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Antimicrobial Resistance Interagency Task Force
2007 Annual Report (Released June 2008)

Action Items 73—79

Action Item #73: Organize Conferences That Address Research Issues Relating to AR.

Project Title: Division of Microbiology and Infectious Diseases Program staff serve as external consultants or liaison to a variety of national and international TB-related groups

• Agency: NIH
• Description: NIAID program staff members serve as external consultants or liaison to a variety of national and international TB-related groups. These collaborative activities inform NIAID's strategic directions for the TB Program to assure maximum utilization of NIAID resources. National groups include the Advisory Council for the Elimination of Tuberculosis (ACET), CDC's TB Clinical Trials Consortium and TB Epidemiologic Studies Consortium, and the Infectious Disease Society of America. International groups include the STOP TB Vaccine Partnership' s Diagnostic, Vaccine, Drug Development and HIV/TB Working Groups, WHO's TDR, International Union against Tuberculosis and Lung Disease (IUATLD), the Global Alliance for TB Drug Development (GATB), and several European research consortia.
• Results: NIAID staff member serves as the Chair of the Scientific Advisory Committee to the Global Alliance for TB Drug Development.
  NIAID staff serve on WHO STOP-TB Partnership Working Groups for New Drugs and New Diagnostic tools to detect TB drug resistance.
  NIAID and CDC's Division of TB Elimination have signed a Memorandum of Understanding to coordinate and promote communications between these two agencies in the area of tuberculosis and TB/HIV co-infections.

Project Title: Novel Antimicrobials in Respiratory Infections

• Agency: NIH
• Description: On February 27-28, 2008, a meeting on novel antimicrobial in respiratory infections was sponsored by the Respiratory Diseases Branch. The sessions included the scope of the Problem, mechanisms of resistance, diagnostic assays, novel approaches, and a final session on recommendations for future research. Participants included investigators from academia and industry from the US, Europe and Japan.
• Results: An Executive Summary of the meeting will be posted on the NIAID website in the near future (www.niaid.nih.gov).

Project Title: American Association for the Study of Liver Diseases Annual Meeting

• Agency: NIH
• Description: The issues concerning antiviral resistance and selection of mutation in genomes of hepatitis viruses B and C were discussed in two sessions organized jointly by NIAID and the American Association for the Study of Liver Diseases in November 2007.
• Results: NIAID and AASLD organized two joint sessions at the AASLD Annual Liver Meeting in November 2007 - (1) "Antiviral Therapy Against Hepatitis Viruses - Understanding and Managing Drug Resistance; (2) "HCV Plasticity: Escape and Resistance."

Project Title: Update of A Public Health Action Plan to Combat Antimicrobial Resistance

• Agency: All Task Force Member Agencies
• Description: The overarching goal of this December 2007 meeting was to gather expert input toward development of a new set of Action Items.
• Results: Information provided to Interagency Task Force, Action Plan in development.

Project Title: Annual meeting of the U.S.-Japan Cooperative Medical Sciences Program

• Agency: NIH
• Description: In January 2007, the U.S.-Japan Cooperative Medical Sciences Program Acute Respiratory Infections Panel held their annual meeting, which was focused on antimicrobial resistance. Presentations and discussions addressed the following areas: assessing the spread and impact of drug resistant bacteria in Japan and other Asian countries; assessing the use of pneumococcal vaccines and their impact; and assessing the clinical significance of co-infections and identifying pathogenic mechanisms and new antimicrobial targets.
• Results: Ongoing. This, and an earlier TB specific meeting held in Zhengzhou, China have stimulated discussions about potential MDR-TB collaborations between US and Chinese scientists that may include clinical studies and basic science collaboration to improve specificity of existing diagnostic.

Action Item #74: Explore the Need To Encourage Preclinical Studies on the Toxicology, Pharmacokinetics of Novel Therapeutic Agents for the Treatment of Multidrug-Resistant Pathogens And Facilitate the Transition of Potential Products from Preclinical to Clinical Studies Leading to Development by Industry of Novel Therapeutic Agents.

Project Title: NIAID MDR/XDR TB Research Agenda

• Agency: NIH
• Description: In early 2007, NIAID convened a special session of the National Advisory Allergy and Infectious Diseases Council to examine needs in tuberculosis research especially for extensively resistant forms and in HIV-infected people. Invited were TB experts from academia, industry, public-private partnerships, international research organizations, and the public.
• Results: In June 2007, NIAID published the MDR/XDR TB Research Agenda at: http://www3.niaid.nih.gov/topics/tuberculosis/research/PDF/MDRXDRTBresearchAgenda06-06-07.pdf

Project Title: Pharmacokinetics and pharmacodynamics animal model contract

• Agency: NIH
• Description: This contract, awarded in June 2004, provides a resource to determine basic pharmacology and efficacy characteristics of new chemical entities in order to best evaluate candidate compounds as potential new drugs for tuberculosis and other infections. This contract will allow NIAID to provide critical support for investigator-initiated drug discovery, to stimulate private sector sponsorship of new drugs, to perform comparison (or confirmatory) studies from different sponsors, and to provide information for selection of antimicrobial drug candidates for design of clinical studies. This contract will serve as the central facility for evaluation of novel compounds for physical, pharmacokinetic, and pharmacodynamic properties.
• Results: Investigations of products from companies such as Sanofi-Aventis have led to renewed interest in research and development of rifapentine for tuberculosis. Pharmacokinetic evaluations of new drug combinations are planned to address regimens for treatment of drug resistant TB. Of note, data on new drug combination regimens from this preclinical research contract has informed and guided the development of new protocols for clinical trials (TB Trials Consortium) coordinated by the CDC. Publications of improved drug combinations may serve as a model of regimens to shorten therapy, thereby reducing the potential of treatment interruptions leading to resistant TB.

** TOP PRIORITY **

Action Item #75: In Consultation with Academia and the Private Sector, Identify and Conduct Human Clinical Studies Addressing AR Issues of Public Health Significance That Are Unlikely To Be Studied in the Private Sector.

Project Title: Division of AIDS Clinical Trials

• Agency: NIH, NIAID
• Description: Numerous trials underway that are monitoring for resistance: R. Chaisson, Johns Hopkins University, “Novel TB Prevention Regimens for HIV-Infected Adults” in South Africa. C. Whalen, Case Western Reserve, “Randomized, Phase II Study of Punctuated Antiretroviral Therapy for HIV Infected Patients with Active Pulmonary Tuberculosis and CD4 count > 350 cells/mm3.”
• Results: Additional study started in 2005: (1) Sok Thim, Cambodian Health Committee: U01-AI-061736 “A Cambodian Clinical Research Network for HIV/TB” (CIPRA). This study is currently enrolling and will determine if early initiation of antiretroviral therapy impacts tuberculosis cure, survival, relapse and control of HIV in urban and rural settings. It is jointly sponsored by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) – ANRS 1295 CAMELIA. Expected total enrollment: 660. Positive cultures will be assessed for resistant TB. Additional study initiated in 2006: AIDS Clinical Trials Group study ACTG 5221 "A strategy study to determine the best time to begin ARV treatment in individuals who have HIV and TB with CD4<200 cells/mm3". TB cultures will be monitored for resistant TB and new diagnostic tests will be incorporated into the study to detect resistant TB early.

Project Title: Tuberculosis Research Unit (TBRU)

• Agency: NIH
• Description: The TBRU contract was recompeted in 2007 and awarded again to Case Western Reserve University. This contract will continue to develop surrogate markers of disease and human protective immunity and has now been redirected to focus more closely on preventive strategies for TB, to complement therapeutic approaches. Activities of the TBRU are coordinated with other major organizations involved in TB research, including the CDC, USAID, FDA, WHO, Aeras Global TB Vaccine Foundation and IUATLD. Study sites for the current TBRU are in Cape Town, South Africa and Kampala, Uganda.
• Results: Information about on-going TBRU supported studies can be found at: http://www.tbresearchunit.org.

Project Title: Bacteriology and Mycology Study Group (BAMSG) and Bacteriology and Mycology Biostatistical and Operations Unit (BAMBU)

• Agency: NIH
• Description: The BAMSG and BAMBU continue to support clinical trials against fungal and resistant bacterial infections. The BAMSG was awarded to the University of Alabama in 2001. A reserve fund to support orphan studies that cannot be funded through industrial sponsors is available through the BAMSG contract.
• Results: Active and Planned Protocols include: BAMSG 3-01 A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of AIDS-associated cryptococcal meningitis” (8 US sites, 5 Thai sites) Enrollment was completed in March 2007; BAMSG 4-01 Strategies to Reduce Transmission of Antimicrobial Resistant Bacteria in Intensive Care Units (STAR*ICU Trial) (20 US sites) study completed; BAMSG 4-02 Randomized, Multi-Center, Comparative Trial of Short-Course Empiric Antibiotic Therapy versus Standard Antibiotic Therapy for Subjects with Pulmonary Infiltrates in the Intensive Care Unit (ICU) (12 US sites) Study terminated; and BAMSG 4-03 Derivation of a Clinical Prediction Rule for Bacterial Pulmonary Infection in Mechanically Ventilated Children (3 US sites)

Project Title: Vaccine and Treatment Evaluation Units (VTEUs)

• Agency: NIH
• Description: The VTEUs are a network of university research hospitals across the United States that conduct Phase I, II, and III clinical trials to test and evaluate vaccine and therapeutic candidates for infectious diseases. Through these sites, researchers can quickly carry out safety and efficacy studies of promising vaccines in children, adult, and specific high-risk populations. The results of these trials may have a profound effect on public health here and abroad. Through numerous studies at the VTEUs, researchers have tested and advanced vaccines for malaria, tuberculosis, pneumonia, cholera, and whooping cough. In the last 6 years alone, NIAID has supported more than 110 clinical trials through the VTEUs.
• Results: The VTEU is planning on sponsoring “Phase I Studies of the Safety and Immunogenicity of Primary and Secondary BCG Vaccination Delivered Intradermally, Orally, and by Combined Routes of Administration in Healthy and Previously Immunologically Naïve Volunteers.” Enrollment to begin in summer 2008.

Project Title: Clinical Trials at Masan National Tuberculosis Hospital in South Korea

• Agency: NIH
• Description: NIAID intramural researchers are collaborating with colleagues at Masan National Tuberculosis Hospital in South Korea to study drug-resistant TB, new therapies, and markers of hypoxia in lung tissue. As part of a consortium of scientists jointly funded by the Bill and Melinda Gates Foundation and the Wellcome trust under the Grand Challenges in Global Health Program, the researchers have also initiated a Phase II trial of metronidazole with an extensive investigation of surrogate drug efficacy endpoints in partnership with the Novartis Institute for Tropical Diseases in Singapore and scientists at the National University of Singapore.
• Results: A natural history clinical research protocol, initiated in 2006 at the Masan National Tuberculosis Hospital in South Korea, has enrolled several hundred volunteers in an effort to understand factors that contribute to MDR-TB. In addition, this patient cohort has allowed an examination of the occurance of XDR (eXtensively Drug Resistant) disease in patients who have failed chemotherapy completely. In 2008, the scientists described risk factors and treatment outcomes among 26 XDR-TB patients enrolled in the study (Clin Infect Dis. 2008 Jan 1;46(1):42-9.). A study of metronidazole therapy for pulmonary tuberculosis was initiated in 2007; enrollment of volunteers continues.

Project Title: Prevention of group B streptococcal (GBS) disease contract

• Agency: NIH
• Description: NIAID continues to support research on the prevention of GBS disease through a five year multidisciplinary contract awarded late in 2002 to the Channing Laboratory, Brigham and Women's Hospital. This collaborative multidisciplinary effort is focused on clinical studies in selected populations to further understand GBS infection and on studies of the host immune response.
• Results: Subject visits have been completed in a clinical trial to evaluate the impact of a GBS vaccine on GBS colonization. Laboratory assays will be completed in 2008 to provide data for statistical analyses to be incorporated into the final study report.

Project Title: Clinical Trial for Community-Acquired Methicillin-Resistant Staphylococcus aureus (CA-MRSA) Infections

• Agency: NIH
• Description: These studies are to define the optimal outpatient treatment with skin and soft tissue infection in areas where prevalence of CA-MRSA is high. The efficacy of off-patent antimicrobials such as clindamycin and trimethoprim/sulfamethoxazole will be evaluated.
• Results: Two contracts were awarded in 2007, one to University of California San Francisco and one to Olive-View University of California Los Angeles.

Project Title: VA research Update

• Agency: VA
• Description: Such topics as spread of resistance in nursing homes, the relationship of resistance to staffing levels, and work practices (organization) as they relate to antibiotic resistance are all part of VA investigators' portfolios and are topics unlikely to be studied in the private sector. VA investigators continue to have an extensive and expanding portfolio in antimicrobial resistance research.
• Results: Overall Medical Service research funding for projects associated with antimicrobial resistance increased 26% from FY 2005 to FY 2006, with both an increase in the number of funded projects and the number of sites receiving funding. For FY 2007 the budget for accepted research projects is a 29% increase over the monies spent on directed-antimicrobial research from FY 2006; the depth and breadth of funded projects remains varied. For FY 2008, funding remains stable with a continued medical service research portfolio of breadth and depth.

** TOP PRIORITY **

Action Item #76: Identify, Develop, Test, and Evaluate New Rapid Diagnostic Methods for Human and Veterinary Uses with Partners, Including Academia and the Private Sector. Such methods Should Be Accurate, Affordable, and Easily Implemented in Routine Clinical Settings.

Project Title: Partnerships to Improve Diagnosis and Treatment of Selected Drug-Resistant Healthcare-Associated Infections

• Agency: NIH
• Description: This initiative was released in June 6 2006 with a receipt date of November 27, 2006 (RFA-AI-06-036). The purpose of the initiative is to support the development of rapid diagnosis capable of identifying specific bacterial strains and drug resistant phenotypes and treatment for the following healthcare-associated pathogens: Clostridium difficile, Pseudomonas, Acinectobacter, Klebsiella, Serratia, Proteus, Enterobacter and Stenotrophomonas.
• Results: Four awards were made in early spring and summer of 2007.

Project Title: Food and Waterborne Diseases Integrated Research Network (FWDIRN)

• Agency: NIH
• Description: NIAID's FWDIRN network includes multidisciplinary research on all food and waterborne pathogens (bacteria, viruses, and protozoa), as well as toxins, to facilitate the development and evaluation of products to rapidly identify, prevent, and treat food and waterborne diseases that threaten public health. The network includes Immunology (IRU), Microbiology (MRU), Zoonoses (ZRU) and Clinical (CRU) Research Units. The Network will be supported by a Coordinating and Biostatistics Center. One of the MRUs will emphasize research aimed at developing and evaluating therapies for botulism.
• Results: Several projects utilizing different methodologies, i.e., RT-PCR, ELISA, antigen microarrays, and oligonucleotide microarrays are underway to develop rapid, sensitive clinical diagnostics. Targeted enteric pathogens include Salmonella, Shigella, Campylobacter, diarrheagenic Esherichia coli, Listeria, caliciviruses, hepatitis A, Francisella tularensis, Vibrio, and Clostridium difficile.

Project Title: Factors affecting microbial ecology of pathogen colonization and AR acquisition

• Agency: USDA
• Description: An automated ribotyping system is being used at the USDA/ARS FFSRU to identify, characterize and monitor gut bacteria isolated by us and others; information obtained from this use is being maintained in the Gastrointestinal Microflora Ribotype Database (GMRD). Molecular typing methods (e.g. ribotyping, denaturing-gradient gel electrophoresis (DGGE), and DNA sequencing) are being used to distinguish bacterial strains inhabiting the gastrointestinal tract with even greater precision and to determine genetic alterations occurring within these bacteria. This database is being used by scientists worldwide to develop a more thorough understanding of the effects of sub-therapeutic antibiotic administration and other stressors on the ecology of the gut microflora.
• Results: Ongoing. Sheffield Food and Feed Safety Research Unit, ARS, College Station, TX.

Project Title: Develop a multiplex PCR method for identifying the most prevalent clinical and animal derived serotypes of Salmonella.

• Agency: USDA
• Description: A new typing technique based on genomics is being developed that detects genes specific for Salmonella serotypes by multiplex PCR.
• Results: This assay can identify the top 31 serotypes isolated which represent 75% of all clinically isolated Salmonella. The technique has been adapted to a high-through put platform by incorporation of capillary analysis of the multiplex PCR products, allowing the determination of up to 90 isolates in a day with very little hands on time. The technique requires little training, no specific anti-sera, and works in standard DNA sequencing instruments. Bacterial Epidemiology and Antimicrobial Resistance Research Unit, ARS, Athens, GA.

Action Item #77: Encourage Basic and Clinical Research in Support of the Development and Appropriate Use of Vaccines in Human and Veterinary Medicine in Partnership with Academia and the Private Sector.

Project Title: Double-blind placebo-controlled clinical effectiveness trial of the 23-valent pneumococcal vaccine

• Agency: DoD
• Description: S. pneumoniae is a leading cause of morbidity in the U.S., causing an estimated 500,000 cases of pneumonia, 3,000 cases of meningitis, 50,000 cases of bacteremia, and 7,000,000 cases of otitis media annually. Data from 1981 to 1991 suggest that S. pneumoniae causes approximately 12% of pneumonia hospitalizations in the military or 9.5 admissions per 100,000 person-years. A 23-valent pneumococcal vaccine is being used at one military basic training facility and at military training facilities. This vaccine provides coverage for 85 - 90% of the serotypes causing bacteremia in the general population, but its clinical benefit needs to be more fully characterized before the impact of its use on the emergence or spread of S. pneumoniae resistance can be determined.
• Results: Completed. Enrollment was completed in June 2003, with a total of 152,765 recruits enrolled. Low incidence of pneumonia cases among both vaccine and placebo groups was observed, and a protective effect was not seen. A five-year follow up period of monitoring electronic records for pneumonia in both vaccine and placebo groups has been completed. Analysis is nearing completion, and a manuscript is being prepared.

Project Title: Vaccine research

• Agency: FDA
• Description: Research in support of the development and appropriate use of vaccines in humans to: 1) prevent viral infections, i.e. influenza, RSV; 2) prevent common bacterial infections i.e. S. pneumoniae, non-typable Haemophilus influenzae, group B streptococcus, N. gonorrhoeae, N. meningitidis. 3) Prevent bacterial infections caused by potential bioterror agents including Bacillus anthracis and Yersinia pestis.
• Results: Fifteen ongoing research projects support development of vaccines for the organisms listed 1) Completed study of protective levels of antibody against neonatal type 1a and 3 group B streptococcal infection (funded through interagency agreement with NICHD) Bacillus anthracis and Yersinia pestis. 2) Ongoing research regarding correlates of protection against other common types of group B streptococcus. 3) Investigating correlates of protection against infection with Streptococcus pneumonia. 4) N. gonorrhoeae. Studying immunogenicity and pathogenicity of associated proteins, funded through the FDA Office of Women's Health. 5) Ongoing regulatory review, research support and guidance for both current vaccines and those vaccines under IND, including vaccines against avian influenza.

Project Title: Vaccine research - Pneumococcal conjugate vaccine

• Agency: FDA
• Description: Indentify mechanisms for establishing efficacy of additional pneumococcal conjugate vaccines with additional serotypes. Participated in multiple WHO Workshops held to discuss serologic correlates of protection. Also, provide regulatory review, conduct research and provide guidance to support licensure of additional pneumococcal vaccines (various products under IND). New research project to develop pneumococcal reference sera.
• Results: Research regarding serologic assessment of response to vaccines ongoing. Also, provide regulatory review, conduct research and provide guidance to support licensure of additional pneumococcal vaccines (various products under IND). CBER scientists have worked with the WHO to derive a set of immunological response endpoints or measures to evaluate possible new higher valent pneumococcal conjugate vaccines.

Project Title: Vaccine development - TB

• Agency: FDA
• Description: Research in support of the development of vaccines to prevent colonization, infection, and transmission of tuberculosis
• Results: Current projects investigate the following vaccine candidates in mouse model of tuberculosis: combination DNA vaccines, multigene DNA constructs, attenuated live vaccines and subunit vaccines. These vaccines are also being tested using prime-boost strategies and post-exposure models. (Kamath AT, et.al., Vaccine 2005; 23(29):3753-3761). Collaborations include the Albert Einstein College of Medicine, the NIH, and the Aeras Global TB Foundation. Also, with support from the NIAID. LMDCI scientists are developing in vitro assays for assessing the potency of TB vaccines. Over 25 peer-reviewed papers published since 2004.

Project Title: Drug therapy

• Agency: FDA
• Description: Research: novel targets for drug therapy (to avoid resistance).
• Results: Two ongoing projects that examine the mechanisms of development of HIV drug resistance.

Project Title: Bacterial Respiratory Pathogen Research Unit (BRPRU)

• Agency: NIH
• Description: This project supports bacterial pre-clinical and clinical studies for the diagnosis, prevention, and management of selected human bacterial respiratory pathogens. The contractor is currently pursuing clinical studies to evaluate vaccines for non-typeable Haemophilus influenzae organisms using a human challenge model, as well as vaccines against Group B Streptococci in a phase I trial. Additional studies include the development of candidate vaccines against Pseudomonas and Moraxella.
• Results: A sub study to examine the emergence of antibiotic-resistant respiratory pathogens in otitis prone children was started in 2006.

Project Title: The tuberculosis research materials and vaccine testing contract (Colorado State University)

• Agency: NIH
• Description: The contract provides exploratory and preclinical evaluation of promising new TB vaccine candidates in state of the art animal models and as such continues to provide critical resources for the interface between fundamental and applied science.
• Results: More than 150 new TB vaccine candidates had been evaluated under this contract, several of which have been or are going to be tested in human clinical trials with several others progressing through various stages of preclinical development.

Project Title: Phase I and II Malaria vaccine trial in Mali

• Agency: NIH
• Description: NIAID, in collaboration with Walter Reed Army Institute of Research (WRAIR), GlaxoSmithKline Biologicals, U.S. Agency for International Development (USAID), the University of Maryland School of Medicine Center for Vaccine Development (Md/CVD), and the University of Bamako, Mali, completed two Phase I trials in Mali of novel candidate vaccines that target the blood-stage of malaria parasites.
• Results: Under the initiative International Collaborations in Infectious Disease Research, NIAID, in collaboration with Walter Reed Army Institute of Research (WRAIR), GlaxoSmithKline Biologicals, U.S. Agency for International Development (USAID), the University of Maryland School of Medicine Center for Vaccine Development (Md/CVD), and the University of Bamako, Mali. The same group of investigators and collaborators have completed Phase I and Phase II trials in children of a different candidate malaria vaccine also targeting the blood-stage of falciparum malaria parasites.

Project Title: Phase I Malaria vaccine trials in USA

• Agency: NIH
• Description: Phase I Malaria vaccine trials in USA
• Results: NIAID has undertaken two Phase I dosage-escalation trials of two novel candidate malaria vaccines at the Baylor College of Medicine, Vanderbilt University, and Stanford University. Enrollment is ongoing in the Vanderbilt and Stanford trials, and data from the Baylor trial are being analyzed.

Project Title: Food and Waterborne Diseases Integrated Research Network (FWDIRN)

• Agency: NIH
• Description: NIAID's FWDIRN network includes multidisciplinary research on all food and waterborne pathogens (bacteria, viruses, and protozoa), as well as toxins, to facilitate the development and evaluation of products to rapidly identify, prevent, and treat food and waterborne diseases that threaten public health. The network includes Immunology (IRU), Microbiology (MRU), Zoonoses (ZRU) and Clinical (CRU) Research Units. The Network is supported by a Coordinating and Biostatistics Center. One of the MRUs will emphasize research aimed at developing and evaluating therapies for botulism.
• Results: Planned clinical activities within the FWDIRN include: "Cell-mediated immunity studies from Salmonella typhi vaccine trials", "Sensitivity of TLR4 polymorphisms to Shigella LPS," "Immunogenicity of tularemia live vaccine strain in humans," "Prime-boost study of the immunogenicity of Vi polysaccharide typhoid vaccine after priming by oral Vi+ S. typhi strain," and evaluating the intestinal microbiome prior to and after dosing with an antibiotic, Ciprofloxacin.

Action Item #78: Encourage Basic and Clinical Research in Support of Novel Approaches to Preventing or Treating Infections with Resistant Organisms That Occur in Humans and Animals by Partnering with Academia and the Private Sector.

Project Title: TB Trials Consortium (TBTC)

• Agency: CDC
• Description: The TBTC is an investigator-driven collaboration involving TB control programs, academic medical researchers, and CDC whose mission is to conduct programmatically relevant clinical research on TB control and prevention. TBTC designs and executes clinical trials of TB treatment and prevention at sites on 4 continents. Trials are designed both to increase the effectiveness of current regimens and to identify new agents. Collaboration with the commercial sector is common. TBTC trials have identified new regimens, clarified risk factors for development of drug resistance, and assessed regimens used to treat drug resistant TB. Growing collaborations exist with the commercial sector, the not-for-profit private sector (GATB, MSF, TAG) and the public sector (FDA, NIAID).
• Results: TBTC is presently in its 10th year of existence as a formal consortium, and its 12th year of trials. Eight major studies and numerous substudies have been undertaken. More information and a list of publications are available at: http://www.cdc.gov/nchstp/tb/tbtc/default.htm.  TBTC studies have identified factors favoring development of rifamycin resistance, and are assessing the efficacy of an intermittent regimen for treatment of INH-resistant TB. TBTC will soon begin a pilot study of the treatment of XDR/MDR TB. TBTC is also working with FDA, the TB Alliance, and others to develop improved biomarkers for TB trials and to facilitate the regulatory process around new TB drug development. It has recently undergone extensive peer review.

Project Title: Randomized clinical trial evaluating efficacy of gentamicin/azithromycin and gemifloxacin/azithromycin combination therapies as a salvage regimen for uncomplicated urogenital gonorrhea.

• Agency: CDC/NIH
• Description: A randomized clinical trial to determine the efficacy of each of two combination antimicrobial regimens for the treatment of uncomplicated gonococcal infection (Regimen A = gentamicin plus azithromycin, Regimen B = gemifloxacin plus azithromycin). For each regimen, 250 patients with cervical or urethral gonorrhea will be enrolled in participating STD clinics in 3 geographically diverse areas. Efficacy of each regimen will be assessed as the proportion of enrollees with a positive gonococcal culture at enrollment who are negative by culture at 12-18 days after treatment.
• Results: Protocol has been developed and is under final review by the Sexually Transmitted Infection Clinical Trials Group.

Project Title: HIV Resistance Network (HIVResNet, International laboratory Branch, Division of Global AIDS, NCHHSTP).

• Agency: WHO, CDC, Academic institutions
• Description: HIVResNet have developed a global strategy for HIV drug resistance prevention, surveillance and monitoring. The strategy aims to build evidence on the scale of HIV drug resistance and equip and prepare countries with knowledge, skills and systems to respond should HIV drug resistance epidemics emerge.
• Results: HIVResNet has developed laboratory guidelines on HIV drug resistance using dried blood spot samples. In the process of developing laboratory networks at different levels to meet the need of HIV drug resistance surveillance and monitoring around the world.

Project Title: Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)

• Agency: NIH
• Description: This contract was established to acquire compounds for screening against virulent Mtb, maintain a computerized chemical database of compound structures, coordinate and distribute compounds for evaluation in vitro and in an animal model, and report data to suppliers. The TAACF has contacted over 3,500 chemists throughout the world seeking candidate anti-TB compounds.
• Results: Over 87, 235 compounds have been received from academic and private sector investigators, principally in the United States and Europe, with growing involvement of scientists from Africa, Asia, Australia, South America, and other geographic sites. Data generated have led to discoveries of new chemical classes of drugs active against M. tuberculosis, advanced and supported research grants in this area, and identified FDA approved drugs with in vitro inhibition of TB. The TAACF recently refocused its efforts following a review panel of academic and industry experts in anti-infective drug discovery and development. TAACF now provides rapid turnaround of data collection to support suppliers with dedicated programs for the discovery of new anti-tubercular agents and who can commit to providing sufficient compounds for advanced testing in vivo. The facility website is http://www.taacf.org/ where data and publications from this activity are posted.

Project Title: Submission of compounds for in vitro evaluation

• Agency: NIH
• Description: Staff has selected for evaluation more than 10,000 compounds, based on their chemical structure, from the National Cancer Institute (NCI) chemical repository of over 500,000 compounds. Of these compounds, many have shown initial in vitro activity against a wild-type strain, and some have promising in vitro activity against isoniazid (INH)-resistant strains. A large part of this effort is conducted under an interagency agreement with the Health Resources and Services Administration at the National Hansen's Disease Programs Center.
• Results: Efficacy evaluations in animal models of TB are being conducted on selected compounds. Novel chemical classes have been identified with in vitro activity against wild-type and drug-resistant strains. Follow-up of compound is continuing.

Project Title: High-throughput screening contract with Southern Research Institute

• Agency: NIH
• Description: This contract provides a high throughput screening capability to develop and implement biochemical, target-specific Mtb drug screening assays and to develop and implement Mtb metabolic stage-specific drug screening assays.
• Results: Selected molecular targets are being screened against large chemical libraries to identify new candidate antibiotics as potential additions to the combined regimen for treatment of tuberculosis, particularly to combat multidrug resistant strains.   Assays have been developed and run for specific biochemical targets of active and persistant TB: inhA, DHFR, isocitrate lyase, pantothenate C, malate synthase, and Mtb growth inhibition. A diverse publicly available library of 100,00 compounds have recently completed screening against virulent m. tuberculosis. Data will be posted to the website for use by the research community.

Project Title: Bacterial Respiratory Pathogen Research Unit (BRPRU)

• Agency: NIH
• Description: This project supports bacterial pre-clinical and clinical studies for the diagnosis, prevention, and management of selected human bacterial respiratory pathogens. DMID is partnering with Emergent Europe Limited to conduct a phase I clinical trial for Group B Streptococci at the University of Iowa.
• Results: A sub study to examine the emergence of antibiotic-resistant respiratory pathogens in otitis prone children was started in 2006.

Project Title: Food and Waterborne Diseases Integrated Research Network (FWDIRN)

• Agency: NIH
• Description: NIAID's FWDIRN network includes multidisciplinary research on all food and waterborne pathogens (bacteria, viruses, and protozoa), as well as toxins, to facilitate the development and evaluation of products to rapidly identify, prevent, and treat food and waterborne diseases that threaten public health. The network includes Immunology (IRU), Microbiology (MRU), Zoonoses (ZRU) and Clinical (CRU) Research Units. The Network will be supported by a Coordinating and Biostatistics Center. One of the MRUs will emphasize research aimed at developing and evaluating therapies for botulism.
• Results: Basic research to support novel prevention and/or treatment of infections include projects that focus on: i) the development of small animal models that mimic human disease caused by Campylobacter and the life-threatening sequelae to infection by Shiga toxin-producing Escherichia coli, the hemolytic uremic syndrome (HUS); ii) comparison of the efficacy and potential side-effects of several antibiotics in the treatment of Shiga toxin-producing Escherichia coli; and iii) evaluation of the intestinal microbiome prior to and after dosing with an antibiotic, Ciprofloxacin.

Project Title: Pharmacokinetics and Pharmacodynamics of Antimicrobials in Animal Models

• Agency: NIH
• Description: This contract, awarded in 2004, provides a resource to determine basic pharmacology and efficacy characteristics of new chemical entities in order to best evaluate candidate compounds as potential new drugs for tuberculosis and other infections. This contract will allow NIAID to provide critical support for investigator-initiated drug discovery, to stimulate private sector sponsorship of new drugs, to perform comparison (or confirmatory) studies from different sponsors, and to provide information for selection of antimicrobial drug candidates for design of clinical studies. This contract will serve as the central facility for evaluation of novel compounds for physical, pharmacokinetic, and pharmacodynamic properties.
• Results: Data on new drug combination regimens from this preclinical research contract has informed and guided the development of new protocols for clinical trials (TB Trials Consortium) coordinated by the CDC. Publications of improved drug combinations may serve as a model of regimens to shorten therapy, thereby reducing the potential of treatment interruptions leading to resistant TB. In addition, this contract contributed to the successful IND application for PA 824 from the Global Alliance for TB Drug Development. PA 824 is a new drug candidate active against multiply resistant M. tuberculosis.

<— Previous Section: Action Items 68–72        Next Section: Action Items 80–82—>

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