Archive for January 26, 2017

Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.

BMJ Open. 2015 Mar 11;5(3):e006723.

Shaw E1, Miró JM2, Puig-Asensio M3, Pigrau C3, Barcenilla F4, Murillas J5, Garcia-Pardo G6, Espejo E7, Padilla B8, Garcia-Reyne A9, Pasquau J10, Rodriguez-Baño J11, López-Contreras J12, Montero M13, de la Calle C2, Pintado V14, Calbo E15, Gasch O16, Montejo M17, Salavert M18, Garcia-Pais MJ19, Carratalà J1, Pujol M1; Spanish Network for Research in Infectious Diseases (REIPI RD12/0015); Instituto de Salud Carlos III, Madrid, Spain; GEIH (Hospital Infection Study Group).

Collaborators (47)

Author information

1Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.

2Hospital Universitari Clínic-IDIBAPS, Barcelona, Spain.

3Hospital Universitari Vall d’Hebron, Barcelona, Spain.

4Hospital Universitari Arnau de Vilanova, Lleida, Spain.

5Hospital Universitari Son Espases, Mallorca, Spain.

6Hospital Universitari Joan XXIII, Tarragona, Spain.

7Hospital Universitari de Terrassa, Terrassa, Barcelona, Spain.

8Hospital Universitario Gregorio Marañon, Madrid, Spain.

9Hospital Universitario 12 de Octubre, Madrid, Spain.

10Hospital Universitario Virgen de las Nieves, Granada, Spain.

11Hospital Universitario Virgen Macarena, Sevilla, Spain.

12Hospital Universitari Santa Creu i Sant Pau, Barcelona, Spain.

13Hospital Universitari Parc de Salut Mar, Barcelona, Spain.

14Hospital Universitario Ramón y Cajal, Madrid, Spain.

15Hospital Universitari Mutúa de Terrassa, Barcelona, Spain.

16Corporació Sanitaria Parc Taulí, Sabadell, Barcelona, Spain.

17Hospital Universitario de Cruces, Barakaldo, Spain.

18Hospital Universitari i Politècnic la Fe, Valencia, Spain.

19Hospital Universitario Lucus Augusti, Lugo, Spain.

Abstract

INTRODUCTION:

Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone.

METHODS AND ANALYSIS:

A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis.

ETHICS AND DISSEMINATION:

The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study.

TRIAL REGISTRATION NUMBER: NCT01898338.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360784/pdf/bmjopen-2014-006723.pdf

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January 26, 2017 at 3:39 pm

Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections.

Open Forum Infect Dis. 2015 May 5;2(2):ofv050.

Morrill HJ1, Pogue JM2, Kaye KS3, LaPlante KL4.

Author information

1Veterans Affairs Medical Center , Infectious Diseases Research Program , Providence, Rhode Island ; College of Pharmacy, Department of Pharmacy Practice , University of Rhode Island , Kingston.

2Department of Pharmacy Services.

3Division of Infectious Diseases , Detroit Medical Center, Wayne State University , Michigan.

4Veterans Affairs Medical Center , Infectious Diseases Research Program , Providence, Rhode Island ; College of Pharmacy, Department of Pharmacy Practice , University of Rhode Island , Kingston ; Division of Infectious Diseases , Warren Alpert Medical School of Brown University , Providence, Rhode Island.

Abstract

This article provides a comprehensive review of currently available treatment options for infections due to carbapenem-resistant Enterobacteriaceae (CRE).

Antimicrobial resistance in Gram-negative bacteria is an emerging and serious global public health threat. Carbapenems have been used as the “last-line” treatment for infections caused by resistant Enterobacteriaceae, including those producing extended spectrum ß-lactamases.

However, Enterobacteriaceae that produce carbapenemases, which are enzymes that deactivate carbapenems and most other ß-lactam antibiotics, have emerged and are increasingly being reported worldwide.

Despite this increasing burden, the most optimal treatment for CRE infections is largely unknown. For the few remaining available treatment options, there are limited efficacy data to support their role in therapy.

Nevertheless, current treatment options include the use of older agents, such as polymyxins, fosfomycin, and aminoglycosides, which have been rarely used due to efficacy and/or toxicity concerns. Optimization of dosing regimens and combination therapy are additional treatment strategies being explored.

Carbapenem-resistant Enterobacteriaceae infections are associated with poor outcomes and high mortality. Continued research is critically needed to determine the most appropriate treatment.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462593/pdf/ofv050.pdf

January 26, 2017 at 3:36 pm

Therapeutic options for carbapenemase-producing Enterobacteriaceae.

Rev Esp Quimioter. 2015 Sep;28 Suppl 1:12-5.

[Article in Spanish]

Salgado P, Gilsanz F, Maseda E1.

Author information

1Emilio Maseda, Servicio de Anestesia y Reanimación, Hospital Universitario La Paz; Paseo de la Castellana 261, 2846, Madrid, Spain. emilio.maseda@gmail.com

Abstract

Carbapenemase-producing Enterobacteriaceae (CPE) has spread worldwide becoming a threat to public health. However, no randomized clinical trials about the efficacy of optimizing antibiotic treatment have been published. Experimental studies have been designed to find combinations of antibiotics with synergistic activity.

Their main aim has been increasing the speed of bacterial destruction and decreasing resistance. The latest guidelines recommend combination therapy. The carbapenems has been chosen as the basis of such therapy.

We face limited therapeutic options. Polymyxins, fosfomycin and gentamicin have reemerged in this context, becoming the basis of multiple combination regimens, with beneficial effects both in vitro and in murine models of infection.

PDF

http://seq.es/seq/0214-3429/28/sup1/salgado.pdf

January 26, 2017 at 3:32 pm

The Antimicrobial Therapy Puzzle: Could Pharmacokinetic-Pharmacodynamic Relationships Be Helpful in Addressing the Issue of Appropriate Pneumonia Treatment in Critically Ill Patients?

Clin Infect Dis. June 15, 2006 V.42 N.12 P.1764-1771

Reviews of Anti-Infective Agents

Louis D. Saravolatz, Federico Pea, and Pierluigi Viale

1Institute of Clinical Pharmacology and Toxicology, Department of Experimental and Clinical Pathology and Medicine, Udine, Italy

2Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine, Udine, Italy

Until recently, the in vitro susceptibility of microorganisms was considered the only fundamental aspect for antibiotic efficacy in treating pneumonia. However, the relevance of pharmacokinetic-pharmacodynamic relationships in optimizing drug exposure has been progressively highlighted.

Antimicrobial agents were divided into concentration-dependent or time-dependent groups, with the most consistently relevant pharmacodynamic parameters for efficacy being either the ration of the plasma peak concentration to the minimum inhibitory concentration or the time the plasma concentration persists above the minimum inhibitory concentration of the etiological agent, respectively.

For the adequate treatment of pneumonia, optimal pharmacodynamic exposure should be ensured also at the infection site. To investigate this, a methodologically correct approach may be to detect drug concentration levels in the epithelial lining fluid and in the alveolar macrophages for extracellular and intracellular pathogens, respectively.

From this perspective, the pharmacokinetic factors—only in some instances—support the achievement of optimal exposure during the treatment of pneumonia with fixed standard dosing regimens of antimicrobials; conversely, in other instances, the pharmacokinetic factors suggest the need for an implemented dosage regimen or even the choice of a different drug.

PDF

http://cid.oxfordjournals.org/content/42/12/1764.full.pdf

January 26, 2017 at 3:26 pm


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