Posts filed under ‘Resistencia bacteriana’

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 A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs.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

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

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

Sustained pediatric antimicrobial stewardship program with consultation to infectious diseases reduced carbapenem resistance and infection-related mortality

International Journal of Infectious Diseases November 2017 V.64 N. P.69–73

Yuho Horikoshi, Junichi Suwa, Hiroshi Higuchi, Tetsuji Kaneko, Mihoko Furuichi, Yuta Aizawa, Kahoru Fukuoka, Kaoru Okazaki, Kenta Ito, Takayo Shoji

Highlights

  • An antimicrobial stewardship program in consultation with the infectious disease service reduced resistance in Pseudomonas aeruginosa.
  • Carbapenem use was correlated with carbapenem resistance in P. aeruginosa.
  • This pediatric antimicrobial stewardship program reduced the length of hospitalization and infection-related mortality.

Objective

The impact of pediatric antimicrobial stewardship programs (ASP) on antimicrobial resistance (AMR) remains largely unknown. This study aimed to evaluate the AMR for carbapenem of Gram-negative bacilli (GNB) and carbapenem use with infectious diseases consultation after the implementation of an ASP.

Methods

This quasi-experimental study was conducted at Tokyo Metropolitan Children’s Medical Center in Japan. The pre- and post-intervention periods were April 2010 to September 2011 and October 2011 to March 2017, respectively. The pre-intervention phase consisted of consultations with the infectious diseases service alone. The ASP was implemented during the post-intervention phase. The carbapenem resistance rates of GNB were calculated. The correlation between carbapenem resistance rates and carbapenem day of therapy (DOT) was examined. The outcome metrics were compared by average length of hospitalization, all-cause mortality, and infection-related mortality.

Results

A positive correlation was observed between the carbapenem resistance rate in Pseudomonas aeruginosa and DOT (0.76, p = 0.04). The carbapenem resistance rate in P. aeruginosa (p < 0.01) and DOT (p < 0.01) decreased significantly in the post-intervention period. The length of hospitalization (p < 0.01) and infection-related mortality (p = 0.05) decreased in the post-intervention period.

Conclusions

A sustained ASP with additional consultation with the infectious disease service reduced carbapenem use and resistance in P. aeruginosa, leading to favorable outcomes in terms of length of hospitalization and infection-related mortality.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30236-9/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30236-9/pdf

February 9, 2018 at 1:23 pm

Maternal colonization or infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in Africa: A systematic review and meta-analysis

International Journal of Infectious Diseases November 2017 V.64 N. P.58–66

Andre N.H. Bulabula, Angela Dramowski, Shaheen Mehtar

Highlights

  • The prevalence of colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in pregnant and/or post-partum women in Africa is 17% (95% confidence interval 10–23%).
  • The pooled proportions from reviewed studies suggest a greater proportion of ESBL-E colonization in pregnant women compared to post-partum women.
  • The rate of maternal colonization with ESBL-E is greater in community settings than in hospital settings.
  • The most frequently reported ESBL-encoding gene in Africa is CTX-M.

Objective

To summarize published studies on the prevalence of and risk factors for maternal bacterial colonization and/or infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in pregnant and/or post-partum women in Africa.

Methods

A systematic review was conducted using the PubMed, Scopus, and Google Scholar databases. Bibliographies of included eligible studies were manually searched to identify additional relevant articles. No language restriction was applied. The timeframe of the search included all records from electronic database inception to July 15, 2017. A random-effects meta-analysis was performed to summarize the prevalence and the 95% confidence intervals (CI) of ESBL-E colonization or infection in pregnant or post-partum women in Africa. The meta-analysis was conducted using STATA IC 13.1 software and the metaprop function/plugin.

Results

Ten studies (seven on pregnant women and three on post-partum women) were included, documenting a 17% prevalence of maternal colonization with ESBL-E in Africa (95% CI 10–23%). The prevalence of ESBL-E in community isolates exceeded that in isolates from the hospital setting (22% vs. 14%). The most frequently reported ESBL-encoding gene was CTX-M (cefotaxime hydrolyzing capabilities). Data on risk factors for maternal ESBL-E colonization and infection are very limited.

Conclusions

The prevalence of colonization and/or infection with ESBL-E in pregnant and post-partum women in Africa exceeds that reported from high- and middle-income settings, representing a risk for subsequent neonatal colonization and/or infection with ESBL-E.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30221-7/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30221-7/pdf

February 9, 2018 at 1:21 pm

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