NIAID

NIAID’S Antibiotic 

Resistance Research 

Framework: 

Current Status and 

Future Directions 

2019
NIAID's Antibiotic Resistance Research Framework: Current Status and Future 

Directions 

Table of Contents 

Executive Summary ............................................................................................................................ 1 

Introduction ......................................................................................................................................... 2 

The Evolution and Accelerating Pace of Antibiotic Resistance (AR) ................................................2 

The Antibiotic Development Pipeline ................................................................................................. 3 

NIAID: Stimulating Research on AR.................................................................................................. 3 

Basic Research................................................................................................................................. 3 

Translational Research .................................................................................................................... 4 

Clinical Research............................................................................................................................. 6 

Research Resources ......................................................................................................................... 8 

Partnerships Facilitate a Concerted Approach .................................................................................... 9 

Innovative Approaches to Addressing the AR Challenge ...................................................................9 

Conclusions ....................................................................................................................................... 11 

References ......................................................................................................................................... 13 

Appendix: 2014 Innovative Approaches and Select Accomplishments ...........................................15 
NIAID’s Antibiotic Resistance Research Framework: Current Status and Future 

Directions 

Executive Summary 

In 2015, the U.S. Government launched the National Action Plan for Combating Antibiotic-Resistant 

Bacteria (CARB), calling for a coordinated federal response to address the growing threat of 

antibiotic resistance (AR). The National Institute of Allergy and Infectious Diseases (NIAID)’s 

longstanding commitment to funding and conducting research related to AR is a critical component of 

this initiative. In 2008, NIAID made a public commitment to addressing AR through basic, 

translational, and clinical research1

. In 2014, NIAID documented the Institute’s significant progress in 

addressing AR and outlined a combination of innovative approaches to be pursued as part of a 

comprehensive strategy. NIAID is again looking towards the future, reexamining goals, and modifying 

approaches to advance the field of AR research while building on previous successes. 

AR is an inevitable outcome of the evolutionary principle that organisms will mutate to escape lethal 

selective pressure. A multifaceted approach including surveillance, infection control, improved antibiotic 

stewardship, new prevention measures, and new diagnostic and therapeutic strategies to combat resistant 

bacteria remain essential to mitigate this global threat. Increased recognition of the need for novel 

treatments and therapeutic approaches and the introduction of new Food and Drug Administration (FDA) 

regulatory approaches and incentives to facilitate antibiotic development are bringing renewed attention 

to this area. However, declining commercial interest in antibiotics threatens the future of the field. With 

some bacterial infections already untreatable by FDA-approved agents, it is imperative to continue to 

expand the antibiotic pipeline. 

This report describes NIAID’s portfolio of basic, translational, and clinical research in AR and 

outlines an updated array of innovative approaches based on the latest scientific advances and 

research opportunities to address this urgent public health priority. 

Strategic Approaches to AR Research: 

• Leverage Data Science to Address AR — Use computational approaches to integrate and analyze 

large, diverse datasets to accelerate the discovery and development of new therapeutics, diagnostics, 

and vaccines for resistant infections 

• Understand Antibiotic Failure — Explore why antibiotics unexpectedly fail in patients with 

drug-sensitive infections 

• Harness the Immune System to Combat Bacterial Infections — Enhance host immune 

responses through vaccines and immune-based products to prevent and treat bacterial 

infections 

• Realize the Promise of Rapid Diagnostics — Develop rapid point-of-need diagnostics to facilitate 

appropriate treatment and antibiotic stewardship and conduct implementation studies on FDAcleared/approved tests to demonstrate potential benefits for patient outcomes and healthcare costs 

• Reinvigorate Gram-negative Drug Discovery — Develop tools and technologies to overcome 

the unique challenges of gram-negative bacteria and drive the discovery of new antibiotics for 

gram-negative infections 

• Non-antibiotic Products to Treat Resistant Infections — Use non-traditional therapeutics, such 

as drugs that decrease bacterial virulence, live microbiome-based therapeutic products, and 

bacteriophages, to limit the emergence of resistance while preserving the microbiome 

• Optimize the Clinical Utility of Antibiotics — Optimize the use of existing drugs and combination 

therapies to suppress the emergence of resistance and minimize toxicity 

1 
NIAID’s Antibiotic Resistance Research Framework: Current Status and Future 

Directions 

Introduction 

In 2014, NIAID released a report, NIAID’s Antibacterial Research Program: Current Status and Future 

Directions, emphasizing the Institute’s commitment to addressing this urgent public health threat. Since 

that time, NIAID has made significant progress through a robust and diverse set of activities spanning 

basic, translational, and clinical research. This updated research framework describes NIAID’s current 

AR research portfolio, highlighting activities in each of these areas. In addition, the report provides 

updates on progress made in addressing the innovative approaches to combat AR laid out in the 2014 

report (see Appendix for detailed examples), as well as updating the innovative approaches to be pursued 

over the next five years. While all types of microbes can exhibit resistance, this research framework is 

focused on bacteria (with the exception of mycobacteria). NIAID’s research strategic priorities for 

tuberculosis are described in the NIAID Strategic Plan for Tuberculosis Research. 

The Evolution and Accelerating Pace of Antibiotic Resistance (AR) 

Bacteria, one of the oldest life forms on the planet, have mastered the art of evading adverse conditions that 

threaten their existence. Selective mutations have enabled them to survive for billions of years, while also 

making them resistant to many of the antibiotics used to treat infections today. Increased exposure to these 

drugs has caused some bacterial pathogens to develop and spread genes that resist the toxicity of some drugs. 

This is an inevitable, natural phenomenon that cannot be eliminated2

. However, certain factors that contribute 

to the accelerating development of resistance, such as infection control precautions and antimicrobial 

stewardship can be controlled, and these factors should be 

modified to slow the progression of AR3,4. 

In recent decades, bacterial resistance has increased at an 

alarming rate. This includes resistance among gramnegative bacteria, which have acquired and spread new 

resistance traits especially rapidly over the past decade. In 

2013, the Centers for Disease Control and Prevention 

(CDC) published a list of “urgent,” “serious,” and 

“concerning” domestic AR threats 7

. The CDC updated 

this list in 2019 and “urgent” threats now include 

Clostridioides difficile, Carbapenem-resistant 

Enterobacteriaceae (CRE), drug-resistant Neisseria 

gonorrhoeae, and Carbapenem-resistant Acinetobacter, as 

well as the fungal pathogen Candida auris. 

The growing problem of AR has generated a sense of 

urgency at national and international levels. Over the past 

five years, the U.S. Government and global partners have 

focused increased attention on AR, including through the 

U.S. National Action Plan for CARB, the World Health 

Organization (WHO) Global Action Plan, a High-Level 

Meeting of the United Nations General Assembly, and 

meetings of the G7 and G20. 

NIAID Research on Drug-resistant Fungal Infections 

As bacteria are becoming increasingly resistant to 

antibiotics, fungal pathogens are developing resistance to 

antifungal drugs. Antifungal resistance is a critical public 

health concern, particularly in patients with invasive 

infections such as those caused by the fungus Candida. 

Candida is one of the leading causes of healthcareassociated bloodstream infections in the United States. 

Antifungal resistance has been identified in several 

Candida species, including the recently emerged and 

rapidly spreading pathogen C. auris, which is often 

multidrug-resistant. Less common fungal pathogens such 

as Aspergillus are also developing resistance to many 

first-line treatments. NIAID is supporting a wide range 

of basic and applied research to better understand the 

mechanisms of resistance and develop new ways to 

detect, treat and prevent fungal infections. This includes 

research to advance new treatment options and 

diagnostics for Candida and Aspergillus, the 

development of tools to determine the cause of drug 

resistance, and support for an experimental vaccine to 

protect against Candida infection. 

2 
The Antibiotic Development Pipeline 

While AR has accelerated, the number of companies engaged in antibiotic discovery and development efforts 

has declined for a variety of reasons, including scientific challenges and the low return on investment of 

antibiotics compared with other therapeutics5. During the past year, numerous biopharmaceutical companies 

have announced plans to curtail their antibiotic research and development programs, and one company with a 

newly approved antibiotic declared bankruptcy6-8 . These developments are worrisome for the future of treating 

patients with antibiotic-resistant infections. 

There continues to be an urgent need to identify ways to preserve currently available antibiotics, develop 

new ones, and identify alternative treatment and prevention strategies. Several recent publications have 

outlined strategies to ensure a more robust antibiotic pipeline3,9-11. The Pew Charitable Trusts has created 

an interactive tool that shows trends along the antibiotic pipeline between 2014-2018. New programs 

have emerged to facilitate antibiotic development12,13. For example, CARB-X, a global public-private 

partnership to bolster innovation in antibacterial product development, was launched in 2016 to accelerate 

the development of products focused on the most serious drug-resistant bacteria identified by the WHO 

and the CDC. NIAID partners with the Biomedical Advanced Research and Development Authority 

(BARDA), the Wellcome Trust, the United Kingdom Government, the German Government, and the Bill 

& Melinda Gates Foundation to support the program and provides drug development expertise and 

preclinical testing services to CARB-X awardees. CARB-X and other “push” incentives have helped 

continually prime the antibiotic pipeline, and the call by the Infectious Diseases Society of America 

(IDSA) for 10 new drugs between 2010 and 2020 was successful, likely due to greater regulatory 

flexibility and financial incentives, such as the GAIN Act14, which provides incentives to increase the 

commercial value of innovative antibiotic drugs. Nevertheless, few agents in clinical development have 

activity against some of the most urgent AR threats, and drug candidates with novel mechanisms of 

action remain rare, so it is imperative to continually expand the antibiotic pipeline. 

NIAID: Stimulating Research on AR 

NIAID continues to make AR research a key priority. To that end, the Institute has significantly 

supported basic, translational, and clinical research in this area, paving the way for innovative solutions 

to advance the prevention, diagnosis, and treatment of drug-resistant infections. NIAID funds numerous 

targeted research initiatives to help drive these efforts, which has resulted in significant growth of 

NIAID’s AR research portfolio. In this section, select examples of NIAID’s AR activities are described, 

as are the comprehensive suite of research resources and preclinical services available to investigators to 

fill gaps in the product development pipeline. 

Basic Research 

NIAID’s basic research portfolio is focused on understanding the mechanisms that pathogens use to 

thwart host defenses; characterizing resistance mechanisms as they emerge; delineating contributors to 

bacterial virulence; identifying new targets for diagnostics, vaccines, and therapeutics; and discovering 

potential new therapeutic approaches. Examples of key findings from NIAID-supported basic research 

follow: 

 With support from NIAID grants and the NIAID-funded Systems Biology Centers, researchers found that 

the sugar substitute trehalose increases the virulence of epidemic strains of C. difficile. They found that 

two epidemic types of C. difficile have the special ability to metabolize low levels of trehalose, and they 

hypothesize that the widespread use of this compound as a dietary additive may have contributed to the 

spread of these strains15. 

 Researchers studied the genetic basis for the development of azithromycin resistance in N. gonorrhoeae. 

Azithromycin belongs to a class of antibiotics known as macrolides. This study was the first to 

demonstrate that N. gonorrhoeae can acquire macrolide resistance from other Neisseria species that in turn 

can serve as a reservoir for resistance genes. These results have public health implications and may be 

3 
used to inform the development of tools to understand the spread of antibiotic-resistant gonorrhea16. 

 Researchers explored treatment options for “heteroresistant bacteria,” in which bacterial subpopulations 

are seemingly genetically identical but look different to different antibiotics. Infections caused by these 

pathogens can be treated with specific combinations of drugs that each kill one subpopulation of bacteria 

that is resistant to another antibiotic; thereby the combination kills the entire population. Studies on CRE 

clinical isolates support this theory. These findings represent a promising approach for treating certain 

patients with seemingly untreatable bacterial infections17. 

 AR can be caused by the temporary expression of genes encoding the bacterium’s efflux pump (a structure 

that ejects antibiotics from bacteria), in addition to other, mutation-based mechanisms. Researchers 

studying an efflux pump (AcrAB-TolC) that expels multiple antibiotics found that the expression of the 

efflux pump’s genes was associated with higher spontaneous mutation frequencies. This study suggests 

that the temporary expression of these genes may trigger the evolution of permanent resistance18. 

 NIAID intramural researchers led an international effort at the intersection of AR and the microbiome to 

reveal that the non-pathogenic probiotic Bacillus can eliminate Staphylococcus aureus. When Bacillus 

species (mostly B. subtilis) were present in fecal samples from study participants in Thailand, S. aureus 

was never detected in their gut or nasal samples. Using a mouse model, the research team discovered that 

Bacillus secretes compounds known as fengycin lipopeptides that block S. aureus quorum-sensing (a 

mechanism which enables groups of bacteria to communicate with one another) and completely eradicates 

intestinal S. aureus. Bacillus-containing probiotics could be used for simple and safe S. aureus 

decolonization strategies. This probiotic approach would have numerous advantages over the present 

standard topical strategy involving antibiotics. The potential for a simple probiotic strategy to prevent 

dangerous staph infections holds immense promise in the healthcare field19. 

 Immunotherapy for treating resistant bacteria is an innovative approach being advanced by NIAID 

intramural scientists. Use of an antibody that recognizes the ST258 capsule polysaccharide type 2 (CPS2) 

can boost killing of bacteria by neutrophils in human blood in vitro. These findings suggest the ST258 

capsule polysaccharide is a viable vaccine target antigen. It is now being tested in non-human primates 

against a carbapenem-resistant Klebsiella pneumoniae strain20. 

Translational Research 

To transform basic research findings into applications that ultimately improve patient care, NIAID has 

expanded its translational research portfolio. NIAID is building on the innovative approaches from the 

2014 report to advance the discovery and development of novel therapeutics, diagnostics, and vaccines 

and other preventive strategies for drug-resistant infections. NIAID has used its long-standing 

Partnerships Program to address important translational research and product development areas for AR. 

Through targeted Partnerships initiatives, NIAID is funding a broad range of projects to further expand 

AR research, including therapeutic discovery for antibiotic-resistant gram-negative bacteria (RFA-AI-16-

081), clinically useful diagnostics for antibiotic-resistant bacteria (RFA-AI-17-014), and 

immunoprophylactics (drugs that harness the immune system to prevent infection) and vaccines targeting 

multiple antibiotic-resistant bacteria (RFA-AI-17-017). In addition, through the Centers of Excellence for 

Translational Research (CETR) program, NIAID is supporting research to discover and develop new 

therapeutic approaches against multidrug-resistant pathogens. 

Therapeutics 

NIAID supports a large and diverse portfolio of therapeutic candidates that focus on both validated and 

novel targets. Scientists are investigating novel classes of antibiotic candidates that interrupt bacterial 

protein synthesis or disrupt the bacterial cell wall, both proven targets for antibiotic drugs. Researchers 

are also exploring alternatives to small molecule antibiotics, such as therapeutic bacteriophage, 

microbiome-based approaches, monoclonal antibodies, small inhibitory oligonucleotides, antibacterial 

4 
peptides, anti-virulence therapies (which target bacterial virulence factors without directly killing 

bacteria), and compounds that modulate innate immunity. In addition, research teams are identifying 

novel antimicrobial compounds from natural sources, including new classes of antibiotics found in soil. 

NIAID has supported multiple targeted solicitations over the past decade to advance promising 

therapeutic products against urgent and serious AR threats, from lead candidate to first-in-human 

clinical trials. Therapeutic development projects include synthetic tetracyclines that can treat different 

types of bacterial infections and are not subject to typical tetracycline resistance mechanisms. In 

August 2018, FDA approved one of these compounds (eravacycline) to treat complicated intraabdominal infections. Antibiotic development for gram-negative infections is particularly difficult due 

to low permeability of the gram-negative cell wall and a variety of efflux pumps. In 2017, NIAID and 

The Pew Charitable Trusts co-sponsored a meeting, “Challenges in the Discovery of Gram-negative 

Antibacterials: The Entry & Efflux Problem.” Building on momentum from the workshop, NIAID 

funded seven projects in 2018 to develop research tools and technologies to advance drug discovery for 

gram-negative infections (RFA-AI-16-081). Researchers are also evaluating combination therapies that 

target both essential functions and resistance factors among these tenacious pathogens5

. NIAID is 

supporting the preclinical development of efflux pump inhibitors and funded Investigational New Drug 

(IND)-enabling studies of an oral β-lactamase inhibitor (VNRX-7145) that will be paired with 

ceftibuten, an existing antibiotic to treat resistant gram-negative infections. VNRX-7145 restores the 

effectiveness of ceftibuten against Enterobacteriaceae expressing certain classes of β-lactamases (i.e., 

Class A, C and/or D). Numerous other combination therapy approaches also are being explored, 

including immunomodulators, biofilm disruptors, and signaling inhibitors. With NIAID support, 

investigators are harnessing innovative technologies to transform antibiotic discovery; exploring 

potential antimicrobial compounds, including those from natural sources; and fostering collaborations 

between academia and industry partners to develop and advance promising lead candidates. 

Another therapeutic approach repurposes old drugs by using new technologies to optimize dosing levels, 

duration, and route of administration, and to identify promising combination drug therapies based on 

current pharmacokinetic and pharmacodynamic (PK/PD) principles. Colistin, an antibiotic approved in 

the late 1950s that no longer was widely used by the 1970s due to toxicity issues, is one such drug. 

Researchers have developed and published dosing algorithms to inform the use of this antibiotic among 

critically ill patients21. As a potential future alternative to colistin, NIAID supports the development of 

next-generation polymyxins, including one candidate (SPR206) that has progressed to an industrysponsored Phase 1 clinical trial. 

Diagnostics 

NIAID supports both the development of rapid, multiplexed diagnostics platforms and research to identify 

solutions to the technical challenges of detection. Better diagnostics could provide needed clarity when 

distinguishing between viral and bacterial infections and deciding whether to treat with antibiotics. 

Diagnostics are also needed to identify the bacterial species causing the infection and determine 

susceptibility profiles to facilitate antibiotic stewardship and reduce the use of broad-spectrum agents. For 

many bacterial species, diagnosis requires culturing the organism followed by species identification and 

susceptibility testing. Together, this form of testing takes 48-96 hours or more, leading to delays in 

initiating appropriate therapy, the potential for unnecessary selective pressure, and worsened patient 

outcomes. Rapid diagnostics also help facilitate the clinical development of new antibiotics by reducing 

the size of and costs associated with performing clinical trials, which often must enroll large numbers of 

patients to overcome diagnostic uncertainties22. 

The National Institutes of Health (NIH) and NIAID are advancing efforts to develop rapid point-of-need 

diagnostic tools. In 2016, NIH and BARDA announced the Antimicrobial Resistance Diagnostic 

Challenge, a $20 million federal prize competition. The three-step competition seeks to identify 

innovative and rapid point-of-need in vitro diagnostic tests, which help inform appropriate antibiotic 

5 
treatment and facilitate antimicrobial stewardship efforts. Up to three winners will be announced in 2020. 

The NIAID Division of Intramural Research initiated a new clinical laboratory program that focuses on 

the mechanisms of antimicrobial resistance. The program emphasizes multidrug-resistant bacteria and the 

development of new approaches for detecting resistance based on proteomics and sequencing. Novel 

approaches to rapid AR diagnostics based on mass spectrometry and nanopore sequencing are a key focus 

of the new laboratory. NIAID-supported researchers are also developing platforms to reduce the time 

needed to detect growth of bacteria that frequently cause healthcare-associated infections. Accelerating 

this process allows for faster identification of these bacteria and their sensitivity to antibiotics. In 

addition, scientists are developing rapid point-of-need diagnostic platforms to identify pathogens and 

determine their antibiotic susceptibility directly from patient samples, instead of culturing bacteria. 

Researchers are exploring this approach for gram-negative bacteria in urine and blood as well as N. 

gonorrhoeae from swab samples. Through the CETR program, investigators developed a new test to 

diagnose bacterial infections directly from blood samples. The test accurately detects a wide variety of 

bacteria and AR genes23. 

Vaccines and Other Preventive Strategies 

Several licensed vaccines target bacterial infections, including Streptococcus pneumoniae and 

Haemophilus influenzae type b and have markedly reduced infections caused by these organisms and the 

need for antibiotics to treat them. According to the CDC’s 2019 report on Antibiotic Resistance Threats 

in the United States, the pneumococcal conjugate vaccine PCV13 alone prevented 30,000 invasive 

pneumococcal infections from 2010-2013. Additional preventive tools to combat AR are needed, but 

progress towards effective countermeasures remains a challenge. In 2018, the Wellcome Trust and the 

Boston Consulting Group issued a report entitled Vaccines to tackle drug resistant infections: An 

evaluation of R&D opportunities. The report assesses vaccine development potential for antibioticresistant pathogens and provides recommended actions to advance the field. Currently, no approved 

vaccines exist for healthcare-associated infections. However, such interventions could significantly 

reduce the burden of disease in a cost-effective manner if applied to selected populations such as older 

adults, patients at hospital discharge, and people at risk for recurrent infection24. Immunoprophylactics 

also hold promise as an effective strategy against AR. While most of these products are still in 

development, the FDA approved in 2016 an anti-toxin monoclonal antibody therapy shown to reduce the 

rate of recurrent C. difficile infection, a potentially life-threatening diarrheal illness. With this as proof 

of concept, NIAID-supported researchers are continuing to develop novel immunoprophylactic and 

vaccine candidates targeting a variety of healthcare-associated pathogens, including drug-resistant gramnegative bacteria as well as C. difficile. For pathogens such as C. difficile, Pseudomonas aeruginosa, 

and S. aureus, some vaccine candidates mitigate the acute symptoms and disease progression, while 

others are being designed to prevent infection by blocking or reducing colonization. 

While the licensed meningococcal B vaccine, Bexsero, has recently shown promise against gonorrhea, 

previous vaccine candidates specifically targeting N. gonorrhoeae were disappointing, likely due to the 

high degree of variation of surface proteins elaborated by the organism25,26. Despite these early setbacks, 

NIAID has continued to support research on N. gonorrhoeae vaccine antigens, disease pathogenesis, and 

the human immune response. In 2019, NIAID funded six Sexually Transmitted Infections Cooperative 

Research Centers to develop vaccines to prevent gonorrhea, chlamydia, and syphilis. The program aims 

to foster the development of early-stage vaccine candidates with the potential for further preclinical 

development and testing in clinical trials. 

Clinical Research 

Leadership Group on AR 

Well-designed and implemented clinical trials, an essential part of NIAID’s AR program, are supported 

through investigator-led efforts and multiple NIAID clinical trial networks. In 2013, NIAID launched a 

major clinical effort to address AR, the Antibacterial Resistance Leadership Group (ARLG). Studies 

conducted by the ARLG include clinical testing of new drugs to treat multidrug-resistant gram-negative 

6 
 

bacteria, evaluating diagnostic devices in clinical settings, and optimizing treatment regimens to reduce 

the emergence of resistance. The ARLG draws on the creativity of the global research community by 

inviting concept submissions to identify and address AR priorities. The ARLG is also committed to 

mentoring the next generation of clinical scientists in the field of AR and accepts applications for 

fellowships and early-stage investigator seed grants. NIAID renewed funding for the program in fiscal 

year 2020. 

Through the ARLG, NIAID is supporting observational studies to help better understand the scope of the 

problem of AR. With international partners, the ARLG is conducting studies, known as SNAP, CRACKLE, 

and POP, to examine the risk factors and outcomes of infections caused by Acinetobacter, CRE, and 

Pseudomonas, respectively. The studies will characterize the global molecular epidemiology of these 

pathogens, provide insight into potential barriers to enrolling patients with these organisms in clinical trials, 

and build a network of sites that can participate in future trials evaluating new interventions. 

Therapeutics 

NIAID-supported clinical trials are evaluating shortened courses of treatment, optimized treatment regimens, 

and the effectiveness of older, off-patent antibiotics. Optimizing dosing levels, duration, route of 

administration, and use of combination drug therapy, according to current PK/PD principles, can suppress the 

emergence of resistance and minimize toxicity. While most clinical trials comparing a short to standard course 

of antibiotics have found no difference, scientists reported in 2016 that a five-day treatment regimen for middle 

ear infections in young children was less effective than the standard 10-day regimen 27. NIAID currently is 

supporting both the SCOUT trial and SCOUT-CAP trial to determine the most effective duration of treatment 

for pediatric urinary tract infections and community-acquired pneumonia. These trials aim to determine if 

a shorter course of antibiotics—five days instead of 10—is effective against these infections in children. Other 

NIAID-funded studies on optimized treatment regimens determined that two common antibiotic treatments, 

clindamycin and trimethoprim–sulfamethoxazole, work well against bacterial skin infections caused by 

community-associated methicillin-resistant S. aureus (MRSA)28-32 . 

Clinical trials are being conducted to evaluate the utility of existing drugs, alone and in novel combination 

regimens. NIAID is funding the OVERCOME trial to assess the use of colistin for the treatment of multi-drug 

resistant gram-negative bacterial infections when used alone or in combination with a carbapenem, and to 

examine whether either treatment strategy is more likely to reduce the emergence of resistance to colistin. The 

ARLG is conducting the COMBINE clinical trial to evaluate the safety, tolerability, and pharmacokinetics of a 

novel combination therapy, ceftazidime-avibactam and aztreonam, that shows promise for certain CRE 

infections. NIAID is also funding a Phase 1 clinical trial of an intravenous formulation of fosfomycin to 

explore the product as a treatment option for bacterial lung infections. Intravenous fosfomycin is approved in 

Europe but not in the United States. 

NIAID has advanced the development of multiple new therapeutic options to treat and prevent resistant 

infections. In 2018, a Phase 2 clinical trial found that a novel antibiotic, zoliflodacin, was well-tolerated and 

successfully cured most cases of uncomplicated gonorrhea33. The candidate antibiotic was awarded Fast Track 

status by the FDA and has progressed to Phase 3 clinical testing, sponsored by the Global Antibiotics Research 

and Development Partnership, in the Netherlands, South Africa, Thailand, and the United States. Additional 

studies on new therapeutics include trials to evaluate novel antibiotics with broad gram-negative antibacterial 

activity, such as the tetracycline TP-271 and β-lactamase inhibitor VNRX-5133 in combination with cefepime 

(a previously approved antibiotic) to treat resistant infections. VNRX-5133 has advanced to a Phase 3 clinical 

trial supported by BARDA. Another novel approach to combat AR is the use of non-antibiotic treatment 

options, including fecal microbiota transplant (FMT). A NIAID-supported clinical trial is assessing the safety 

and efficacy of microbial restoration using full-spectrum fecal microbiota preparations, pre-screened for 

infectious agents and antibiotic-resistant organisms, in individuals with one or more recurrences of C. difficile 

infection. 

7 
Diagnostics 

The development of rapid, accurate diagnostics is critical to ensuring optimal stewardship of antibiotics. 

NIAID funds multiple studies on new diagnostic products that can quickly and simply identify infectious 

agents and help guide treatment. Researchers are seeking to determine if a molecular bacterial DNA test can 

reliably identify gonorrhea infections that may be successfully treated with a single dose of ciprofloxacin. This 

test potentially could allow healthcare providers to reintroduce ciprofloxacin as an oral treatment for 

gonorrhea, instead of the current practice of using antibiotics delivered by injection. Through the ARLG, 

scientists are developing ways to help healthcare workers determine if antibiotic treatment is needed. In the 

TRAP-LRTI study, ARLG investigators are evaluating whether low blood levels of the protein procalcitonin 

can reliably indicate whether a person’s lower respiratory tract infection is caused by a viral or bacterial 

pathogen. Through the RADICAL study, ARLG scientists are harnessing gene expression patterns to develop a 

simple blood test to determine if a patient’s respiratory symptoms stem from a bacterial infection, viral 

infection, or no infection at all. These studies could aid in collective efforts to reduce the inappropriate use of 

antibiotics. 

NIAID is also supporting studies on improving the utility of current diagnostics. Recently, an ARLG study 

known as MASTER GC found that two licensed diagnostics accurately detected gonorrhea and chlamydia in 

extragenital samples. The two tests were previously approved for testing samples from the reproductive system 

and urinary tract. Chlamydia and gonorrhea can be found in the pharynx and rectum among undiagnosed 

individuals – many of whom have no symptoms – who can continue to spread the infections. Based on data 

from the MASTER GC study, both diagnostics were approved for testing in extragenital sites, filling a 

significant gap in the prevention and control of gonorrhea and chlamydia. 

Preventive Strategies 

NIAID is supporting multiple clinical trials evaluating ways to prevent bacterial infections. A large clinical 

trial known as ABATE, initiated through the NIH Common Fund and managed by NIAID, compared two 

infection control techniques in non-intensive care units. The study found that daily bathing with the antiseptic 

soap chlorhexidine—and in those patients with MRSA, adding the nasal antibiotic mupirocin – substantially 

benefitted patients with medical devices, such as central venous catheters or lumbar drains34. The 

decolonization strategy has since been implemented in hospitals involved in the trial as a best practice for 

patients needing these devices. 

NIAID is funding trials on novel monoclonal antibody therapies aimed at preventing resistant infections. One 

trial, called EVADE, is being partially conducted through the ARLG to evaluate the safety of the 

investigational medicine MEDI3902 and its ability to prevent pneumonia caused by P. aeruginosa in 

mechanically-ventilated patients. 

NIAID also is supporting research to evaluate whether certain approved vaccines are cross-protective. For 

example, NIAID is planning to conduct a Phase 2 clinical trial to examine whether Bexsero, a vaccine licensed 

to prevent meningitis caused by N. meningitidis Type B, can also protect against infection with N. 

gonorrhoeae. The study is expected to enroll approximately 2,000 healthy adults at risk for gonorrhea. 

Research Resources 

NIAID has built a comprehensive set of product development services and research tools and 

technologies to facilitate the development of the next generation of vaccines, diagnostics, and 

therapeutics. These services make critical data, expertise, standardized research materials, and state-of-the 

art technologies available to eligible investigators worldwide at no charge. The purpose of these resources 

is not to develop a product from start to finish but rather to lower the financial risk to product developers 

by providing critical information and resources to fill specific gaps in the product development pipeline. 

NIAID provides cutting-edge technologies, such as genome sequencing, structural genomics, and 

bioinformatics, which are essential to understanding the genetic basis of resistant organisms, to the scientific 

8 
community. The Institute supports several Bioinformatics Resource Centers that host data on infectious disease 

pathogens and vectors and provide critical tools to help scientists use high-performance computing, machine 

learning, and other approaches to advance infectious disease research. NIH has also developed the open-access 

National Database of Antibiotic Resistant Organisms, which contains genomic data for pathogen isolates 

collected from publicly available information. Scientists from all over the world can access and leverage these 

databases to foster understanding of resistance mechanisms and inform development of improved diagnostics, 

vaccines, therapeutics, and antibiotic strategies. 

Preclinical programs to advance drug development include in vitro and animal model screening tools and a 

comprehensive suite of capabilities to enable Investigational New Drug applications. In addition to being made 

available to the scientific community, these preclinical services are being used to support the product 

development efforts of a diverse portfolio of projects, including CARB-X awardees. NIAID also provides wellcharacterized reagents such as bacterial isolates for researchers through NIAID-funded repositories. These 

repositories include the BEI Resources Repository, which provides microorganisms and reagents to the 

scientific community, and a virtual biorepository established by the ARLG to provide well-characterized grampositive and gram-negative clinical isolates for the development of diagnostic tests, novel antimicrobial 

compounds, and for studies evaluating mechanisms of resistance. 

Finally, NIAID supports a number of clinical trials networks to evaluate new products and approaches to 

address AR. These include the Phase 1 Clinical Trial Units for Therapeutics and the Vaccine and Treatment 

Evaluation Units. Information regarding NIAID resources may be found at: 

https://www.niaid.nih.gov/research/resources. 

Partnerships Facilitate a Concerted Approach 

Because AR is a complex problem with many drivers, combating it requires a multifaceted approach. 

Besides research other components of an effective response to the challenge include the following: 

improved surveillance, better infection control, improved stewardship of antibiotics in human and 

veterinary medicine and agriculture, expanded campaigns to raise public awareness, incentives for the 

development of new products, and new regulatory paradigms. Therefore, collaboration among partners 

from multiple disciplines is essential for achieving a coordinated and flexible approach to addressing AR 

threats as they emerge. NIAID works closely with many partners responsible for these other essential 

areas, most notably through CARB-X, the federal interagency CARB Task Force, and the Trans-Atlantic 

Taskforce on Antimicrobial Resistance (TATFAR). 

Innovative Approaches to Addressing the AR Challenge 

In the 2014 report, NIAID identified several approaches as the most promising components of a 

comprehensive strategy to address the AR challenge. NIAID has made a concerted effort to investigate 

and advance these approaches through scientific workshops, targeted funding opportunities, and other 

research activities (see Appendix). These strategies were meant to be dynamic and evolve over time. To 

that end, in preparing this 2019 update, NIAID released a Request for Information to solicit feedback 

from the research community about ways to refine and expand upon this list. In addition to stakeholder 

input, NIAID AR experts reviewed the latest scientific advances to identify the following promising 

areas that have the potential to transform our understanding of and ability to prevent, diagnose, and treat 

antibiotic-resistant infections. 

• Leveraging Data Science to Address AR 

Computational approaches are expected to accelerate the discovery and development of new 

therapeutics, diagnostics, and vaccines for antibiotic-resistant infections and inform more personalized 

treatment plans in clinical settings. Researchers are generating large and diverse datasets through highthroughput experimental technologies (e.g., genomics, proteomics, and metabolomics) that provide 

insights into the interactions between bacteria, hosts, the microbiome, and antibiotics. Researchers 

9 


often conduct sophisticated computational analyses to combine publicly available and shared data 

across studies to answer new questions and inform future experiments. Computational approaches that 

mine electronic health records, data from digital health devices, and social media are also used to 

generate evidence to enhance findings from AR-related clinical trials. Optimally, enabling these datadriven approaches requires efforts by the scientific community to develop shared computational tools, 

such as research software, algorithms, and data analysis platforms. Additionally, adoption of FAIR 

(Findable, Accessible, Interoperable, and Re-usable) principles across the scientific community is 

expected to expand and enrich biomedical knowledge to better inform the diagnosis, treatment, and 

prevention of antibiotic-resistant infections35.   

• Understanding Antibiotic Failure 

Antibiotic treatment failure is easily explained when caused by an antibiotic-resistant organism. 

However, for a small fraction of patients, antibiotic treatment fails even when the pathogen is 

not resistant but susceptible to the antibiotic. Several explanations could account for this 

discrepancy, including the ability of bacteria to resist antibiotics through non-inherited 

mechanisms like heteroresistance, tolerance, or persistence; cloaking of bacteria within biofilms 

where antibiotics cannot penetrate; or host factors that reduce the patient’s ability to fight 

infection. Improved understanding of the various causes of resistance that are not clearly 

explained by bacterial genetics and their contribution to clinical failure in different types of 

infections has the potential to increase successful outcomes in the clinic. 

Harnessing the Immune System to Combat Bacterial Infections 

Vaccines have proven effective in reducing the incidence of certain bacterial pathogens that may 

become resistant (e.g., S. pneumoniae). Vaccine development against many other pathogens 

causing urgent and serious health threats has proven much more challenging. However, the recent 

finding that the meningococcal Type B vaccine may protect against N. gonorrhoeae suggests that 

vaccination against certain bacterial resistance threats may be effective25,26. In addition, several 

monoclonal antibody candidates are being clinically tested to potentially prevent and/or treat 

certain healthcare-associated infections in at-risk or infected populations, and strategies to 

modulate the innate immune system are also being explored. It is important to continue to better 

understand correlates of immunity and vaccine protection, employ state-of-the-art vaccinology 

and platform approaches, such as the use of adjuvants and alternative vaccination routes, and 

develop target product profiles to successfully develop these products. 

• Realizing the Promise of Rapid Diagnostics 

Diagnostics have the promise to help patients receive optimal treatment faster, markedly 

improve antibiotic stewardship, prevent outbreaks, and co-facilitate antibiotic development. 

Technologies for rapid identification of pathogens and drug susceptibility have advanced over 

the past five years. However, many research and development gaps remain, including better 

tests to detect pathogens directly from normally sterile primary specimens, such as blood and 

cerebrospinal fluid; tests that can distinguish colonization from infection; tests to rapidly 

distinguish between bacterial and respiratory infections caused by viruses or fungi; rapid, 

phenotypic antimicrobial susceptibility tests; and tests that can be performed at point-of-need 

decision/provision or that can themselves be provided over-the-counter. In certain settings, tests 

to rapidly identify non-bacterial agents causing acute febrile illness or respiratory symptoms 

would also reduce the unnecessary use of antibiotics for these conditions. In addition, in order to 

optimally implement FDA-approved tests, clinical laboratories, clinicians, and payors need to 

have access to data from implementation studies. Data from these studies help demonstrate that 

use of a new diagnostic test improves patient outcomes, facilitates improved antibiotic 

stewardship, and/or reduces overall patient care costs. These studies are often not performed for 

FDA licensure but are critical for optimal deployment. 

10 
• Reinvigorating Gram-negative Drug Discovery 

The development of new antibiotics is a major focus of NIAID’s translational work to address 

AR. However, discovery of new antibiotics, especially for gram-negative bacteria, remains a 

major barrier to a robust drug pipeline. The double membrane of the gram-negative cell wall 

presents a significant obstacle for potential drugs to cross (penetration), and harbors special 

proteins that actively pump potential drugs out of the cell (efflux). In order to facilitate 

therapeutic discovery for gram-negative bacteria, there is a need for predictive assays, new 

models, and improved research tools to better understand cell wall penetration and efflux of small 

molecules. In addition, libraries of chemical compounds optimized for antibiotic discovery are 

needed to conduct more fruitful screening campaigns and to generate a more comprehensive 

understanding of chemical modifications that may increase the activity of potential drugs for 

gram-negative pathogens. Further exploring natural products, the source of many existing 

antibiotics, could also enhance libraries of new chemical starting points for antibiotic compounds. 

Finally, if barriers to the development and use of narrow spectrum drugs can be overcome, 

additional narrow spectrum compounds may be available for development. 

 Non-antibiotic Products to Treat Resistant Infections 

Since the publication of NIAID’s AR report in 2014, interest and investment in a diverse array 

of non-traditional therapeutics has grown substantially. Non-traditional therapeutics, such as 

drugs that disarm bacterial virulence, live microbiome-based therapeutic products, and 

bacteriophages, represent innovative ways to combat AR. These novel approaches, which may 

be less likely to promote resistance or to negatively impact the microbiome than traditional 

antibiotics, should be further explored and developed. NIAID will continue to stimulate these 

approaches by directly funding basic, translational, and clinical research to develop specific 

products, further defining the critical path to licensure, and convening public scientific 

meetings to discuss challenges in to developing these products. 

• Optimizing the Clinical Utility of Antibiotics 

There have been a number of new antibiotics approved over the past five years that may 

represent better treatment options for patients with resistant or recalcitrant infections. However, 

data on specific indications of interest to clinicians or in high-risk patient populations are often 

not generated as part of regulatory approval packages. Comparative effectiveness studies 

evaluating different drugs or drug combinations, innovations in clinical trial designs (novel 

endpoints, pragmatic and adaptive designs, platform trials), and pharmacokinetic studies of how 

antibiotics or drug combinations are processed by the body (in vitro, animal, and human) are 

critical to inform optimal treatment strategies. Furthermore, many data gaps remain regarding 

the optimal dose, duration, route of administration, and use of combination drug therapy in 

older, off-patent antibiotics to suppress the emergence of resistance. Finally, strategies to inhibit 

bacterial adaptation or reduce the spread of AR genes through plasmids or other mobile 

elements may limit the development of resistance and prolong the use of existing antibiotics. 

Conclusions 

The biomedical research and product development supported by NIAID are critical for developing novel 

ways to diagnose, prevent, and treat bacterial infections. The CDC’s updated Antibiotic Resistance 

Threats Report is a stark reminder of the challenges that face the world now and in the immediate future. 

While AR is an inescapable fact of biology that will always present formidable challenges, NIAID is 

committed to mitigating the morbidity, mortality, and costs of the growing problem by: 

• Supporting basic research to better understand resistant bacteria and identify new ways to combat 

them; 

• Facilitating the translation of basic research findings into new products and approaches; 

11 
• Conducting clinical research to test new interventions and better understand how to use the 

existing arsenal of antibiotic drugs; 

• Offering tools and resources to the scientific community to facilitate the highest-quality research 

and provide a flexible infrastructure to respond to emerging needs; 

• Encouraging the development of vaccines and other preventive measures, rapid diagnostics, and 

new therapeutics with limited resistance potential; and 

• Working collaboratively to ensure a multifaceted approach to combat bacterial resistance. 

12 
 

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14 
Appendix: 2014 Innovative Approaches and Select Accomplishments 

The 2014 edition of NIAID’s Antibacterial Resistance Program: Current Status and Future Directions report outlined seven innovative AR. These approaches were the most promising components identified for a comprehensive research strategy. Since the publication of has made significant investments and advances for each approach. Select achievements are outlined in this Appendix. The Appendix is 

comprehensive. Information on awards made under each funding opportunity announcement included below can be found by querying NIH’s Research Reporting Tools (RePORT) at: https://report.nih.gov/index.aspx. For answers to frequently asked questions about NIH RePORT data an

please visit: https://report.nih.gov/faq.aspx?sid=2. 

I. Systems Biology and Antibacterial Resistance: New Directions for Drug Discovery—Using a holistic approac

molecular networks of host-pathogen interactions and global changes in response to drug exposure. 

• In FY 2016, NIAID awarded 6 projects to model the host-pathogen molecular networks for bacteria such as S. au

CRE using experimental and computational techniques (RFA-AI-14-064, Systems Biology and Antibacterial Resnetwork models will provide a framework to identify more effective therapeutic targets and strategies for address

• Researchers reported that the sugar substitute trehalose increases the virulence of epidemic strains of C. difficile. T

epidemic types of C. difficile have the special ability to metabolize low levels of trehalose, and they hypothesize t

of this compound as a dietary additive may have contributed to the spread of these strains (https://www.ncbi.nlm.nih.gov/pubmed/29310122). 

• Researchers found that autologous fecal microbiota transplantation (auto-FMT) is a safe, effective way to help rep

bacteria in cancer patients who require intense antibiotics during allogenic hematopoietic stem cell transplantation (https://www.ncbi.nlm.nih.gov/pubmed/30257956). 

• Researchers are using big data and machine learning algorithms to predict risk of C. difficile in hospitalized patien

infection (https://www.ncbi.nlm.nih.gov/pubmed/29576042). 

II. Harnessing the Immune System to Combat Bacterial Infections—Enhancing host immune response through 

immunoprophylactics, and other immunological interventions. 

• In FY 2019, NIAID established six Sexually Transmitted Infections Cooperative Research Centers focused on dev

prevent syphilis, gonorrhea and chlamydia. The grants will support collaborative, multidisciplinary research on ththe sexually transmitted infections (RFA-AI-18-005, Sexually Transmitted Infections Cooperative Research CentDevelopment). 

• In FY 2016, NIAID awarded five projects focusing on the development of host-targeted therapeutics for infection

pathogens, including MRSA and CRE (RFA-AI-15-024, Partnerships for the Development of Host-Targeted TherAntibacterial Resistance). 

• In FY 2018, NIAID funded three projects for vaccine and immunoprophylactics targeting AR gram-negative bact

settings (RFA-AI-17-017, Partnerships for the Development of Vaccines and Immunoprophylactics Targeting MuResistant Bacteria). 

• NIAID is supporting early development of several vaccine candidates for C. difficile and N. gonorrhoeae. 
• NIAID is supporting research exploring monoclonal antibodies for prevention and treatment of bacterial infection

Proof-of-concept Study to Evaluate the Efficacy and Safety of MEDI3902 in Mechanically Ventilated Patients fo

Nosocomial Pneumonia Caused by Pseudomonas Aeruginosa (EVADE, https://www.clinicaltrials.gov/ct2/show/N

• NIAID has hosted and co-hosted several workshops focused on vaccine development for drug-resistant pathogens

Staphylococcus (2010 and 2013), multidrug-resistant gonococci (2015), and C. difficile (2018). 

III. Disarm, But Leave Unharmed: Exploring Anti-Virulence Strategies—Targeting bacterial virulence factors w

killing bacteria is less likely to induce selective pressure. 

• In FY 2016, NIAID awarded 24 research projects for the development of non-traditional therapeutics (RFA-AI-14

Therapeutics that Limit Antibacterial Resistance). Funded projects support development of secretion system inhibinhibitors, quorum sensing and biofilm inhibitors, anti-toxin approaches, and other anti-virulence drugs. 

• In FY 2015, NIAID made 14 awards for the discovery and early stage development of new antibacterial products 

Development of Novel Therapeutics for Select Pathogens). Many of these projects are focused on novel strategies antibacterial resistance, such as anti-virulence, immune-based therapies, adjunctive therapies and biofilm inhibito

IV. Synthetic Microbiota: An Ecobiological Approach—Designing microbial communities as biologic products t

diseases and their sequelae. 

• NIAID is supporting research on microbiome-based therapeutics, including efforts to identify protective bacterial 

them into products to prevent and treat C. difficile infection. 

• In FY 2019 under targeted program announcements, NIAID funded seven projects to advance research focused on 

nature of microbial communities, how antibiotics affect them, and how they can be harnessed to prevent disease, exploring combination antibiotic therapies to address the emergence of resistance (PA-18-724 and PA-18-725, Ge

and Mechanistic Understanding of Antibiotic Resistance Development). 

• In FY 2016, NIAID awarded 24 research projects for the development of non-traditional therapeutics, including m

therapeutics (RFA-AI-14-066, Non-Traditional Therapeutics that Limit Antibacterial Resistance). 

• NIAID is supporting a Phase 1/2 clinical trial: Microbial Restoration for Individuals With One or More Recurrenc

Difficile Associated Disease (https://www.clinicaltrials.gov/ct2/show/NCT03548051) 

• NIAID, in collaboration with the American Gastroenterological Association, is supporting the establishment of a 

Transplant National Registry (https://clinicaltrials.gov/ct2/show/study/NCT03325855) 

• NIAID has co-hosted several workshops on the microbiota and microbiome-based products, including the “Scienc

Live Microbiome-Based Products Used to Prevent, Treat, or Cure Diseases in Humans” workshop with FDA (201

V. Less is Better: Diagnostics to Guide Use of Narrow-Spectrum Therapeutics—Decreasing selective pressure b

therapeutics targeted to a pathogen or group of pathogens. 

• NIH and BARDA continue progress on the Antimicrobial Resistance Diagnostic Challenge, which launched in Se

competition seeks to identify innovative and rapid point-of-need diagnostic in vitro tests, which help inform appr

treatment and facilitate antimicrobial stewardship efforts. This 3-Step competition was developed with technical aexpertise from the CDC and FDA, as well as public input. The total prize for the Challenge is $20M with prizes to 

phases, starting in 2017 and concluding in 2020. NIH and BARDA each contributed $10 million to the challenge. 
• In FY 2015, NIAID awarded nine projects to support enhanced diagnostics to rapidly detect antimicrobial-resistan

pathogens that frequently cause healthcare-associated infections (RFA-AI-14-019, Partnerships for Diagnostics to Antimicrobial Resistance of Select Bacterial Pathogens). 

• In FY 2018, NIAID awarded five projects to support development of diagnostic platforms that detect bacterial pa

CDC’s 2013 report Antibiotic Resistance Threats in the United States, and determine associated antimicrobial senresistance. (RFA-AI-17-014, Partnerships for Development of Clinically Useful Diagnostics for Antimicrobial-Re

• The ARLG is developing and testing diagnostic tools to help inform treatment options. Specific project examples 

o A Randomized Double-Blinded, Placebo-Controlled Trial of Antibiotic Therapy in Patients With Lower R

Infection (LRTI) and a Procalcitonin Level (TRAP-LRTI, https://www.clinicaltrials.gov/ct2/show/NCT03

o Performance of Nucleic Acid Amplification Tests for the Detection of N. gonorrhoeae and Chlamydia tra

Extragenital Sites (MASTER GC, https://clinicaltrials.gov/ct2/show/NCT02870101). 

o A simple blood test that analyzes patterns of gene expression to determine if a patient’s respiratory sympt

bacterial infection, viral infection, or no infection at all (RADICAL) 

o Two rapid diagnostic candidates that can accurately predict whether Pseudomonas, Acinetobacter, E. coli 

isolates were susceptible or resistant to carbapenems (PRIMERS IV https://www.ncbi.nlm.nih.gov/pubm

PRIMERS III https://www.ncbi.nlm.nih.gov/pubmed/27795336, PRIMERS I and II 

https://www.ncbi.nlm.nih.gov/pubmed/26409063). 

• NIAID has supported development of five new FDA-cleared diagnostic products, including tests for urinary tract 

and sexually transmitted infections (i.e., gonorrhea and chlamydia).The ARLG helped advance several of these pr

• NIAID supported a study on the Clinical Validation of a Molecular Test for Ciprofloxacin-Susceptibility in N. Go

(https://www.clinicaltrials.gov/ct2/show/NCT02961751) 

VI. Exploiting Natural Predators: The Specificity of Phage Therapy—Using phage or phage-derived lysins to kill 

while preserving microbiota. 

• In FY 2020, NIAID issued a funding opportunity to support basic and translational research to address knowledge 

development and regulation of bacteriophage used to prevent and treat drug-resistant bacterial infections (RFA-AUnderstanding Phage Biology to Support the Development of Bacteriophage Therapy). 

• In FY 2016, NIAID funded 24 research projects to develop non-traditional therapeutics, including several focused 

(RFA-AI-14-066, Non-Traditional Therapeutics that Limit Antibacterial Resistance). 

• In 2015, NIH established an Interagency Agreement with FDA’s Center for Biologics Evaluation and Research to 

regulatory considerations relevant to using bacteriophages for decolonization of the drug-resistant nosocomial patresistant Enterococci and MRSA. 

• In 2015, NIAID organized a workshop on “Bacteriophage Therapy: An Alternative Strategy to Combat Drug Res

NIAID co-sponsored a follow-up workshop “Bacteriophage Therapy: Scientific and Regulatory Issues” in 2017. 

• NIAID is conducting preclinical testing of several phage-based products including efficacy testing in animal mod

and product development planning services. 

VII. Teaching Old Drugs New Tricks: Extending the Clinical Utility of Antibacterial Drugs—Optimizing use of e

combination therapies to suppress emergence of resistance and minimize toxicity. 
• NIAID is supporting research to guide the optimal use of existing antibiotics for gram-negative infections. Intern

NIAID-funded researchers are making progress in diverse areas involving PK and rational combinations for existantibiotics as well as drug discovery and development for next-generation polymyxins. NIAID-supported researchfor critically ill patients receiving intravenous colistin. Based on their findings, they developed and published dosinform use of this antibiotic (https://www.ncbi.nlm.nih.gov/pubmed/28011614). 

• NIAID has supported or is continuing to support a number of clinical trials aimed at optimizing the use of existing 

combination therapies. Select examples include: 

o Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant 

Aureus (https://www.clinicaltrials.gov/ct2/show/NCT00730028; https://www.ncbi.nlm.nih.gov/pubmed/2

https://www.ncbi.nlm.nih.gov/pubmed/28657870) 

o Strategies Using Off-Patent Antibiotics for Methicillin Resistant S. Aureus "STOP MRSA" 

(https://www.clinicaltrials.gov/ct2/show/NCT00729937, https://www.ncbi.nlm.nih.gov/pubmed/2853523https://www.ncbi.nlm.nih.gov/pubmed/27025829, https://www.ncbi.nlm.nih.gov/pubmed/26962903) 

o Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection (Bacterem

(https://clinicaltrials.gov/ct2/show/NCT01191840, https://www.ncbi.nlm.nih.gov/pubmed/30264119) 

o The SCOUT Study: "Short Course Therapy for Urinary Tract Infections in Children" 

(https://clinicaltrials.gov/ct2/show/NCT01595529) 

o Efficacy of Short-Course Antimicrobial Treatment for Children With Acute Otitis Media and Impact on R

(https://clinicaltrials.gov/ct2/show/NCT01511107, https://www.ncbi.nlm.nih.gov/pubmed/28002709) 

o Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME, 

https://clinicaltrials.gov/ct2/show/NCT01597973) 

o The Pharmacokinetics of Extended Duration High-Dose Cefixime Co-administered With Azithromycin fo

Susceptibility of Neisseria Gonorrhoeae: A Phase I Pilot Study (https://www.clinicaltrials.gov/ct2/show/N

o A Phase IV Double-Blind, Placebo-Controlled, Randomized Trial to Evaluate Short Course vs. Standard 

Therapy of Community Acquired Pneumonia in Children (SCOUT-CAP, (https://www.clinicaltrials.gov/ct2/show/NCT02891915) 

o A Trial to Evaluate the Pharmacokinetics and Safety of AVYCAZ in Combination With Aztreonam (COM

https://www.clinicaltrials.gov/ct2/show/NCT03978091). This trial is based on findings from earlier NIA(https://www.ncbi.nlm.nih.gov/pubmed/29020404, https://www.ncbi.nlm.nih.gov/pubmed/28167541). 

o Minocycline Pharmacokinetics (ACUMIN, https://www.clinicaltrials.gov/ct2/show/NCT03369951)