Archive for February, 2018

Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

Antimicrobial Agents & Chemotherapy March 2018 V.62 N.3 e02163-17

Yutaka Saisho, Takayuki Katsube, Scott White, Hiroyuki Fukase and Jingoro Shimada

Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection.

The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects.

A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort).

A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort).

There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs.

Dose-proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg.

The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose).

There was little accumulation of Cmax and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

abstract

http://aac.asm.org/content/62/3/e02163-17.abstract

PDF

http://aac.asm.org/content/62/3/e02163-17.full.pdf+html

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February 23, 2018 at 5:03 pm

A systems biology approach to the effect of aging, immunosenescence and vaccine response.

Current Opinion in Immunology August 2014 V.29 P.62-8.

Poland GA1, Ovsyannikova IG2, Kennedy RB2, Lambert ND2, Kirkland JL3.

Author information

1 Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA. Electronic address: poland.gregory@mayo.edu.

2 Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, USA.

3 Robert & Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.

Abstract

Aging can lead to immunosenescence, which dramatically impairs the hosts’ ability to develop protective immune responses to vaccine antigens. Reasons for this are not well understood.

This topic’s importance is reflected in the increases in morbidity and mortality due to infectious diseases among elderly persons, a population growing in size globally, and the significantly lower adaptive immune responses generated to vaccines in this population.

Here, we endeavor to summarize the existing data on the genetic and immunologic correlates of immunosenescence with respect to vaccine response.

We cover how the application of systems biology can advance our understanding of vaccine immunosenescence, with a view toward how such information could lead to strategies to overcome the lower immunogenicity of vaccines in the elderly.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119552/pdf/nihms589246.pdf

February 19, 2018 at 9:12 am

The microbiota and microbiome in aging: potential implications in health and age-related diseases.

J Am Geriatr Soc. April 2015 V.63 N.4 P.776-81.

Zapata HJ1, Quagliarello VJ.

Author information

1 Infectious Diseases Section, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut.

Abstract

Advances in bacterial deoxyribonucleic acid sequencing allow for characterization of the human commensal bacterial community (microbiota) and its corresponding genome (microbiome).

Surveys of healthy adults reveal that a signature composite of bacteria characterizes each unique body habitat (e.g., gut, skin, oral cavity, vagina).

A myriad of clinical changes, including a basal proinflammatory state (inflamm-aging), that directly interface with the microbiota of older adults and enhance susceptibility to disease accompany aging.

Studies in older adults demonstrate that the gut microbiota correlates with diet, location of residence (e.g., community dwelling, long-term care settings), and basal level of inflammation.

Links exist between the microbiota and a variety of clinical problems plaguing older adults, including physical frailty, Clostridium difficile colitis, vulvovaginal atrophy, colorectal carcinoma, and atherosclerotic disease.

Manipulation of the microbiota and microbiome of older adults holds promise as an innovative strategy to influence the development of comorbidities associated with aging.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406803/pdf/nihms-644813.pdf

February 19, 2018 at 9:11 am

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

LANCET 17 February 2018 V.391 N.10.121 P.668-678

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,

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

PDF

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

 

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

PDF

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

 

February 18, 2018 at 10:48 pm

Clinical and epidemiological features of chronic Trypanosoma cruzi infection in patients with HIV/AIDS in Buenos Aires, Argentina

International Journal of Infectious Diseases February 2018 V.67 P.118–121

Andrés Guillermo Benchetrit, Marisa Fernández, Amadeo Javier Bava, Marcelo Corti, Norma Porteiro, Liliana Martínez Peralta

Highlights

  • Chagas disease reactivation is an AIDS-defining illness with a high mortality rate.
  • Besides the vector-borne route, other means of T. cruzi infection acquisition must be assessed.
  • HIV-infected patients with lower CD4 T-cell counts are at higher risk of Chagas disease reactivation.
  • Severely immunecompromised patients infected with T. cruzi may have negative serological assay results.
  • Direct parasitological techniques should be performed in the diagnosis of patients for whom there is a suspicion of T. cruzi reactivation.

Objectives

Trypanosoma cruzi reactivation in HIV patients is considered an opportunistic infection, usually with a fatal outcome. The aim of this study was to describe the epidemiological and clinical features of T. cruzi infection in HIV patients and to compare these findings between patients with and without Chagas disease reactivation.

Methods

The medical records of T. cruzi–HIV co-infected patients treated at the Muñiz Infectious Diseases Hospital from January 2005 to December 2014 were reviewed retrospectively. Epidemiological and clinical features were assessed and compared between patients with and without Chagas disease reactivation.

Results

The medical records of 80 T. cruzi–HIV co-infected patients were reviewed. The most likely route of T. cruzi infection was vector-borne (32/80 patients), followed by intravenous drug use (12/80). Nine of 80 patients had reactivation. Patients without reactivation had a significantly higher CD4 T-cell count at diagnosis of T. cruzi infection (144 cells/μl vs. 30 cells/μl, p = 0.026). Chagas disease serology was negative in two of nine patients with reactivation.

Conclusions

Serological assays for T. cruzi infection may be negative in severely immunocompromised patients. Direct parasitological techniques should be performed in the diagnosis of patients for whom there is a suspicion of T. cruzi reactivation. HIV patients with a lower CD4 count are at higher risk of reactivation.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30309-0/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30309-0/pdf

February 18, 2018 at 4:05 pm

Early-onset prosthetic valve endocarditis definition revisited: Prospective study and literature review

International Journal of Infectious Diseases February 2018 V.67 P.3–6

Rinaldo Focaccia Siciliano, Bruno Azevedo Randi, Danielle Menosi Gualandro, Roney Orismar Sampaio, Márcio Sommer Bittencourt, Christian Emmanuel da Silva Pelaes, Alfredo José Mansur, Pablo Maria Alberto Pomerantzeff, Flávio Tarasoutchi, Tânia Mara Varejão Strabelli

Highlights

  • Studies reporting the etiology of prosthetic valve endocarditis (PVE) are an unmet clinical need.
  • A prospective cohort study was performed along with a literature review to describe the distribution of the etiology of PVE.
  • At >120 days after valve surgery, there is a decrease in the incidence of resistant microorganisms.
  • PVE occurring at >120 days after surgery may be treated with the same empirical treatment as for late PVE.
  • This approach could lead to higher antibiotic efficacy and less damage to the patient’s natural flora.

Objective

To determine the annual incidence of prosthetic valve endocarditis (PVE) and to evaluate its current classification based on the epidemiological distribution of agents identified and their sensitivity profiles.

Methods

Consecutive cases of PVE occurring within the first year of valve surgery during the period 1997–2014 were included in this prospective cohort study. Incidence, demographic, clinical, microbiological, and in-hospital mortality data of these PVE patients were recorded.

Results

One hundred and seventy-two cases of PVE were included, and the global annual incidence of PVE was 1.7%. Most PVE cases occurred within 120 days after surgery (76.7%). After this period, there was a reduction in resistant microorganisms (64.4% vs. 32.3%, respectively; p = 0.007) and an increase in the incidence of Streptococcus spp (1.9% vs. 23.5%; p = 0.007). A literature review revealed 646 cases of PVE with an identified etiology, of which 264 (41%) were caused by coagulase-negative staphylococci and 43 (7%) by Streptococcus spp. This is in agreement with the current study findings.

Conclusions

Most PVE cases occurred within 120 days after valve surgery, and the same etiological agents were identified in this period. The current cut-off level of 365 days for the classification of early-onset PVE should be revisited.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30228-X/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30228-X/pdf

February 18, 2018 at 4:03 pm

REVIEW – Environmental cleaning and disinfection of patient areas

International Journal of Infectious Diseases Ferbuary 2018 V.67 P.52–57

Michelle Doll, Michael Stevens, Gonzalo Bearman

Abstract

The healthcare setting is predisposed to harbor potential pathogens, which in turn can pose a great risk to patients.

Routine cleaning of the patient environment is critical to reduce the risk of hospital-acquired infections.

While many approaches to environmental cleaning exist, manual cleaning supplemented with ongoing assessment and feedback may be the most feasible for healthcare facilities with limited resources.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30270-9/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30270-9/pdf

February 10, 2018 at 9:18 am

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