RELEASE DATE:  October 15, 2003

NOTICE:  NOT-HL-03-018

National Heart, Lung and Blood Institute (NHLBI)

RESPONSE DUE DATE:  November 17, 2003


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.  


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 

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 
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.  

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 


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 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

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