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ABSTRACT: Background. Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. Methods. We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001-10) and correlated treatment outcome with MIC results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin [ANF], caspofungin [CSF], and micafungin [MCF]) and FKS1 and FKS2 gene sequences were determined. Results. Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectfully. Among the 78 FLC resistant isolates, 14.1% were resistant to one or more echinocandins. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, OR 19.647, 95% CI 7.19-58.1). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but recurred. Conclusions. Echinocandin resistance is increasing, including among FLC resistant isolates. The new CLSI clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.
Clinical Infectious Diseases 03/2013; · 9.15 Impact Factor
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ABSTRACT: Lung transplantation is associated with a relatively high incidence of invasive fungal infections that directly affect the
morbidity and mortality associated with the procedure. In addition, these infections may have immunologic consequences that
play a role in the evolution of lung injury syndromes and result in earlier loss of graft than otherwise would be expected
to occur. This article is an overview of the epidemiology and prophylaxis of invasive fungal infections following lung transplantation.
Current Fungal Infection Reports 04/2012; 2(2):103-111.
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Theo S Plantinga,
Melissa D Johnson,
William K Scott,
Esther van de Vosse,
Digna R Velez Edwards,
P Brian Smith, Barbara D Alexander,
John C Yang,
Dennis Kremer,
Gregory M Laird,
Marije Oosting,
Leo A B Joosten,
Jos W M van der Meer,
Jaap T van Dissel,
Thomas J Walsh,
John R Perfect,
Bart Jan Kullberg,
Mihai G Netea
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ABSTRACT: Candidemia is a severe invasive fungal infection with high mortality. Recognition of Candida species is mediated through pattern recognition receptors such as Toll-like receptors (TLRs). This study assessed whether genetic variation in TLR signaling influences susceptibility to candidemia.
Thirteen mostly nonsynonymous single nucleotide polymorphisms (SNPs) in genes encoding TLRs and signaling adaptors MyD88 and Mal/TIRAP were genotyped in 338 patients (237 white, 93 African American, 8 other race) with candidemia and 351 noninfected controls (263 white, 88 African American). The SNPs significant in univariate analysis were further analyzed with multivariable logistic regression to determine association with clinical outcomes. Functional consequences of these polymorphisms were assessed via in vitro stimulation assays.
Analyses of TLR SNPs revealed that 3 TLR1 SNPs (R80T, S248N, I602S) were significantly associated with candidemia susceptibility in whites. This association was not found in African Americans, likely due to lower power in this smaller study population. Furthermore, these TLR1 polymorphisms displayed impaired cytokine release by primary monocytes. No associations with susceptibility to candidemia were observed for SNPs in TLR2, TLR4, TLR6, TLR9, MyD88, or TIRAP.
Nonsynonymous SNPs in TLR1 are associated with impaired TLR1 function, decreased cytokine responses, and predisposition to candidemia in whites.
The Journal of Infectious Diseases 03/2012; 205(6):934-43. · 6.41 Impact Factor
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ABSTRACT: Invasive candidiasis (IC) is a devastating disease. While prompt antifungal therapy improves outcomes, empiric treatment based on the presence of fever has little clinical impact. Β-D-Glucan (BDG) is a fungal cell wall component detectable in the serum of patients with early invasive fungal infection (IFI). We evaluated the utility of BDG surveillance as a guide for preemptive antifungal therapy in at-risk intensive care unit (ICU) patients.
Patients admitted to the ICU for ≥ 3 days and expected to require at least 2 additional days of intensive care were enrolled. Subjects were randomized in 3:1 fashion to receive twice weekly BDG surveillance with preemptive anidulafungin in response to a positive test or empiric antifungal treatment based on physician preference.
Sixty-four subjects were enrolled, with 1 proven and 5 probable cases of IC identified over a 2.5 year period. BDG levels were higher in subjects with proven/probable IC as compared to those without an IFI (117 pg/ml vs. 28 pg/ml; p<0.001). Optimal assay performance required 2 sequential BDG determinations of ≥ 80 pg/ml to define a positive test (sensitivity 100%, specificity 75%, positive predictive value 30%, negative predictive value 100%). In all, 21 preemptive and 5 empiric subjects received systemic antifungal therapy. Receipt of preemptive antifungal treatment had a significant effect on BDG concentrations (p< 0.001). Preemptive anidulafungin was safe and generally well tolerated with excellent outcome.
BDG monitoring may be useful for identifying ICU patients at highest risk to develop an IFI as well as for monitoring treatment response. Preemptive strategies based on fungal biomarkers warrant further study.
Clinical Trials.gov NCT00672841.
PLoS ONE 01/2012; 7(8):e42282. · 4.09 Impact Factor
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Melissa D Johnson,
Theo S Plantinga,
Esther van de Vosse,
Digna R Velez Edwards,
P Brian Smith, Barbara D Alexander,
John C Yang,
Dennis Kremer,
Gregory M Laird,
Marije Oosting,
Leo A B Joosten,
Jos W M van der Meer,
Jaap T van Dissel,
Thomas J Walsh,
John R Perfect,
Bart-Jan Kullberg,
William K Scott,
Mihai G Netea
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ABSTRACT: Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied.
A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro- and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients.
None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia.
Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.
Clinical Infectious Diseases 12/2011; 54(4):502-10. · 9.15 Impact Factor
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Benjamin J Park,
Peter G Pappas,
Kathleen A Wannemuehler, Barbara D Alexander,
Elias J Anaissie,
David R Andes,
John W Baddley,
Janice M Brown,
Lisa M Brumble,
Alison G Freifeld, [......],
Kieren A Marr,
Vicki A Morrison,
Genovefa Papanicolaou,
Thomas F Patterson,
Trish M Perl,
Mindy G Schuster,
Randall Walker,
John R Wingard,
Thomas J Walsh,
Dimitrios P Kontoyiannis
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ABSTRACT: Recent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001-2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.
Emerging Infectious Diseases 10/2011; 17(10):1855-64. · 6.79 Impact Factor
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Diana C Rosentul,
Theo S Plantinga,
Marije Oosting,
William K Scott,
Digna R Velez Edwards,
P Brian Smith, Barbara D Alexander,
John C Yang,
Gregory M Laird,
Leo A B Joosten,
Jos W M van der Meer,
John R Perfect,
Bart-Jan Kullberg,
Mihai G Netea,
Melissa D Johnson
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ABSTRACT: Candidemia is an important cause of morbidity and mortality in critically ill patients or patients undergoing invasive treatments. Dectin-1 is the main β-glucan receptor, and patients with a complete deficiency of either dectin-1 or its adaptor molecule CARD9 display persistent mucosal infections with Candida albicans. The role of genetic variation of DECTIN-1 and CARD9 genes on the susceptibility to candidemia is unknown.
We assessed whether genetic variation in the genes encoding dectin-1 and CARD9 influence the susceptibility to candidemia and/or the clinical course of the infection in a large cohort of American and Dutch candidemia patients (n = 331) and noninfected matched controls (n = 351). Furthermore, functional studies have been performed to assess the effect of the DECTIN-1 and CARD9 genetic variants on cytokine production in vitro and in vivo in the infected patients.
No significant association between the single-nucleotide polymorphisms DECTIN-1 Y238X and CARD9 S12N and the prevalence of candidemia was found, despite the association of the DECTIN-1 238X allele with impaired in vitro and in vivo cytokine production.
Whereas the dectin-1/CARD9 signaling pathway is nonredundant in mucosal immunity to C. albicans, a partial deficiency of β-glucan recognition has a minor impact on susceptibility to candidemia.
The Journal of Infectious Diseases 10/2011; 204(7):1138-45. · 6.41 Impact Factor
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Michael A Pfaller,
David Andes,
Maiken C Arendrup,
Daniel J Diekema,
Ana Espinel-Ingroff, Barbara D Alexander,
Steven D Brown,
Vishnu Chaturvedi,
Cynthia L Fowler,
Mahmoud A Ghannoum,
Elizabeth M Johnson,
Cynthia C Knapp,
Mary R Motyl,
Luis Ostrosky-Zeichner,
Thomas J Walsh
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ABSTRACT: We reassessed the Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) for voriconazole. We examined i) the essential (EA: ±2 dilutions) and categorical agreement between 24-h CLSI and EUCAST methods for voriconazole testing of Candida, ii) wild-type (WT) MICs and epidemiologic cutoff values (ECVs) for voriconazole by both CLSI and EUCAST methods, and iii) correlation of MICs with outcomes from previously published data using CLSI methods. We applied these findings to propose new 24-h species-specific CLSI CBPs. Adjusted 24-h CBPs for voriconazole and C. albicans, C. tropicalis, and C. parapsilosis (susceptible, ≤ 0.125 μg/mL; intermediate, 0.25-0.5 μg/mL; resistant, ≥ 1 μg/mL) should be more sensitive for detecting emerging resistance among common Candida species and provide consistency with EUCAST CBPs. In the absence of CBPs for voriconazole and C. glabrata (and less common species), we recommend that their respective ECVs be used to detect the emergence of non-WT strains.
Diagnostic microbiology and infectious disease 07/2011; 70(3):330-43. · 2.45 Impact Factor
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ABSTRACT: Pharmaceutical aerosols have the potential to prevent pulmonary infectious diseases. Liposomal amphotericin B (LAMB, Ambisome, Astellas Pharma US, Deerfield, IL, USA) is approved as an intravenous infusion for empiric treatment of presumed fungal infections in neutropenic, febrile patients, as well as patients infected with Aspergillus, Cryptococcus, and other fungal pathogens. In this study, four different nebulizers were tested for their ability to deliver LAMB in aerodynamic droplet-size ranges relevant to lung deposition by an inertial sampling technique Mass median aerodynamic diameter (MMAD) and fine particle fraction percent <3.3 μm (FPF(3.3)) and <5.8 μm (FPF(5.8)) were determined by cascade impaction during a 2 min sampling period for each of three trials of all nebulizers. The MMADs for all nebulizers ranged from 1.72 ± 0.11 μm to 2.89 ± 0.12 μm; FPF(3.3) and FPF(5.8) were approximately 80% and 90%, respectively. Although all nebulizers appear acceptable for delivery of LAMB, the Pari LC Star and the Aeroeclipse II were considered the best in terms of delivery of aerosol efficiently and the proportion suitable for lung deposition. Additional research on pulmonary delivery and clinical tolerability is warranted.
Pharmaceutical Development and Technology 06/2011; 16(6):577-82. · 1.36 Impact Factor
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ABSTRACT: One potential limitation of DNA-based molecular diagnostic tests for Candida bloodstream infection (BSI) is organism burden, which is not sufficiently characterized. We hypothesized that the number of CFU per milliliter (CFU/ml) present in an episode of Candida BSI is too low for reliable DNA-based diagnostics. In this study, we determined Candida burden in the first positive blood culture and explored factors that affect organism numbers and patient outcomes. We reviewed records of consecutive patients with a positive blood culture for Candida in the lysis-centrifugation blood culture system (Isolator, Wampole Laboratories, Cranbury, NJ) from 1987 to 1991. Descriptive statistics and logistic regression analyses were performed. One hundred fifty-two episodes of Candida BSI were analyzed. Patient characteristics included adult age (72%), indwelling central venous catheters (83%), recent surgery (29%), neutropenia (24%), transplant (14%), and other immune suppression (21%). Rates of treatment success and 30-day mortality for candidemia were each 51%. The median CFU/ml was 1 (mode 0.1, range 0.1 to >1,000). In the multivariate analysis, pediatric patients were more likely than adults to have high organism burdens (odds ratio [OR], 10.7; 95% confidence interval [95% CI], 4.3 to 26.5). Initial organism density did not affect patient outcome. Candida CFU/ml in the first positive blood culture of a BSI episode varies greatly; >50% of cultures had ≤1 CFU/ml, a concentration below the experimental yeast cell threshold for reliable DNA-based diagnostics. DNA-based diagnostics for Candida BSI will be challenged by low organism density and the need for sufficient specimen volume; future research on alternate targets is warranted.
Journal of clinical microbiology 06/2011; 49(8):2879-83. · 4.16 Impact Factor
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ABSTRACT: Recent shifts in the epidemiology of invasive fungal infections (IFIs) among transplant and oncology populations have led to new recommendations on treatment; however, they have also brought new controversies. New pharmacologic therapies are being studied and guidelines for management of several IFIs have been changed accordingly. More information is being discovered about unique genetic factors that put some transplant recipients at greater risk than others for fungal infection. The role of immunomodulation continues to be investigated, and the delicate balance of maintaining some immune integrity while assuring protection of the graft remains critical. For transplant and oncology patients, the diagnosis and management of IFIs remain challenging, and improving outcomes depends on continued progress in all of these arenas. This article highlights recent advances and important factors to consider when treating transplant and oncology patients with IFIs.
Hematology/oncology clinics of North America 02/2011; 25(1):193-213. · 2.05 Impact Factor
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ABSTRACT: To determine the optimal nebulization system for aerosolizing micafungin and to further assess the physiochemical properties of aerosolized micafungin.
In vitro experiment.
University research center. NEBULIZERS: Pari LC Star, Hudson Updraft, Small Volume Nebulizer, and Aeroclipse II.
Using a commercially available cascade impactor, the four nebulizers were tested for their ability to deliver micafungin to the lungs. Mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) percent less than 3.3 μm (FPF(3.3)) and less than 5.8 μm (FPF(5.8)) were determined during two sampling periods for each of three trials of all nebulizers. The mean ± standard error of the mean MMAD for the nebulizers ranged from 1.93 ± 0.09 to 2.49 ± 0.25 μm; FPF(3.3) and FPF(5.8) were approximately 50% and 90%, respectively, for all nebulizers.
Although all nebulizers appeared acceptable to deliver micafungin to the lungs, the Pari LC Star had the smallest MMAD and highest FPF(3.3) and FPF(5.8). These properties of the Pari LC Star should result in greater delivery of the aerosol to the lungs. Additional research on pulmonary delivery and clinical tolerability is warranted.
Pharmacotherapy 01/2011; 31(1):52-7. · 2.90 Impact Factor
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ABSTRACT: Phaeohyphomycosis, a term first introduced by Ajello and colleagues [1], is an encompassing clinical designation for a spectrum
of infections caused by darkly pigmented moulds [2, 3]. In its simplest definition, phaeohyphomycosis is an infection caused
by fungi that are characterized by a brown-to-black coloration of their vegetative or spore cell walls. Dark pigmentation
of the moulds is caused by deposition within the cell wall of dihydroxynaphthalene melanin that is formed through pentaketide
metabolism. These moulds collectively are known as dematiaceous fungi. In most cases the brown coloration of the fungus is
apparent in host tissue, but at times it is revealed only when the fungus is grown in culture. The term phaeohyphomycosis
(phaeo: dusky or brown; hypho: hyphal) is based on characteristics of the fungi as seen in infected tissue and thus includes
many genera and species.
12/2010: pages 305-317;
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ABSTRACT: With improved laboratory techniques and the availability of new antifungal agents, complexity in the treatment of invasive
fungal disease has rapidly increased over the past decade, stimulating a debate on the best management strategies. In this
chapter, we address four important areas of current uncertainty, including (1) the role of therapeutic drug monitoring for
voriconazole and posaconazole, (2) the utility of in vitro antifungal susceptibility testing of yeasts and moulds, (3) the
optimal treatment of zygomycosis, and (4) the value of combination therapy for invasive aspergillosis. For each topic, we
examine the available evidence surrounding the ambiguity and then offer data-driven recommendations on how to proceed with
management.
KeywordsVoriconazole–Posaconazole–Drug level–Monitoring–Antifungal susceptibility testing–Combi-nation antifungal therapy
12/2010: pages 301-316;
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Ryosuke Osawa, Barbara D Alexander,
Graeme N Forrest,
G Marshall Lyon,
Jyoti Somani,
Ramon del Busto,
Timothy L Pruett,
Costi D Sifri,
Ajit P Limaye,
Goran B Klintmalm, [......],
Susan L Orloff,
Sally H Houston,
Dannah Wray,
Shirish Huprikar,
Leonard B Johnson,
Raymund R Razonable,
Robert A Fisher,
Marilyn M Wagener,
Shahid Husain,
Nina Singh
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ABSTRACT: Whether there are geographic differences in clinical presentation of cryptococcosis in solid organ transplant (SOT) recipients in the United States (US) is not known.
Patients comprised a cohort of 120 SOT recipients from US transplant centers who fulfilled the EORTC/MSG criteria for cryptococcal disease.
Central nervous system, pulmonary, and cutaneous cryptococcal disease were observed in 51% (61/120), 64% (77/120), and 15% (18/120) of the patients, respectively. Cutaneous disease was documented in 9% (3/32) of the patients from South Atlantic region, 19% (6/32) from Mid Atlantic, 26% (6/23) from Southern, 7% (2/29) from Midwestern, and in 1 of 4 patients from the Northwestern region of the US. When controlled for age, immunosuppressive regimen, type of transplant, and renal failure at baseline, patients from the Southern compared with other regions of the US were significantly more likely to have cutaneous cryptococcal disease (OR 3.8, 95% CI 1.1-14, P=0.045).
Post-transplant cryptococcosis is more likely to present with cutaneous disease in the Southern region compared with other regions in the US. This predilection for cutaneous cryptococcosis could not be explained on the basis of differences in immunosuppression or the type of transplant. Whether our findings are related to strain-related variations in characteristics of the yeast or other transplant variables remains to be determined.
Annals of transplantation: quarterly of the Polish Transplantation Society 12/2010; 15(4):77-83. · 2.02 Impact Factor
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ABSTRACT: The Fungitell assay for (1,3)β-D-glucan (BG) detection in serum has been evaluated in patients with invasive fungal infections (IFIs) and healthy controls and for the early diagnosis of IFI in cancer patients. We evaluated the BG assay for the detection of IFI in lung transplant recipients. Serial serum samples were prospectively collected from patients undergoing lung transplants at Duke Hospital. Fungal infections were classified according to revised European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. A receiver operator characteristic (ROC) curve was generated; possible causes for false-positive and false-negative tests were investigated by linear regression analysis. Seven hundred fifty-six serum specimens from 59 subjects without IFI and 41 specimens from 14 patients with proven or probable IFI were tested. The area under the ROC curve was 0.69. Based on a 60-pg/ml positive cutoff, per-patient sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 64%, 9%, 14%, and 50%, respectively; per-test estimates were 71%, 59%, 9%, and 97%, respectively. The majority (92%) of patients not diagnosed with an IFI had at least one BG level of ≥60 pg/ml, and 90% had at least one BG level of ≥80 pg/ml. Respiratory colonization with mold and hemodialysis significantly affected mean BG levels. In conclusion, the accuracy of the BG test is marginal and its utility as a tool for the early diagnosis of IFI is questionable in the lung transplant population. Although the NPV of the BG test is high, the low PPV limits its utility as a screening tool for early diagnosis of IFI.
Journal of clinical microbiology 11/2010; 48(11):4083-8. · 4.16 Impact Factor
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Hsin-Yun Sun, Barbara D Alexander,
Olivier Lortholary,
Francoise Dromer,
Graeme N Forrest,
G Marshall Lyon,
Jyoti Somani,
Krishan L Gupta,
Ramon Del Busto,
Timothy L Pruett, [......],
Sally H Houston,
Dannah Wray,
Shirish Huprikar,
Leonard B Johnson,
Atul Humar,
Raymund R Razonable,
Robert A Fisher,
Shahid Husain,
Marilyn M Wagener,
Nina Singh
[show abstract]
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ABSTRACT: Clinical manifestations, treatment, and outcomes of cutaneous cryptococcosis in solid organ transplant (SOT) recipients are not fully defined. In a prospective cohort comprising 146 SOT recipients with cryptococcosis, we describe the presentation, antifungal therapy, and outcome of cutaneous cryptococcal disease. Cutaneous cryptococcosis was documented in 26/146 (17.8%) of the patients and manifested as nodular/mass (34.8%), maculopapule (30.4%), ulcer/pustule/abscess (30.4%), and cellulitis (30.4%) with 65.2% of the skin lesions occurred in the lower extremities. Localized disease developed in 30.8% (8/26), and disseminated disease in 69.2% (18/26) with involvement of the central nervous system (88.9%, 16/18), lung (33.3%, 6/18), or fungemia (55.6%, 10/18). Fluconazole (37.5%) was employed most often for localized and lipid formulations of amphotericin B (61.1%) for disseminated disease. Overall mortality at 90 days was 15.4% (4/26) with 16.7% in disseminated and 12.5% in localized disease (P = 0.78). SOT recipients who died were more likely to have renal failure (75.0% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) than those who survived. Cutaneous cryptococcosis represents disseminated disease in most SOT recipients and preferentially involves the extremities. Outcomes with appropriate management were comparable between SOT recipients with localized and disseminated cryptococcosis.
Medical mycology: official publication of the International Society for Human and Animal Mycology 09/2010; 48(6):785-91. · 2.13 Impact Factor
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ABSTRACT: Fungal polymerase chain reaction (PCR)-based diagnostic methods are at risk for contamination. Sample collection containers were investigated for fungal DNA contamination using real-time PCR assays. Up to 18% of blood collection tubes were contaminated with fungal DNA, probably Aspergillus fumigatus. Lower proportions of contamination in other vessels were observed.
Diagnostic microbiology and infectious disease 08/2010; 67(4):392-4. · 2.45 Impact Factor
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ABSTRACT: For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through >or=3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 microg/ml, but all demonstrated caspofungin MICs of >2 microg/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 microg/ml, but 4/5 had micafungin MICs of >2 microg/ml. The remaining isolates retained echinocandin MICs of <or=2 microg/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin treatment occurred predominantly in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild-type MIC distribution is also responsible for micafungin MICs of >2 microg/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.
Journal of clinical microbiology 07/2010; 48(7):2373-80. · 4.16 Impact Factor
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John W Baddley,
David R Andes,
Kieren A Marr,
Dimitrios P Kontoyiannis, Barbara D Alexander,
Carol A Kauffman,
Robert A Oster,
Elias J Anaissie,
Thomas J Walsh,
Mindy G Schuster,
John R Wingard,
Thomas F Patterson,
James I Ito,
O Dale Williams,
Tom Chiller,
Peter G Pappas
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ABSTRACT: Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (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 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. 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 patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.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 central nervous system 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.
Clinical Infectious Diseases 06/2010; 50(12):1559-67. · 9.15 Impact Factor
