Antibiotic prophylaxis isn't needed for removal of below the knee orthopedic implants?

Wow, it has been wicked cold this week and it's only going to get colder. It's so cold that I stayed inside and read JAMA RCTs instead of racing to the mall and fighting for discounted gift wrap. Besides adding to my ID knowledge, perhaps this latest polar vortex is also behind the reduced flammability of the ID profession? One can only hope.

The folks that follow me on twitter know the real reason I'm staying current on JAMA studies is that I've recently accepted a position as an Associate Editor for a new JAMA journal called JAMA Network Open. This open-access journal will begin accepting manuscripts in early 2018. Get those fingers typing - one way to protect yourself from frostbite...

In the Boxing Day issue of JAMA there was a very nice multicenter, double-blind RCT comparing surgical site infection rates post removal of below-the-knee orthopedic implants in patients receiving 1g cefazolin vs saline placebo. The 470 randomized patients were from 19 hospitals in the Netherlands and patients were excluded if they had active infection, fistula or were receiving antibiotics. Outcomes followed CDC definitions. Implant removal is considered a clean procedure with expected SSI rates of 2 to 3.3%, so apparently antibiotic prophylaxis isn't indicated; although reported SSI rates have been higher in removal vs implantation procedures, so some recommend prophylaxis.

Spoiler alert: The study was negative. 13.2% of patients in the cefazolin arm and 14.9% in the placebo arm developed SSI, (absolute risk difference, −1.7 [95% CI, −8.0 to 4.6], P = .60). Results below in Table 2. Thus, with a negative study, I headed to the sample size calculations section where the authors stated that they powered the study with an estimated SSI rate of 3.3% in the cefazolin arm and 10% in the placebo arm based on the SSI rates in clean-contamined procedures and recent Dutch retrospective studies, respectively.

Few thoughts. First, this is an underpowered study. It's true that they hit their target sample size, but their estimates were completed using rosy expectations for the benefits of cefazolin and were not selected based on clinically meaningful reductions in SSI. Many might think a 2% absolute reduction in SSI is clinically meaningful. Second, the authors suggest that the high rates of SSI might have resulted from very low thresholds for starting antibiotics if there was "the slightest suspicion of a SSI." Since CDC definitions define SSI based on receipt of antibiotic treatment, this behavior could have biased the rates. Finally, deep SSI rates were 0.4% (1 patient) in the cefazolin group and a far higher 2.9% (7 patients) in the placebo group, (absolute risk difference, −2.5 [95% CI, −5.7 to 0.4]). Since the study was powered for the primary outcome, all SSI, not much was made of the big difference in deep SSI. 

The end result might be disappointing but this is no discredit to the authors and clinicians behind the study - RCTs are very hard to design and implement  - thumbs up for all their efforts. With that said, I would prescribe cefazolin as a peri-operative antibiotic during implant removal below the knee since a 2% absolute reduction in all SSI and a 2.5% reduction in deep SSI are both clinically meaningful benefits. I will then wait for another larger study powered using clinically meaningful SSI targets, including deep SSI.

Disaggregating the Benefits of Ventilator Bundle Components

There is a very nice study by Michael Klompas and colleagues in September's JAMA Internal Medicine. The team sought to disentangle the benefits or harms of the individual components of current ventilator bundles including: head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine.

Prior studies had found potential harm associated with stress ulcer prophylaxis (pneumonia) and oral chlorhexidine (higher mortality). This same group published a meta-analysis that called into question the benefits of routine oral care with chlorhexidine (CHG) in ventilated patients. For this retrospective cohort, they examined the associations between exposure to individual ventilator bundle components on a day-by-day basis and ventilator-associated events (VAEs), duration of mechanical ventilation, ventilator mortality, hospital length of stay, and hospital mortality.

The cohort included 5539 consecutive patients who were exposed to mechanical ventilation for at least 3 days. They measured the association between individual process measures and VAEs using Cox proportional hazards regression models with fixed and time-varying covariates and censored patients on extubation or death, whichever came first. Interestingly, they calculated hazard ratios for each bundle component "as the contrast between 4 days of continually performing the process measure vs 4 days of not doing so", since they wanted to allow for the possibility that process measures might have an immediate or delayed effect on each outcome.

I have included the patient-outcomes table below. The most interesting finding, among many tested associations, was that oral care with chlorhexidine was associated with an increased risk for ventilator mortality (HR, 1.63; 95% CI, 1.15-2.31; P = .006). In another table, they reported that stress ulcer prophylaxis was associated with an increased risk for possible ventilator-associated pneumonia (HR, 7.69; 95% CI, 1.44-41.10; P = .02).

This was a very thoughtfully completed and written study - I encourage you to read it (and the accompanying invited editorial) beyond my quick overview. The authors concluded: "we should revisit the classic ventilator bundle. Possible revisions include... a reappraisal of whether oral care protocols should be revised to exclude chlorhexidine therapy, and the reservation of stress ulcer prophylaxis for patients at marked and immediate risk for upper gastrointestinal tract bleeding rather than prescribing them for all patients undergoing ventilation."  It will be interesting to see how slowly these recommended changes occur...

2013 Studies in Memoriam - A Tribute to Studies Almost Lost

Each year the Academy Awards honors those actors and directors who've died in the prior year. It's one of my favorite tributes. Recently, I found myself with a stack of unread journals about four feet high and one of my routines is to clean my office before the start of each year. Thus, I am catching up on what studies I missed or failed to mention when they were first published. This post is a tribute to those studies that have "almost" died in my journal pile...happy holiday reading...

1) I'm particularly embarrassed that we haven't yet mentioned this review written by Dan. He and Michael Pfaller published a review in the June 1 CID on the promise of rapid microbiological detection of MDRO for infection prevention. Sections cover MRSA, VRE and MDR-GNR. What I really like about this review is that it covers the barriers to successful implementation of rapid detection including the "post-analytic" turn-around time and the current dearth of data supporting the clinical utility for many of these approaches. A must read. (NOTE: Currently the CID website is down, I will update with a direct link to the paper once they are back online)

2) Bevin Cohen from Elaine Larson's group at Columbia published a retrospective cohort study in JGIM investigating gender differences in BSI and SSI risk.  The study included three years (2006-2008) of data from a single center. Odds of these HAI were between 15 to 22% lower in women.

3) John Hollingsworth. Sanjay Saint and colleagues from the University of Michigan published a systematic review and meta-analysis of non-infectious complications of indwelling urethral catheters in Annals this past fall. After identifying and reviewing 37 studies they found that minor complications were quite common. For example, urinary leakage ranged from 10.6% in short-term catheterized patients to 52% in those with long-term catheterization. Serious complications were also quite common. If CAUTI isn't reason enough to remove a urinary catheter, these non-infectious complications should be!

4) And to follow up on the urinary catheter removal theme, there was a meta-analysis published in BMJ that quantified the benefits of antibiotic prophylaxis after urinary catheter removal. When analyzing seven controlled studies (5 from surgical patients), they found antibiotic prophylaxis was associated with an absolute risk reduction of 5.8% for UTI and a risk ratio of 0.45. I suspect there are trade-offs in increased antimicrobial resistance that should be assessed before this is more widely adopted.

Credit: James Taylor at the 2010 Academy Awards - one of my favorite tunes

The end of post-op prophylactic antibiotics?

One of the best approaches we have for dealing with in-hospital antimicrobial resistance is stewardship - using antibiotics only when the patient is most likely to benefit. It's been known for a long time that there is little benefit in extending prophylactic antibiotics beyond the end of surgery, yet this practice still persists. Imamura et al. just published an RCT in Lancet ID that examined the possible benefits of extending prophylaxis in patients with gastric cancer undergoing distal gastrectomy for cure.

The trial was an open-label, stratified (by ASA score) randomized trial in seven hospitals. All patients were assigned (1:1) to receive cefazolin 1g before incision and every 3 hours. Those in the extended prophylaxis group received 1g at closure and twice daily for two  postoperative days.  Using CDC definitions, infection control staff monitored for SSI while in hospital and surgeons monitored post-discharge for 30 days.

In the intention-to-treat analysis, 176 patients received standard prophylaxis and 179 received extended prophylaxis.  Randomization appeared adequate with similar operative times and estimated blood loss in each arm; however, 4 patients in the extended prophylaxis arm received transfusions versus none in the standard arm.  I've pasted Table 2 above, so you can see the results broken down into superfical and deep SSI.  Twice as many patients in the extended arm developed an SSI (RR 0.51 95% CI 0.22-1.16), but this was not statistically significant. Caveats: open-label study and SSI not monitored by independent researchers after discharge.

The authors and the accompanying editorial (both behind a paywall) each conclude that extended prophylaxis is not recommended. Although it is likely true, as Hedrick and Sawyer state in their editorial, that "the study is unlikely to have a major impact in the USA and other countries where the maximum duration of perioperative antibiotics is limited to 24 h and is carefully monitored and regulated."

PEP, PrEP, or even PeEP?

I finally got around to reading the paper in the New England Journal on the use of daily antiretroviral therapy for the prevention of HIV infection (full text here). In hospital epidemiology we're very familiar with post-exposure prophylaxis (PEP) for healthcare workers who sustain percutaneous exposures or blood/body fluid exposures to mucous membranes. This paper evaluated pre-exposure prophylaxis (PrEP) for men who have sex with men by having the study subjects take a daily dose of truvada. New HIV infections were compared in the treatment group to men who were assigned to take a placebo daily. There were roughly 1200 men in each study arm. On average the men were in their late 20s, had more than 1 sex partner weekly, about 60% reported unprotected anal intercourse, and they were followed for roughly 1 year. There were 36 new HIV infections in the Truvada group (2.9%) and 64 new infections in the placebo group (5.3%). This represents a 44% relative risk reduction. Sounds pretty good, but that translates to only a 2.4% absolute risk reduction (the infection rate in the treated group subtracted from the infection rate in the placebo group). When the subset of men with detectable drugs levels (i.e., those who were compliant with Truvada) were compared to those without detectable drug levels, the relative risk reduction was 92%. "That's huge," exclaimed Dr. Anthony Fauci, the head of the National Institutes of Allergy and Infectious Diseases, in the New York Times.

So here we have an intervention that appears to be efficacious but not effective (that is, it works when you take the drug, but in the real world many people just won't take it--we've talked about this before). By my calculations, compliance appeared to be about 38% in the study. However, I think we can be sure that compliance would have been even less in the real world if the study subjects had to pay for the Truvada at the retail price of $13,000 yearly. We're also not told whether those who took the drug faithfully may have also been highly compliant with condom use, which may make the drug appear to be more effective than it actually is. So, in the end, I don't think that the impact of this study will be huge. In fact, I doubt it will have much impact at all. The real issue, it seems to me, is helping people to reduce risk the old fashioned way (fewer sexual partners and consistent use of condoms), until the day finally arrives when we have an effective vaccine for HIV.

Switching gears, as a hospital epidemiologist, I wondered if there is a role for PrEP in the hospital. Let's consider the case of a an untreated HIV infected patient with a high viral load who needs cardiac or orthopedic surgery soon. Should the operative team be given PrEP or perhaps peri-exposure prophylaxis (PeEP), with dosing the day before, the day of the procedure, and the day after? If I were the surgeon, I would be interested in that.

Public health vs. clinical medicine

It’s a typical mid-summer day in Richmond—really hot and very humid. It’s my favorite time of the year (I must have been a plant in a previous life!). So I went to soak up the weather by washing my car. This is a mindless activity that I enjoy because it gives me time to think. I began to think some more about the issue of giving camp kids Tamiflu that I blogged about this morning. It’s a good example of the tension that exists between public health and clinical medicine. As an epidemiologist and a clinician, I can appreciate both arguments. But I have often found myself at odds with public health practitioners over issues like post-exposure prophylaxis. It seems to me that a lot of people in public health have a purist approach and a willingness to play the odds with risk that makes the clinician uncomfortable. Moreover, there’s a detachment that those of us who see patients can’t accept. Don’t get me wrong—I have great admiration for public health practitioners and the important work they do for little money or recognition.

As an example, following a case of meningococcal meningitis, my approach to who should receive postexposure prophylaxis is typically more lenient than my public health colleagues. Given the severity of the disease, the ease of giving a single dose of ciprofloxacin, and the comfort this provides to the contact and family members (a placebo effect of sorts), it doesn’t seem appropriate to me to make a big production of “the rules” about who should receive prophylaxis, especially since the rules are relatively arbitrary anyway. A death from an infectious disease may be viewed as a case by the public health community. To the clinician, it’s a patient—someone’s child, mother, father, brother or sister. A few years ago, I attended a conference about a rabies case given by a public health colleague. It was technically an excellent presentation, but what I remember most was how proud she was about how few doses of rabies prophylaxis were given to contacts of the case. All I could think about was how would she have felt if one of those contacts developed rabies? In the New York Times article from this morning we see the tension between Dr. Marc Siegel (the parent and clinician) and Dr. Anne Schuchat (the public health official), who seems to be applying the rigid rules in a not too empathic way. Maybe public health doctors should spend some time in the clinical setting to be reminded that behind every case of a reportable disease is a real human being and that decisions at the bedside are rarely so black and white.