Archive for December, 2017

In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria

Antimicrobial Agents and Chemotherapy January 2018 V.62 N.1

Akinobu Ito, Takafumi Sato, Merime Ota, Miki Takemura, Toru Nishikawa, Shinsuke Toba, Naoki Kohira, Satoshi Miyagawa, Naoki Ishibashi, Shuhei Matsumoto, Rio Nakamura, Masakatsu Tsuji and Yoshinori Yamano

aShionogi & Co., Ltd., Toyonaka, Osaka, Japan

Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii.

Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime.

A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane.

The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.


December 25, 2017 at 12:21 pm

In Vitro Activity of Meropenem-Vaborbactam against Clinical Isolates of KPC-Positive Enterobacteriaceae

Antimicrobial Agents and Chemotherapy January 2018 V.62 N.1

Meredith A. Hackel, Olga Lomovskaya, Michael N. Dudley, James A. Karlowsky and Daniel F. Sahm

aInternational Health Management Associates, Inc., Schaumburg, Illinois, USA

bThe Medicines Company, San Diego, California, USA

cDepartment of Medical Microbiology and Infectious Diseases, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Vaborbactam (formerly RPX7009) is a novel inhibitor of serine β-lactamases, including Ambler class A carbapenemases, such as KPCs.

The current study evaluated the in vitro activity of the combination agent meropenem-vaborbactam against a global collection of 991 isolates of KPC-positive Enterobacteriaceae collected in 2014 and 2015 using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method.

The MIC90 of meropenem (when tested with a fixed concentration of 8 μg/ml of vaborbactam) for isolates of KPC-positive Enterobacteriaceae was 1 μg/ml, and MIC values ranged from ≤0.03 to >32 μg/ml; 99.0% (981/991) of isolates had meropenem-vaborbactam MICs of ≤4 μg/ml, the U.S. FDA-approved MIC breakpoint for susceptibility to meropenem-vaborbactam (Vabomere).

Vaborbactam lowered the meropenem MIC50 from 32 to 0.06 μg/ml and the MIC90 from >32 to 1 μg/ml. There were no differences in the activity of meropenem-vaborbactam when the isolates were stratified by KPC variant type.

We conclude that meropenem-vaborbactam demonstrates potent in vitro activity against a worldwide collection of clinical isolates of KPC-positive Enterobacteriaceae collected in 2014 and 2015.


December 25, 2017 at 12:20 pm

Reduced Chlorhexidine and Daptomycin Susceptibility in Vancomycin-Resistant Enterococcus faecium after Serial Chlorhexidine Exposure

Antimicrobial Agents and Chemotherapy January 2018 V.62 N.1

Pooja Bhardwaj, Amrita Hans, Kinnari Ruikar, Ziqiang Guan and Kelli L. Palmer

aDepartment of Biological Sciences, University of Texas at Dallas, Richardson, Texas, USA

bDepartment of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA

Vancomycin-resistant Enterococcus faecium strains (VREfm) are critical public health concerns because they are among the leading causes of hospital-acquired bloodstream infections.

Chlorhexidine (CHX) is a bisbiguanide cationic antiseptic that is routinely used for patient bathing and other infection control practices. VREfm are likely frequently exposed to CHX; however, the long-term effects of CHX exposure have not been studied in enterococci.

In this study, we serially exposed VREfm to increasing concentrations of CHX for a period of 21 days in two independent experimental evolution trials. Reduced CHX susceptibility emerged (4-fold shift in CHX MIC).

Subpopulations with reduced daptomycin (DAP) susceptibility were detected, which were further analyzed by genome sequencing and lipidomic analysis.

Across the trials, we identified adaptive changes in genes with predicted or experimentally confirmed roles in chlorhexidine susceptibility (efrE), global nutritional stress response (relA), nucleotide metabolism (cmk), phosphate acquisition (phoU), and glycolipid biosynthesis (bgsB), among others.

Moreover, significant alterations in membrane phospholipids were identified for some populations with reduced DAP susceptibility. Our results are clinically significant because they identify a link between serial subinhibitory CHX exposure and reduced DAP susceptibility.

In addition, the CHX-induced genetic and lipidomic changes described in this study offer new insights into the mechanisms underlying the emergence of antibiotic resistance in VREfm.


December 25, 2017 at 12:18 pm

Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial

Lancet Infectious Diseases January 2018 V.18 N.1 P.47-57

Prof James G Hakim, FRCP, Jennifer Thompson, MSc, Cissy Kityo, MSc, Anne Hoppe, PhD, Andrew Kambugu, MMed, Prof Joep J van Oosterhout, PhD, Abbas Lugemwa, MD, Abraham Siika, MMed, Raymond Mwebaze, MMed, Aggrey Mweemba, MMed, George Abongomera, PhD, Margaret J Thomason, PhD, Philippa Easterbrook, MD, Prof Peter Mugyenyi, FRCP, Prof A Sarah Walker, PhD*, Prof Nicholas I Paton, MD*



Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.


We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.


Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.


Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.


European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.



Lancet Infectious Diseases January 2018 V.18 N.1 P.3-5


The unexpected success of NRTIs in second-line treatment

Andrew M Hill, Francois Venter

Genotype-defined resistance to antiretrovirals supposedly predicts future virological failure. Findings from clinical studies, including the 144 week results from the EARNEST trial, published in The Lancet Infectious Diseases,1 challenge this decades-long dogma, certainly when it comes to nucleoside analogues.

WHO currently recommends second-line treatment with two nucleoside reverse-transcriptase inhibitors (NRTIs) and a boosted protease inhibitor.2 However, there is evidence for widespread resistance to NRTIs after virological failure of first-line treatment in low-income countries, which might limit future treatment options.3 …


December 22, 2017 at 8:16 am

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



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.


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.


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).


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


UK National Institute for Health Research Health Technology Assessment.




LANCET December 16, 2017 V.390 N.10.113


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…..



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.



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.


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.


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.


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


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:


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.



December 7, 2017 at 8:34 am

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