Antibiotics that treat bacterial infections can be classified as broad-spectrum or narrow-spectrum. Antibiotics that are active against a mixture of Gram-positive, Gram-negative and anaerobic bacteria are referred to as broad-spectrum. Antibiotics that are active only against a select subset of bacteria are referred to as narrow-spectrum. Because it usually takes from 24 to 72 hours from the time a specimen is received in the laboratory to definitively diagnose a particular bacterial infection, physicians may be required to prescribe antibiotics for serious infections without having identified the bacteria. As such, effective first-line treatment of serious infections requires the use of broad-spectrum antibiotics with activity against a broad range of bacteria at least until the bacterial infection can be diagnosed.
Many strains of bacteria have mutated over time and have developed resistance to existing drugs, resulting in infections that are increasingly serious or more difficult to treat. These drug-resistant pathogens have become a growing menace to all people, regardless of age, gender or socioeconomic background. They endanger people in affluent, industrial societies like the United States, as well as in less-developed nations. Gram-positive bacteria that have developed resistance to existing drugs include:
- Streptococcus pneumoniae that cause pneumonia, ear infections, bloodstream infections and meningitis;
- Staphylococcus aureus that cause skin, bone, lung and bloodstream infections; and
- Enterococci that are responsible for infections transmitted in healthcare settings.
Gram-negative bacteria that have developed resistance to existing drugs include:
- Escherichia coli that cause urinary tract, skin and bloodstream infections;
- Salmonella and Escherichia coli that cause foodborne infections; and
- Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella spp. that are responsible for infections transmitted in healthcare settings.
Reducing MRSA, a Gram-positive bacterium, in both the healthcare and community settings continues to be a high priority for the Centers for Disease Control and Prevention, or CDC. However, encouraging results from a CDC study published in the Journal of the American Medical Association and other reports such as the March 2011 CDC Vital Signs article provide evidence that rates of invasive MRSA infections in the United States are being controlled by Gram-positive drugs and falling.
As such, at present, the more acute need is for new drugs to treat multi-drug resistant Gram-negative bacteria. Currently approved products, such as Merrem and Levaquin are becoming increasingly ineffective against Gram-negative bacteria due to increasing resistance, limiting patients’ treatment options, particularly for patients with multi-drug resistant infections, and few new therapeutic agents are in clinical development. A survey of infectious disease specialists published in the June 2012 edition of Clinical Infectious Disease rated multi-drug resistant Gram-negative infections as the most important unmet clinical need in current practice, significantly outranking infections caused by MRSA and multi-drug resistant Mycobacterium tuberculosis. In the survey, 63% of physicians reported treating a patient in the past year whose bacterial infection was resistant to all available antibacterial agents. This resistance was confirmed by the SENTRY Antimicrobial Surveillance Program, which evaluated Enterobacteriaceae and Acinetobacter spp., two Gram-negative species of bacteria, from 31 U.S. medical centers from 2005 to 2009. Specifically, the SENTRY Program found that, with respect to the Enterobacteriaceae family of bacteria, 6.8% of the Escherichia coli strains studied and 15.4% of the Klebsiella spp. strains studied exhibited an extended-spectrum beta lactamase, or ESBL, phenotype, and that 22.2% of Enterobacter spp. strains studies were ceftazidime-resistant. ESBLs are enzymes present in certain multi-drug resistant bacteria that destroy classes of beta lactam antibiotics, such as penicillins, cephalosporins and carbapenems. In addition, Klebsiella pneumoniae carbapenemase, or KPC, producing bacteria have emerged as a highly drug resistant Gram-negative bacteria associated with mortality rates ranging from 32% to 48%, as compared to 9% to 17% for strains of Klebsiella pneumoniae that are not carbapenem-resistant.
As a further example of the seriousness of the threat of Gram-negative bacteria resistant to all available antibacterial agents, in 2012, the national media including The New York Times, The Wall Street Journal and The Washington Post reported that the Clinical Center of the National Institutes of Health had an outbreak of Gram-negative Klebsiella pneumoniae bacteria strains that were resistant to all available antibiotics that resulted in seven deaths. In addition, there have been numerous reports recently that physicians have resorted to prescribing colistin for Gram-negative bacteria resistant to all other drugs. Colistin was discovered in 1949 and has not been widely used for decades because of serious toxicities, including nephrotoxicity. In our Phase 2 intravenous clinical trial, eravacycline dosed once or twice per day as a monotherapy was effective against multi-drug resistant Klebsiella pneumoniae.
The growing issue of antibiotic-resistant bacterial infections has been widely recognized as an increasingly urgent public health threat, including by the World Health Organization, the CDC, and the Infectious Disease Society of America, or IDSA. In April 2011, IDSA issued a report warning that unless significant measures are taken to increase the pipeline of new antibiotics active against drug-resistant bacteria, people will start to die from common, formerly treatable infections, and medical interventions such as surgery, chemotherapy, organ transplantation and care of premature infants will become increasingly risky. In the pre-antibiotic era before penicillin began to be available in 1942, patients frequently died from what subsequently became easily cured infections. The important need for new treatment options for serious bacterial infections was further highlighted by the passage in July 2012 of the Generating Antibiotic Incentives Now Act, which provides incentives for the development of new antibacterial or antifungal drugs intended to treat serious or life-threatening infections that are resistant to existing treatment. In September 2012, the Food & Drug Administration (FDA) announced the formation of an internal task force to support the development of new antibacterial drugs, which they called "a critical public healthcare goal and a priority for the agency."