Rising Antibiotic Resistance

The emergence of antimicrobial resistance in bacteria has created a global public health crisis, featuring increased patient morbidity and mortality and major costs to healthcare facilities, individuals, and society. This rising rate of resistance is due to multiple factors, including widespread use of antibiotics and the ability of bacteria to rapidly develop and transfer antibiotic resistance. As a result, many currently-available antibiotics have limited or no activity against important bacterial pathogens causing human infectious diseases. In fact, infections that are resistant to all current antibiotic options now occur. Resistant gram-negative pathogens may contribute to treatment failure, increased length of hospital stay, increased medical costs, morbidity, and mortality. In the US, the Centers for Disease Control and Prevention (CDC) has estimated that antibiotic-resistant organisms are responsible for >2 million infections and 23,000 deaths each year, at a direct cost of $20 billion and additional productivity losses of $35 billion. More recent estimates suggest as many as 162,044 deaths occur from multidrug-resistant infections annually in the US, which are nearly seven times higher than the 2013 estimates from the CDC; in fact, death due to multidrug-resistant infection was the third leading cause of death in the US based on these 2010 data.

Increasing antimicrobial resistance has already led to a change in antimicrobial prescribing; for example, novel combinations of antibiotics are being used in the community setting, and powerful broad-spectrum intravenous agents such as the carbapenems are being used increasingly as first-line therapy in combination for severe infections in the hospital setting. The increased rate of resistance to traditional first-line therapies is creating an unmet need for novel drugs to treat infections caused by multidrug-resistant pathogens.

Need for New Anti-Infective Agents

The United States Food and Drug Administration (FDA) has recognized that the research and development pipeline for new drugs in general is “distressingly low”, and that the range of new antibiotics is “disturbingly limited”. The Infectious Diseases Society of America (IDSA) also has concerns about the lean pipeline for novel antimicrobials to treat drug-resistant infections. The FDA and IDSA agree that there is an urgent, immediate need for new agents with activity against multidrug-resistant pathogens. In order to create a robust and sustainable antibiotic research and development infrastructure, the IDSA has called for increased collaborative action between industry, academia, the National Institutes of Health, FDA, the Centers for Disease Control and Prevention, and other government agencies. In order to help incentivize such development, PDUFA V legislation recently enacted includes a five-year exclusivity extension, priority review and fast track pathways for drugs targeting a list of qualifying pathogens. In recognition of the these challenges, the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) was established to provide significant funding resources for early antibacterial discover and development programs. However, despite public awareness of the issues of antibiotic resistance in gram-negative pathogens, there has been little progress in discovery and development of new antibiotic classes active against major resistant gram-negative organisms.

Both gram-positive and gram-negative bacteria are continuously developing resistance to commonly used antibiotics; however, the CDC has singled out gram-negative pathogens as particularly problematic because “pan-resistant” isolates (resistant to nearly all antibiotic classes used for treatment) have been increasingly encountered. Although notable progress has been made recently in introducing new anti-staphylococcal antibiotics (e.g., tedizolid, oritavancin, dalbavancin, omadacycline, delafloxacin) and antibiotics with variable activity against carbapenem-resistant Enterobacteriaceae (CRE) (e.g., ceftazidime-avibactam, meropenem-vaborbactam, plazomicin), there has been no real breakthrough in the development of novel antibiotics with potent activity against problematic multidrug-resistant gram-negative organisms, such as metallo-β-lactamase-producing CRE and extremely drug-resistant non-fermenting gram-negative bacilli, most notably carbapenem-resistant Pseudomonas aeruginosa and CR Acinetobacter baumannii. No truly novel class of anti-gram-negative agents has been successfully developed in the last half century since the introduction of fluoroquinolones. As a result, among the increasingly reported, commonly identified multidrug-resistant or even pan-resistant bacteria, multidrug-resistant non-fermenting gram-negative pathogens (including carbapenem-resistant P. aeruginosa and carbapenem-resistant A. baumannii] and CRE (especially metallo-β-lactamase producers) are those with the greatest unmet need for new therapeutic agents.  Accordingly, safe and potent antibiotics are needed to effectively treat infections caused by emerging multidrug-resistant gram-negative pathogens, including multidrug-resistant Enterobacteriaceae and multidrug-resistant non-fermenting gram-negative bacilli (especially carbapenem-resistant P. aeruginosa and carbapenem-resistant A. baumannii).

Sepsis and Septic Shock Caused by Gram-Negative Pathogens

Sepsis and septic shock are clinical disorders that represent another, related unmet need.  Sepsis can be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Their pathogenesis involves release of endotoxin — bacterial lipopolysaccharide — due to infection — and antibiotic treatment itself – that creates an overwhelming inflammatory cascade, frequently irreversible.

The incidence of sepsis is increasing. One study in the U.S. using clinical criteria identified a total of 173,690 sepsis cases (mean age, 66.5 years [Standard Deviation, 15.5]; 42.4% women) among 2,901,019 adults in 2014 (6.0% incidence).  From 2009-14, the incidence increased 10.3% per year [95% confidence interval, 7.2% to 13.3%] (P < .001). Notably, 15.0% of these patients died in the hospital and 10,731 (6.2%) were discharged to hospice care.  Sepsis accounts for some 8 million deaths/year; the incidence is projected to accelerate as people live longer with chronic illnesses.

The incidence of septic shock also rose: from 12.8 to 18.6 cases per 1,000 hospitalizations (average, 4.9% increase).

These disorders have very high direct and indirect costs, plus of course a major humanistic impact. No effective drug has been approved for treatment of sepsis.

Chronic Lung Infections in Cystic Fibrosis Patients

Cystic fibrosis (CF) affects more than 30,000 children and adults in the United States alone, with approximately 1,000 new patients diagnosed each year. In CF, a mutated gene leads to the production of unusually thick, sticky mucus that changes normal processes in the lung and other organs. The airways of patients with CF are colonized from various host and environmental sources. Patients subsequently develop chronic bacterial infections caused mainly by P. aeruginosa. The combination of diverse colonization sources, environmental factors, and patient therapy mediates patient outcomes. Eventually, chronic pulmonary infection results in a decline in lung function, especially during pulmonary exacerbations and late-stage disease progression.  Respiratory failure is the primary cause of morbidity and mortality in CF patients. Therefore, appropriate management of chronic bacterial colonization maintains lung function and improves quality of life for CF patients.   Inhaled antibiotics have been routinely used in managing CF by reducing bacterial density to improve lung function. However, P. aeruginosa from CF patients have adapted various resistance mechanisms so that they have ability to resist different class antibiotics, including aminoglycosides and beta-lactams as well as polymyxin. New treatment options for patients with CF are critically needed because the median age for survival is still in the mid-30s. There is a clear unmet medical need for a new class of inhaled antibiotics with activity against MRD P. aeruginosa in CF patients. 

RC-01: A New, Broad-Spectrum LPXC Inhipitor

A safe and well tolerated new antibiotic class with improved activity against nosocomial pathogens, including activity against multidrug-resistant strains, would have high medical utility. RC-01 is an LpxC inhibitor, a novel antibiotic class with potent activity against a broad range of gram-negative pathogens. RC-01 inhibits bacterial LpxC, a key enzyme in Lipid A biosynthesis. Lipid A is a major component of endotoxin, which is largely responsible for the human toxicity of gram-negative bacterial infections.  RC-01 has a broad spectrum of in vitro and in vivo activity against Enterobacteriaceae and P. aeruginosa.  It is also highly active against P. aeruginosa isolates from patients with cystic fibrosis. In addition, it is active in vivo against A. baumannii in animal infection models. RC-01 demonstrated rapid bactericidal activity and directly inhibited endotoxin release by gram-negative bacteria. Unlike most previous LpxC inhibitors, RC-01 showed high drug exposure with a favorable pharmacokinetic profile and was also very well tolerated preclinically.

Current Market Opportunity

The fluoroquinolone and beta-lactam classes of antimicrobials have provided important therapeutic options for clinicians and their patients for more than a half century and are among two of the most commonly prescribed antimicrobial classes in the U.S. Approximately 25 million people receive antibiotics in the US each year in the hospital. However, increasing bacterial resistance to first-line antibiotic agents is causing physicians to change prescribing behaviors, and is creating a major market opportunity for new antibiotic classes that have activity against these resistant pathogens.

Recida Therapeutics, Inc. is developing RC-01 for the treatment of serious nosocomial and community-acquired bacterial infections, with special attention to the treatment of infections due to multidrug-resistant gram-negative organisms. Based on currently available preclinical data, RC-01 is a promising novel bactericidal agent with the potential to address unmet medical needs.

Selected References

  • Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the US, 2013 available at: https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf
  • Development of New Drugs Active Against Gram-Negative Bacilli – An Update from The Infectious Diseases Society of America. Clin Infect Dis. 2013 Jun 15; 56(12): 1685–1694.
  • The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 February 23; 315(8): 775–787
  • Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017;318(13):1241-1249.
  • The quadruple burden of sepsis. CMAJ 2017 September 11;189:E1128-9.
  • Estimating Ten-Year Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data. CHEST 2017; 151(2):278-285.