Applied Research in Emerging InfectionsGenetics of Antimicrobial Resistance and Novel Methods for Detection of Antiviral Resistance

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

[Announcement Number 663]

Applied Research in Emerging Infections--Genetics of

Antimicrobial Resistance and Novel Methods for Detection of Antiviral

Resistance

Introduction

The Centers for Disease Control and Prevention (CDC) is

implementing a program for competitive cooperative agreement and/or

research project grant applications to support applied research on

emerging infections. CDC announces the availability of fiscal year (FY)

1996 funds to provide assistance for a grant/cooperative agreement

program to conduct research on the genetic analysis of antimicrobial

resistance determinants.

The CDC is committed to achieving the health promotion and disease

prevention objectives of Healthy People 2000, a national activity to

reduce morbidity and mortality and improve the quality of life. This

announcement is related to the priority area of Immunization and

Infectious Diseases. (For ordering a copy of Healthy People 2000, see

the section WHERE TO OBTAIN ADDITIONAL INFORMATION.)

Authority

This program is authorized under sections 301 and 317 of the Public

Health Service Act, as amended (42 U.S.C. 241 and 247b).

Smoke-Free Workplace

The CDC strongly encourages all grant recipients to provide a

smoke-free workplace and to promote the nonuse of all tobacco products,

and Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking

in certain facilities that receive Federal funds in which education,

library, day care, health care, and early childhood development

services are provided to children.

Eligible Applicants

Applications may be submitted by public and private, nonprofit and

for-profit organizations and governments and their agencies. Thus,

universities, colleges, research institutions, hospitals, other public

and private organizations, including State and local governments or

their bona fide agents, federally recognized Indian tribal governments,

Indian tribes or Indian tribal organizations, and small, minority- and/

or women-owned businesses are eligible to apply.

Availability of Funds

Approximately $250,000 is available in FY 1996 to fund up to three

awards. It is expected that the average award will be $125,000, ranging

from $80,000 to $250,000.

It is expected that the awards will begin on or about September 30,

1996, and will be made for a 12-month budget period within a project

period of up to two years. Funding estimates may vary and are subject

to change. Continuation awards within an approved project period will

be made on the basis of satisfactory progress and availability of

funds.

Purpose

The purpose of the emerging infections extramural research program

is to provide financial and technical assistance for applied research

projects on emerging infections in the United States. As a component of

the emerging infections extramural research program, the purpose of

this grant/cooperative agreement announcement is to provide assistance

for projects addressing the following two focus areas:

1. Mechanisms of Dissemination of Antimicrobial Resistance Genes

The focus of the investigations should be the examination of the

role of plasmids, transposons, and integrons in antimicrobial

resistance gene dissemination, the natural variation of the nucleotide

sequences of resistance genes, and the impact of those changes on the

resistance phenotype mediated by the genes. This should include

examination of the role of antimicrobial use in institutions and its

effect on gene dissemination. Assistance under this focus area will be

provided for projects specifically addressing either of the following:

a. Improving understanding of the mechanisms by which vancomycin

resistance genes in enterococci or genes encoding extended-spectrum

- lactamases in Klebsiella pneumoniae are spread in hospitals

or other healthcare institutions (including nursing homes and clinics)

and become part of the endemic flora of the institution.

b. Improving understanding of the mechanisms by which macrolide

resistance genes (such as those encoding erythromycin resistance) are

acquired and disseminated in Streptococcus pneumoniae in communities.

2. Antiviral Susceptibility Determination Methods: Development of

improved methods for measuring the susceptibility of herpes simplex

virus (HSV) isolates to acyclovir. Current methods for measuring drug

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susceptibility of HSV isolates are labor-intensive, expensive, and have

not been standardized. These shortcomings stand as impediments to

surveillance for acyclovir-resistant HSV or resistance in other viral

pathogens. Specifically, assistance will be provided for projects

focusing on development of assays based on novel methods or approaches

for measuring the susceptibility of HSV to acyclovir. Such assays

should be capable of providing results comparable to current plaque

reduction and dye-uptake assays.

Applicants may submit separate applications for projects under one

or both focus areas.

Program Requirements

Recipients may separately apply and receive support for projects

under one or both of the two focus areas. In conducting activities to

achieve the purpose of this program, the recipient shall be responsible

for the activities under A.1. or A.2. (depending upon which focus areas

the recipient applies and receives support for) and CDC shall be

responsible for conducting activities under B., below:

A. Recipient Activities

1. Mechanisms of Dissemination of Antimicrobial Resistance Genes

a. Select study sites: Study sites may include (a) one or more

hospitals or related health care institutions known to have endemic or

emerging problems with antimicrobial-resistant organisms in which

extensive monitoring of antimicrobial-resistant strains has been

conducted or (b) communities with extensive active surveillance.

b. Collect isolates with corresponding epidemiologic and clinical

data: Assure that the isolates are well characterized with respect to

phenotype, genotype, and mode of transmission from patient to patient.

Collect bacterial strain typing information such as that derived by

pulsed-field gel electrophoresis (PFGE), arbitrary primed polymerase

chain reaction (PCR), restriction fragment length polymorphism (RFLP),

plasmid fingerprinting, serotyping, or other highly discriminatory

strain typing methods. Obtain antibiograms expressed as minimal

inhibitory concentrations (MICs) of common antibiotics. One example of

an appropriate approach to collection of isolates and data would be to

assemble a series of isolates of vancomycin-resistant enterococci (VRE)

from a single hospital with the corresponding PFGE data documenting the

routes of transmission of the isolates among patients in the

institution. The overall rates of infections over several years and the

diversity of strains present in the institutions or communities would

be determined. This would presumably involve microbiology laboratories,

infection control practitioners (for health care institutions), public

health officials, and epidemiologists. Additionally, collection of data

regarding antimicrobial use (expressed as Defined Daily Doses per 1000

patient-days) by area of the institution (e.g., intensive care unit or

other inpatient ward) or in communities would be useful.

c. Characterize the resistance determinants present by phenotypic

and molecular methods: Obtain MICs to an extended array of

antimicrobial agents to classify the phenotype (e.g., teicoplanin to

distinguish VanA from VanB). Determine strain types (when appropriate),

the presence of plasmids or other genetic elements, and the presence of

resistance genes in the strains as identified by using DNA probes or

specific PCR, LCR, or other genetic assays.

d. Monitor transmission and evaluate data: Characterize the

resistance genes present in the isolates, the modes of genetic exchange

of the resistance determinants among isolates in the institutions or

communities, and determine whether changes in the DNA or amino acid

sequences of the genes are associated with broadening of the phenotype

of the isolates carrying the genes. Consider the influence of

antimicrobial use on frequency and mode of gene transmission and on

changes in the phenotype of the isolates. Depending on the studies

conducted, questions that could be addressed include: (1) Is an initial

period of plasmid transfer among organisms followed by dissemination of

a transposable element to multiple plasmids in strains of enterococci

resulting in the vancomycin resistance phenotype being present in

multiple strains of enterococci (as evidenced by widely divergent

pulsed-field gel electrophoresis types)? (2) Do changes in the sequence

of vanB correlate with increased resistance to teicoplanin? (3) Do the

mode of transfer and the phenotype vary by antimicrobial use patterns

in the institution or in certain wards of the institution?

e. Disseminate research findings: Disseminate research results by

appropriate methods such as publication in journals, presentation at

meetings and conferences, etc.

2. Antiviral Susceptibility Determination Methods

a. Study isolates: Identify a source of HSV isolates for study.

Ideally, this should include isolates from fresh clinical specimens

that can be tested in parallel with the plaque reduction or dye uptake

methods and for which acyclovir resistance has previously been

documented.

b. Devise a novel assay for determining the level of acyclovir

susceptibility of clinical HSV isolates: Establish a quality control

system to insure the reproducibility of the assay. A quality control

strain of HSV should be designated as part of the testing method and

data showing its effectiveness should be established. A useful novel

assay should be at least equivalent in performance and (ideally)

substantially less expensive than current assays. The new method should

be adaptable to a high-throughput, semi- automated format. Establish

criteria for designating HSV isolates as ``susceptible'' or

``resistant'' to acyclovir.

c. Evaluate the performance of the new assay in comparison with the

plaque reduction assay. To be useful for surveillance of resistance,

any new assay should be substantially equivalent to those in current

use (Am. J. Med. 73:380-382,1982).

B. CDC Activities

1. Research Project Grants

A research project grant is one in which substantial programmatic

involvement by CDC is not anticipated by the recipient during the

project period. Applicants for grants must demonstrate an ability to

conduct the proposed research with minimal assistance, other than

financial support, from CDC. This would include possessing sufficient

resources for clinical, laboratory, and data management services and a

level of scientific expertise to achieve the objectives described in

their research proposal without substantial technical assistance from

CDC.

2. Cooperative Agreements

In a cooperative agreement, CDC will assist recipients in

conducting the proposed research. The application should be presented

in a manner that demonstrates the applicant's ability to address the

research problem in a collaborative manner with CDC. In addition to the

financial support provided, CDC will collaborate by (1) providing

technical assistance in the design and conduct of the research; (2)

performing selected laboratory tests as appropriate; (3) participate in

data management, the analysis of research data, and the interpretation

and presentation of research findings; and

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(4) providing biological materials (e.g., strains) as necessary for

studies, etc.

C. Determination of Which Instrument to Use

Applicants must specify the type of award for which they are

applying, either grant or cooperative agreement. CDC will review the

applications in accordance with the Evaluation Criteria. Before issuing

awards, CDC will inform the proposed grantee whether a grant or

cooperative agreement is the appropriate instrument based upon the need

for substantial CDC involvement in the project.

Notice of Intent To Apply

In order to assist CDC in planning for and executing the evaluation

of applications submitted under this Program Announcement, all parties

intending to submit an application are requested to inform CDC of their

intention to do so at their earliest convenience prior to the

application due date. Notification should include 1) name and address

of institution, 2) name, address, and phone number of contact person,

and 3) under which focus area(s) application(s) will be submitted.

Notification should be provided to Greg Jones, M.P.A., by facsimile

(404) 639-4195, E-mail [email protected] or postal mail at

National Center for Infectious Diseases, Centers for Disease Control

and Prevention, 1600 Clifton Road, NE., Mailstop C-19, Atlanta, Georgia

30333.

Application Process

Applicants may apply for assistance for projects in one or both of

the specific programmatic focus areas identified under Purpose and

Program Requirements above. If applying for assistance for more than

one of the two focus areas, a separate and complete application must be

submitted for each project/focus area.

Evaluation Criteria

The applications will be reviewed and evaluated according to the

following criteria:

1. Background and Need (20 points): Extent to which applicant's

discussion of the background for the proposed project demonstrates a

clear understanding of the purpose and objectives of this grant/

cooperative agreement program. Extent to which applicant illustrates

and justifies the need for the proposed project that is consistent with

the purpose and objectives of this grant/cooperative agreement program.

2. Capacity (40 points total):

a. Extent to which applicant describes adequate resources and

facilities (both technical and administrative) for conducting the

project. (10 points)

b. Extent to which applicant documents that professional personnel

involved in the project are qualified and have past experience and

achievements in research related to that proposed as evidenced by

curriculum vitae, publications, etc. (20 points)

c. Extent to which applicant includes letters of support from non-

applicant organizations, individuals, etc. Extent to which the letters

clearly indicate the author's commitment to participate as described in

the operational plan. (10 points)

3. Objectives and Technical Approach (40 points total):

a. Extent to which applicant describes specific objectives of the

proposed project which are consistent with the purpose and goals of

this grant/cooperative agreement program and which are measurable and

time-phased. (10 points)

b. Extent to which applicant presents a detailed operational plan

for initiating and conducting the project, which clearly and

appropriately addresses all Recipient Activities. Extent to which

applicant clearly identifies and describes appropriate study sites (per

Recipient Activities 1.a.) or HSV isolates (per Recipient Activities

2.a.). Extent to which applicant clearly identifies specific assigned

responsibilities for all key professional personnel. Extent to which

the plan clearly describes applicant's technical approach/methods for

conducting the proposed studies and extent to which the plan is

adequate to accomplish the objectives. Extent to which applicant

describes specific study protocols or plans for the development of

study protocols that are appropriate for achieving project objectives.

If the proposed project involves human subjects, the degree to

which the applicant has met the CDC policy requirements regarding the

inclusion of women, ethnic, and racial groups in the proposed research.

This includes:

(1) The proposed plan for the inclusion of both sexes and racial

and ethnic minority populations for appropriate representation.

(2) The proposed justification when representation is limited or

absent.

(3) A statement as to whether the design of the study is adequate

to measure differences when warranted.

(4) A statement as to whether the plans for recruitment and

outreach for study participants include the process of establishing

partnerships with community(ies) and recognition of mutual benefits

will be documented. (see Other Requirements for additional information

regarding this requirement for research projects). (15 points)

c. Extent to which applicant describes adequate and appropriate

collaboration with CDC and/or others during various phases of the

project. (10 points)

d. Extent to which applicant provides a detailed and adequate plan

for evaluating study results and for evaluating progress toward

achieving project objectives. (5 points)

4. Budget (not scored):

Extent to which the proposed budget is reasonable, clearly

justifiable, and consistent with the intended use of grant/cooperative

agreement funds.

5. Human Subjects (not scored):

If the proposed project involves human subjects, whether or not

exempt from the DHHS regulations, the extent to which adequate

procedures are described for the protection of human subjects. Note:

Objective Review Group (ORG) recommendations on the adequacy of

protections include: (1) Protections appear adequate and there are no

comments to make or concerns to raise, or (2) protections appear

adequate, but there are comments regarding the protocol, or (3)

protections appear inadequate and the ORG has concerns related to human

subjects, or (4) disapproval of the application is recommended because

the research risks are sufficiently serious.

Executive Order 12372 Review

This program is not subject to Executive Order 12372,

Intergovernmental Review of Federal Programs.

Public Health System Reporting Requirements

This program is not subject to the Public Health System Reporting

Requirements.

Catalog of Federal Domestic Assistance Number

The Catalog of Federal Domestic Assistance Number is 93.283.

Other Requirements

Paperwork Reduction Act

Projects that involve the collection of information from ten or

more individuals and funded by the grant/cooperative agreement will be

subject to review by the Office of Management and Budget (OMB) under

the Paperwork Reduction Act.

Human Subjects

If the proposed project involves research on human subjects, the

applicant must comply with the

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Department of Health and Human Services Regulations (45 CFR Part 46)

regarding the protection of human subjects. Assurance must be provided

to demonstrate that the project will be subject to initial and

continuing review by an appropriate institutional review committee. In

addition to other applicable committees, Indian Health Service (IHS)

institutional review committees also must review the project if any

component of IHS will be involved or will support the research. If any

American Indian community is involved, its tribal government must also

approve that portion of the project applicable to it. The applicant

will be responsible for providing evidence of this assurance in

accordance with the appropriate guidelines and form provided in the

application kit.

Women, Racial and Ethnic Minorities

It is the policy of the Centers for Disease Control and Prevention

(CDC) and Agency for Toxic Substances and Disease Registry (ATSDR) to

ensure that individuals of both sexes and the various racial and ethnic

groups will be included in CDC/ATSDR-supported research projects

involving human subjects, whenever feasible and appropriate. Racial and

ethnic groups are those defined in OMB Directive No. 15 and include

American Indian, Alaskan Native, Asian, Pacific Islander, Black, and

Hispanic. Applicants shall ensure that women, racial and ethnic

minority populations are appropriately represented in applications for

research involving human subjects. Where clear and compelling rationale

exists that inclusion is inappropriate or not feasible, this situation

must be explained as part of the application. This policy does not

apply to research studies when the investigator cannot control the

race, ethnicity and/or sex subjects. Further guidance to this policy is

contained in the Federal Register, Vol. 60, No. 179, pages 47947-47951,

dated Friday, September 15, 1995.

Application Submission and Deadline

The original and two copies of each application Form PHS-5161-1

(revised 7/92, OMB Control Number 0937-0189) must be submitted to

Sharron P. Orum, Grants Management Officer, Grants Management Branch,

Procurement and Grants Office, Centers for Disease Control and

Prevention (CDC), 255 East Paces Ferry Road, NE., Room 300, Mailstop E-

18, Atlanta, Georgia 30305, Attention: Marsha Driggans, on or before

August 5, 1996:

1. Deadline: Applications shall be considered as meeting the

deadline if they are either:

a. Received on or before the deadline date; or

b. Sent on or before the deadline date and received in time for

submission to the objective review group. (Applicants must request a

legibly dated U.S. Postal Service postmark or obtain a legibly dated

receipt from a commercial carrier or U.S. Postal Service. Private

metered postmarks shall not be acceptable as proof of timely mailing.)

2. Late Applications: Applications which do not meet the criteria

in 1.a. or 1.b. above are considered late applications. Late

applications will not be considered in the current competition and will

be returned to the applicant.

Where To Obtain Additional Information

A complete program description and information on application

procedures are contained in the application package. An application

package and business management and technical assistance may be

obtained from Marsha Driggans, Grants Management Specialist, Grants

Management Branch, Procurement and Grants Office, Centers for Disease

Control and Prevention (CDC), 255 East Paces Ferry Road, NE., Mailstop

E-18, Room 300, Atlanta, Georgia 30305, telephone (404) 842-6523, E-

mail [email protected], facsimile (404) 842-6513.

Programmatic technical assistance may be obtained from Dr. Fred C.

Tenover, Hospital Infections Program, National Center for Infectious

Diseases, Centers for Disease Control and Prevention (CDC), 1600

Clifton Road, NE., Mailstop G-08, Atlanta, Georgia 30333, E-mail

[email protected], telephone (404) 639-3246.

Please refer to Announcement Number 663 when requesting information

regarding this program.

Important Notice: Atlanta, Georgia, will be the host of the 1996

Summer Olympics Games, July 19 through August 4, 1996. As a result of

this event, it is likely that the Procurement and Grants Office (PGO),

CDC, may experience delays in the receipt of both regular and overnight

mail deliveries. Contacting PGO employees during this time frame may

also be hindered due to the possible telephone disruptions. To the

extent authorized, please consider the use of voice mail, E-mail, and

facsimile transmission to the maximum extent practicable. However, do

not fax lengthy documents or grant applications.

You may obtain this announcement from one of two Internet sites on

the actual publication date: CDC's homepage at http://www.cdc.gov or at

the Government Printing Office homepage (including free on-line access

to the Federal Register at http://www.access.gpo.gov).

Potential applicants may obtain a copy of Healthy People 2000 (Full

Report, Stock No. 017-001-00474-0) or Healthy People 2000 (Summary

Report, Stock No. 017-001-00473-1) referenced in the Introduction

through the Superintendent of Documents, Government Printing Office,

Washington, DC 20402-9325, telephone (202) 512-1800.

Dated: June 11, 1996.

Joseph R. Carter,

Acting Associate Director for Management And Operations, Centers for

Disease Control and Prevention (CDC).

[FR Doc. 96-15558 Filed 6-18-96; 8:45 am]

BILLING CODE 4163-18-P