Saturday, March 28, 2015

What's wrong with Indiana?

It's been a bad couple of weeks for Indiana. First, Indiana University and Butler were knocked out of the NCAA basketball tournament while their capital city was mocked in a widely-played television ad. (above) Then Indiana Governor Mike Pence signed a law allowing businesses to refuse service to same-sex couples. The NY Times suggests that the law might be part of the Governor's plans to run for President in 2016. There's been a backlash against the state with many crying for a boycott. Although most folks demanding such action have never been to Indiana and probably couldn't find it on a map, so it's unclear if it will have any effect.

If passing the 'Religious Freedom' bill is a sign that the Lord giveth, certainly the ongoing 79-person outbreak of HIV in rural Indiana is a sign that the Lord hath taken away. Thursday, the same Indiana Governor declared a public health emergency and approved a 30-day needle exchange program since all cases could be linked to intravenous drug use. Since Governor Pence has been a vocal opponent of needle exchange programs, this 180 must be quite humbling. But it's only funded for 30 days - so he has a political out and could still run for President.

From 538: "There were at least 194 needle exchange programs in 33 states in 2014, according to the Foundation for AIDS Research, and almost all were in states that have explicitly lifted or modified their laws. All of those programs are paid for by states, local governments or other organizations, since federal funding for needle exchange programs has been banned since 1980 (the ban was briefly lifted in 2009 by President Obama, and reinstated by Congress in 2012)"

A colleague mentioned to me today that it's nice that this program now exists to prevent HIV among rural folks but suspects that higher levels of HIV are occurring daily among urban Gary, Indiana residents and they'll never get even a temporary needle exchange program. America!! Perhaps Charles Barkley (above video) was smart to head to "In The Annapolis" instead of Indianapolis after all.

Addendum:  Notre Dame (Indiana) just lost in the NCAA tournament

Tuesday, March 24, 2015

MDRO Prevention Bundle in Nursing Homes: A Randomized Trial

In keeping with our long-term care theme (more on this later in the week), there is a new trial published in JAMA Internal Medicine by Lona Mody and colleagues at the University of Michigan. The team completed a cluster-randomized trial of a bundled intervention to prevent MDROs in nursing homes. Specifically, residents with indwelling urinary catheters, feeding tubes or both in 6 nursing homes were randomized to a targeted infection program (TIP) bundle that included (1) preemptive barrier precautions; (2) active surveillance for MDROs (baseline, day 15 and monthly at nares, oropharynx, feeding tube, supra-pubic catheter, groin, peri-rectal, and wound sites) and infections, with data feedback; and (3) NH staff education on key infection prevention practices, including minimum criteria for initiating antibiotics, and hand hygiene promotion. Inclusion required a signed inform consent. Six other nursing homes served as controls.

The outcomes assessed were quite broad. The primary outcome was "overall MDRO prevalence density rate, defined as each participant’s total number of MDRO-positive anatomic sites across all MDROs per visit averaged over the duration of his or her participation." This would result in residents "with persistent MDRO colonization (having) a higher prevalence than someone with intermittent or no colonization" and residents colonized at more sites (up to seven were tested) having a higher prevalence. Secondary outcomes included new MDRO acquisition and device-associated HAI both with 1000 device-day denominators.

For the primary outcome, 27% of swabs were positive in the intervention NH residents while 33% were positive in the control NH residents. The adjusted rate ratio was significant 0.77 (0.62-0.94). This outcome seems largely driven by lower MRSA colonization in residents with urinary catheters, feeding tubes, or both and lower ceftazidime-resistant GNR colonization in residents with urinary catheters in the intervention NHs. However, rates of VRE were higher in the feeding tube requiring residents but this increase was not significant. (see Table 3) Interestingly, new MRSA acquisition rates were lower in the intervention NH residents (see Table 4, below) and first new CAUTI rates were also lower in the intervention NH residents, HR 0.54 (0.30-0.97).

Overall, an important study and one that should be read closely. Clearly this was a very difficult RCT to undertake, especially with informed consent, and the research team should be congratulated. The primary outcome of MDRO prevalence density rate is an interesting choice and the authors make a compelling argument for why they chose it. However, it is unclear if the interventions in the TIP bundle are major components in the causal pathway for limiting MDRO colonization density or reducing CAUTI. However, the lower MRSA acquisition rate in the intervention NHs is an important outcome and does fit with how we expect barrier precautions to work. Minor quibbles aside, this RCT should be discussed widely and many components of it are worth testing in other settings in future trials. 

Saturday, March 21, 2015

Close Proximity Interaction and S. aureus Spread in Long-Term Care

There is little doubt that S. aureus is transmitted between patients via contaminated hands, white coats or fomites carried by healthcare workers. Fortunately, that doesn't curb the enthusiasm of scientists seeking to understand the mechanisms of transmission in clinical settings. A case in point is a recent study in PLOS Computational Biology by Thomas Obadia and colleagues that tracked healthcare worker (HCW) and patient close proximity interactions (CPI) via small wireless sensors and correlated the interactions to incident S. aureus colonization.

The study was conducted in a 200-bed LTCF in France and utilized data collected from 329 patients and 261 HCWs over a 4-month period. Using weekly nasal swabs from all patients and HCW, they spa-typed and determined the resistance profiles to antibiotics of each detected S. aureus. Isolates were considered identical if they shared the same spa type and resistance profile. Incident cases were only considered in patients since HCWs could have been transiently colonized and missed by the weekly swab interval. Each incident case was evaluated to confirm that at least one time-consistent CPI in the prior three weeks with the same strain was possible. The 3-week interval was chosen since all but 4 cases could be linked to another patient with the same strain during that time period.

Without going into all of the statistical modeling methods, major findings include:

(1) When limiting the analysis to the 201 patients not already colonized on admission, 73 acquired S. aureus. The one-month acquisition rate was 33%.

(2) Time to acquisition among new admissions did not change based on the number of colonized neighbors in the preceding week using either raw number of CPIs nor cumulative duration of CPIs.

(3) There were 237 incident cases throughout the 4 months in 111 patients. Only 173 had candidate transmitters. The analysis was limited to 153 because sensors failed to record a CPI in the prior week in 20 cases.

(4) A CPI path existed for 149 of 153 episodes. As seen in the example figure above, P1 (patient) and H1 (HCW) were two-hops away from the incident case. P2 was three-hops away. In the same figure, distance between a transmitter and an incident case (black) was shorter than random simulations predicted (white). Additionally, a direct contact between candidate transmitter and incident case (i.e one hop away) occurred in 48% of cases vs. 30% expected by random chance. These findings supported that CPI predicts S. aureus incident colonization.

(5) HCWs spent about 20% of their shifts in direct contact with patients (110 minutes over 8 hours) and had CPIs with 15 unique individuals during their day (9 were patients, 6 other HCW) with 3.7 hours spent in contact with others. 36.3% of HCW were colonized with S. aureus.

(6) Interestingly, patients had CPIs with 12 unique individuals each day (half were other patients). Overall, patients spent half of their day (12.2 hours) in contact with another person.

A few thoughts. Studying social interactions and transmission in long-term care settings using these methods is quite brilliant. Given that LTCF cohorts are more stable with longer lengths of stay, it is easier to catch acquisition events through repeated screening. It is also important to note the huge amount of contact that LTCF residents have directly with each other - around 10 hours/day. This sort of social interaction among residents is not seen in acute care hospitals and goes a long way to explain why infection control in LTCF is so critical (and so extremely difficult). Given the richness of the CPI data, including frequency and duration of contacts, new mathematical models using these parameters could provide more accurate estimates of S. aureus transmission and effectiveness of candidate control strategies.

One issue that I think the authors might want to address in future studies is the use of spa typing to link transmission events. It is true that they also used susceptibility data, but it is my understanding (from one of Dan's earlier posts) that the discriminatory power of spa typing may be suboptimal. I hope Dan will provide his thoughts on this in the comments.

Additional reference: NPR Shots blog by Scott Hensley with comments from David Hartley on this study. 

Thursday, March 12, 2015

On penicillin

Today, we have a guest post by Philip Lederer, an Infectious Disease fellow at Massachusetts General Hospital and Brigham and Women’s Hospital, and a former Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention (CDC). His views do not represent any of those organizations.

Bright and alert, the elderly woman sat in a chair in the corner of her hospital room. Snow fell lightly outside. An IV ran into her arm, giving her antibiotics for a bloodstream infection. Meanwhile, she told me her story:

“I started nursing school in 1943 and soon after we first started giving penicillin. I don’t remember my first patient who got it, but we ended up giving it to many people. We didn’t realize at the time that penicillin would turn out to be so amazing. What I remember most clearly was the size of the 18-gauge needle we used. It was so big. We had to inject intramuscularly, into the patients’ buttocks, every four hours. It would turn their buttocks black. And the injections were so painful. 
When I would walk into a patient’s room, I would think, ‘Oh God, do I really have to do this again?’ 
But before penicillin, people died, and afterwards, they lived. The patients loved it and hated it at the same time. It was wonderful and horrible.”
Now, more than seventy years later, we are heading towards an era of untreatable bacterial infections. The penicillin miracle may someday be a memory. As an infectious disease physician-in-training, I see antibiotic resistant bacterial infections every day. I believe the writing is on the wall.

While the Centers for Disease Control and Prevention (CDC) and the White House have issued reports and launched initiatives, little is changing in the trenches, our hospitals and clinics. Antibiotics are prescribed widely and often carelessly. There are no easy solutions, other than a wholesale change in the practice of medicine and an emphasis on antibiotic stewardship.

Tuesday, March 10, 2015

Post-exposure Vaccination for Ebola

The ongoing Ebola virus outbreak in West Africa continues to underscore the importance of a strong international public health infrastructure and continued investment in both basic and clinical research targeting infectious pathogens. The first line of defense for infectious diseases, if available, is a safe and effective vaccine. However, approved vaccines do not exist for many pathogens like Ebola, so well-designed personal protective equipment becomes critical. But even the best available PPE can't protect us from sharps injuries. Which brings us to a fascinating case report of post-exposure vaccination of a physician with a needlestick injury obtained while working in an Ebola treatment center in Sierra Leone.

The report by Lilin Lai and colleagues was just published online in JAMA along with a very well-written editorial. The 44-year-old physician from the US was stuck by an 18-guage hollow-bore needle through two layers of gloves after caring for Ebola patients with very high viral loads. Because doffing procedures had to be followed, there was a 10-minute delay in cleaning the wound with bleach, soap/water and CHG. The patient was evacuated and while boarding the jet received an experimental vaccine - a first-generation recombinant vesicular stomatitis virus–based Ebola vaccine (VSVΔG-ZEBOV) - 43 hours post-exposure.

Post-vaccination, he developed fever and malaise but made it safely to the NIH Clinical Center for further care and evaluation. His course was a bit rocky the first few days with fever, lymphopenia and diminished O2-sats but symptoms and signs slowly improved over 3-5 days and he was asymptomatic by day 7. He was discharged to complete the 21-day mandatory isolation-period at home. Ebola virus was never detected.

You can read the full report (free online) if you're interested in the many tables and figures outlining his immune responses. Briefly, the vaccine did elicit a strong innate and virus-specific immune responses. Most importantly (per the editorial) it was "able to induce an IgG antibody response against the Ebola virus glycoprotein at a level that has been associated with protection of nonhuman primates." However, the editorial correctly notes that no definitive conclusions can be drawn since it is unclear if the patient was ever infected with the virus and the adverse events the patient experienced could have been secondary to his concurrent travelers diarrhea.

What is important is that while numerous candidate Ebola vaccines have been shown to effectively prevent transmission in nonhuman-primate models, post-exposure treatments and vaccines have been harder to develop. I wonder if a trial seeking to reduce sharps injuries in Ebola-treatment settings is in the works or if NIH would fund such a trial? Last time I checked, sharps injuries were on the rise, so investment in prevention research remains critical.

image source: wikipedia

Monday, March 9, 2015

The dumpster fire burns on...

I'm in Park City, UT at the Infectious Diseases Winter Course, always a great review of the hot topics in ID. This morning I led a meet-the-professor breakfast session. I assumed that the discussion would revolve around topics in hospital epidemiology, but interestingly, the participants were most interested in discussing the future of Infectious Diseases as a specialty (i.e., the dumpster fire). After about 20 minutes, one participant suggested that we change topics since everyone seemed to be getting depressed.

We've previously blogged on the problems that the specialty faces, particularly the compensation issues and the dying interest in the field by physicians in training. Along these lines, there are two new papers that are worth reviewing. The first is a paper in CID that very nicely outlines the value that ID physicians add in the care of individual patients and also in population health. The second is a commentary by Dick Wenzel and myself that focuses on infectious diseases in the academic setting. Still missing, in my opinion, is a fully engaged advocacy group for ID doctors that plays an effective role in addressing our issues.

Photo: The view from my hotel room at the ID Winter Course

Sunday, March 8, 2015

Antibiotic Discovery: Two Steps Back?

This didn't take too long...

We've written often about the need for new antibiotic classes, so called antimicrobial discovery. Over the past 3-4 years there have been significant US efforts and European efforts to expand the search for novel antibiotics. Well, as they say, two steps forward and one step back.

The Boston Business Journal is reporting that Merck is closing Cubist's entire 120-person early drug discovery unit. Per the report, "Merck remains committed to the development of antibiotic drugs, and an unspecified number of drugs still in pre-clinical testing will continue development in other sites. All of Cubist's drugs in clinical trials will continue to be developed."

On the other side, Derek Lowe over at Seeking Alpha - a crowd-sourced financial site - writes: "So anyone who thought that this might be about some sort of long-term commitment to antibiotic discovery, well, think again. This is about getting Cubist's existing drugs, back to some unspecified point in development, but the discovery work gets raked off into the compost pile."

I suspect many others will be upset with Merck's move. Given the oversized role that Cubist has played in antibiotic discovery recently, the unit's closure is frustrating. Where will new antibiotics come from if large pharmaceutical companies do not invest in novel antimicrobial discovery? Maybe they just aren't the right place.