Full Text PA-97-026
 
ASPERGILLOSIS, EHRLICHIOSES AND DRUG RESISTANCE
 
NIH GUIDE, Volume 26, Number 3, January 31, 1997
 
PA NUMBER:  PA-97-026
 
P.T. 34

Keywords: 
  Infectious Diseases/Agents 
  Pathogenesis 
  Diagnosis, Medical 
  Biology, Molecular 
  Drug Resistance+ 

 
National Institute of Allergy and Infectious Diseases
 
PURPOSE
 
The purpose of this program announcement (PA) is to stimulate
research on selected topics in three separate areas:aspergillosis,
the ehrlichioses, and antibacterial or antifungal drug resistance.
For aspergillosis, the goal is to support research on clinically
relevant aspects of Aspergillus fumigatus and/or A. flavus.  For the
ehrlichioses, the goal is to support investigations on the diagnosis
and pathogenesis of the agents of human ehrlichiosis. For drug
resistance, the goal is to support research projects elucidating the
molecular biology and molecular epidemiology of antibiotic resistance
mechanisms in health care associated bacteria and fungi, including
the molecular mechanisms of acquisition, expression, maintenance, and
dissemination of resistance genes. Specific organisms of interest
include but are not limited to: vancomycin-resistant enterococci,
methicillin-resistant staphlyococci, drug-resistant pneumococci, Gram
negative bacteria and the fungi of greatest significance in the
nosocomial setting.  Pathogens covered under other NIAID PAs or
recent initiatives (e.g., Mycobacterium tuberculosis) will not be
considered responsive to this PA.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This PA,
Aspergillosis, Ehrlichioses and Drug Resistance, is related to the
priority areas of immunization and infectious diseases.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-0325 (telephone 202-512-1800).
 
ELIGIBILITY
 
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
Traditional research project grant (R01), FIRST award (R29), and
small research grant (R03) applications may be submitted in response
to this program announcement.  Applications for R01 grants may
request up to five years of support; applications for R29 grants must
request five years of support.
 
The NIAID uses R03 grants to support small, highly innovative or
pilot projects.  Applicants for R03 grants may request up to $50,000
annual direct costs for a period not to exceed three years.  Funds
and time requested should be appropriate for the research proposed.
Applicants for R03 grants must follow the special application
guidelines and Terms and Conditions of Award in the NIAID SMALL
RESEARCH GRANTS brochure (September 1996); this brochure is available
via the WWW at:
http://www.niaid.nih.gov/newsletter/maya/tools/broch.htm
 
Responsibility for the planning, direction, and execution of the
proposed research for all applicable mechanisms of support will be
solely that of the applicant.
 
RESEARCH OBJECTIVES
 
Background
 
The purpose of this initiative is to advance the development of
research in three specific areas: aspergillosis, ehrlichioses and
drug resistance.
 
Aspergillosis:
 
Aspergillosis is representative of a large group of health care
associated infections caused by filamentous fungi.  Aspergillosis is
a disease with exceptionally high health care costs, not only because
of the chronic course of disease and high mortality rates, but also
because of the lost investment in expensive medical procedures such
as bone marrow (BMTx) and organ transplantation that place patients
at risks for infection. Incidence of aspergillosis is estimated at 10
to 20 percent of all BMTx, with >10,000 new transplants each year in
the U.S.  Incidence is also increasing in AIDS.  Major limitations
exist in diagnosis and treatment of this infection as highlighted in
the June 1994 NIAID mycology workshop, Molecular and Immunologic
Approaches to the Diagnosis and Treatment of Systemic Mycoses.
 
Ehrlichioses:
 
Several new or previously unrecognized vector-borne or zoonotic human
diseases, such as human the ehrlichioses, either have just been
described or have been found to be on the increase in recent years.
Ehrlichia chaffeensis was considered to be the sole causative agent
of human ehrlichiosis (human monocytic ehrlichiosis, HME); however, a
second ehrlichial species now has been documented in human disease.
The ability to cultivate the agent of human granulocytic ehrlichiosis
(HGE) in vitro is a major advance and now opens up new possibilities.
There is potential for the development of new and more sensitive
diagnostic procedures for the rapid detection of Ehrlichia species,
and for definitive studies on mechanisms of pathogenesis alteration
of host cells and host defense mechanisms.  A recent (September 1996)
NIAID workshop on the human ehrlichioses identified research
opportunities in relation to the natural history, transmission,
pathogenesis, and diagnosis of disease.
 
Antibacterial/Antifungal Drug Resistance:
 
Antimicrobial resistance is emerging in virtually all nosocomial
pathogen-antimicrobial combinations.  Several bacterial infections
may soon be untreatable.  These include: methicillin-resistant
Staphylococcus aureus, vancomycin-resistant Enterococci, and numerous
Gram negative species.
 
Factors leading to the emergence of resistance among nosocomial
pathogens include: the use of broad-spectrum antibiotics; increasing
numbers of susceptible, immunocompromised patients; technologic
changes (implants, catheters, intravenous  lines) leading to
increased exposure to resistant microorganisms; and the breakdown in
hygiene, infection control, and disease control programs that lead to
increased transmission of resistant bacteria.
 
Penicillin-resistant pneumococci have emerged as an important problem
over the past decade.  Clusters of isolates have been reported from
five continents.  In the United States, the prevalence of these
resistant organisms increased from 3.6 percent to 14.5 percent
between 1987 and 1994 according to reporting from 12 sentinel
hospitals.
 
Between 1989 and 1994, the percentage of reported nosocomial
enterococcal infections that were due to vancomycin-resistant
enterococci (VRE) increased from 0.3 percent to 9.1 percent.  In
intensive care units (ICUs), the increase of VRE was even larger,
growing from 0.4 to 13.6 percent; however, in 1994, the reports of
VRE from other care units showed a much greater proportional increase
(the percentage almost doubled) compared to the increase observed
from ICUs, suggesting that VRE was spreading from the ICUs to other
parts of the hospitals.  The development of vancomycin resistant
enterococci has coincided with the emergence of high levels of
enterococcal resistance to penicillin and the aminoglycosides, which
further limited the options available to physicians trying to care
for patients infected with these organisms.
 
Methicillin was one of the synthetic penicillins that was developed
for treating infections due to staphylococci that were resistant to
penicillin.  Shortly after its introduction, methicillin resistant
staphylococci began to appear.  Their prevalence increased
dramatically during the 1980's and by 1991, approximately 40 percent
of isolates from large teaching hospitals were resistant.
 
These developments highlight the need to stimulate further research
into strategies aimed at preserving the effectiveness of currently
available antibacterial agents and finding new classes of
antibacterial agents.
 
Research Objectives and Experimental Approaches
 
Aspergillosis: Efforts should be focused on clinically relevant
aspects of Aspergillus fumigatus and Aspergillus flavus.
 
Relevant projects for aspergillosis will address one or more of the
following objectives:
 
o  The development of contemporary model systems for A. fumigatus or
A. flavus that focus on the factors endowing these fungi with
pathogenic potential. Basic biological studies should include
components that hold short term potential to improve diagnosis or
treatment of human disease.
 
o  The identification of fungal nucleic acids, antigens or products
that can be utilized in a rapid, sensitive and specific assay to
identify patients with aspergillosis.  Projects should include
specific aims that validate the choice of target in preliminary in
vitro or animal model experiments.
 
Ehrlichioses: Studies should be directed toward the agents of HME and
HGE and could include any of the following:
 
o  Detailed and definitive studies on the mechanisms involved in the
transmission and pathogenesis of the human ehrlichioses, especially
those that influence intracellular growth and alter host defense
functions.
 
o  Analysis of factors that influence susceptibility or resistance to
infection.
 
o  Isolation and characterization of the major components or products
of Ehrlichia for use in highly specific and more sensitive diagnostic
procedures that will have practical (rapid, economically feasible)
application, and/or their potential use in the development of
vaccines to induce protective immunity.
 
Antibacterial/Antifungal Drug Resistance: This announcement is
intended to stimulate innovative research on drug resistance of
health care associated pathogens with a strong emphasis on studies to
develop improved means of rapid detection of resistance.
 
Research efforts aimed at preserving the effectiveness of current
antimicrobials could include:
 
o  Basic research toward understanding the molecular biology and
genetics of resistance gene acquisition, maintenance, and
transmission among health care associated bacterial and fungal
pathogens.
 
o  Development of new diagnostic technologies to facilitate rapid
detection of resistance.
 
o  Identification of new classes of antimicrobials or new targets for
rational drug development and their validation in an appropriate
preclinical model.
 
o Evaluation of alternative technologies for the treatment of
bacterial and fungal diseases where resistance is established.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.
 
Investigators may obtain copies from these sources or from the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applicants are strongly encouraged to contact the program staff
listed under INQUIRIES early in project development with any
questions regarding the proposed project(s).
 
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95) and will be accepted on the standard application
deadlines as indicated on the application kit and at the beginning of
this PA.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division
of Extramural Outreach and Information, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910,
telephone (301) 710-0267, email: [email protected].
 
For purposes of identification and processing, the number and title
of this program announcement must be typed in item 2 and the "YES"
box must be marked.
 
Applicants from institutions that have a General Clinical Research
Centers (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
Applicants for small research (R03) grants are to follow the
application guidelines in the NIAID SMALL RESEARCH GRANTS brochure
(September 1996), which is available from the program staff listed
under INQUIRIES and via the WWW at:
http://www.niaid.nih.gov/newsletter/maya/tools/broch.htm.  R03
applications that do not conform to the instructions in the brochure
will be judged non-responsive and returned to the applicant.
 
ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS.
The NIH policy update on acceptance for review of unsolicited
applications that request more than $500,000 direct cost for any one
year applies to applications in response to this PA.  The Policy
Update was published in the NIH Guide for Grants and Contracts, Vol.
25, No. 14, May 3, 1996, and became effective June 1, 1996.  NIAID
has (1) policies that require pre-approval by the Institute before
acceptance of applications that request $500,000 or more in annual
direct costs and (2) guidelines for preparation of multi-project
research grant applications.  Potential applicants must contact the
appropriate program staff listed in INQUIRIES below to initiate
clearance processes for acceptance of their applications.
 
The completed, signed original and five legible, single-sided copies
of the application must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Upon receipt, applications will be reviewed for
completeness by the Division of Research Grants (DRG).  Incomplete
applications will be returned to the applicant without further
consideration.
 
R01 and R29 applications will be reviewed for scientific and
technical merit by study sections of the DRG in accordance with the
standard NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique and undergo
a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under
review, will be discussed, assigned a priority score, and receive a
second level review by the appropriate national advisory council.
 
R03 applications will be evaluated for scientific and technical merit
by an appropriate peer review group convened by the NIAID.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
the proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance among research areas of
the program announcement, and availability of funds.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dennis M. Dixon, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A-06 - MSC 7640
Bethesda, MD  20892-7640
Telephone:  (301) 496-7728
FAX:  (301) 402-2508
Email:  [email protected]
 
Requests for the NIAID brochure "NIAID SMALL RESEARCH GRANTS" may be
directed to:
 
Olivia T. Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C19
Bethesda, MD  20892-7610
Telephone:  (301) 496-8208
FAX:  (301) 402-2638
Email:  [email protected]
 
Direct inquiries regarding fiscal matters to:
 
Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B35
Bethesda, MD  20892-7610
Telephone:  (301) 492-5512
FAX:  (301) 480-3780
Email:  [email protected]
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410, as amended. The
Catalogue of Federal Domestic Assistance Citation is (No. 93.855 -
Immunology, Allergy, and Transplantation Research and No. 93.856 -
Microbiology and Infectious Disease Research [or] both of the
preceding).  Awards will be administered under PHS grants policies
and Federal Regulations 24 CFR Part 52 and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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