New Antibiotics for Severe Soft Tissue Infections - LECOM Education System

New Antibiotics for Severe Soft Tissue Infections

Tuesday, 02 June 2015

Diviya Patel, PharmD Candidate; Marcus Campbell, PharmD, BC-ADM

According to the 2013 Centers for Disease Control and Prevention (CDC) report, more than 2 million people each year become infected with bacteria that are resistant to antibiotics. As a result, about 23,000 people die from these infections.1 Bacterial drug resistance has rapidly spread in hospitals and communities worldwide, and the development of new antibiotics has faced a sharp downward trend since the early 1980s and is now minimal (Figure 1). Over the past year, the FDA has approved 3 new antibiotics to treat patients with acute bacterial skin and skin structure infections caused by gram-positive bacteria including methicillin-resistant staphylococcus aureus (MRSA). Dalbavancin, tedizolid, and oritavancin have been approved as a result of the Qualified Infectious Disease Product (QIDP) under the GAIN Act. To encourage research and development, this legislation, signed into law by President Barack Obama on July 9, 2012, gave manufacturers an additional 5 years of exclusive rights where antibiotics can be sold without generic competition.

Dalbavancin (Dalvance®)

Dalbavancin, developed by Durata Pharmaceuticals, is a lipoglycopeptide antibiotic. On May 23, 2014, the FDA approved dalbavancin for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults. Dalbavancin provides coverage for gram-positive microorganisms, is administered intravenously (IV), and dosed 1000 mg IV x 1, then 500 mg IV 1 week later. Discover 1 and Discover 2 were identically designed randomized trials that demonstrated noninferiority of dalbavancin compared to vancomycin or linezolid for the treatment of ABSSSI. Approximately 1,300 patients were included in both studies. The primary end point was an early clinical response, defined as no spread of erythema and afebrile at 48-72 hours. For patients infected with methicillin-resistant staphylococcus aureus, clinical success was relatively high in both the dalbavancin (97.3%) and vancomycin-linezolid (98.0%) groups. Adverse events were less common in the dalbavancin group (32.8%) compared to the vancomycin-linezolid group (37.9%). The most reported adverse effects for both groups were constipation nausea, diarrhea, and pruritus.2

Tedizolid (Sivextro®)

Tedizolid, developed by Cubist Pharmaceuticals, is an oxazolidinone-class antibiotic. The FDA approved tedizolid for the treatment of ABSSSI in adults on June 20, 2014. This mechanism of action involves binding to the 50S subunit of the bacterial ribosome inhibiting protein synthesis. Tedizolid is available as both IV and tablet formulations, and it has been shown to have activity against gram-positive aerobic and anaerobic bacteria. A randomized, double blind, phase-3 study demonstrated non-inferiority of once daily tedizolid compared to twice daily linezolid. 666 patients were included in the study, and the primary end-point was early clinical response 48-72 hours after start of treatment defined as ≥20% reduction in lesion area compared with baseline. The recommended duration of therapy for tedizolid is 6 days compared to 10-14 days with linezolid. The treatment-emergent adverse events were similar between study groups; however, nausea, diarrhea, and vomiting were less common in the tedizolid group.

Oritavancin (Nuvocid®)

On August 6, 2014, the FDA approved oritavancin for the treatment of ABSSSI in adults.  Oritavancin, developed by Targanta Therapeutics, is a lipoglycopeptide antibiotic that has bactericidal activity against gram-positive bacteria. Oritavancin is concentration dependent and has a longer half-life compared to dalbavancin. Oritavancin is administrated intravenously and is dosed 1200 mg IV x 1 dose. A randomized, double blind, phase-3 trial in approximately 900 patients, showed oritavancin was noninferior to vancomycin. The primary end point was no growth or reduction in the size of the baseline lesion, absence of fever, and the absence of a need for a rescue antibiotic 48-72 hours after receiving oritavancin. Efficacy of oritavancin was measured by type of pathogen, including MRSA infection and was similar in both treatment groups. Overall adverse effects for oritavancin (7.4%) and vancomycin (7.3%) were similar. However, nausea was more common with oritavancin (11%) than with vancomycin (8.9%). 4 

Managing the treatment of ABSSSI can be a difficult challenge for healthcare professionals and hospitals. The approval of new antibiotics provides additional options. Recent changes in legislation aim to open up avenues for drug manufactures to research and invest in the development of novel antibiotics to keep pace with emergence, persistence and spread of resistant bacteria in healthcare settings worldwide.

 

References:

  1. Antibiotic Resistance Threats in the United States, 2013.http://www.cdc.gov/drugresistance/threat-report-2013/. Accessed January 25, 2015.
  2. Boucher HW, Wilcox M, Talbot, GH, Puttagunta S, Das, AF, Dunne MW. Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection. New England Journal of Medicine. 2014;370:2169-2179.
  3. Moran, GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid For 6 Days Versus Linezolid for 10 Days for Acute Bacterial Skin and Skin-Structure Infections (ESTABLISH-2): A Randomised, Double-Blind, Phase 3, Non-inferiority Trial. Lancet Infectious Disease. 2014;14:696-705.
  4. Corey GR, Kabler H, Mehra P, Gupta S, Overcash JS, Porwal A, Giordano, et.al. Single-Dose Oravancin in the Treatment of Acute Bacterial Skin Infections. New England Journal of Medicine. 2014; 370:2180-2190.
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