adverse events were nausea and vomiting (four patients each).
A short course of IV anidulafungin, followed by early step-down to oral azole therapy, is an effective and well-tolerated approach for the treatment of C/IC.
Trial registration NCT00496197
PMCID: PMC3944438  PMID: 24559321
Anidulafungin; Azole; Candidemia; Step-down strategy
7.  Pneumocystis Pneumonia in Hospitalized Patients; A Detailed Examination of Symptoms, Management, and Outcomes in HIV-infected and HIV-uninfected Persons 
Pneumocystis jiroveci pneumonia is a life-threatening infection for immunocompromised individuals. There are robust data and clear guidelines for prophylaxis and treatment of HIV-related Pneumocystis jiroveci pneumonia (HIV-PCP), yet few data and no guidelines for non-HIV related Pneumocystis pneumonia (NH-PCP). We postulated that prevention and inpatient management of HIV-PCP differed from NH-PCP.
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.
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 vs 1.1 days, P<0.005). Among transplant patients, NH-PCP was diagnosed a mean of 1,066 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.
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 empiric therapy for PCP.
PMCID: PMC3889465  PMID: 22548840
Pneumocystis Pneumonia; Transplant; Infectious Complications
8.  Association of Vancomycin-Resistant Enterococcus Bacteremia and Ceftriaxone Usage 
Vancomycin-resistant Enterococci (VRE) have become a public health concern with implications for patient mortality and costs. Hospital antibiotic usage may impact VRE incidence, but the relationship is poorly understood. Animal investigations suggest ceftriaxone may be associated with VRE proliferation. We measured antimicrobial usage and VRE bloodstream infection (BSI) incidence to test our hypothesis that increased ceftriaxone use would be associated with a higher incidence of VRE-BSI.
The University of Alabama at Birmingham Medical Center is a 900-bed urban tertiary-care hospital
Retrospective analysis of antimicrobial usage and VRE-BSI from 2005 to 2008 (43 months). Antimicrobial usage quantified as days of therapy/1,000 patient-days (DOT). VRE-BSI incidence calculated as cases/1,000 patient-days. Negative binomial regression with adjustment for correlation between consecutive observations measured the association between antimicrobial usage and VRE-BSI incidence at the hospital- and care-unit levels.
VRE-BSI incidence increased from 0.06 to 0.17 infections/1,000 patient-days. Hospital VRE-BSI incidence was associated with prior-month ceftriaxone DOT (Incidence Rate Ratio 1.38 per 10 DOT; p=0.005). After controlling for ceftriaxone, prior-month cephalosporin use (class) was not predictive of VRE-BSI (p=0.70). Similarly, prior-month use of piperacillin-tazobactam, ceftazidime, cefepime, cefazolin, or vancomycin was not predictive of VRE-BSI when considered individually (p≥0.4 for all comparisons). The final model suggests that type of intensive care unit was related to VRE-BSI incidence.
Ceftriaxone use in the prior month, but not cephalosporin (class) or vancomycin use, was related to VRE-BSI incidence. These findings suggest that an antimicrobial stewardship program that limits ceftriaxone may reduce nosocomial VRE-BSI incidence.
PMCID: PMC3879097  PMID: 22669234
9.  Predictors of Mortality and Differences in Clinical Features among Patients with Cryptococcosis According to Immune Status 
PLoS ONE  2013;8(3):e60431.
Cryptococcosis is an invasive fungal infection causing substantial morbidity and mortality. Prognostic factors are largely derived from trials conducted prior to the modern era of antifungal and potent combination antiretroviral therapies, immunosuppression, and transplantation. Data describing the clinical features and predictors of mortality in a modern cohort are needed.
We conducted a retrospective cohort study of patients at our institution diagnosed with cryptococcosis from 1996 through 2010. Data included demographics, clinical features, diagnostics, treatment, and outcomes.
We identified 302 individuals: 108 (36%) human immunodeficiency virus (HIV)-positive, 84 (28%) organ transplant recipients (OTRs), and 110 (36%) non-HIV, non-transplant (NHNT) patients including 39 with no identifiable immunodeficiency. Mean age was 49 years, 203 (67%) were male and 170 (56%) were white. All-cause mortality at 90 days was 21%. In multivariable logistic regression analyses, cryptococcemia (OR 5.09, 95% CI 2.54–10.22) and baseline opening pressure >25 cmH2O (OR 2.93, 95% CI 1.25–6.88) were associated with increased odds of mortality; HIV-positive patients (OR 0.46, 95% CI 0.19–1.16) and OTRs (OR 0.46, 95% CI 0.21–1.05) had lower odds of death compared to NHNT patients.
Predictors of mortality from cryptococcosis in the modern period include cryptococcemia, high intracranial pressure, and NHNT status while drug(s) used for induction and historical prognostic factors including organ failure syndromes and hematologic malignancy were not associated with mortality.
PMCID: PMC3608592  PMID: 23555970
10.  Prototheca wickerhamii algaemia presenting as cholestatic hepatitis in a patient with systemic lupus erythematosus: A case report and literature review 
Human protothecal infection is uncommon and could be localized or systemic disease. Disseminated Prototheca algaemia tends to occur in immunocompromised patients (solid organ transplants, hematological malignancies) with high mortality. Diagnosis could be missed or delayed due to unusual clinical presentation and/or under-recognition of characteristic microscopic features of Prototheca species. Combined approach that includes removal of source of infection and intravenous amphotericin B provides the best chance of cure.
PMCID: PMC3885926  PMID: 24432207
Prototheca spp; Algaemia; Cholestatic hepatitis; Systemic lupus erythematosus
11.  Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients 
HIV medicine  2009;11(4):276-281.
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.
A randomized trial was conducted in HIV-infected patients receiving 3 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 hours after dosing) and CSF samples were taken at Baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography.
Sixty-four treated patients had fluconazole measurements; 11 in AmB group, 12 in AmB+Fluc400 group and 41 in 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 for AmB+Fluc800 (p<0.001, r=0.873) and for AmB+Fluc400 (p=0.005, r=0.943). Increased Serum AUC appears 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, 4.08; respectively).
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 associated with increased survival and primary composite endpoint success.
PMCID: PMC3418324  PMID: 20002501
12.  In Vitro Echinocandin Susceptibility of Aspergillus Isolates from Patients Enrolled in the Transplant-Associated Infection Surveillance Network▿ 
We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin.
PMCID: PMC3147660  PMID: 21670187
13.  Comparison of In Vitro Susceptibility Characteristics of Candida Species from Cases of Invasive Candidiasis in Solid Organ and Stem Cell Transplant Recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006▿ 
Journal of Clinical Microbiology  2011;49(7):2404-2410.
Invasive fungal infections (IFI) are a major cause of morbidity and mortality among both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Candida is the most common cause of IFI in SOT recipients and the second most common cause of IFI in HSCT recipients. We determined susceptibilities to fluconazole, voriconazole, itraconazole, posaconazole, amphotericin B, and caspofungin for 383 invasive Candida sp. isolates from SOT and HSCT recipients enrolled in the Transplant-Associated Infection Surveillance Network and correlated these results to clinical data. Fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis isolates was low (1%), but the high percentage of C. glabrata and C. krusei isolates within this group of patients increased the overall percentage of fluconazole resistance to 16%. Voriconazole resistance was 3% overall but was 8% among C. glabrata isolates. On multivariable analysis, among HSCT recipients fluconazole nonsusceptibility was independently associated with C. glabrata, non-Hodgkin's lymphoma, cytomegalovirus (CMV) antigenemia, diabetes active at the time of the IFI, and any prior amphotericin B use; among SOT recipients, fluconazole nonsusceptibility was independently associated with any fluconazole use in the 3 months prior to the IFI, C. glabrata, ganciclovir use in the 3 months prior to the IFI, diabetes acquired since the transplant, and gender.
PMCID: PMC3147873  PMID: 21562099
14.  Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome 
BMC Infectious Diseases  2011;11:261.
Candida albicans is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to C. albicans exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic Candida infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by C. albicans, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences.
Global responses at end of intravenous study treatment in patients with C. albicans infection were compared post-hoc. Multivariate logistic regression analyses were performed to predict response and to adjust for differences in independent baseline characteristics. Analyses focused on time to negative blood cultures, persistent infection at end of intravenous study treatment, and 6-week survival.
In total, 135 patients with C. albicans infections were identified. Among these, baseline APACHE II scores were similar between treatment arms. In these patients, global response was significantly better for anidulafungin than fluconazole (81.1% vs 62.3%; 95% confidence interval [CI] for difference, 3.7-33.9). After adjusting for baseline characteristics, the odds ratio for global response was 2.36 (95% CI, 1.06-5.25). Study treatment and APACHE II score were significant predictors of outcome. The most predictive logistic regression model found that the odds ratio for study treatment was 2.60 (95% CI, 1.14-5.91) in favor of anidulafungin, and the odds ratio for APACHE II score was 0.935 (95% CI, 0.885-0.987), with poorer responses associated with higher baseline APACHE II scores. Anidulafungin was associated with significantly faster clearance of blood cultures (log-rank p < 0.05) and significantly fewer persistent infections (2.7% vs 13.1%; p < 0.05). Survival through 6 weeks did not differ between treatment groups.
In patients with C. albicans infection, anidulafungin was more effective than fluconazole, with more rapid clearance of positive blood cultures. This suggests that the fungicidal activity of echinocandins may have important clinical implications.
Trial registration NCT00058682
PMCID: PMC3203347  PMID: 21961941
echinocandins; Candida; efficacy; safety; survival
15.  Factors Associated with Mortality in Transplant Patients with Invasive Aspergillosis 
Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA.
Transplant patients from 23 U.S. centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network (TRANSNET). IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression.
Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT (239/415, 57.5%) when compared to SOT patients (78/227, 34.4%; p<0.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition and CNS disease were poor prognostic indicators; whereas, prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death.
There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.
PMCID: PMC2874071  PMID: 20450350
Aspergillosis; transplant; Aspergillus; mortality
17.  Patterns of Susceptibility of Aspergillus Isolates Recovered from Patients Enrolled in the Transplant-Associated Infection Surveillance Network▿  
Journal of Clinical Microbiology  2009;47(10):3271-3275.
We analyzed antifungal susceptibilities of 274 clinical Aspergillus isolates from transplant recipients with proven or probable invasive aspergillosis collected as part of the Transplant-Associated Infection Surveillance Network (TRANSNET) and examined the relationship between MIC and mortality at 6 or 12 weeks. Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth dilution method for amphotericin B (AMB), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), and ravuconazole (RAV). The isolate collection included 181 Aspergillus fumigatus, 28 Aspergillus niger, 27 Aspergillus flavus, 22 Aspergillus terreus, seven Aspergillus versicolor, five Aspergillus calidoustus, and two Aspergillus nidulans isolates and two isolates identified as Aspergillus spp. Triazole susceptibilities were ≤4 μg/ml for most isolates (POS, 97.6%; ITR, 96.3%; VOR, 95.9%; RAV, 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were ≥4 μg/ml. AMB inhibited 93.3% of isolates at an MIC of ≤1 μg/ml. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 μg/ml. One of 181 isolates of A. fumigatus showed resistance (MIC ≥ 4 μg/ml) to two of three azoles tested. Although there appeared to be a correlation of higher VOR MICs with increased mortality at 6 weeks, the relationship was not statistically significant (R2 = 0.61; P = 0.065). Significant relationships of in vitro MIC to all-cause mortality at 6 and 12 weeks for VOR or AMB were not found.
PMCID: PMC2756905  PMID: 19692558
18.  Molecular Identification of Aspergillus Species Collected for the Transplant-Associated Infection Surveillance Network▿  
Journal of Clinical Microbiology  2009;47(10):3138-3141.
A large aggregate collection of clinical isolates of aspergilli (n = 218) from transplant patients with proven or probable invasive aspergillosis was available from the Transplant-Associated Infection Surveillance Network, a 6-year prospective surveillance study. To determine the Aspergillus species distribution in this collection, isolates were subjected to comparative sequence analyses by use of the internal transcribed spacer and β-tubulin regions. Aspergillus fumigatus was the predominant species recovered, followed by A. flavus and A. niger. Several newly described species were identified, including A. lentulus and A. calidoustus; both species had high in vitro MICs to multiple antifungal drugs. Aspergillus tubingensis, a member of the A. niger species complex, is described from clinical specimens; all A. tubingensis isolates had low in vitro MICs to antifungal drugs.
PMCID: PMC2756904  PMID: 19675215
19.  Defining Responses to Therapy and Study Outcomes in Clinical Trials of Invasive Fungal Diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria 
Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.
PMCID: PMC2671230  PMID: 18637757
20.  Revised Definitions of Invasive Fungal Disease from 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 (EORTC/MSG) Consensus Group 
Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies.
After the introduction of the original 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 (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved.
The revised definitions retain the original classifications of “proven,” “probable,” and “possible” invasive fungal disease, but the definition of “probable” has been expanded, whereas the scope of the category “possible” has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only.
These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
PMCID: PMC2671227  PMID: 18462102
21.  Nonsporulating Clinical Isolate Identified as Petromyces alliaceus (Anamorph Aspergillus alliaceus) by Morphological and Sequence-Based Methods▿  
Journal of Clinical Microbiology  2007;45(8):2701-2703.
Concerted morphological and sequencing-based strategies revealed the identity of a nonsporulating clinical isolate as Petromyces alliaceus (anamorph Aspergillus alliaceus). This rare Aspergillus sp. was recovered as the etiological agent of invasive pulmonary aspergillosis and had reduced in vitro susceptibilities to amphotericin B and caspofungin, which correlated with clinical failure of therapy.
PMCID: PMC1951206  PMID: 17537938
22.  Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis 
A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.
PMCID: PMC549259  PMID: 15728888
23.  Fungemia Caused by Zygoascus hellenicus in an Allogeneic Stem Cell Transplant Recipient 
Journal of Clinical Microbiology  2004;42(7):3363-3365.
Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast.
PMCID: PMC446251  PMID: 15243118
24.  Epidemiology of Aspergillus terreus at a University Hospital 
Journal of Clinical Microbiology  2003;41(12):5525-5529.
Invasive fungal infections due to Aspergillus species have become a major cause of morbidity and mortality among immunocompromised patients. Aspergillus terreus, a less common pathogen, appears to be an emerging cause of infection at our institution, the University of Alabama hospital in Birmingham. We therefore investigated the epidemiology of A. terreus over the past 6 years by using culture data; antifungal susceptibility testing with amphotericin B, voriconazole, and itraconazole; and molecular typing with random amplification of polymorphic DNA-PCR (RAPD-PCR). During the study period, the percentage of A. terreus isolates relative to those of other Aspergillus species significantly increased, and A. terreus isolates frequently were resistant to amphotericin B. Molecular typing with the RAPD technique was useful in discriminating between patient isolates, which showed much strain diversity. Further surveillance of A. terreus may better define epidemiology and determine whether this organism is becoming more frequent in relation to other Aspergillus species.
PMCID: PMC308992  PMID: 14662934
25.  Antifungal Susceptibility Survey of 2,000 Bloodstream Candida Isolates in the United States 
Antimicrobial Agents and Chemotherapy  2003;47(10):3149-3154.
Candida bloodstream isolates (n = 2,000) from two multicenter clinical trials carried out by the National Institute of Allergy and Infectious Diseases Mycoses Study Group between 1995 and 1999 were tested against amphotericin B (AMB), flucytosine (5FC), fluconazole (FLU), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), caspofungin (CFG), micafungin (MFG), and anidulafungin (AFG) using the NCCLS M27-A2 microdilution method. All drugs were tested in the NCCLS-specified RPMI 1640 medium except for AMB, which was tested in antibiotic medium 3. A sample of isolates was also tested in RPMI 1640 supplemented to 2% glucose and by using the diluent polyethylene glycol (PEG) in lieu of dimethyl sulfoxide for those drugs insoluble in water. Glucose supplementation tended to elevate the MIC, whereas using PEG tended to decrease the MIC. Trailing growth occurred frequently with azoles. Isolates were generally susceptible to AMB, 5FC, and FLU. Rates of resistance to ITR approached 20%. Although no established interpretative breakpoints are available for the candins (CFG, MFG, and AFG) and the new azoles (VOR and POS), they all exhibited excellent antifungal activity, even for those strains resistant to the other aforementioned agents.
PMCID: PMC201160  PMID: 14506023

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