SENTRY at 20: So many bugs!

The SENTRY Antimicrobial Surveillance Program was begun at the University of Iowa in 1997, moving a few years later to JMI Laboratories (also in Iowa!). Since inception, it’s been an industry-funded platform that performs central laboratory testing of clinical isolates of bacteria and fungi from centers around the world. The isolate submission process has been consistent over time, involving submission of organisms from consecutive episodes of infection at specified body sites (more information here and in the many publications that have come from SENTRY). 

So SENTRY has been operating for >20 years, and there are hundreds of thousands of isolates characterized. The major trends are reported in an OFID supplement and in recent publications in JAC and AAC. The supplement articles and the AAC report on trends in 20 years of bloodstream infection (BSI) isolates are open access—take a look if interested! 

I’ll focus briefly just on the AAC report (which I first-authored, so that’s shameless self-promotion right there)—two major points, each of which confirms on a large scale what regional surveillance programs have reported:

• S. aureus and E. coli dominate the BSI landscape—together account for >40% of all episodes reported to SENTRY. Continued focus on prevention, detection and treatment of these two bad actors is critical, and IMO should include vaccine approaches, despite the disappointments to date.
• There’s an interesting divergence in proportion of BSI caused by important resistance phenotypes among Gram-positives (MRSA, VRE, DRE, etc.) versus Gram-negatives (ESBL, CRE) over the second decade of surveillance (2005-2016). The Gram-positive resistance phenotypes are stable-to-declining, whereas Gram-negative phenotypes steadily increase (as proportion of BSI episodes) over the entire surveillance period.

The decline in MRSA as a proportion of all SA BSI is particularly striking, occurring as it does at the same time worldwide (and at all body sites, both healthcare- and community-onset, as more detail in the OFID report of all SENTRY S. aureus confirms). As Eli and I discussed in this JAMA editorial almost 10 years ago*, this is not easily explained by hospital-based infection control interventions. The waxing and waning of epidemic clones of MRSA is more likely to be informative. There is so much we still don’t understand about an organism (S. aureus) that lives in relative harmony with 20-30% of the human population when it isn’t causing horrendous, difficult-to-treat infections.

Finally, the scope and number of isolates collected by SENTRY and similar programs represent an underutilized public health resource. Regulatory requirements for drug development and approval mandate surveillance for AMR. Better partnerships between public health authorities and the industry sponsors of such surveillance programs could enhance surveillance and response, particularly in the genomic era when ready access to large isolate collections can be so powerful. Some of this is already happening, but more could be done.

*still behind a paywall after 10 years?  What gives?

Progress on HAI progress: CDC portals and data

I spent about 2 hours with the new CDC HAI Progress Report – loosen your belt, it’s a big meal!  We probably had mixed perceptions about the recent alert to the 2016 HA progress report. Loads of information and analysis condensed down to a handful of bullets, all pointing to improvements in patient safety! The (very pleasant) surprise to me was that the format and delivery of the report has advanced to digital!! CDC has added the HAI progress report to the existing (and now updated) HAI AR Patient Safety Atlas Portal If you stop reading now – at least click on that link and explore and I will call this blog a success!

This report is several steps forward.  First, it pushes all of us to go to a place where we, being inquisitive minds, can wander and perhaps connect some dots within and between datasets. With the digitalization and visualization provided in the portal, the novice and experienced can more easily access and utilize these data. One can click through four distinct datasets, which now include state-summary statistics HAI infection rates/SIRs, inpatient stewardship activities, outpatient antibiotic prescribing rates, and inpatient antibiotic resistance metrics.

Now – the email alert. This year, well 2016 data, is the first to use the 2015 “re-baseline” efforts.

Unstated, but implied – the re-baseline effort includes the use of MBI (mucosal barrier injury) LCBSI as an event excluded from reported CLABSI rates, exclusion of yeasts (or low colony counts) from CAUTI rates, exclusion of “infection present on admission” for SSI (along with better patient-level risk adjustment), first use of risk adjusted metrics for VAE, and maybe slightly better models using more contemporary data for MRSA and CDI. 

With that said, 2016 performance suggests nationally patients are safer overall compared to the experience of 2015. Other than VAE which decreased by only 2%, everything else declined about 7-10% (I am rounding) compared to 2015. I understand many of the problems with risk adjustment and reporting bias that make these surveillance events poor performance measures for individual hospitals – but on the national level – I think these data do suggest fewer infections (o.k., perhaps some  widespread under-reporting—mixed reports on validation efforts in place).

Next – the overview of the current HAI Progress Report.   Although at first glance it seems the same as the info posted in the emails – CDC is offering more ways to track progress nationally – the number of states showing improvements (or worsening) compared to 2015, as well as the number states currently performing at levels better (or worse) then their 2016 contemporaries: 12 state perform better on at least 3 infection types compared to other states at the same time (2016). Now positive deviance nerds need to learn from these states to help the other states (or perhaps identify accuracy and validation issues at these states). The contemporary juxtaposition of SIRs is new, perhaps confusing (especially with CDC’s arcane explanation on how to interpret this: “SIRs statistically significantly lower than the 2016 national SIR are considered better than the 2016 national SIR”; curious if it ends up being useful to state programs. This year also is the first with more detail on inpatient rehabilitation facilities and long-term acute care facilities. Fewer data mean fewer statistical significant results, but these data are ripe for academic partners to latch onto as they try to partner with ARHQ, CDC, and state-programs to branch out into stewardship and prevention efforts in these types of facilities.

Finally, the portal – access it here.  Use the table view. No graphics to export for HAIs, only for other datasets. My pet peeve is that CDC still refused to list the no. of SSIs reported next to the number of surgical procedures reported to allow a crude attack rate. We still need to go to the technical tables for these values and calculate ourselves (see below). CDC, please stop making us jump through this hoop to be able to use attack rates for other purposes like planning studies, clinical trials, vaccine research! To all researchers and data nerds - the detailed technical tables should be downloaded examined (here), perhaps parsed out to our students and trainees, and used for different purposes that simply a “reporting requirement”.  I know there are many limitations to the accuracy of any one facilities reports and likely aggregate data up to the state or national level. However, as a long time national surveillance nerd all too familiar with the warts and ugliness of surveillance data, they do inform us, approximate the truth, and can help us ask the right questions and target the right populations. The more eyes using these data the more transparent the process will become, more uses of the data will be identified, patient safety should improve, and CDC will become more accountable to update (c’mon, where’s 2015 and 2016 NHSN AR data?! update the portal please!!),  maintain, and advance the public accessibility of useful data in our field.

Antimicrobial resistance visualized

Click here to view an amazing video that dramatically visualizes the development of antimicrobial resistance.

Hat tip: Brian Hoff, PharmD

At first he was only prescribed for me, now he's messing around with EVERYBODY !

This study is boring, and we need more just like it

What is there to say about a study that compares the treatment of an infection with X versus Y days of antibiotics? The recently published STOP-IT trial didn’t reveal groundbreaking new approaches to treatment or prevention, or provide keen insights into pathogenesis or transmission. The investigators simply compared two antibiotic treatment durations for abdominal sepsis: a short course after source control (~4 days), versus a more standard course that continued until fever, elevated white cell count and ileus had resolved for 2 days or so (to a maximum of 10 days). The verdict? No difference in outcomes (a composite of surgical site infection, recurrent intraabdominal infection, or death within 30 days). Our own Mike Edmond and Dick Wenzel penned the excellent accompanying editorial, to which I refer you for more detailed commentary.

I like this study, and we clearly need more studies that test our current approaches to antimicrobial treatment of common infections. “How long do we need to treat this infection?” is one of the most frequent questions we get as ID consultants, and it’s amazing how scant the evidence base is regarding duration of therapy. Studies like this one, and this oft-cited study that helped reduce our duration of treatment for ventilator-associated pneumonia, have the potential to markedly reduce unnecessary antimicrobial therapy, thereby reducing risk for C. difficile and antimicrobial resistance emergence, among other adverse effects of antimicrobial overuse.

Also of note, this study was published just in time for the White House Antimicrobial Stewardship Forum!

The world will end in 2050 because...resistance

UK Prime Minister David Cameron requested a review of the health and economic burden of antimicrobial resistance in July. Quicker than you can say supercalifragilisticexpialidocious, economist Jim O'Neill has delivered his report and the results are surprising (at least for those who don't follow this blog). Utilizing commissioned studies from KPMG and Rand Europe, the Review estimates that the economic losses attributable to antimicrobial resistance will total $100 trillion and 10 million excess deaths will occur annually by 2050. In fact deaths do to resistance will surpass other major causes of death even the 8.2 million due to cancer. (see figure on right) Of course, cancer deaths might rise due to the fact that we can no longer safely give chemotherapy without effective antibiotics. The report covers these issues in a sobering section titled: "The secondary health effects of AMR: a return to the dark age of medicine?"

Good times.

The independent Review will outline recommendations for an international response by 2016. In the meantime, I leave you with my favorite figure from the report below. Just for reference, $100.2 trillion is 6 times the size of the US GDP (2013). Perhaps this will wake up the world to antimicrobial resistance?

Additional Source: BBC

Meager and unsatisfactory

It’s nice to see antimicrobial resistance featured in a Sunday NY Times editorial—nothing that we haven’t already covered in Eli’s recent post on the WHO report, but worth reading nonetheless. 

If you believe that “you can’t improve what you can’t measure”*, the most disheartening sentence in this editorial about the WHO report is “…few countries track and monitor antibiotic resistance comprehensively, and there is no standard methodology for doing so."

*This saying is a paraphrase of Lord Kelvin, who also said:

“When you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind.” 

“Meager and unsatisfactory” is a great description of the status of our current response to the antimicrobial resistance threat.

1955 - Dawn of the Antibiotic Era and Lessons for the Future

It's easy to fall into despair when pondering the decades long rise of antibiotic-resistant bacterial pathogens and the simultaneous decline in funding for antibacterial discovery, surveillance systems and infection prevention. But this wasn't always the case.  Back before 1969 when it may or may not have been said that "It is time to close the book on infectious diseases, and declare the war against pestilence won," clinicians appreciated antibiotics and even understood the idea of antimicrobial stewardship.

A case in point is this 1955 article in JAMA by GE Burch titled "Cardiology for General Practitioners." After pointing out that the first therapy mentioned by Dr. Burch was antibiotics, I would like to call your attention to a few of his thoughts:

"The most important single therapeutic development in the field of cardiology has been the advent of antibiotics. These drugs have not only made it possible to convert almost all fatal diseases, such as bacterial endocarditis and endarteritis, to almost nonfatal ones but have played an important role in control of infections in all cardiovascular disease states. Until the introduction of these drugs, the physician was often able to manage satisfactorily the cardiac disturbances, such as congestive failure, only to have the patient die of bronchopneumonia or urinary tract infection. The fear of secondary infection as a threat to life was constantly present, and the more chronic or prolonged the illness and the older or more debilitated the patient, the greater was the chance for infection. Once it developed, the physician was virtually helpless, despite the many therapeutic rituals used. Most physicians well remember the preantibiotic era."

and the homage to stewardship:
"It is not necessary, or even advisable, however, to administer those of the so-called broad spectrum type to all patients with cardiovascular disease, without regard for the specific problem."

---
After reading Dr. Burch's review I'm convinced that our current situation has several potentially modifiable causes: (1) a lack of understanding of how critical effective antimicrobials are to the practice of modern medicine, (2) a failure to include clinical judgment when selecting antimicrobials and finally (3) a pre-antibiotic era that has been completely lost to history. Addressing all of these will be required if we are to avert a post-antibiotic future.

Bacteriophages and the spread of antimicrobial resistance

One component of the human microbiome which is garnering more attention lately is the “phageome” or “virome”, that portion of our microbial ecosystem comprised of viruses (phages) that infect and replicate within bacteria. A recent Nature paper demonstrated that antibiotic treatment of mice resulted in an expansion of phages bearing antibiotic resistance genes that could then spread back to wild-type bacteria and confer resistance. In this month’s issue of Antimicrobial Agents and Chemotherapy, a group from Spain examined the phage DNA in fecal samples of 80 healthy adults. Almost 80% of the samples revealed one or more of the six genes they sought (genes encoding two beta-lactamases (TEM and CTX-M), methicillin resistance (mecA), high-level aminoglycoside resistance (armA) and quinolone resistance (qnrA and qnrS). 

Phages survive well in the environment, probably better than do their bacterial hosts. In addition, they aren’t detected using culture methods designed to find resistant bacteria. They almost certainly play a key role in the transmission of antimicrobial resistance genes.

Antibiotic Resistance - A Global Problem

Today, The Lancet Infectious Diseases Commission on Antibiotic Resistance led by Otto Cars from the Swedish Institute for Communicable Disease Control has published "Antibiotic resistance—the need for global solutions." The stated goal of this 42-page tour-de-force is to "explore why antibiotic resistance has become such a problem worldwide, and, most importantly, propose solutions to avert the impending crisis."  The Commission is broken down into nine parts with each group of authors responsible for their individual sections. I've pasted the table of contents to the right (click to enlarge). The document discusses antimicrobial use in humans and animals including stewardship, improved diagnostics (hopefully Dan will comment on part 3), novel therapeutics and antibacterial drug discovery.

The Commission is accompanied by 7 commentaries from the global community, which are each worth a read. All articles are free to access once you set up a username and password.

These documents are largely focused on antibacterial use and development, which are incredibly important global problems that will require collaborative responses at the local, national and international level.

But much like the recent Frontline documentary that, as Dan mentioned, did not have "enough discussion of the hard work of basic infection prevention," infection control is only briefly mentioned in the main document. (Section 2, page 7) You can get the sense of the Commission's approach with this quote: "From a resistance perspective, prevention reduces antibiotic use and the spread of resistant bacteria; however, prevention is not the main strategy to control resistance because antibiotic use also needs to be controlled."

Of course, "benchmarking (open comparison of health-care facilities) of frequencies of health-care-associated infections is useful." Yet public reporting is only useful as far as we have effective methods to prevent the reported infections.

Despite these minor quibbles, this is an incredibly timely and tremendously useful report. The authors and the Journal should be congratulated. Let's hope it moves the needle towards more recognition and funding for antimicrobial discovery, antibiotic stewardship, and perhaps... infection prevention?

Prevention, anyone?

Thanks to Eli’s recommendation, I watched the Frontline documentary on antimicrobial resistance last night. The culprits (MRSA, pan-resistant Stenotrophomonas, NDM- and KPC-producers) are fearsome, and the stories are riveting. The most haunting line is exactly ten minutes in, when Will Lyman (the somber voice of Frontline) intones that “Addy and her mother had entered the post-antibiotic era”. The statement is both shocking and true, and one we’ve covered before. Overall, this is perhaps the best lay media treatment of this issue that I’ve seen, and features many of our eloquent friends and colleagues. In particular, pay attention to Dr. John Quinn, an expert in gram negative resistance who died earlier this month after a battle with cancer. He will be sorely missed. You can watch the documentary in full here. 

One minor criticism: too much emphasis on drug development and new technology (e.g. whole genome sequencing, “robot” cleaning), not enough discussion of the hard work of basic infection prevention (hand hygiene, contact precautions, environmental cleaning). I know from discussion with those involved that these topics were discussed during interviews, but probably not deemed compelling enough to survive the editing process. New drugs buy some time and can be life-saving, but only until bacteria catch up…..and genome sequencing didn’t halt the NIH outbreak, strict enforcement of basic prevention measures did. I hear a lot of general nihilism about hand hygiene (adherence rates will never exceed 60%, high rates can never be sustained, etc., etc.). The truth is that we have much more work to do to better understand and solve the hand hygiene problem. 

Frontline plans a second show in the spring of 2014 that covers the role of antimicrobial use in driving resistance, which I look forward to seeing. Might I suggest they begin planning a third installment, dedicated exclusively to the problem of hand hygiene in healthcare settings?

Photo of Ignaz Semmelweis from Wikipedia Commons

The Antimicrobial Hospital Room

Earlier this month I gave a talk at ICAAC where I shared my thoughts concerning the role that environmental coatings and antimicrobial textiles might play in limiting pathogen spread in hospital settings.  Several readers asked for copies of my talk, so I thought I'd just post a (moderately) modified version here.  In the same session, Mike gave an excellent talk describing the primary importance of hand hygiene, Andrew Stewardson discussed the counter point that hand hygiene wasn't the most important intervention and Andreas Widmer covered no touch disinfection methods (e.g. UV light hydrogen peroxide vapor). A great session - wish you were there!

Are "PSSA" coming back?

On the way to Lac St. Francois a couple weeks ago, we drove near St. Albans, Vermont, the location of the hospital outbreak mystery described in one of Mike’s recent posts (you may remember, the “case of the circumstantial evidence of a complicated conspiracy of hospital personnel using laboratory control strains to intentionally infect patients in order to ruin a doctor who claimed to have uncovered an illegal kickback scheme involving radiology services…”, yeah, that’s the one!).

In expert testimony from this case, the statement is made that penicillin-susceptible Staphylococcus aureus (PSSA) are extremely rare (“less than 2% of all S. aureus isolates”). This widely-held assumption (that PSSA are basically “extinct”) is incorrect, and in some centers there appears to have been a substantial increase in PSSA over the past few years. See this report from John Crane that 15% of all S. aureus from ICU patients in Buffalo, NY, are now PSSA, and this report from IDWeek 2012 that PSSA accounted for 20% of all MSSA (and 13% of all S. aureus) from positive blood cultures in the Kaiser Permanente system (regional reference laboratory in LA). We plan to examine this issue as well in the next round of our nationwide S. aureus resistance surveillance.

The perception that PSSA no longer exist persists in part because many labs don’t test or report the drug (to detect inducible beta-lactamases, labs have to perform a beta-lactamase test on any S. aureus that tests susceptible, before reporting it).

Why is this important? It is another indication of how complex is the epidemiology of S. aureus, demonstrating that emergence and virulence are not necessarily tied to resistance, and that the “loss” of a drug may not be the end of the story—and also, of course, as a reminder that the drug of choice for PSSA is…..penicillin.