MD Conference Express ICAAC 2011 - (Page 23)

PTK0796 is a new C-9-aminomethyl minocycline analog that has shown efficacy against S. aureus, E. faecalis, and E. coli in mouse models of infection [McKenney D et al. ICAAC 2003]. It is under development for intravenous and oral use in humans. PTK0796 is in Phase 2/3 development for skin and skin structure infections, with plans to study it in community-acquired pneumonia. The 8-aminomethyl tetracycline class demonstrates activity that is comparable with tigecycline against key gramnegative pathogens, including ESBL-producing strains. From this class, TP-2758 has broad-spectrum activity, including excellent coverage of MRSA and gram-negatives, excluding Pseudomonas, and has entered Phase 1 clinical trials as an oral formulation. Other notable pipeline tetracyclines include TP-834, a pentacycline that is in development against MRSA community-acquired pneumonia, and TP434, a 7,9 disubstituted analog with broad spectrum activity against aerobes, anaerobes, gram-positives, and gramnegatives except Pseudomonas. TP-434 is currently in Phase 2 for treating complicated IAI. Stuart Johnson, MD, Loyola University Medical Center, Maywood, Illinois, USA, discussed a new option in the treatment of Clostridium difficile infections (CDIs). Approved in May 2011, fidaxomicin, a narrow-spectrum, nonabsorbed bactericidal RNA polymerase inhibitor that is effective against C. difficile, is the first FDAapproved agent for use in the treatment of CDI in 25 years, making it one of two approved CDI therapies, along with vancomycin. Vancomycin use is complicated by a greaterthan-20% recurrence rate for CDI and has the potential to select for vancomycin-resistant strains in the gut [Kelly and LaMont. N Engl J Med 2008]. In two large, multicenter, double-blinded, randomized Phase 3 trials, fidaxomicin (200 mg BID) was shown to be noninferior to vancomycin (125 mg 4x/day) for clinical cure—88% versus 86%, respectively—in the modified intent-to-treat population. Notably, fidaxomicin treatment was associated with reduced rates of CDI recurrence compared with vancomycin (15% vs 25%; p=0.005) in the first trial [Louie TJ et al. New Engl J Med 2011]. Adverse events were similar between the two drugs, and results were similar in the second study. The mechanism by which fidaxomicin prevents recurrence may be related to suppression of Enterobacteria overgrowth in the gut [Tannock GW et al. Microbiol 2010]. In a separate analysis of the combined Phase 3 trials of fidaxomicin- and vancomycin-treated patients, the use of concomitant antibiotics with CDI treatment was a risk factor for prolonged duration of diarrhea [Mullane KM et al. Clin Infect Dis 2011]. This is consistent with what is known about risk factors for CDI, including antibiotic use and alterations of gastrointestinal microbiota. The adverse effect of concomitant antibiotic use on cure and recurrence rates was significantly (p<0.05) more prominent among vancomycin-treated patients. Vancomycin and fidaxomicin performed similarly against infections with epidemic strain BI/NAP1/027 [Patrella L. et al. ICAAC 2011]. Looking to the future, Dr. Johnson suggested that CDI prevention strategies include immunotherapy and more effective probiotics. With tremendous increases in the incidence of tuberculosis (TB) infection due to the HIV epidemic and the emergence of multidrug-resistant TB (MDR-TB), antituberculosis drug development has resurfaced as a major priority. Citing 2010 World Health Organization data, William Burman, MD, University of Colorado, Denver, Colorado, USA, said that a 55% increase globally in new MDR-TB cases has occurred in the past decade, with 440,000 new cases occurring each year, most of which remain undiagnosed. Treatment of MDR-TB takes 18 to 24 months, is very expensive, and has high rates of side effects. Therefore, there is a critical need for new agents for MDR-TB. The most advanced pipeline agent in this area is TMC207 (bedaquiline). Bedaquiline is an ATPase synthetase inhibitor with good activity against MDR-TB and has the advantage of having no activity against bacterial pathogens. Since it interacts with rifampin, bedaquiline was evaluated as an add-on agent to optimized background therapy (excluding rifampin) in a prospective trial among patients with MDR-TB. Treatment substantially reduced (by 50%) time to sputum culture conversion (Figure 3) and was well tolerated [McNeeley DF et al. IUATLD 2010]. A FDA application is planned for 2012 for accelerated approval as an MDR treatment. Figure 3. Time to Sputum Culture Conversion Among Patients with MDR-TB Treated with Optimized Background Therapy plus Placebo or TMC207. 1.0 Proportion of Culture Positive Patients 0.8 0.6 Placebo Time to 50% culture conversion: 18 weeks 58% 0.4 TMC207 Time to 50% culture conversion: 18 weeks 0.2 79% 0 Baseline W4 W8 W12 W16 Time to Culture Conversion (Days) W20 W24 Reproduced with permission from W. Burman, MD. Official Peer-Reviewed Highlights from the 51st ICAAC 23 http://www.mdconferencexpress.com

Table of Contents for the Digital Edition of MD Conference Express ICAAC 2011

MD Conference Express ICAAC 2011
Contents
Infectious Disease Genomics
Emerging Resistance Among Gram-Negative Pathogens
Procalcitonin-Guided Antibiotic Therapy In Patients with Lower Respiratory Tract Infections
Combination Therapy with Flucytosine Improves Survival in AIDS-Related Cryptococcal Meningitis
CXA-201 Effective Against Common ICU Pathogens
Tigecycline Plus Standard Therapy Is More Effective For Treating Infections in Febrile Neutropenic Cancer Patients
Interventions Aimed at Reducing MRSA BSIs Led to Decreased Rates of Nosocomial MSSA BSIs
Is the Effectiveness of aP Vaccine in Pre-Adolescents Insufficient?
TMC435 Effective in the Treatment of HCV Genotype 1 Infection
HIV
Vaccines
Antibiotic Resistance
Drug Discovery
The Conundrum of MDR TB and Combination Therapy
New Drugs to Treat MDR Pathogens
Immunizations in Reproductive Health
Why Can’t Microbes Just Get Along?
The Role of Adjunctive Steroids in the Treatment of Bacterial Meningitis
Human and Animal Viruses Share “One World” and Emerging Zoonotic Infections Continue to Threaten

MD Conference Express ICAAC 2011

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