At the start of the year, Dr John Bartlett made nine predictions for the field of infectious diseases in 2015, ranging from Ebola to epidemics. Although we are only at the halfway point, many new developments have proved some of these predictions to be well founded and others a little premature, while some important developments were missed altogether.
Here, Dr Bartlett reports on the progress, or lack of progress, of his predictions, providing a succinct review of major and minor advances in the field of infectious diseases so far this year.
Prediction: Sustained transmission of Ebola in the United States is unlikely.
Ebola was considered the most important medical story of 2014. The epidemic was concentrated in West Africa but there was substantial concern about the sparse number of cases in Europe and the 11 cases in the United States, including two endemically transmitted cases. This prompted the appropriation of $6 billion to support a response that included 55 designated Ebola centers in the United States. The prediction that Ebola would never materialize as a serious problem in developed countries was voiced by Dr Peter Piot, the epidemiologist who investigated the original epidemic in Zaire in 1976. My prediction was drawn from his more recent report, which observed that conditions in West Africa created a “perfect storm” for Ebola owing to continuous civil wars, the lack of a healthcare system or healthcare providers, and religious and burial practices that promoted transmission.
These conditions do not exist in developed countries, making it easy to predict that Ebola would never be a serious threat in the United States. And it wasn’t. However, the more important outcome from the Ebola experience was the “wake-up call” about our vulnerability to a serious threat, as emphasized by Bill Gates in his editorial comment in the New England Journal of Medicine. Government responses to this threat included the following:
- The United States procured 1.7 million courses of brincidofovir, a drug for smallpox. Smallpox is the only infection successfully eradicated from the globe, but Russia did not allow inspections of their stores and is now thought to have several hundred thousand tons of the smallpox virus. This could be an incredibly powerful biological weapon in a world where most people no longer have vaccine protection from smallpox.
- Congress published a primer on responding to major disasters and emergencies.
- The Department of Defense published a request for proposal (RFP) for a “National Collaborative for Bio-Preparedness.”
- The United States announced plans for a $1.2 billion biocontainment center to study emerging zoonotic diseases.
- The Department of Homeland Security issued a $3 million grant request for bio-preparedness.
The 55 empty Ebola centers were converted to use for other infectious diseases that pose potentially serious epidemic risks, such as Middle East respiratory syndrome (MERS), Lassa fever, or a pandemic influenza similar in virulence to the 1918 “Spanish flu” strain. My predictions about Ebola were correct, but I clearly failed to anticipate the much more significant outcome of the Ebola experience and its impact on improving the nation’s preparedness for a far broader menu of microbial threats, an important outcome for us all.
Prediction: The problem of antibiotic resistance will continue, and gains will be incremental.
In the world of infectious diseases, antibiotic resistance is the major threat in modern medicine, a concern made public by the Infectious Diseases Society of America (IDSA) in 2004 and 8-10 years later defined as a “crisis” by the Centers for Disease Control and Prevention, the World Health Organization, and even President Obama. My prediction that antibiotic resistance would be a continuing problem with incremental gains was probably obvious and turned out to be a fair assessment of what transpired.
The President’s $1.2 billion plan for a broad attack on resistance is most welcome, but the obvious concern is that it requires congressional passage in part or whole, so there is no assurance that this will happen. We need to move forward with attempts to reduce antibiotic abuse and continue efforts to convince pharmaceutical companies to get back into the antibiotic development business.
That said, a few new antibiotics are now available and there is progress in better antibiotic guidance:
- A recent trial showed that 4 days of antibiotics are adequate for treatment of intra-abdominal sepsis.
- A review of short vs standard courses of antibiotics for five types of infections (community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, pyelonephritis, urinary tract infection) showed that short courses were always equivalent to standard duration.
- The use of procalcitonin is effective in discouraging unnecessary use of antibiotics in multiple clinical settings, such as avoiding antibiotics for most upper respiratory tract infections and early antibiotic discontinuation in community-acquired pneumonia.
- Placement of a sign in the office stating that the physician would only prescribe antibiotics according to guidelines resulted in 20% fewer antibiotic prescriptions.
- The American Academy of Otolaryngology published sinusitis guidelines recommending “watchful waiting” for patients with sinusitis regardless of severity.
- IDSA recommended against antibiotics for asymptomatic bacteriuria.
- The Centers for Medicare & Medicaid Services (CMS) announced its intention to require hospitals to have an antibiotic stewardship program as a condition for payment.
Prediction: The year 2015 will see the introduction or expanded use of three new antistaphylococcal agents.
The antibiotic resistance crisis has two parts: antibiotic abuse and a dry supply chain owing to the simple economics of new drug development, estimated at about $2 billion per drug approved by the US Food and Drug Administration (FDA). At the time of my original prediction, three new agents for methicillin-resistant Staphylococcus aureus (MRSA) had been introduced: Sivextro® (tedizolid), Dalvance® (dalbavancin), and Orbactiv™ (oritavancin). This is good news, but what we really need are drugs for resistant gram-negative bacilli (GNB).
Two new agents responsive to this need have recently achieved FDA approval. Zerbaxa™ (ceftolozane/tazobactam), approved in 2014, and Avycaz™ (ceftazidime/avibactam) approved in 2015, are active against most GNB, including most extended-spectrum beta-lactamase (ESBL)-producing GNB. These antibiotics are notable additions, but even more promising is the increased activity of pharmaceutical companies in this space, which had previously been so quiet.
Prediction: Hospitals and health systems will implement methods to reduce nosocomial infections, with emphasis on the “big five” nosocomial infections.
The “big five,” according to CMS, are central line bacteremia, ventilator-associated pneumonia, surgical-site infection,Clostridium difficile infection (CDI), and catheter-associated urinary tract infection. These account for 80% of nosocomial infections and are the chief targets for reporting and financial consequences.
My prediction that these five infections would take priority is correct but this has not yet led to substantial progress in reducing rates of these targeted complications. An exception is central line bacteremia, because reported cases of this complication have declined by 50%. The record with CDI is particularly disappointing after an ambitious program in the United Kingdom achieved a 70% reduction for the entire country, proving that antibiotic control can be highly effective.
Prediction: The microbiome will transform biomedical research.
The National Institutes of Health (NIH) has a highly ambitious multicenter collaborative program to define the microbiome, with the hope that this will lead to successful interventions with antibiotics or probiotics. Progress, however, seems very slow.
Two reports of particular interest have been published. Studies in rodents show that obesity is strongly influenced by cesarean section and early life exposure to penicillin, making obesity far more complicated than genes and diet.
In another series of studies showing that the gut flora has an important role in mental health, the authors concluded that this gives new meaning to the phrase “gut feelings.”
While the prediction is probably correct and progress is painfully slow in terms of practical applications, a potential exception is SER109, a construct of fecal microbiome bacteria that has been used for treating recurrent CDI with promising results.
Prediction: The year 2015 will bring a vaccine for all four viral agents of dengue, as well as another for Ebola.
The predictions for dengue and Ebola vaccines are both works in progress and are dwarfed by two other, unanticipated vaccine developments. The big vaccine news this year was the 9-valent human papillomavirus (HPV-9) vaccine, which was well studied and then quickly FDA approved for standard use. This fills in the blanks for HPV causes of cervical cancer and most anal cancers, as well as some less well-recognized upper airway cancers.
The second major new vaccine development is the new herpes zoster subunit vaccine (HZ/su), which was tested in 7698 participants aged > 50 years (including a subset aged > 70 years). The efficacy of this vaccine was a remarkable 97.2%! A third recent vaccine entry is Prevnar 13® (pneumococcal 13-valent vaccine) for adults > 65 years, based on a study from The Netherlands.
Prediction: Gene sequencing will become more standard and affordable.
The reason for enthusiasm here is the utility of this technology for informing infection control, especially with such highly resistant bacteria as the carbapenemase-producing GNB that were so infamous at the NIH Clinical Center, as well as the C difficile problem in the United Kingdom. My prediction was that this technology would be “increasingly affordable, necessary, and available.” This does not appear to be happening, or at least not at the pace that I had anticipated.
What I did not realize about the experience at the NIH Clinical Center was that gene sequencing was particularly critical, because the major source of the infections appeared to be elements such as plasmids (not microbes) that were widely distributed in the hospital environment. This suggests that traditional infection control methods based on cultures may be far less effective. I still think gene sequencing will revolutionize infection control as we know it, but the methods need to become faster and cheaper for routine use.
Stool Transplant for CDI
Prediction: Use of stool transplant for CDI will increase substantially.
Stool transplant for relapsing CDI has certainly caught the attention of providers and patients. Insertion methods include enema, colonoscopy, upper endoscopy and, more recently, the oral route via capsules. All methods show a success rate of 88%-90%.
What has been less well appreciated is concern about the gut flora (microbiome) of the donor, in light of research demonstrating the health impact of the microbiome. Attention to this issue came from a report on the “Open Forum” of a previously thin recipient who gained 42 pounds after a transplant from an overweight donor.
The FDA has requested long-term studies. Those who do this procedure can expect patient queries about these issues.
Prediction: We will see outbreaks of measles, mumps, pertussis, norovirus, and other foodborne infections.
It is safe to predict epidemics in the field of infectious diseases, and 2015 does not disappoint.
- Measles was a major concern, with 23 outbreaks and 644 cases in 2014, including a large number from Disneyland, which attracts many European visitors, whose home countries do not require measles vaccination.Compounding this problem is the fact that most adults in the United States are not aware of their measles vaccine status. The simple solution to inadequate measles protection is a dose of measles-mumps-rubella vaccine.
- Bird flu (H5N2), which has until recently been largely limited to China, has become a devastating problem in the United States. H5N2 infections in more than 48 million birds have resulted in a doubling of the cost of eggs.
- MERS-CoA is a highly lethal cause of pneumonia originally reported in the Arabian Peninsula and with imported cases in other countries. There have been 458 deaths in 1293 confirmed cases (mortality, 35%). A big epidemiologic challenge is asymptomatic carriers, especially healthcare workers. The recent outbreak in South Korea and a case in Thailand raise concern that, like SARS, this might bring outbreaks to multiple countries.
- A total of 243 cases of ciprofloxacin-resistant Shigella infections.
- The Blue Bell Creameries Listeria problem resulting in a recall of 40 million gallons of ice cream.
- Eighteen cases of botulism at a potluck supper.
- An outbreak of HIV infection involving 135 injection drug users in Indiana.
- A multistate outbreak of infections with carbapenemase-producing Escherichia coli, transmitted from duodenoscopes used for endoscopic retrograde cholangiopancreatography, which cannot be sterilized.
Predicting an “epidemic” is easy. Picking the time, place, and pathogen is the challenge.
Where do we stand?
Infectious diseases must be the most kinetic and unpredictable field of medicine, and this past year is a grand example: Resistance to antibiotics is the top concern. Major recent developments include the global acceptance of this as a “crisis.” combined with a Presidential Resistance Plan and the welcome surprise of five new FDA-approved antibiotics.
Epidemics seem impossible to predict with specificity, and this year brought a large crop: Ebola, MERS, influenza H5N2, and measles, as well as infection control issues such as duodenoscopes that can’t be sterilized.
Major (and largely unanticipated) vaccine developments were HPV-9 and the new zoster vaccine. Stool transplant received lots of deserved attention for relapsing CDI, and this probably represents the first important clinical application of the microbiome, with all of the questions about its unknown long-term consequences.
The major laboratory advance was in molecular diagnostics, but most exciting to me was the gene sequencing that seems poised to revolutionize infection control.
Although Ebola was the top story in the past year and was seemingly overrated as a potential threat to the United States, the good news was the recognized need to be prepared for an unanticipated bio-threat, a message largely forgotten since anthrax was in the news 14 years ago.
Source: Medscape Infectious Diseases