Therapy Analysis - Antibiotic-resistance: fighting the superbugs
Treatments for resistant infections
In recent years, there has been active development of antimicrobial drugs to treat antibiotic-resistant infections. Currently there are 5 drugs launched for antibiotic resistant infection, with many more in the late stages of development (Graph 1). In particular, 1999 saw the launch of Sanofi- Aventis' Synercid, an injectable drug consisting of two synergistic streptogramin antibiotics, dalfopristin and quinupristin. Dalfopristin inhibits bacterial ribosomes, preventing the early phase of protein synthesis, while quinupristin targets the late phase of protein synthesis by inhibiting translocation. A Phase III trial in 443 patients with skin and skin structure infections caused by S. aureus, including MRSA, showed a cure and improvement rate of 71.2%, and an eradication rate of 66% for S. aureus. Synercid is launched in several countries worldwide, and for both MRSA and vancomycin-resistant E. faecium. It was previously made available on an emergency use programme for the treatment of Gram positive bacterial infections.
In 2002, Wyeth launched Tygacil (tigecycline) for the treatment of nosocomial antibiotic-resistant infections, such as MRSA. A derivative of tetracycline, tigecycline represents the first clinically-available drug in a new class of antibiotics known as glycylcyclines. While structurally similar to tetracycline, a substitution at the D-9 position gives tigecycline a broader spectrum of action. It is bacteriostatic, and acts by inhibiting the bacterial 30S ribosomal subunit. In Phase III trials, tigecycline demonstrated non-inferiority to vancomycin, with an MIC for MRSA of 0.12µg/ml, compared to 1.0µg/ml for vancomycin. Tigecycline is launched in several markets, including Australia, Germany, the UK and the US, and is awaiting registration in Canada, India, South Africa, Switzerland and Venezuela.
Another novel development in antibiotic therapy is Pfizer's Zyvox (linezolid), a first-in-class oxazolidinone antibiotic. Linezolid is the only currently available agent in this class. Oxazolidinones inhibit the initiation of bacterial protein synthesis by preventing interaction between the 30S and 50S ribosomal subunits. In a Phase III trial in patients with MRSA infection, treatment with linezolid decreased hospital admission time over a 2 week period compared to vancomycin. Linezolid is currently launched in Japan for the treatment of MRSA and VRE infections, and is launched in several other markets for the treatment of VRE, as well as nosocomial and community-acquired pneumonia.
In addition, the San Fransican outfit Theravance has developed telavancin (TD-6424), a lipidated glycopeptide antibiotic, for the treatment of Gram positive infections. It has a broad spectrum of action, inhibiting the transglycosylation step of peptidoglycan synthesis, thereby disrupting the formation of bacterial cell walls. In December 2006, Theravance filed a US NDA based on the Phase III ATLAS I and II trials, for the treatment of complicated skin and skin structure infections (cSSSIs), including infections involving MRSA. An EU filing for cSSSIs has also been made. In these Phase III trials, telavancin treatment achieved clinical cure in 78% of patients, compared with 70% for vancomycin. In 1867 cSSSI patients, including 719 MRSA patients, 10mg/kg oncedaily for 7-14 days produced clinical cure and microbiological eradication rates of 90.6 and 89.9%.
