COMMENTARY

What Were the Top Infectious Diseases Stories in 2015?

John G. Bartlett, MD

Disclosures

December 11, 2015

The Year in Infectious Diseases

The infectious diseases (ID) bucket for 2015 is overflowing with new observations that have important medical consequences, representing good news and bad news. The following is the author's view of the 10 most important stories in this field for the past year.

Antimicrobial Stewardship

The major concern in contemporary ID practice is the alarming threat of the "postantibiotic era," reflecting the loss of medicine's arguably greatest advance: the use of antibiotics to treat and prevent microbial infections. This threat comprises a combination of increasing resistance and sparse new antibiotics to answer the challenge. This situation was forewarned in 2004 with a publication titled "Bad Bugs Need Drugs."[1] By 2015, this was considered a "crisis" by multiple authoritative sources, including the Infectious Diseases Society of America, the Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO), and President Obama.

Although not new, the antibiotic crisis has reached the point of substantial impact on daily practice, and emphasizes the need to limit the abuse of antibiotics through an antibiotic stewardship initiative. New regulations will affect nearly all antibiotic prescribers in the United States by requiring healthcare facilities to have an antibiotic stewardship program as a condition of participation under the Centers for Medicare & Medicaid Services (CMS).[2] Essential features include the requirement for a lead antibiotic steward, financial support for the program, the use of electronically reported relevant data, and audited review based on benchmarks established for healthcare facilities with a similar patient mix and with established historic norms.

The penalty for perceived misuse of antibiotics will take the form of financial consequences from CMS, which accounts for approximately 60% of healthcare payments. Thus, after extensive conversations and generation of data on the consequences of antibiotic abuse, 2015 brought a program with enough clout to influence the majority of antibiotic prescribers (and healthcare facilities) in a fashion similar to the requirements for infection control.

New Antibiotics

Part of the problem of evolving antimicrobial resistance is the paucity of new antibiotics to deal with the long record of "use it and lose it." The consistent decline in new US Food and Drug Administration (FDA)-approved antibiotics reflects the financial risk associated with developing new antibiotics that are relatively low-priced, considering that development costs average $2.6 billion per FDA-approved agent. Thus, from 1983 to 1987, a total of 16 new antibiotics were approved, compared with just one new agent from 2008 to 2012.

However, from 2013 to 2015, six new antibiotics—three antistaphylococcal drugs (tedizolid, dalbavancin, oritavancin), two drugs for resistant gram-negative bacilli (ceftazidime/avibactam and ceftolozane/tazobactam), and one agent for Clostridium difficile (fidaxomicin)—have been approved. Admittedly, only the two agents for gram-negative bacilli actually address antibiotic resistance, but having six agents in the face of a severe drought is encouraging. Furthermore, the pipeline contains several promising new drugs for challenging pathogens—minocycline, new polymyxins, meropenem/RPX7009, plazomicin, and several others.

Ebola

At least two different messages were gleaned from the experience with Ebola. First are the observations about those who were infected. The initial report[3] from 1976 in Zaire showed a high mortality rate, a lack of treatment, and a high transmission risk to care providers. A clinical consequence that was not appreciated until recently was the existence of "sanctuary sites" with viral persistence, the potential for sexual transmission, and the potential for relapse after apparent recovery. Of particular interest is the detection of viable virus in aqueous humor at 98 days after resolution of clinically active infection and other potential sites of persistence, including semen, breastmilk, and vaginal secretions.[4,5]

One question raised by these findings is the possibility that in other IDs characterized by "postinfection inflammatory complications," these may actually reflect microbial persistence. The second important message from the experience with Ebola is the fact that the world was caught by surprise. As noted in an editorial by Bill Gates,[6] we need better preparedness for earlier detection of these unusual and often devastating infections before they progress too far, as seen previously with severe acute respiratory syndrome, swine flu, HIV, and anthrax (in 2001).

Community-acquired Pneumonia

Many people consider community-acquired pneumonia (CAP) to be the most important ID in terms of frequency and clinical consequences. Despite this importance, few studies of microbial pathogens for CAP have been conducted in the United States since CMS introduced the "6-hour rule," mandating rapid institution of antibiotics and making pretreatment diagnostics unrealistic.[7] The assumption has been that Streptococcus pneumoniae was the most common pathogen and that "atypical agents" were the second most common pathogens.

In 2015, the CDC published a report[8] using extensive microbial testing in more than 2200 patients with CAP, concluding that S pneumoniae accounted for only 5% of cases, and that the three atypical agents (Chlamydia pneumoniae, Legionella, and Mycoplasma pneumoniae) accounted for only 4%. One could argue that some of the microbiology studies were suboptimal, but this does not account for the extraordinary paucity of pneumococci, atypical bacteria, or other treatable pathogens.

This finding contradicts standard assumptions and teaching about CAP on the basis of historical data, and emphasizes the surprisingly sparse data on the causes of CAP in the United States. It is difficult to extrapolate data from other countries, owing to major variations in pneumococcal vaccination policies and in the epidemiology of atypical agents. The only "good news" arising from this enigma is the availability of strong data from the CMS database on CAP to inform antibiotic prescribing.[9]

Antiretroviral Therapy for HIV Infection

The multitude of drugs available to treat HIV work well, but controversy has arisen over the question of when to start antiretroviral therapy (ART). In 2012, the two major national groups that provide guidance for US-based HIV practitioners—the Department of Health and Human Services and the International AIDS Society-USA—recommended ART for all patients with HIV infection regardless of CD4 count or viral load. By contrast, virtually all advisory groups outside of the United States (Europe, China, Russia, Africa, and WHO) recommended that ART be restricted to patients with CD4 counts < 350 cells/µL.

This distinction led to a rigorous debate, which in turn evolved into a large study, the START trial,[10] with randomization to initiation of ART only when the CD4 count was < 350 cells/µL vs > 500 cells/µL. The study was robust, with 4400 HIV infected participants in 230 clinics in 36 countries. The investigators planned to review the data in 2016, but decided to take an early peek at the data in 2015. The findings showed a striking mortality benefit and reduction in complications by treating all HIV-infected persons, regardless of CD4 count.

The result is that the WHO and virtually all country-specific HIV guideline panels in the world now recommend ART for everyone with HIV infection. This represents a dramatic change in contemporary management of HIV.

Stool Transplant

Stool transplant treatment of relapsing C difficile infection has been periodically used since 1980, starting with the "Waring mixer method," but it was never extensively used until the past 2-3 years. A significant contribution of stool transplant is that it represents the first important clinical application of the rapidly evolving science of the human microbiome.

Of particular note is OpenBiome, a nonprofit organization based at Harvard Medical School, Massachusetts Institute of Technology, and the University of Minnesota Microbiome Project. The donors undergo extensive screening for diseases associated with colonic microbiome changes (eg, inflammatory bowel disease, diabetes, metabolic syndrome, obesity); only 2.8% make the cut. Donors provide three specimens per week, which are available for treatment through agreements with health facilities in 49 states and six countries. Specimens are delivered on dry ice at a cost of $250. Insertion of the donor stool can be accomplished with oral pills, enema, endoscopy, or nasogastric tube.

Results from 7114 transplants show a response rate of 86%, which is the national norm for stool transplant using alternative donor sources. Stool transplant could prove to have broader applications to many other medical conditions, although these are very early in evolution.

Hepatitis C Virus Infection

Rarely has an important viral disease been potentially conquered so rapidly, thus justifying the title of a recent review titled "The Arc of a Medical Triumph."[11] Estimates are that 453,000 persons are infected in the United States, and 130-175 million worldwide.[12]

The CDC estimates only about 40% of persons with hepatitis C virus (HCV) infection are aware of their status, and about 15,000 deaths per year are attributed to HCV infection.[13] The new treatments have achieved cure rates exceeding 95% with oral agents administered for 8 weeks.

Non-HCV providers need to find cases for referral, with an emphasis on HCV risks, including birth cohort (1945-1965), history of injection drug use, blood transfusions before 1992, or unexplained abnormal liver function tests. The major controversy concerns the cost of these drugs, which are considered cost-effective but unaffordable. Of more than 8000 reports on HCV within the past 2 years, the great majority are about cure and cost.

C difficile Infection

C difficile infection (CDI) is possibly the highest priority for the CDC, on the basis of humbling evidence of iatrogenic infection. Last year in the United States, there were 354,000 cases of and 29,000 deaths from CDI, at a cost of about $1,200,000,000.[14] There is consequently a high-priority effort to save lives and money. CDI is now reportable and will probably carry financial penalties for healthcare facilities with excessive rates in the future.

The polymerase chain reaction (PCR) test is the most sensitive, but the evidence of C difficile infection and the need for treatment of CDI requires clinical correlations, owing to high carrier rates in hospitalized patients. Approximately 75% of hospital patients with CDI are colonized at admission, so they are an infection control concern; however, they are not necessarily candidates for treatment, unless they have otherwise unexplained diarrhea.[15,16,17]

The United Kingdom had a major CDI problem and succeeded in reducing rates by 80% for the entire country. They did this through antibiotic control (primarily fluoroquinolones and cephalosporins) and gene sequencing to inform infection control; the latter showed that patient-to-patient transmission accounted for only 23% of cases.[16]

Molecular Diagnostics in the Field of ID

This is a hot field, with a constant stream of new tests and new data. Gene sequencing has been used to show that current concepts about C difficile[16]and Staphylococcus aureus transmission[18]are generally wrong. Molecular testing is also done to detect pathogens with great accuracy and speed, and it is used in disease outbreaks to link cases and sources (such as ice cream contaminated with Listeria),[19] and to trace transmission routes of the carbapenemase-producing gram-negative bacilli at the National Institutes of Health Clinical Center.[20]

Molecular testing is also used in sexually transmitted diseases clinics to rapidly detect Neisseria gonorrhoeae and Chlamydia trachomatis, and in offices and emergency departments to detect influenza. These rapid molecular tests for specific pathogen detection at the site of care make great sense for efficient care.

One has the impression that the microbiology lab of 2020 will resemble a chemistry lab, but we aren't totally there yet, especially for some of the more complex and expensive testing. For example, a study[21,22] at the Mayo Clinic showed that the rapid PCR-based blood culture test succeeded in rapid identification of blood culture isolates, but required 24/7 decision management and concurrent traditional blood cultures owing to limits identification of the instrument. Although enthusiasm for this new and more complex technology is great, there are also concerns about cost, the lack of sensitivity data, the inability to identify all pathogens, and the difficulty in distinguishing pathogens from contaminants without quantitation.

Miscellaneous "Wows"

  • Medical management with antibiotics seems to work as well or better than surgery for acute appendicitis.[23]

  • Varicella zoster is implicated in giant-cell arteritis, and an anecdotal case shows an impressive response to acyclovir.[24,25]

  • Fusobacterium necrophorum is implicated as an important possible cause of pharyngitis by Robert M. Centor (creator of the "Centor group A strep pharyngitis criteria") and colleagues.[26]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....