REQUEST FOR INFORMATION ON THE PREVENTION AND TREATMENT OF STAPHYLOCOCCUS AUREUS INFECTIONS AFTER CARDIAC SURGERY RELEASE DATE: October 15, 2003 NOTICE: NOT-HL-03-018 National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) RESPONSE DUE DATE: November 17, 2003 PURPOSE The NHLBI is planning to release in the future a Request for Proposals for a Clinical Trials Program for the Prevention and Treatment of Staphylococcus aureus Infections after Cardiac Surgery. In view of this Clinical Trials Program, the NHLBI is interested in obtaining information from the academic and industrial community as to the availability and current development status of immunologic products to prevent and treat S. aureus infections. Specifically, the NHLBI is interested in vaccines, hyperimmunoglobulin, monoclonal antibody, chimeric and humanized antibody products directed at S. aureus infections that would be efficacious in the face of infections resulting from cardiothoracic surgery. The Institute is also interested in topical decolonizing agents that would be effective in preventing infection to surgical sites of patients colonized with S. aureus. BACKGROUND Cardiovascular infections caused by S. aureus are an urgent national medical problem. The continued expanding use of invasive cardiovascular procedures and devices in medical practice has exacerbated the growing clinical problems posed by S. aureus. Since 1980, the National Nosocomial Infectious Surveillance Systems (NNIS) of the Centers of Disease Control has reported increases in the rate of S. aureus bacteremia ranging from 122% to 283% in individual hospitals. Even more concerning is the changing nature of antibiotic resistance among S. aureus. Over 50% of S. aureus isolates from intensive care units reported to the NNIS in 1999 were methicillin-resistant, a 43% increase compared to 1994 through 1998. Studying the incidence or even prevalence of serious S. aureus and other infections associated with cardiothoracic surgeries is hampered by the small number of patients in a given study, and the lack of prospective studies. The data from these studies show a relatively low incidence of infections, and because of the above listed limitations further analyses are of very limited value. The multiplicity of organisms involved in hospital infections has made antimicrobial treatment complex, outcomes difficult to measure, and prevention approaches complicated. Several large databases, including those maintained by the Veterans Administration Hospitals, the Society for Thoracic Surgeons, the Cleveland Clinic Foundation, and a registry of adult patients with S. aureus bacteremia at Duke University Medical College, contain identification of causative organism, location of infection, and incidence of infections of interest, such as mediastinitis, prosthetic valve endocarditis and simple wound infection. Cardiovascular infections are primarily caused by coagulase positive and negative staphylococci and by other antimicrobial-drug resistant pathogens. The increasing frequency of methicillin-resistant staphylococci as pathogens in the clinical setting has led to extensive use of vancomycin, currently the most commonly used antibiotic for empiric therapy of these infections. The potential for development of glycopeptide intermediate or resistant staphylococcal infections, and concerns about vancomycin’s therapeutic range and safety profile have mandated the establishment of guidelines for its use in many intensive care units. One alternative approach to prophylaxis that has not been thoroughly studied is the elimination of S. aureus nasal colonization. A number of new antimicrobial agents on the market (linezolid, quinupristin/dalfopristin, etc.) are active against antimicrobial-resistant Gram positive bacteria. During the period of use and availability on the market of linezolid, resistance to it has been reported in an S. aureus isolate. Other investigational drugs such as lysostaphin show promise as adjunctive therapies or preventive agents. Use of some of these newer agents may allow earlier discharge of patients, or prevent the spread of multi-drug resistant infections in the ICU environment. Infections related to cardiac surgery increase morbidity and mortality, and also increase cost and use of health resources. The widespread use of synthetic materials conduits has led to bacterial infections, and more rarely, fungal complications that can be devastating, requiring prolonged antimicrobial therapy and at times reoperations with a high morbidity and mortality. With the U.S. population aging and living longer, cardiac surgery is applied to an older population with significant co-morbidities, making the threat from infectious complications significant. The dwindling armamentarium of effective antimicrobial agents, a limited pharmaceutical pipeline of future therapies, and the emergence of antimicrobial resistant bacteria have increased the challenge of treating cardiothoracic infections. Thus, there is critical need to address the existing and emerging issues in this area to develop new safe and effective strategies to address the clinical challenges facing cardiothoracic surgeons. INFORMATION REQUESTED The NHLBI seeks your help in identifying (a) potential immunologic products such as vaccines, hyperimmunoglobulin, monoclonal antibody, chimeric and humanized antibody products and nasal decolonizing agents to prevent and/or treat S. aureus infections after cardiac surgery; b) the critical steps or barriers to their use in the proposed clinical trials; and c) the interest of the academic and industrial community to provide products free of charge to the NHLBI for the conduct of such trials. Your thoughts, ideas, and suggestions will help the NHLBI test the best approaches to prevent and/or treat S. aureus infections that may arise after cardiac surgery. Respondents are asked to comment on the issues below. 1. Identify and describe potential products that would prevent and/or treat S. aureus infections and its indications for use. 2. Provide the licensure status of any products identified in response to item 1. 3. For unlicensed products, provide the current development status such as filing of an IND, and the initiation or completion of Phase I, II, and III clinical trials. 4. For any potential products, provide the availability of the product, including the timeframe for scale-up and production. 5. Comment on your interest in collaborating with NHLBI on conducting a treatment or prevention trial with the designated product and your willingness to donate the product to the NHLBI for use in a treatment or prevention trial. 6. Provide any additional comments or suggestions that you think would be useful. RESPONSE AND PROCESS Response in any of the areas are welcome; respondents should not feel compelled to address all items. Please respond no later than November 17, 2003. We look forward to your thoughts, opinions, and suggestions, and hope you will share this document with your colleagues. All responses will be kept confidential. Thank you very much for your help. To respond, please link to the online form in the What’s New section on the NHLBI home page http://www.nhlbi.nih.gov/new/whatsnew.htm or send a letter, fax, or email to the following address: Ms. Sharon Fair National Heart, Lung and Blood Institute Division of Heart and Vascular Diseases Vascular Biology Research Program Two Rockledge Centre 6701 Rockledge Drive Suite 10193 - MSC 7956 Bethesda, Maryland 20892-7956 Tel: 301-435-0545 Fax: 301-480-2849 E-mail: fairs@mail.nih.gov

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