Predictions for the Field of Infectious Diseases for 2015
John G. Bartlett, MD January 29, 2015
Predictions in this field are particularly dangerous, on the basis of a history that is dense with surprises in nearly all facets of the discipline. For example, Ebola was most everyone's choice for medical story of the year for 2014, but this infection was barely on the radar screen 1 year ago.
The influenza vaccine recommended for the current epidemic was created for the anticipated H1N1 strain, but the influenza now causing widespread disease is largely the H3N2 strain. Chikungunya is hard to pronounce and was rarely seen until the enormous epidemic in the Caribbean that spilled over to the United States in returning travelers—and, more worrisome, it achieved endemic transmission by mosquitoes in Florida.
Antibiotic resistance has been a notorious concern for more than a decade, but 2014 brought federal legislation (the President's Council of Advisors on Science and Technology report) signed by executive order to address the problem, with a $1.1 billion price tag that came to most as a surprise. For years, we lamented that there were no new antibiotics, and suddenly we have four.
With this rather humble disclaimer, the following are predictions for the field of infectious diseases for 2015.
The epidemic in West Africa is devastating and tragic, but sustained endemic transmission in the United States and other developed countries is very unlikely. This is the assessment of an acknowledged leader in the field, Dr Peter Piot, who co-discovered the virus in 1976.
The difference in outcomes in the United States vs West Africa is the healthcare environment in West Africa, where there is a long history of civil wars, lack of a healthcare system, a paucity of providers, burial and religious practices that promote transmission, and chaotic healthcare administration, highlighted in an extensive review in the December 29, 2014, New York Times. These conditions do not exist in developed countries, so Ebola seems likely to be limited to the occasional case transferred from West Africa.
The 35 designated Ebola centers in the United States (for which $6 billion has been allocated) will probably be unnecessary and be justified as centers for emerging contagious diseases. This scenario is reminiscent of the federal response to bioterrorism in 2001 that prompted the creation of a bioweapon defense funding source and multiple academic bioterrorism centers. The lack of a subsequent bioweapon threat resulted in the diversion of the mission of these resources.
For Africa, the epidemic seems to need better coordination between agencies that are on the ground, but it looks as though progress is being made, especially in Nigeria. A vaccine seems probable.
The alarming crisis of antibiotic resistance was predicted by the Infectious Diseases Society of America (IDSA) in 2004 and has now become a recognized crisis by the Centers for Disease Control and Prevention (CDC), the World Health Organization, and President Obama. Its genesis is simple: vast use and abuse, leading to microbial resistance by Mendelian laws and a reduction in antibiotic development that previously kept us ahead.
The resistance genes have been traced back 3.5 million years, long before human life, and the paucity of new antibiotics is simply a product of economic and regulatory realities: Antibiotics are short-course and historically cheap compared with other drug classes, and they are the only drugs that lose potency with excessive use.
Recognizing the frightening consequences of the "postantibiotic era," there is now progress, with incentives for new drug development and diminished US Food and Drug Administration (FDA) regulatory hurdles. The result has been reentry into the market by major pharmaceutical companies, such as Merck, and several new smaller companies that have seen this as a niche market opportunity, prompting a modest surge in new antibiotics.
It is anticipated that this progress will continue in 2015, but the challenge is substantial, owing to the extent of the problem, the cost of new drug development (now estimated at $2 billion), and the stronger attraction of drugs that are taken for decades (such as statins) or those with the price tags of cancer chemotherapeutics.
The attempt to salvage antibiotics also requires efforts to deter unnecessary use. The President's PCAST report includes nine categories of response, but two are especially important to practitioners.[8,9] First is a comprehensive surveillance system that is combined with whole-gene sequencing and global connections. This may prove very useful for informing intervention efforts, especially those involving infection control.
The second important component is the requirement for an antibiotic stewardship program in every hospital as a Centers for Medicare & Medicaid Services (CMS) condition of payment. This is potentially great news, but there is no timetable and no definition of "antibiotic stewardship." Under total government control, however, it could deter alternative efforts.
At this point, for 2015, it seems best to encourage compliance, but to also march ahead with local planning. Resistance is a crisis with immediate needs.
2015 will see the introduction or expanded use of three antistaphylococcal agents:
• Tedizolid (Sivextro®), an agent similar to linezolid, with the advantages of once-daily administration, cost advantages, and possibly fewer side effects;
• Dalbavancin (Dalvance™), a parenteral lipoglycopeptide with a vancomycin-like spectrum but a half-life of 6 days, permitting a total regimen for most skin and soft-tissue infections with two doses separated by 7 days; and
• Oritavancin (Orbactiv™), another long half-life lipoglycopeptide that provides a total 2-week course with a single intravenous dose.
These three agents share the advantage of potential for outpatient management or early hospital discharge for selected staphylococcal infections.
The big challenge is new drugs for infections involving gram-negative bacilli. Recent progress is the FDA approval of ceftolozane/tazobactam (Zerbaxa™), a novel antipseudomonal cephalosporin with a well-established beta-lactamase inhibitor that has activity against extended spectrum beta-lactamase–producing Enterobacteriaceae and some highly resistant Pseudomonas aeruginosa.  This recent progress after a long drought is welcome and would appear to predict continued development of urgently needed drugs.
In 2015, emphasis will be on hospital-associated infections, with demands to address the problem and substantial financial consequences levied by CMS on the basis of institutional performance. A major concern in the US healthcare system is to reduce rates of healthcare-associated infection, with annual costs now calculated at $23 billion and 115,000 deaths per year.
The hospital setting is now recognized as posing unacceptable risks for infection, and substantial efforts are under way to identify alternative settings for healthcare. This concern is national and, in fact, international. For example, health authorities in the United Kingdom recently recommended home delivery as being suitable for low-risk multiparous pregnant women, "because the rate of interventions is lower" (thereby reducing the risk for nosocomial infection).
For the practitioner, the focus for infection reduction is on "the big five":
• Central line-associated bloodstream infection;
• Ventilator-associated pneumonia;
• Surgical-site infection (primarily after colonic surgery and vaginal hysterectomy);
• Clostridium difficile infection (CDI); and
• Catheter-associated urinary tract infection.
These five infections account for 80% of nosocomial infections, and they will now be audited and incur payment penalties by CMS. At the operational level, this means that hospital administrators will need to support efforts to reduce nosocomial infections, with particular emphasis on these five infections.
This is the subject of a large National Institutes of Health-sponsored initiative, with funding of 27 centers at about $180 million per year to define the microbiome in health and disease. The good news is that many justifiably see this as one of the most exciting and potentially transforming areas of biomedical research. The bad news is that to date, there are lots of reports, but nothing yet to take to the clinic.
What we do know from studies in experimental animals, and some in adults, is that human life is incredibly complex. There is a unique flora in each organ system; this flora is generally easy to manipulate with antibiotics; the constituents are largely organisms not encountered in clinical laboratories; and most are extremely fastidious, so they can't be grown in clinical laboratories. We also know that currently available probiotics play no clearly established role in clinical care (with the possible exception of preventing antibiotic-associated diarrhea).
Many associations have been established between the microbiome and such disease states as inflammatory bowel disease, obesity, diabetes, autoimmune disease, the metabolic syndrome, cancer, and atherosclerosis. The hope is that the flora can be manipulated with antibiotics or probiotics to improve health. This is supported by some promising data showing that manipulation of the gut flora with antibiotics can have an impact on markers of atherosclerosis.
The most promising immediate application is stool transplant for relapsing CDI. This treatment is now more than five decades old and has a relatively small following of long-term enthusiasts, but finally seems ready for prime time.
These products, like antibiotics, are the major weaponry of infectious disease management and prevention, especially for viral pathogens. In terms of new products, it appears likely that 2015 will bring a universal vaccine that includes all four viral agents of dengue, and an Ebola vaccine is a high priority and a likely success.
Further back are two C difficile vaccine products (from Sanofi and Pfizer); both of these are in 15,000-patient trials, and the Pfizer product has an FDA "fast-track" designation. This situation merits watching, although these vaccines will not be available in 2015.
This method of establishing transmission patterns appears to be almost ready for widespread use in many hospitals for infection control. Testimony to its utility is its use for defining risk for CDI in the United Kingdom, and for informing infection control in the devastating outbreak of infections involving carbapenemase-producing Klebsiella pneumoniae. This technology has become increasingly affordable, necessary, and available, so expanded use in large centers is likely in 2015. This work seems to revolutionize some of the current concepts of nosocomial infections.
Fecal microbiota transplant (FMT) is now recognized as the best answer to the challenge of managing repeated relapses of CDI. Most trials show good results with stool acquired from properly screened donors that is then inserted by enema, endoscope, or nasogastric tube. Some clinicians use OpenBiome (Medford, Massachusetts) as the source for screened stool, which is stored in a frozen state and available commercially for $250 per specimen.
More recent data also support the use of capsules containing stool that are delivered by mouth. A recent review concludes that this is the most clinically effective and cost-effective approach for managing relapsing CDI.
FMT is highlighted here because it is new, practical for general use, and cost-effective (if you avoid endoscopy), and it demonstrates nicely the first and possibly only application of the microbiome project. Consequently, it seems clear that 2015 will see substantial increased use of FMT, with debates about the insertion method: capsule, nasogastric tube, endoscope, or enema. A more challenging issue is the possible long-term health consequences of ingesting someone else's colonic flora, assuming it is retained in whole or in part.
We know that there will be epidemics, but the mystery is what type and where. Particularly concerning from 2014 is chikungunya, with > 600,000 cases in the Caribbean and 240 cases in the United States, including some that were not related to travel; this indicates that mosquito transmission is taking place in Florida, where chikungunya seems likely to become endemic. Dengue is a similar problem, and both diseases are associated with extraordinary morbidity.
A long-term follow-up of patients with chikungunya acquired during an outbreak on Réunion showed that symptoms, including arthritic complaints, persisted for longer than 2 years in 30% of affected persons. Both of these viral infections carry substantial morbid consequences and are likely to be endemic in Southern states, especially Texas and Florida.
The other unexpected and even more devastating new epidemic is enterovirus D68. This virus causes severe and sometimes fatal respiratory infections or a polio-like illness in children.
We can also expect periodic outbreaks of measles, mumps, pertussis, and norovirus and other foodborne infections. These are all anticipated for 2015, and although time and place cannot be predicted, all are important in terms of rapid detection for management, reporting, and public health response.
Expectations for 2015 That Will Have the Most Impact on Providers
• Antibiotic resistance: There will be great emphasis on antibiotic conservation—short-course, molecular diagnostics for antibiotic selection, use of procalcitonin to guide when to start and stop antibiotics, use of automatic stop orders, early intravenous-to-oral switch (leading to quicker hospital discharges), and avoidance of unnecessary antibiotics for upper respiratory infections and bronchitis.
• Enhanced concern about infection control: Particular emphasis will be placed on "the big 5" that account for 80% of nosocomial infections and will be audited by CMS—ventilator-associated pneumonia, surgical-site infection (primarily after colonic surgery and hysterectomy), CDI, primary bacteremia (especially central line-associated bloodstream infection), and catheter-associated urinary tract infection.
• Increased use of molecular diagnostics: These tests are very sensitive, fast, and specific, but they cannot distinguish contaminants, generally do not provide sensitivity data, and are expensive.
• Stool transplant: FMT is the best treatment for relapsing CDI. Questions remain about the number of previous relapses before using this treatment (typically, it is used after two), the source of donor stool, and the method of insertion.
• Epidemics: Expect new (surprise) epidemics, especially new zoonosis from equatorial areas (eg, severe acute respiratory syndrome, Middle East respiratory syndrome, and Ebola).
• Global travelers: Be alert to prevent infections in persons going to areas with malaria, chikungunya, and dengue (all of these diseases had US records for imported cases in the past 2 years).
• Hepatitis C: Because this disease is now curable, there is a new emphasis on diagnostic testing of any patient with standard risks, unexplained abnormal liver function tests, and belonging to the 1945-1965 birth cohort ("baby boomers").