Release Date:  December 1, 1999

PA NUMBER:  PA-00-014

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Child Health and Human Development



Total joint replacement has been shown to be a highly effective treatment for 
end-stage arthritis of the major weight-bearing joints.  Despite this 
success, complications persist, including dislocation, deep infection, 
aseptic loosening and osteolysis.  Although relatively uncommon, deep 
infections in a total joint replacement are potentially catastrophic events 
for patients and for society.  Through this program announcement (PA), the 
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 
and the National Institute of Child Health and Human Development (NICHD) seek 
to stimulate the receipt of a broad range of basic science and clinical 
studies to better understand the pathophysiology, diagnosis and treatment of 
deep infections around total joint replacement implants. The National 
Institute of Allergy and Infectious Diseases (NIAID) has interests in related 
areas, and applications responding to this PA may receive assignment to NIAID 
in accordance with assignment guidelines.


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 Program Announcement 
(PA), Deep Infections of Total Joint Replacements, is related to the priority 
area of chronic diseases.   Potential applicants may obtain a copy of 
"Healthy People 2000" at


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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 


This PA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this PA may 
not exceed 5 years.  Applications that are responsive to Program 
Announcements are candidates for discretionary funding.  Additional 
information regarding NIAMS funding policy regarding these applications can 
be located at:


Total joint replacement (TJR) is an effective salvage operation for end-stage 
arthritis of a diarthrodial joint.  The success of these surgeries was noted 
by the 1994 NIH Consensus Development Conference on Total Hip Replacement.  
In 1996, approximately 400,000 total hip and knee replacements were performed 
within the United States.  By 2030, it is anticipated that this number may 
increase to over 700,000.

Although current deep infection rates of less than 1% at 1 year post-
operative are now being reported, infection of a TJR remains a devastating 
complication from both the patient’s, and from a cost, perspective.  An 
increased risk of infection is associated with inflammatory arthropathies, 
diabetes mellitus, poor nutrition, obesity, urinary tract infection, oral use 
of steroids, previous operation(s) on the affected joint, active concurrent 
infection elsewhere, debris particles, advanced age, and prolonged operative 
time and hospitalization.

Deep infections of prosthetic devices have the following characteristics:
(1) there is a high rate of infection around a prosthetic device; (2) they 
are caused by pathogens that usually are of low virulence; and (3) once 
established, are difficult to treat.  Several theories for why these deep 
infections around orthopaedic implants behave in this manner have been 
developed.  In general, they look at either the interaction of the device 
with the bacterial pathogen, or of the device with the host.

Previous studies on the interaction of the device with bacterial pathogens 
showed that bacteria readily attach to devices.  In addition, once attached, 
many encase themselves in a protective biofilm.  Finally, surface attached 
bacteria are intrinsically more resistant to the action of white blood cells, 
and they may produce factors that impair the host response or cause direct 
tissue damage.

Previous studies investigating the interaction of the device with the host 
have shown that commonly used materials in TJRs (polymethylmethacrylate, 
stainless steel, cobalt chromium alloy, and polyethylene, all increase the 
host's susceptibility to infection.  It has been proposed that since the host 
is preoccupied in responding to the device (a foreign object), attack by 
bacterial pathogens meets diminished resistance.  It is suggested that there 
is a direct suppression of host defense function in device-related 
infections.  In addition, there are reports of deficits in bactericidal 
activity, chemotaxis, superoxide function by polymorphonuclear leukocytes and 
decreased proliferation of lymphocytes in response to mitogens.  Finally, the 
inflammatory response to the device can also result in damage to the host 
(i.e., IL-1B, IL-6 and TNF-alpha are all capable of producing bone 

From a clinical standpoint, both the diagnosis and treatment of deep 
infections of TJRs remain a challenge.  Only 25% of these infection can be 
diagnosed based upon the history and physical examination alone.  Another 50% 
require extensive laboratory investigation with the final 25% eluding 
detection by commonly used diagnostic means.  Once diagnosed, there is 
controversy surrounding what is the most effective treatment alternative.  In 
the United States, most patients with deep infections are treated with 
surgical extirpation, usually in a two stage procedure (initial removal and 
debridement followed by a period of antibiotic treatment, then replacement of 
the implants).  Other treatments include a one-stage procedure (removal, 
debridement and replacement at the same setting) or a three stage procedure 
(removal and debridement, insertion of a bone graft(s), and implant 
replacement).  The latter protocols also include a course of antibiotics and 
may include cement (polymethylmethacrylate) mixed with antibiotics.  Other 
concomitant treatments have been reported.

A final controversy here surrounds the use of antimicrobial prophylaxis to 
prevent deep infections of TJRs.  Although beyond the scope of this PA, more 
research is necessary to identify whether late infection around prosthetic 
joints is caused by transient bacteremia secondary to invasive procedures, 
and whether antimicrobial prophylaxis can prevent them.

The following list, which is not all-inclusive, indicates potential areas for 
further investigation of the pathophysiology, diagnosis and treatment of deep 
infections of TJRs:

Define the role of non-operative treatment of these infections, including the 
optimum route and duration of antibiotic therapy.

Better understand the interactions between the implant device and bacterial 
Better understand the interactions between the implant device and the host.
Develop new technologies or validate current strategies for diagnosis.
-- What is the role here for diagnostic imaging (i.e. conventional 
imaging modalities and newer technologies such as Indium-111 polyclonal 
antibody scans)?
-- Is there a role for polymerase chain reaction testing of joint fluid 
Define the role of non-operative treatment of these infections, including the 
optimum route and duration of antibiotic therapy.
Elucidate optimal treatment strategies:
-- One versus two versus three stage revision procedures;
-- Optimal timing between removal and re-implantation;
-- Efficacy of antibiotic-impregnated bone cement;
-- Optimal ratios of antibiotics in bone cement for optimal 
bactericidal effect and optimal fixation;
-- Efficacy of antibiotic-loaded polymethylmethacrylate beads at the 
time of closure to eradicate remaining microorganisms, and a 
determination of optimal time period before removal;
-- Optimal time interval between bone grafting and re-implantation in a 
three-stage procedure;
-- Efficacy of antibiotic-impregnated spacers; and
-- Insertion of prosthesis without cement.
Determine the role of arthrodesis in treating a deep infection of a total 
knee replacement, including optimal timing and technique(s).
Define the optimal post-operative rehabilitation strategies following the 
various treatments for an infected TJR.


It is the policy of the NIH that women and members of minority groups and 
their subpopulations 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).

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 in the NIH Guide for Grants and Contracts, Vol. 
23, No. 11, March 18, 1994 available on the web at the following URL address:

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


To comply with Grants policy changes beginning with the June 1, 1999 
application receipt date, specific application instructions have been 
modified to reflect “MODULAR GRANT” and “JUST IN TIME” streamlining efforts.  
The modular grant concept establishes specific modules in which direct costs 
may be requested under this approach.  The just-in-time concept allows 
applicants to submit certain information only when there is a possibility for 
an award.  It is anticipated that these changes will reduce the 
administrative burden for the applicants, reviewers and institute/center 
staff.  Complete and detailed instructions and information on Modular Grants 
can be found at
Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year.  Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS398 application instructions.  A typical modular grant 
application will request the same number of modules in each year.  
Application budgets will be simplified.  Detailed categorical budget 
information will not be submitted with the application; budget form pages of 
the application kits will not be used.  Instead, total direct costs requested 
for each year will be presented.  Information, in narrative form, will be 
provided only for personnel and, when applicable, for Consortium/Contractual 

The modular grant applications, total direct costs must be requested in 
accordance with the  program guidelines and the modifications made to the 
standard  PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative  (F&A) costs] for the initial 
budget period Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

of the PHS 398. It is not required and will not be accepted with the 

categorical budget table on Form Page 5 of the PHS 398. It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See for sample 
pages.) At the top of the page, enter the total direct costs requested for 
each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language  
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project. Indicate whether the collaborating institution 
is foreign or domestic. The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for 
all key personnel, following the instructions below. No more than three pages 
may be used for each person. A sample biographical sketch may be viewed at:

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
  research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

The title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

Application kits are available at most institutional offices of sponsored 
research and may be obtained from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:

Applicants planning to submit an investigator-initiated, new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e, as plans for the study are being developed.  Furthermore, the 
application must obtain agreement from the IC staff that the IC will accept 
the application for consideration for award.  Finally, the applicant must 
identify, in a cover letter sent with the application, the staff member and 
Institute or Center who agreed to accept assignment of the application.  
This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment.  Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at

Submit a signed, typewritten original of the application, including the 
Checklist, and five signed photocopies in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical 
merit by an appropriate scientific review group convened 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 applications under review, will 
be discussed, assigned a priority score, and receive a second level review by 
the appropriate national advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

The initial review group will also examine the provisions for the protection 
of human subjects and the safety of the research environment.


Applications will compete for available funds with all other recommended 
applications. The following will be considered in making funding decisions:  
Quality of the proposed project as determined by peer review, availability of 
funds, and program priority.  Applications that are responsive to Program 
Announcements are candidates for discretionary funding.  Additional 
information regarding NIAMS funding policy regarding these applications can 
be located at:


Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

James S. Panagis, MD, MPH
Director, Orthopaedics Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building (45), Room 5AS-37K
6500 Center Drive
Bethesda, MD 20892-6500
Telephone:	301-594-5055
FAX:	301-480-4543

Ralph M. Nitkin, PhD
Biological Sciences and Career Development Program
National Center for Medical and Rehabilitation Research
National Institute of Child Health and Human Development
Executive Building, Room 2A03
6100 Executive Blvd., MSC 7510
Bethesda, MD 20892-7510
Telephone:  301-402-2242
FAX:  301-402-0832

Direct inquiries regarding fiscal matters to:

Sally A. Nichols
Grants Management Office
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building (45), Room 5AS-49F
6500 Center Drive
Bethesda, MD 20892-6500
Telephone:	301-594-3535
FAX:	301-480-5450
Email: NicholsS@ep/

Mary Ellen Colvin
Grants Management Branch
National Institute of Child Health and Human Development
Executive Building, Room 8A17G
6100 Executive Blvd., MSC 7510
Bethesda, MD 20892-7510
Telephone:  301-496-1304
FAX:  301-496-0915


This program is described in the Catalog of Federal Domestic Assistance No. 
93.846.  Awards are made under authorization of the Public Health Service 
Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 
USC 241 and 285) and administered under PHS grants policies and Federal 
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency 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, and 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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