Posts filed under ‘Antimicrobianos’

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 A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs.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

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

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

First case of New Delhi metallo-β-lactamase in Klebsiella pneumoniae from Ecuador: An update for South America

International Journal of Infectious Diseases December 2017 V.65 N. P.119–121

Daniel Romero-Alvarez, Jorge Reyes, Viviana Quezada, Carolina Satán, Nelson Cevallos, Sofía Barrera, Gabriel Trueba, Luis E. Escobar, José E. Villacís

Highlights

  • The New Delhi metallo-β-lactamase (NDM) resistance plasmid has autochthonous circulation in Ecuador.
  • A Klebsiella pneumoniae ST147 harboring the NDM-1 gene in an IncA/C plasmid is described for the first time in Quito, Ecuador.
  • The circulation of NDM in South America has been addressed mainly by Brazil and Colombia.

Objectives

To describe a clinical case of Klebsiella pneumoniae harboring a New Delhi metallo-β-lactamase (NDM) plasmid in Ecuador and to present a map of reports of NDM isolates in South America.

Methods

The modified Hodge test, carbapenem inactivation method, imipenem–EDTA disk method (synergy), and Rapidec Carba NP test were used to identify antibiotic resistance mechanisms. The presence of resistance genes was explored with a conjugation assay, and molecular confirmation of NDM was performed by PCR and DNA sequencing. Plasmid characterization was conducted by PCR-based replicon typing. A literature review was performed in Google Scholar and PubMed to identify reports from South America.

Results

An HIV-infected patient, who had never traveled abroad, developed a bloodstream infection caused by K. pneumoniae ST147 harboring the NDM-1 resistance gene in a plasmid from the IncA/C group. Local circulation of NDM has also been described in other South American countries, in particular in Colombia and Brazil, although published scientific records were not found for other countries.

Conclusions

This report presents the first evidence of autochthonous circulation of the NDM-1 resistance gene harbored by an IncA/C plasmid isolated from a K. pneumoniae ST147 in Ecuador. Efforts should be implemented to monitor and characterize the spatial and temporal distribution of NDM in Ecuador and other countries of South America.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30268-0/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30268-0/pdf

February 10, 2018 at 9:09 am

Staphylococcus saprophyticus: Which beta-lactam?

International Journal of Infectious Diseases December 2017 V.65 N. P.63–66

Hélène Pailhoriès, Viviane Cassisa, Rachel Chenouard, Marie Kempf, Matthieu Eveillard, Carole Lemarié

Highlights

  • The treatment of Staphylococcus saprophyticus urinary tract infections is difficult.
  • This study analysed the epidemiology of S. saprophyticus urinary tract infections.
  • Susceptibility of S. saprophyticus to ceftriaxone was studied.
  • A high rate of ineffective empirical antibiotic therapy for S. saprophyticus was noted.
  • High ceftriaxone minimum inhibitory concentrations were noted for methicillin-susceptible S. saprophyticus.

Background

Staphylococcus saprophyticus is resistant to the drugs most often used for the empirical treatment of urinary tract infections (UTI). The adequacy of antimicrobial treatments prescribed for UTI due to S. saprophyticus is not usually questioned. This study described the epidemiology of such infections and assessed the susceptibility of S. saprophyticus to ceftriaxone and amoxicillin–clavulanic acid.

Methods

Methicillin-susceptible S. saprophyticus (MSSS) isolated from clinical samples between November 2014 and July 2016 were included. Clinical data were recorded. The minimum inhibitory concentrations (MICs) of amoxicillin–clavulanic acid and ceftriaxone were measured for these MSSS strains and for 17 randomly selected methicillin-susceptible Staphylococcus aureus (MSSA) strains.

Results

Of the S. saprophyticus isolates from urine, 59.5% were associated with a diagnosis of cystitis and 33.3% with pyelonephritis. Sixty percent of S. saprophyticus cystitis cases and 25% of pyelonephritis cases were given an inappropriate antibiotic regimen. The MICs of ceftriaxone ranged from 4 to >32 μg/ml for MSSS, and from 1.5 to 4 μg/ml for MSSA.

Conclusions

Many UTIs were treated with an empirical antibiotic therapy that was ineffective for S. saprophyticus, revealing that S. saprophyticus is an aetiology that is insufficiently considered in UTI. High MICs for ceftriaxone in MSSS were observed, which raises questions about the use of this antibiotic in UTIs due to S. saprophyticus.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30252-7/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30252-7/pdf

February 9, 2018 at 1:27 pm

Emerging group C and group G streptococcal endocarditis: A Canadian perspective

International Journal of Infectious Diseases December 2017 V.65 N. P.128–132

Sylvain A. Lother, Davinder S. Jassal, Philippe Lagacé-Wiens, Yoav Keynan

Objectives

The aim of this study was to determine the incidence of infective endocarditis (IE) in patients with bacteremia caused by group C and group G streptococci (GCGS) and to characterize the burden of disease, clinical characteristics, and outcomes through a case series of patients with GCGS IE.

Methods

Individuals with blood cultures growing GCGS in Manitoba, Canada, between January 2012 and December 2015 were included. Clinical and echocardiographic parameters were collected retrospectively. IE was suspected or confirmed according to the modified Duke criteria.

Results

Two hundred and nine bacteremic events occurred in 198 patients. Transthoracic echocardiography (TTE) was performed in 33%. Suspected or confirmed IE occurred in 6% of all patients and in 18% of those with TTE. Native valve infection was more common than prosthetic valve and device-related infections (75%, 17%, and 8%, respectively). Metastatic infection was observed in 64%, primarily to the lungs (57%), skin (43%), osteoarticular system (29%), and central nervous system (29%). Sepsis occurred in 58% and streptococcal toxic shock syndrome in 50% of those with IE, with overall mortality of 17%.

Conclusions

IE from GCGS bacteremia is common and is frequently associated with severe disease, embolic events, and mortality. In the appropriate clinical context, GCGS bacteremic events should prompt investigation for IE.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30274-6/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30274-6/pdf

February 9, 2018 at 1:25 pm

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