Snigdha Vallabhaneni

Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses

Background. Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries. Methods. To understand the global emergence and epidemiology of C. auris, we obtained isolates from 54 patients with C. auris infection from Pakistan, India, South Africa, and Venezuela during 2012–2015 and the type specimen from Japan. Patient information was available for 41 of the isolates. We conducted antifungal susceptibility testing and whole-genome sequencing (WGS). Results. Available clinical information revealed that 41% of patients had diabetes mellitus, 51% had undergone recent surgery, 73% had a central venous catheter, and 41% were receiving systemic antifungal therapy when C. auris was isolated. The median time from admission to infection was 19 days (interquartile range, 9–36 days), 61% of patients had bloodstream infection, and 59% died. Using stringent break points, 93% of isolates were resistant to fluconazole, 35% to amphotericin B, and 7% to echinocandins; 41% were resistant to 2 antifungal classes and 4% were resistant to 3 classes. WGS demonstrated that isolates were grouped into unique clades by geographic region. Clades were separated by thousands of single-nucleotide polymorphisms, but within each clade isolates were clonal. Different mutations in ERG11 were associated with azole resistance in each geographic clade. Conclusions. C. auris is an emerging healthcare-associated pathogen associated with high mortality. Treatment options are limited, due to antifungal resistance. WGS analysis suggests nearly simultaneous, and recent, independent emergence of different clonal populations on 3 continents. Risk factors and transmission mechanisms need to be elucidated to guide control measures.

The changing natural history of HIV disease: before and after the introduction of generic antiretroviral therapy in southern India.

The number of individuals seeking treatment for infection with human immunodeficiency virus increased as the cost of highly active antiretroviral therapy (HAART) decreased 20-fold after the introduction of generic HAART in India in the year 2000. The incidence of tuberculosis and opportunistic infections decreased to <2 cases per 100 person-years. Death rates decreased from 25 to 5 deaths per 100 person-years between 1997 and 2003.

Reasons for modification of generic highly active antiretroviral therapeutic regimens among patients in southern India.

Objective:To describe reasons for modification and discontinuation of antiretroviral regimens in association with adverse events (AEs), treatment failure, and cost among patients in southern India. Methods:Secular trends of patients initiating highly active antiretroviral therapy (HAART) between January 1996 and October 2004 at a tertiary HIV referral center in India were analyzed using a previously validated natural history database. Results:All previously antiretroviral therapy-naive patients who initiated HAART (N = 1443) and had at least 1 follow-up visit were evaluated. The median CD4 count at the time of initiating HAART was 108 cells/μL The most common first-line regimens were stavudine (d4T) plus lamivudine (3TC) plus nevirapine (NVP) (63%), zidovudine (AZT) plus 3TC plus NVP (19%), d4T plus 3TC plus efavirenz (EFV) (9%), and AZT plus 3TC plus EFV (4%). Twenty percent of patients modified their first-line regimen. The most common reason for modifying therapy was the development of an AE (64%), followed by cost (19%) and treatment failure (14%), with median times to modify therapy being 40, 151, and 406 days, respectively. Common AEs were itching and/or skin rash (66%), hepatotoxicity (27%), and anemia (23%). Nine percent of patients discontinued therapy entirely after a median duration of 124 days, primarily because of cost (64%). Conclusion:The most common reason for modifying therapy was the occurrence of AEs, whereas cost was the most common reason for discontinuing therapy. Despite increasing access to lower cost generic HAART in India, even less expensive and more tolerable first-line regimens and cost-effective treatment monitoring tools need to be introduced to achieve better treatment outcomes and access in resource-constrained settings.

Neurocognitive consequences of HIV in southern India: A preliminary study of clade C virus

The neurocognitive impact of the clade C viral strain of human immunodeficiency virus (HIV) has not been determined. The purpose of this study was to examine neurocognitive function in southern India among individuals with the clade C virus with advanced HIV. A battery of cognitive tasks sensitive to the effects of HIV on brain function was translated and administered in Tamil and Telegu, two widely spoken languages in southern India. A sample of 30 treatment-naïve HIV-positive individuals with a median CD4 cell count of 97, and 30 age and education matched healthy controls obtained from the same region of India, were included in the study. Results revealed significant differences on most cognitive tests, with lower performances obtained by the HIV-positive individuals. These results suggest that cognitive difficulties are present among individuals with the clade C virus in India, with as many as 56% of the patients with advanced HIV meeting the criterion for impairment in two cognitive domains. Additional study is needed to determine if clade C HIV infection is more or less prone to cause neurocognitive deficit than the clade B virus. Furthermore, the impact of antiretroviral therapy on neurocognitive dysfunction in clade C virual infection needs to be determined.

The Global Burden of Fungal Diseases

Fungal diseases require greater attention today than ever before, given the expanding population of immunosuppressed patients who are at higher risk for these diseases. This article reports on distribution, incidence, and prevalence of various fungal diseases and points out gaps in knowledge where such data are not available. Fungal diseases that contribute substantially to global morbidity and mortality are highlighted. Long-term, sustainable surveillance programs for fungal diseases and better noninvasive and reliable diagnostic tools are needed to estimate the burden of these diseases more accurately.

Epidemiology and Risk Factors for Echinocandin Nonsusceptible Candida glabrata Bloodstream Infections: Data From a Large Multisite Population-Based Candidemia Surveillance Program, 2008–2014

Background. Echinocandins are first-line treatment for Candida glabrata candidemia. Echinocandin resistance is concerning due to limited remaining treatment options. We used data from a multisite, population-based surveillance program to describe the epidemiology and risk factors for echinocandin nonsusceptible (NS) C glabrata candidemia. Methods. The Centers for Disease Control and Preventions Emerging Infections Program conducts population-based laboratory surveillance for candidemia in 4 metropolitan areas (7.9 million persons; 80 hospitals). We identified C glabrata cases occurring during 2008–2014; medical records of cases were reviewed, and C glabrata isolates underwent broth microdilution antifungal susceptibility testing. We defined echinocandin-NS C glabrata (intermediate or resistant) based on 2012 Clinical and Laboratory Standards Institute minimum inhibitory concentration breakpoints. Independent risk factors for NS C glabrata were determined by stepwise logistic regression. Results. Of 1385 C glabrata cases, 83 (6.0%) had NS isolates (19 intermediate and 64 resistant); the proportion of NS isolates rose from 4.2% in 2008 to 7.8% in 2014 (P < .001). The proportion of NS isolates at each hospital ranged from 0% to 25.8%; 3 large, academic hospitals accounted for almost half of all NS isolates. In multivariate analysis, prior echinocandin exposure (adjusted odds ratio [aOR], 5.3; 95% CI, 2.6–1.2), previous candidemia episode (aOR, 2.5; 95% CI, 1.2–5.1), hospitalization in the last 90 days (aOR, 1.9; 95% CI, 1.0–3.5, and fluconazole resistance [aOR, 3.6; 95% CI, 2.0–6.4]) were significantly associated with NS C glabrata. Fifty-nine percent of NS C glabrata cases had no known prior echinocandin exposure. Conclusion. The proportion of NS C glabrata isolates rose significantly during 2008–2014, and NS C glabrata frequency differed across hospitals. In addition to acquired resistance resulting from prior drug exposure, occurrence of NS C glabrata without prior echinocandin exposure suggests possible transmission of resistant organisms.

Notes from the Field: Ongoing Transmission of Candida auris in Health Care Facilities — United States, June 2016–May 2017

Ongoing Transmission of Candida auris in Health Care Facilities — United States, June 2016–May 2017 Sharon Tsay, MD1,2; Rory M. Welsh, PhD1; Eleanor H. Adams, MD3; Nancy A. Chow, PhD1; Lalitha Gade, MPharm1; Elizabeth L. Berkow, PhD1; Eugenie Poirot, PhD2,4; Emily Lutterloh, MD3,5; Monica Quinn, MS3; Sudha Chaturvedi, PhD3,5; Janna Kerins, VMD2,6; Stephanie R. Black, MD6; Sarah K. Kemble, MD6; Patricia M. Barrett, MSD7; Kerri Barton, MPH8; D.J. Shannon, MPH9; Kristy Bradley, DVM10; Shawn R. Lockhart, PhD1; Anastasia P. Litvintseva, PhD1; Heather MoultonMeissner, PhD11; Alicia Shugart, MA11; Alex Kallen, MD11; Snigdha Vallabhaneni, MD1; Tom M. Chiller, MD1; Brendan R. Jackson, MD1

Rapid viral load suppression following generic highly active antiretroviral therapy in Southern Indian HIV-infected patients.

We prospectively studied the initial results of 6 months of generic efavirenz-based therapy on the plasma viral load in 40 patients at YRG Centre for AIDS Research and Education, a tertiary HIV referral centre in southern India. The median baseline plasma viral load was 259 000 copies/ml and at 6 months 95% of patients had plasma viral loads less than 400 copies/ml. The data support the use of generic non-nucleoside reverse transcriptase inhibitor-based regimens in resource-limited settings.

Cryptococcal antigen screening and early antifungal treatment to prevent cryptococcal meningitis: a review of the literature.

Background:Screening individuals with AIDS for serum cryptococcal antigen (CrAg), followed by treatment of CrAg positives with antifungals, may prevent cryptococcal meningitis. This review examined data on CrAg screening and treatment in resource-limited settings. Methods:We searched articles published during 2007–2014 on the effectiveness and cost-effectiveness of CrAg screening and treatment on the outcomes of mortality, morbidity, retention in care, quality of life, and/or prevention of ongoing HIV transmission. We rated overall quality of individual articles, summarized the body of evidence, the expected impact, and cost-effectiveness for each outcome. Results:We identified 2613 articles. Eight met all inclusion criteria. Five studies addressed mortality and/or morbidity outcomes; all were observational and had small sample sizes; 3 lacked a comparison group. Ratings of study quality ranged from “medium” to “weak,” and the quality of the overall body of evidence for mortality and morbidity outcomes was rated as “fair.” The interventions expected impact on mortality and morbidity was rated as “moderate.” The 4 cost-effectiveness studies included in the analysis showed that CrAg screening and treatment interventions are highly cost-effective. No studies addressed retention in care, quality of life, or HIV transmission. Conclusions:Although limited, the body of evidence regarding CrAg screening and treatment suggests that the intervention may have an impact on preventing cryptococcal meningitis and death in persons with AIDS. Additional research is needed to quantify the interventions effectiveness and identify optimal treatment dosing and implementation best practices.

Approach to the Investigation and Management of Patients With Candida auris, an Emerging Multidrug-Resistant Yeast

Candida auris is an emerging, multidrug-resistant yeast that can spread in healthcare settings. It can cause invasive infections with high mortality and is difficult to identify using traditional yeast identification methods. Candida auris has been reported in more than a dozen countries, and as of August 2017, 112 clinical cases have been reported in the United States. Candida auris can colonize skin and persist in the healthcare environment, allowing for transmission between patients. Prompt investigation and aggressive interventions, including notification to public health agencies, implementation of contact precautions, thorough environmental cleaning and disinfection, infection control assessments, contact tracing and screening of contacts to assess for colonization, and retrospective review of microbiology records and prospective surveillance for cases at laboratories are all needed to limit the spread of C. auris. This review summarizes the current recommended approach to manage cases and control transmission of C. auris in healthcare facilities.