Christopher D. Pfeiffer

Diagnosis of invasive aspergillosis using a galactomannan assay:a meta-analysis

BACKGROUND A double-sandwich enzyme-linked immunosorbent galactomannan assay has been approved for surveillance for invasive aspergillosis in immunocompromised patients. We undertook a meta-analysis to assess the accuracy of a galactomannan assay for diagnosing invasive aspergillosis. METHODS Studies of the galactomannan assay that used the European Organization for Research and Treatment of Cancer or similar criteria as a reference standard and provided data to calculate sensitivity and specificity were included. Pooled sensitivity and specificity and summary measures of accuracy, Q* (the upper left-most point on the summary receiver-operating characteristic curve), mean D (a log odds ratio), and Youden index were calculated. Subgroup analyses were performed to explore heterogeneity. RESULTS Twenty-seven studies from 1966 to 28 February 2005 were included. Overall, the galactomannan assay had a sensitivity of 0.71 (95% confidence interval [CI], 0.68-0.74) and specificity of 0.89 (95% CI, 0.88-0.90) for proven cases of invasive aspergillosis. The Youden index, mean D, and Q* were 0.54 (95% CI, 0.41-0.65), 2.74 (95% CI, 21.12-3.36), and 0.80 (95% CI, 0.74-0.86), respectively, indicating moderate accuracy. Subgroup analyses showed that the performance of the test differed by patient population and type of reference standard used. Significant heterogeneity was present. CONCLUSIONS The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients. The test is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients. Further studies with attention to the impact of antifungal therapy, rigorous assessment of false-positive test results, and assessment of the utility of the test under nonsurveillance conditions are needed.

Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations

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 (2001-2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) 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, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 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 experienced a recurrence. CONCLUSIONS Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute 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.

Breakthrough Invasive Candidiasis in Patients on Micafungin

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 ≥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 μg/ml, but all demonstrated caspofungin MICs of >2 μg/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 μg/ml, but 4/5 had micafungin MICs of >2 μg/ml. The remaining isolates retained echinocandin MICs of ≤2 μg/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 μg/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.

β-D-glucan Surveillance with Preemptive Anidulafungin for Invasive Candidiasis in Intensive Care Unit Patients: A Randomized Pilot Study

Background 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. Methods 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. Results 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. Conclusions 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. Trial Registration Clinical Trials.gov NCT00672841

Quantitation of Candida CFU in Initial Positive Blood Cultures

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.

The State of Infectious Diseases Clinical Trials: A Systematic Review of ClinicalTrials.gov

Background There is a paucity of clinical trials informing specific questions faced by infectious diseases (ID) specialists. The ClinicalTrials.gov registry offers an opportunity to evaluate the ID clinical trials portfolio. Methods We examined 40,970 interventional trials registered with ClinicalTrials.gov from 2007–2010, focusing on study conditions and interventions to identify ID-related trials. Relevance to ID was manually confirmed for each programmatically identified trial, yielding 3570 ID trials and 37,400 non-ID trials for analysis. Results The number of ID trials was similar to the number of trials identified as belonging to cardiovascular medicine (n = 3437) or mental health (n = 3695) specialties. Slightly over half of ID trials were treatment-oriented trials (53%, vs. 77% for non-ID trials) followed by prevention (38%, vs. 8% in non-ID trials). ID trials tended to be larger than those of other specialties, with a median enrollment of 125 subjects (interquartile range [IQR], 45–400) vs. 60 (IQR, 30–160) for non-ID trials. Most ID studies are randomized (73%) but nonblinded (56%). Industry was the funding source in 51% of ID trials vs. 10% that were primarily NIH-funded. HIV-AIDS trials constitute the largest subset of ID trials (n = 815 [23%]), followed by influenza vaccine (n = 375 [11%]), and hepatitis C (n = 339 [9%]) trials. Relative to U.S. and global mortality rates, HIV-AIDS and hepatitis C virus trials are over-represented, whereas lower respiratory tract infection trials are under-represented in this large sample of ID clinical trials. Conclusions This work is the first to characterize ID clinical trials registered in ClinicalTrials.gov, providing a framework to discuss prioritization, methodology, and policy.

Disseminated Mycobacterium immunogenum infection presenting with septic shock and skin lesions in a renal transplant recipient.

Mycobacterium immunogenum is a relatively new species within the Mycobacterium chelonae‐Mycobacterium abscessus group of rapidly growing mycobacteria (RGM). M. immunogenum was first characterized in 2001 and, similar to other RGM, is an ubiquitous environmental organism. This organism has most commonly been implicated in cutaneous infection in both healthy and immunosuppressed patients. To our knowledge, this is the first reported case of septic shock in the setting of disseminated M. immunogenum infection. Definitive identification of this organism requires gene sequencing at specialized centers, which may limit its detection. M. immunogenum is resistant to many anti‐mycobacterial agents, and treatment can be especially challenging in transplant patients, given potential drug interactions and added toxicities. It is important to distinguish M. immunogenum from other RGM and determine the susceptibility profile to devise a successful treatment plan, particularly in the transplant population in which it can potentially cause severe, disseminated disease.

Establishment of a statewide network for carbapenem-resistant Enterobacteriaceae prevention in a low-incidence region

OBJECTIVE To establish a statewide network to detect, control, and prevent the spread of carbapenem-resistant Enterobacteriaceae (CRE) in a region with a low incidence of CRE infection. DESIGN Implementation of the Drug Resistant Organism Prevention and Coordinated Regional Epidemiology (DROP-CRE) Network. SETTING AND PARTICIPANTS Oregon infection prevention and microbiology laboratory personnel, including 48 microbiology laboratories, 62 acute care facilities, and 140 long-term care facilities. METHODS The DROP-CRE working group, comprising representatives from academic institutions and public health, convened an interdisciplinary advisory committee to assist with planning and implementation of CRE epidemiology and control efforts. The working group established a statewide CRE definition and surveillance plan; increased the state laboratory capacity to perform the modified Hodge test and polymerase chain reaction for carbapenemases in real time; and administered surveys that assessed the needs and capabilities of Oregon infection prevention and laboratory personnel. Results of these inquiries informed CRE education and the response plan. RESULTS Of 60 CRE reported from November 2010 through April 2013, only 3 were identified as carbapenemase producers; the cases were not linked, and no secondary transmission was found. Microbiology laboratories, acute care facilities, and long-term care facilities reported lacking carbapenemase testing capability, reliable interfacility communication, and CRE awareness, respectively. Survey findings informed the creation of the Oregon CRE Toolkit, a state-specific CRE guide booklet. CONCLUSIONS A regional epidemiology surveillance and response network has been implemented in Oregon in advance of widespread CRE transmission. Prospective surveillance will determine whether this collaborative approach will be successful at forestalling the emergence of this important healthcare-associated pathogen.

Skin Infections in Returned Travelers: an Update

Dermatologic manifestations of travel-related illness are particularly vexing due to the broad differential diagnosis and clinicians’ unfamiliarity with uncommonly seen diseases. This paper aims to educate and update the reader on selected infectious diseases in the returned traveler whose disease manifestations are primarily dermatologic. First, the evolving epidemiology of these infections is examined; understanding the geographic distribution of infectious etiologies helps refine and narrow the differential diagnosis. This is followed by a discussion of six important clinical syndromes including cutaneous larva migrans (CLM), cutaneous leishmaniasis, tungiasis, myiasis, antibiotic-resistant skin and soft tissue infection, and selected infections associated with fever and rash (e.g., measles, chikungunya virus infection, dengue fever, rickettsial spotted fevers). Familiarity with these syndromes and a situational awareness of their epidemiology will facilitate a prompt, accurate diagnosis and lead to appropriate treatment and prevention of further disease spread.

Evaluation of the Carba NP test in Oregon, 2013

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent public health threat. We evaluated the capacity of the Carba NP test to detect carbapenemase production in 206 isolates: 143 Enterobacteriaceae identified by Oregons CRE surveillance program in 2013 and 63 known carbapenemase-positive organisms. Overall, test sensitivity and specificity were 89% (59/66 isolates; 95% confidence interval [CI], 81 to 97%) and 100% (140/140 isolates; 95% CI, 98 to 100%), respectively. All KPC, NDM-1, VIM, and IMP producers but no (0/7 isolates) OXA-48-like strains were Carba NP positive prior to a post hoc protocol modification. We subsequently incorporated Carba NP into Oregons CRE screening algorithm.