Archive for June 23, 2017

Identification of Acute HIV-1 Infection by Hologic Aptima HIV-1 RNA Qualitative Assay

Clin. Microbiol. July 2017 55:2064-2073

Mark M. Manak, Leigh Anne Eller, Jennifer Malia, Linda L. Jagodzinski, Rapee Trichavaroj, Joseph Oundo, Cornelia Lueer, Fatim Cham, Mark de Souza, Nelson L. Michael, Merlin L. Robb, and Sheila A. Peel

aU.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

bHenry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA

cArmed Forces Research Institute of Medical Sciences, Bangkok, Thailand

dWalter Reed Project, Kericho, Kenya

eMbeya Medical Research Centre, Mbeya, Tanzania

fMakerere University Walter Reed Project, Kampala, Uganda

The Hologic Aptima HIV-1 Qualitative RNA assay was used in a rigorous screening approach designed to identify individuals at the earliest stage of HIV-1 infection for enrollment into subsequent studies of cellular and viral events in early infection (RV 217/Early Capture HIV Cohort [ECHO] study).

Volunteers at high risk for HIV-1 infection were recruited from study sites in Thailand, Tanzania, Uganda, and Kenya with high HIV-1 prevalence rates among the populations examined. Small-volume blood samples were collected by finger stick at twice-weekly intervals and tested with the Aptima assay.

Participants with reactive Aptima test results were contacted immediately for entry into a more comprehensive follow-up schedule with frequent blood draws. Evaluation of the Aptima test prior to use in this study showed a detection sensitivity of 5.5 copies/ml (50%), with all major HIV-1 subtypes detected. A total of 54,306 specimens from 1,112 volunteers were examined during the initial study period (August 2009 to November 2010); 27 individuals were identified as converting from uninfected to infected status.

A sporadic reactive Aptima signal was observed in HIV-1-infected individuals under antiretroviral therapy. Occasional false-reactive Aptima results in uninfected individuals, or nonreactive results in HIV-1-infected individuals not on therapy, were observed and used to calculate assay sensitivity and specificity.

The sensitivity and specificity of the Aptima assay were 99.03% and 99.23%, respectively; positive and negative predictive values were 92.01% and 99.91%, respectively.

Conversion from HIV-1-uninfected to -infected status was rapid, with no evidence of a prolonged period of intermittent low-level viremia.

PDF

http://jcm.asm.org/content/55/7/2064.full.pdf+html

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June 23, 2017 at 3:39 pm

Whole-Genome Sequencing Reveals the Contribution of Long-Term Carriers in Staphylococcus aureus Outbreak Investigation

Clin. Microbiol. July 2017 55:2188-2197

C. Gordon, B. Pichon, T. Golubchik, D. J. Wilson, J. Paul, D. S. Blanc, K. Cole, J. Collins, N. Cortes, M. Cubbon, F. K. Gould, P. J. Jenks, M. Llewelyn, J. Q. Nash, J. M. Orendi, K. Paranthaman, J. R. Price, L. Senn, H. L. Thomas, S. Wyllie, D. W. Crook, T. E. A. Peto, A. S. Walker, and A. M. Kearns

aNational Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom

bNuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

cAntimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, Colindale, United Kingdom

dPublic Health England, Royal Sussex County Hospital, Brighton, United Kingdom

eLausanne University Hospital, Service of Preventative Medicine, Lausanne, Switzerland

fNewcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom

gPortsmouth Hospitals NHS Trust, Portsmouth, United Kingdom

hBrighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom

iPlymouth Hospitals NHS Trust, Plymouth, United Kingdom

jBrighton and Sussex Medical School, Falmer, United Kingdom

kEast Kent Hospitals NHS Foundation Trust, Canterbury, United Kingdom

lRoyal Stoke University Hospital, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom

mPublic Health England, London, United Kingdom

nNational Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, Oxford, United Kingdom

Whole-genome sequencing (WGS) makes it possible to determine the relatedness of bacterial isolates at a high resolution, thereby helping to characterize outbreaks.

However, for Staphylococcus aureus, the accumulation of within-host diversity during carriage might limit the interpretation of sequencing data. In this study, we hypothesized the converse, namely, that within-host diversity can in fact be exploited to reveal the involvement of long-term carriers (LTCs) in outbreaks.

We analyzed WGS data from 20 historical outbreaks and applied phylogenetic methods to assess genetic relatedness and to estimate the time to most recent common ancestor (TMRCA).

The findings were compared with the routine investigation results and epidemiological evidence.

Outbreaks with epidemiological evidence for an LTC source had a mean estimated TMRCA (adjusted for outbreak duration) of 243 days (95% highest posterior density interval [HPD], 143 to 343 days) compared with 55 days (95% HPD, 28 to 81 days) for outbreaks lacking epidemiological evidence for an LTC (P = 0.004). A threshold of 156 days predicted LTC involvement with a sensitivity of 0.875 and a specificity of 1.

We also found 6/20 outbreaks included isolates with differing antimicrobial susceptibility profiles; however, these had only modestly increased pairwise diversity (mean 17.5 single nucleotide variants [SNVs] [95% confidence interval {CI}, 17.3 to 17.8]) compared with isolates with identical antibiograms (12.7 SNVs [95% CI, 12.5 to 12.8]) (P < 0.0001).

Additionally, for 2 outbreaks, WGS identified 1 or more isolates that were genetically distinct despite having the outbreak pulsed-field gel electrophoresis (PFGE) pulsotype.

The duration-adjusted TMRCA allowed the involvement of LTCs in outbreaks to be identified and could be used to decide whether screening for long-term carriage (e.g., in health care workers) is warranted.

Requiring identical antibiograms to trigger investigation could miss important contributors to outbreaks.

PDF

http://jcm.asm.org/content/55/7/2188.full.pdf+html

June 23, 2017 at 3:37 pm

Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study

Lancet Infectious Diseases July 2017 V.17 N.7

Dr Richard J Vickers, PhD’, Glenn S Tillotson, PhD, Richard Nathan, MD, Sabine Hazan, MD, John Pullman, MD, Christopher Lucasti, DO, Kenneth Deck, MD, Prof Bruce Yacyshyn, MD, Benedict Maliakkal, MD, Yves Pesant, MD, Bina Tejura, MD, Prof David Roblin, FRCP, Prof Dale N Gerding, MD, Prof Mark H Wilcox, MD for the show CoDIFy study group†

Background

Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection.

Methods

We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935.

Findings

Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation.

Interpretation

Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted.

Funding

Wellcome Trust and Summit Therapeutics.

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(17)30235-9.pdf

 

Lancet Infectious Diseases July 2017 V.17 N.7

COMMENT – Expanding the armamentarium for the treatment of Clostridium difficile infection 

Simon D Goldenberg

In The Lancet Infectious Diseases, Richard Vickers and colleagues1 report results of a phase 2 study of ridinilazole, a promising new drug for the treatment of Clostridium difficile infection. Although efforts to improve infection control practices and antimicrobial stewardship have led to significant reductions in some countries, C difficile infection remains a substantial problem worldwide.

All-cause 30-day mortality associated with C difficile infection has been reported to be in the region of 9–38%.3, 4 Furthermore, cases are associated with excess length of hospital stay of approximately 7 days (and 12 days in severe cases). C difficile infection usually occurs following disruption of the intestinal microbiota resulting from exposure to antibiotics. The risk of C difficile infection increases by up to six times during antibiotic therapy and in the month thereafter.

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(17)30237-2.pdf

June 23, 2017 at 7:56 am


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