Archive for February 19, 2014

Community-Acquired Pneumonia

N Engl J of Medic Feb.6, 2014 V.370 P.543-551

CLINICAL PRACTICE

Richard G. Wunderink, M.D., and Grant W. Waterer, M.B., B.S., Ph.D.

From the Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago (R.G.W., G.W.W.); and the University of Western Australia, Perth (G.W.W.).

A 67-year-old woman with mild Alzheimer’s disease who has a 2-day history of productive cough, fever, and increased confusion is transferred from a nursing home to the emergency department.

According to the transfer records, she has had no recent hospitalizations or recent use of antibiotic agents. Her temperature is 38.4°C (101°F), the blood pressure is 145/85 mm Hg, the respiratory rate is 30 breaths per minute, the heart rate is 120 beats per minute, and the oxygen saturation is 91% while she is breathing ambient air.

Crackles are heard in both lower lung fields. She is oriented to person only. The white-cell count is 4000 per cubic millimeter, the serum sodium level is 130 mmol per liter, and the blood urea nitrogen is 25 mg per deciliter (9.0 mmol per liter).

A radiograph of the chest shows infiltrates in both lower lobes.

How and where should this patient be treated? …

PDF

http://www.nejm.org/doi/pdf/10.1056/NEJMcp1214869

February 19, 2014 at 10:31 pm

Tedizolid for the Management of Human Infections – In Vitro Characteristics

Clinical Infectious Diseases January 2014 V.58 Suppl.1 P.35-24

Jeffrey B. Locke1, Gary E. Zurenko2, Karen Joy Shaw1, and Kenneth Bartizal1

1Cubist Pharmaceuticals, San Diego, California

2ZML Consulting, LLC, Kalamazoo, Michigan

Correspondence: Jeffrey B. Locke, PhD, Cubist Pharmaceuticals, 6310 Nancy Ridge Dr, Ste 101, San Diego, CA 92121 (jeffrey.locke@cubist.com).

Abstract

The emerging antibiotic resistance of Gram-positive pathogens represents a significant challenge to the management of human infections.

The novel oxazolidinone tedizolid demonstrates antimicrobial activity across a broad range of Gram-positive pathogens and greater potency than linezolid against wild-type and drug-resistant pathogens, including linezolid-resistant Staphylococcus aureus strains possessing mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins L3 or L4.

Strains harboring such mutations are also selected for much less frequently with tedizolid than with linezolid.

In addition, tedizolid has a significant potency advantage over linezolid-resistant strains carrying the horizontally transferable cfr gene.

Methylation of A2503 of 23S rRNA by the Cfr methyltransferase confers resistance to linezolid (and a variety of other 50S ribosomal subunit–targeted antibiotics) but not to tedizolid because of structural differences in A-ring C5 substituents between the 2 drugs.

The greater potency and improved resistance profile of tedizolid provides the microbiologic basis for considering this molecule as an alternative to linezolid for the treatment of serious infections caused by Gram-positive pathogens.

PDF

http://cid.oxfordjournals.org/content/58/suppl_1/S35.full.pdf+html

February 19, 2014 at 10:29 pm

Use of Pharmacokinetic-Pharmacodynamic Systems Analyses to Inform Dose Selection of Tedizolid Phosphate

Clinical Infectious Diseases January 2014 V.58 Suppl.1 P.28-34

Thomas P. Lodise1 and G. L. Drusano2

1Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York

2Department of Medicine, Institute for Therapeutic Innovation, University of Florida, Orlando, Florida

Correspondence: Thomas P. Lodise, PharmD, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, NY, 12208 (thomas.lodise@acphs.edu).

Abstract

In the Staphylococcus aureus neutropenic murine thigh-infection model, the ratio of the free area under the 24-hour concentration-time curve to the minimum inhibitory concentration (fAUC/MIC) was found to be the pharmacodynamic index most closely linked to bacterial effect, with a ratio of approximately 50 producing a static effect.

Further work was undertaken in neutropenic versus non-neutropenic animals. The presence of granulocytes increased the activity of tedizolid considerably, 25-fold on average, and maximal effect was achieved at an exposure equivalent to approximately 200 mg tedizolid phosphate per day in humans (dosing regimen used in phase 2 and 3 clinical trials).

The fAUC/MIC was also found to be the pharmacodynamically linked variable in the S. aureus neutropenic murine pneumonia model; the fAUC/MIC ratio required for a static effect was approximately 20.

Pharmacokinetic (PK) data demonstrate that tedizolid penetrates well into the epithelial lining fluid (ELF) of the lung.

Data from the pneumonia infection model and ELF penetration PK study support exploring its use in pneumonia.

PDF

http://cid.oxfordjournals.org/content/58/suppl_1/S28.full.pdf+html

February 19, 2014 at 10:27 pm


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