At the dawn of the 20th century, the top three causes of death in the U.S. were infectious diseases - pneumonia, influenza, and tuberculosis. By mid-century the balance in the longstanding battle between bacteria and the human race shifted in our favor. Public health policy which encouraged widespread immunization helped tip the balance. The real game changer though was the rapid development of multiple antibacterial drugs, beginning with the introduction of penicillin in 1947. During the so-called "golden age of antibiotics" between 1940 and 1962, more than 20 new novel classes of antibiotics were discovered. Bacterial resistance to an antibiotic was met with a new and stronger drug. As we began the 21st century, the death rate due to infections had declined 97%! Heart disease and cancer now topped the mortality rankings. Seemingly the "bugs" were on the ropes. Antibiotics were the widely acclaimed "wonder drugs." Unfortunately, multiple bacteria resistant to one or more classes of antibiotics have emerged over the last decade, while the development of new antibiotics has slowed significantly. Only 2 new classes of systemic antibiotics have been introduced since 2000. Deaths in the U.S. related to multiple drug resistant (MDR) bacterial infections now exceed 23,000 per year. A just released report commissioned by the U.K. estimates that these so-called "superbugs" could account for 10 million deaths internationally by 2050 - one death every three seconds! To confront the escalating national and international threat, in 2015 the White House published an executive order outlining a national action plan for combating antibiotic resistant bacteria. Antibiotic stewardship programs are a key element of the multi-pronged strategy.
The Evolutionary Response to Antibiotics: Superbugs
Bacteria are have survived on the planet for more than 3 billion years. They are a normal inhabitant of our own bodies, e.g. in the gut. Because they reproduce rapidly - minutes rather than days or weeks, bacteria are capable of rapidly evolving in response to selective pressure including antibiotics. As the drug effectively eliminates most "sensitive" bacteria, those with genes conferring resistance survive and become dominant. Bacteria are capable of rapidly sharing genes for resistance to an antibiotic, commonly via transmission of plasmids - DNA containing structures carrying resistance genes for multiple antibiotics. With these advantages, development of antibiotic resistance is not surprising and somewhat inevitable. Unfortunately, doctors and patients have accelerated the process by overusing and misusing antibiotics. A common scenario is regular prescription of an antibiotic for cold or flu symptoms which are usually viral in origin. Antibiotics kill bacteria, not viruses. Needlessly eliminating non-resistant bacteria promotes survival and selection of more resistant strains. A recent study of outpatient antibiotic prescribing in office based and emergency room settings found 30% of prescriptions were inappropriate based on national guidelines. This is probably an underestimate as the study didn't include non physician prescribers such as nurse practitioners and dentists. Fully 50% of antibiotic prescriptions for upper respiratory conditions were deemed inappropriate. Similarly, insufficient dose or duration of treatment may promote selection of resistant strains. Widespread use of preventive antibiotic therapy in livestock or crops may hasten development of antibiotic resistant strains of bacteria in these food sources.
The Scourge of the Superbugs
The consequences of MDR bacteria are the growing number of difficult-to-treat, life-threatening infections. I'll describe a few examples but the list is much longer. The most common cause of Clostridium Difficile diarrheal illness is antibiotic exposure. About 250,000 cases of C. Difficile illness were reported in 2013, commonly in hospitalized or recently discharged patients. Approximately 14,000 deaths from the infection occur annually, a near 400% increase since the mid-2000's, largely a result of development of antibiotic resistance to previously effective fluoroquinolone antibiotics. 90% of deaths occur in persons over 65 years of age.
The ESKAPE pathogens (Enterococcus, Staph, Kebsiella, Acinetobacter, Pseudomonas, Enterobacter) are a group of 6 bacterial classes which are responsible for most serious in hospital infections due to MDR bacteria. Methicillin-resistant staph aureus (MRSA) is best known but the others are equally threatening and difficult to treat. For example, more than 50% of Acinetobacter infections are now MDR, accounting for 500 deaths annually.
Infections typically treated in the outpatient setting are also increasingly resistant to previously very effective antibiotics. Camphylobacter infection causes a gastrointestinal illness usually acquired by eating uncooked or raw chicken infected with the bacteria, some of which are antibiotic resistant due to preventive treatment of the animal. 25% of the 1.3 million Camphylobacter infections occurring in the US each year are now antibiotic resistant. Of the 820,000 cases of gonorrhea reported in the U.S. in 2013, 30% were resistant to at least one antibiotic.
It's important to note that these infections are not only life-threatening in some cases, but very costly. Roberts, et al reported the cost of a bacterial resistant infection between $18,588 - $29,069 with an increased hospital of stay ranging up to almost 13 days.
These examples underline the urgency of the problem. Kickstarting a search for new antibiotic classes to combat resistance is important but even with federal support will take years. Antibiotic stewardship programs aimed at reducing the misuse and overuse of antibiotics in health care and food production offer an immediate approach to decrease the emergence and spread of resistant bacterial infections. The White House executive order sets a goal of having antibiotic stewardship programs in all hospitals by 2020.
What is Antibiotic Stewardship?
Antibiotic stewardship programs seek to ensure that patients receive the right antibiotic at the right dose and right duration to achieve a superior clinical outcome while minimizing the impact of development of resistance. An important corollary of this approach is "de-escalation" to treatment directed at the specific bacteria causing the infection. In essence this involves earliest possible identification of the involved bug and using antibiotics aimed directly at that bacteria once culture information is available. Usually this means switching from a "big gun" broad spectrum antibiotic (more likely to accelerate MDR) to a narrower spectrum drug to which the organism is susceptible. Most programs restrict the use of selected antibiotics, requiring pre-approval by the program's steward, usually either an infectious disease physician or pharmacist. Educating prescribers is a high priority. The Joint Commission is in the process of establishing antibiotic stewardship programs as a requirement for health care institutions and providers across the continuum of care.
The Infectious Disease Society of America and the Society for Healthcare Epidemiology of America recently released a guideline outlining 28 recommendations meant to serve as foundation for antibiotic stewardship programs. Selected key elements include:
- Pre-authorization of antibiotics and/or prospective audit of usage
- Facility specific clinical practice guidelines
- Use of order prompting - time outs and stop orders
- Clinical decision support in the EMR
- Increased use of rapid viral and bacterial testing
- Inclusion of nursing homes and other post acute settings
The Central Role of Health IT
Leveraging health IT to provide institution specific, up-to-date evidence-based guidance in antibiotic selection, appropriate dosing and duration of therapy to clinicians at the point of is an extremely effective tool in reducing misuse. Dorsata has partnered with Barnes Jewish Hospital to provide such information in an easily accessible Iphone application. As bacterial succeptibility and sensitivites change, the app is easily updated, promptly disseminating this critical information to clinicians. Within the "smart" EMR, clinical decision support programs have been shown to decrease antibiotic use and length of hospital stay while increasing prescriber satisfaction with considerable cost saving. In addition to flagging allergies, smart EMR based ordering systems can incorporate other stewardship features such as recommended adjustments for kidney function, required laboratory monitoring, and recommended consultations. As many serious infections such as osteomyelitis or bacterial endocarditis require several weeks to months of ongoing treatment, a well designed EMR should promote antibiotic management across the full continuum of care from acute hospitalization into the outpatient post acute home care phase of treatment.
The White House National Action Plan for Combating Antibiotic-Resistant Bacteria reinforces the seriousness of the threat nationally and internationally. Antibiotic stewardship programs supported by smart health IT are the first line of defense. Technology must be our ally in this fight.
I welcome your thoughts and comments.