Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

LANCET December 16, 2017 V.390 N.10.113

Prof Guy E Thwaites, FRCP, Matthew Scarborough, PhD, Alexander Szubert, MSc, Emmanuel Nsutebu, FRCP, Robert Tilley, MBChB, Julia Greig, FRCP, Sarah A Wyllie, FRCPath, Prof Peter Wilson, MD, Cressida Auckland, FRCPath, Janet Cairns, MSc, Denise Ward, BSc, Pankaj Lal, MD, Achyut Guleri, MD, Neil Jenkins, PhD, Julian Sutton, MD, Prof Martin Wiselka, FRCP, Gonzalez-Ruiz Armando, MD, Clive Graham, MD, Paul R Chadwick, FRCPath, Gavin Barlow, FRCP

Summary

Background

Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.

Methods

In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.

Findings

Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).

Interpretation

Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.

Funding

UK National Institute for Health Research Health Technology Assessment.

FULL TEXT

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32456-X/fulltext?elsca1=etoc

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http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)32456-X.pdf

 

LANCET December 16, 2017 V.390 N.10.113

Comment

Rifampicin for Staphylococcus aureus bacteraemia: give it ARREST

Thomas L Holland, Vance G Fowler Jr

Although Staphylococcus aureus bacteraemia is both common and potentially lethal, clinical decisions involving its treatment remain largely unencumbered by high-quality data.1 With the ARREST multicentre, randomised, double-blind, placebo-controlled trial, Guy Thwaites and colleagues2 have contributed high-quality evidence and addressed an unresolved question involving the role of adjunctive rifampicin in treatment regimens for patients with S aureus bacteraemia…..

FULL TEXT

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33294-4/fulltext?elsca1=etoc

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http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)33294-4.pdf

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December 16, 2017 at 8:21 am

HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study.

PLoS Med. November 4, 2017 V.14 N.11 e1002417.     

Henrich TJ1, Hatano H2, Bacon O2,3, Hogan LE1, Rutishauser R1,2, Hill A4, Kearney MF5, Anderson EM5, Buchbinder SP2,3, Cohen SE2,3, Abdel-Mohsen M2,6, Pohlmeyer CW7, Fromentin R8, Hoh R2, Liu AY2,3, McCune JM1, Spindler J5, Metcalf-Pate K7, Hobbs KS1, Thanh C1, Gibson EA1, Kuritzkes DR9,10, Siliciano RF11,12, Price RW13, Richman DD14,15, Chomont N8, Siliciano JD10, Mellors JW16, Yukl SA17,18, Blankson JN7, Liegler T2, Deeks SG2.

Author information

1 Division of Experimental Medicine, University of California, San Francisco, California, United States of America.

2 Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, California, United States of America.

3 San Francisco Department of Public Health, San Francisco, California, United States of America.

4 Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America.

5 HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.

6 The Wistar Institute, Philadelphia, Pennsylvania, United States of America.

7 Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

8 Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.

9 Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America.

10 Harvard Medical School, Boston, Massachusetts, United States of America.

11 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

12 Howard Hughes Medical Institute, Baltimore, Maryland, United States of America.

13 Department of Neurology, University of California, San Francisco, California, United States of America.

14 University of California San Diego, La Jolla, California, United States of America.

15 Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.

16 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

17 San Francisco Veterans Affairs Medical Center, San Francisco, California, United States of America.

18 University of California, San Francisco, California, Unites States of America.

Abstract

BACKGROUND:

It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.

METHODS AND FINDINGS:

Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.

CONCLUSIONS:

We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675377/pdf/pmed.1002417.pdf

December 11, 2017 at 8:42 am

Predictors of pneumonia in lower respiratory tract infections – 3C prospective cough complication cohort study.

European Respiratory Journal ERJ  November 2017 V.50 N.5

Michael Moore1, Beth Stuart 1, Paul Little1, Sue Smith2, Matthew J. Thompson3, Kyle Knox2, Anne van den Bruel2, Mark Lown1 and David Mant2

Affiliations:

1 University of Southampton, Primary Care Medical Group, Aldermoor Health Centre, Southampton, UK.

2 Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK.

3 Dept of Family Medicine, University of Washington, Seattle, WA, USA.

Correspondence: Michael Moore, University of Southamptom K. E-mail: mvm198@soton.ac.uk

ABSTRACT

The aim was to aid diagnosis of pneumonia in those presenting with lower respiratory tract symptoms in routine primary care. A cohort of 28 883 adult patients with acute cough attributed to lower respiratory tract infections (LRTIs) was recruited from 5222 UK practices in 2009–13. Symptoms, signs and treatment were recorded at presentation and subsequent events followed-up for 30 days by chart review. The predictive value of patient characteristics, presenting symptoms and clinical findings for the diagnosis of pneumonia in the first 7 days was established.

Of the 720 out of 28 883 (2.5.%) radiographed within 1 week of the index consultation, 115 (16.0%; 0.40% of 28 883) were assigned a definite or probable pneumonia diagnosis. The significant independent predictors of radiograph-confirmed pneumonia were temperature >37.8°C (RR 2.6; 95% CI 1.5–4.8), crackles on auscultation (RR 1.8; 1.1–3.0), oxygen saturation <95% (RR 1.7; 1.0–3.1) and pulse >100·min–1 (RR 1.9; 1.1–3.2). Most patients with pneumonia (99/115, 86.1%) exhibited at least one of these four clinical signs; the positive predictive value of having at least one of these signs was 20.2% (95% CI 17.3–23.1).

In routine practice, radiograph-confirmed pneumonia as a short-term complication of LRTI is very uncommon (one in 270). Pulse oximetry may aid the diagnosis of pneumonia in this setting.

FULL TEXT

http://erj.ersjournals.com/content/50/5/1700434?etoc

PDF

http://erj.ersjournals.com/content/erj/50/5/1700434.full.pdf

December 7, 2017 at 8:34 am

Ceftriaxone-Resistant Neisseria gonorrhoeae, Canada, 2017.

Emerging Infectious Diseases February 15, 2018 Feb 15 V.24 N.2

Lefebvre B, Martin I, Demczuk W, Deshaies L, Michaud S, Labbé AC, Beaudoin MC, Longtin J.

Author affiliations: Institut National de Santé Publique du Québec, Québec, Québec, Canada (B. Lefebvre, J. Longtin); Public Health Agency of Canada, Winnipeg, Manitoba, Canada (I. Martin, W. Demczuk); Centre Intégré Universitaire de Santé et de Services Sociaux de la Capitale-Nationale, Québec (L. Deshaies); Direction de Santé Publique du Centre Intégré Universitaire de Santé et de Services Sociaux de la Capitale-Nationale, Québec (S. Michaud); Université de Montréal, Québec (A.-C. Labbé); Centre de Recherche en Infectiologie, Université Laval, Québec (M.-C. Beaudoin, J. Longtin)

Abstract

We identified a ceftriaxone-resistant Neisseria gonorrhoeae isolate in a patient in Canada. This isolate carried the penA-60 allele, which differs substantially from its closest relative, mosaic penA XXVII (80% nucleotide identity). Epidemiologic and genomic data suggest spread from Asia. Antimicrobial susceptibility surveillance helps prevent spread of highly resistant N. gonorrhoeae strains.

FULL TEXT

https://wwwnc.cdc.gov/eid/article/24/2/17-1756_article

December 5, 2017 at 7:10 am

Avian Influenza A(H7N2) Virus in Human Exposed to Sick Cats, New York, USA, 2016

Emerging Infectious Diseases December 2017 V.23 N.12

Atanaska Marinova-Petkova, Jen Laplante, Yunho Jang, Brian Lynch, Natosha Zanders, Marisela Rodriguez, Joyce Jones, Sharmi Thor, Erin Hodges, Juan A. De La Cruz, Jessica Belser, Hua Yang, Paul Carney, Bo Shu, LaShondra Berman, Thomas Stark, John Barnes, Fiona Havers, Patrick Yang, Susan C. Trock, Alicia Fry, Larisa Gubareva, Joseph S. Bresee, James Stevens, Demetre Daskalakis, Dakai Liu, Christopher Lee, Mia Kim Torchetti, Sandra Newbury, Francine Cigel, Kathy Toohey-Kurth, Kirsten St. George, David E. Wentworth, Stephen Lindstrom, and C. Todd Davis

Author affiliations:

Centers for Disease Control and Prevention, Atlanta, Georgia, USA (A. Marinova-Petkova, Y. Jang, B. Lynch, N. Zanders, M. Rodriguez, J. Jones, S. Thor, E. Hodges, J.A. De La Cruz, J. Belser, H. Yang, P. Carney, B. Shu, L. Berman, T. Stark, J. Barnes, F. Havers, P. Yang, S.C. Trock, A. Fry, L. Gubareva, J.S. Bresee, J. Stevens, D.E. Wentworth, S. Lindstrom, C.T. Davis); New York State Department of Health, Albany, New York, USA (J. Laplante, K. St. George); New York City Department of Health and Mental Hygiene, Long Island City, New York, USA (D. Daskalakis, D. Liu, C.T. Lee); US Department of Agriculture, Ames, Iowa, USA (M.K. Torchetti); University of Wisconsin, Madison, Wisconsin, USA (S. Newbury, F. Cigel, K. Toohey-Kurth)

An outbreak of influenza A(H7N2) virus in cats in a shelter in New York, NY, USA, resulted in zoonotic transmission. Virus isolated from the infected human was closely related to virus isolated from a cat; both were related to low pathogenicity avian influenza A(H7N2) viruses detected in the United States during the early 2000s.

PDF

https://wwwnc.cdc.gov/eid/article/23/12/pdfs/17-0798.pdf

 

December 4, 2017 at 8:14 am

Predictors of pneumonia in lower respiratory tract infections: 3C prospective cough complication cohort study

European Respiratory Journal  November 22, 2017        

Michael Moore, Beth Stuart, Paul Little, Sue Smith, Matthew J. Thompson, Kyle Knox, Anne van den Bruel, Mark Lown, David Mant

Abstract

The aim was to aid diagnosis of pneumonia in those presenting with lower respiratory tract symptoms in routine primary care.

A cohort of 28 883 adult patients with acute cough attributed to lower respiratory tract infections (LRTIs) was recruited from 5222 UK practices in 2009–13.

Symptoms, signs and treatment were recorded at presentation and subsequent events followed-up for 30 days by chart review.

The predictive value of patient characteristics, presenting symptoms and clinical findings for the diagnosis of pneumonia in the first 7 days was established.

Of the 720 out of 28 883 (2.5.%) radiographed within 1 week of the index consultation, 115 (16.0%; 0.40% of 28 883) were assigned a definite or probable pneumonia diagnosis.

The significant independent predictors of radiograph-confirmed pneumonia were temperature >37.8°C (RR 2.6; 95% CI 1.5–4.8), crackles on auscultation (RR 1.8; 1.1–3.0), oxygen saturation <95% (RR 1.7; 1.0–3.1) and pulse >100·min–1 (RR 1.9; 1.1–3.2).

Most patients with pneumonia (99/115, 86.1%) exhibited at least one of these four clinical signs; the positive predictive value of having at least one of these signs was 20.2% (95% CI 17.3–23.1).

In routine practice, radiograph-confirmed pneumonia as a short-term complication of LRTI is very uncommon (one in 270).

Pulse oximetry may aid the diagnosis of pneumonia in this setting.

FULL TEXT

http://erj.ersjournals.com/content/50/5/1700434

PDF

http://erj.ersjournals.com/content/erj/50/5/1700434.full.pdf

 

December 2, 2017 at 8:37 am

Use of Linezolid, an Oxazolidinone, in the Treatment of Multidrug-Resistant Gram-Positive Bacterial Infections

Clinical Infectious Diseases January 2000 V.30 N.1 P.146-151

Jason W. Chien, Michelle L. Kucia, and Robert A. Salata

Division of Infectious Diseases, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, Ohio

We report our experience with linezolid in an investigation of its use against resistant gram-positive bacterial infections.

Fifteen patients who had renal failure (n = 6), recent liver transplantation (n = 5) or surgery (n = 6), cancer (n = 3), endocarditis (n = 2), or human im-munodeficiency virus infection (n = 1), along with infections due to vancomycin-resistant entero-coccus (VRE), and 2 patients with infections due to methicillin-resistant Staphylococcus species who had adverse reactions to vancomycin were treated with linezolid (600 mg every 12 h for 5–42 days (mean ± SD, 20.5 ± 3.5 days).

Abscess drainage or prosthetic device removal was undertaken. Microbiological cure occurred in all 10 patients who completed therapy, and all 7 patients alive at follow-up were free of infection.

No deaths were attributable to the index infection. Adverse events associated with linezolid use were mild leukopenia in 1 patient and nausea in another.

It appears that administration of linezolid, in conjunction with surgical intervention or device removal, is an effective treatment option for serious resistant gram-positive bacterial infections.

PDF

http://cid.oxfordjournals.org/content/30/1/146.full.pdf

December 2, 2017 at 8:00 am

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