Since the introduction of penicillin in the 1940s, antibiotics have significantly reduced the morbidity and mortality associated with bacterial infection. Due to widespread and indiscriminate use of antibiotics, bacteria have and will continue to develop resistance to antibiotics. Particularly troubling bacteria accumulate resistance to multiple antibiotics and are termed multi-drug resistant (MDR). MDR bacteria are spreading at an alarming rate, with resistance being reported rapidly following the introduction of each new antibiotic class. In extreme cases, bacteria accumulate resistance to nearly all available antibiotics (termed extremely-drug resistant or XDR), and some Gram-negative bacteria have been identified that are resistant to all available antibiotics, classified as pan-drug resistant (PDR).
Although hospitals have implemented antibiotic stewardship efforts to reduce the emergence and spread of MDR bacteria by avoiding unnecessary antibiotic use and selecting optimal antimicrobial regimens, these practices often cause hospitals to: (a) hold the most effective antibiotics in reserve and (b) discourage the prophylactic administration of antibiotics to high-risk patients. In addition, there are growing numbers of immunocompromised patients for whom traditional antibiotics are less effective, irrespective of bacterial resistance.
The Cost of Serious Bacterial Infections
Infections caused by resistant pathogens are difficult to treat, requiring the use of last-line antibiotics and sometimes older antibiotics that have serious toxicities. According to the US Centers for Disease Control and Prevention (CDC), more than 2 million people annually become infected with antibiotic-resistant bacteria, and more than 23,000 patients die as a direct result of these infections, primarily in healthcare settings such as hospitals and nursing homes. In addition, many more patients will die from other conditions complicated by antibiotic-resistant infections. Global healthcare costs associated with antibiotic-resistant infections are growing and are currently estimated at $5 billion annually.
The Shortcomings of Existing Antibacterial Approaches
Traditional antibiotic and vaccine approaches are becoming increasingly insufficient in addressing the problem of acute bacterial infections in healthcare settings for multiple reasons.
- Bacteria can and will develop resistance to antibiotics, leading to the decreased effectiveness of these agents for the treatment of serious infections.
- Broad spectrum antibiotics cause dysbiosis, an imbalance in the body’s natural microbiome, leading to collateral damage such as life-threatening Clostridium difficile-associated diarrhea (CDAD).
- Antibiotic efficacy is constrained by dose-limiting toxicities. Despite potent in vitro efficacy against MDR bacteria, many antibiotics cannot be dosed to the levels needed to achieve target therapeutic concentrations in the patient.
- Most antibiotics do not target bacterial virulence factors and are unable to directly impact bacterial pathogenicity.
- The number of new antibiotic approvals continues to decline and most are incremental improvements to existing antibiotic classes, either through minor structural modifications or the addition of resistance enzyme inhibitors. Very few antibiotics approved in the last 20 years represent truly novel compounds with new mechanisms of action.
- While vaccination has reduced the prevalence of some community-acquired infectious diseases, traditional vaccination approaches are not effective for acute hospital-associated infections and in vulnerable populations, since vaccine efficacy requires both an intact immune system and adequate time to develop protective immunity prior to contracting the infection.