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.

Guest Post: AHRQ Report Calls for Environmental Cleaning Research

This guest post was written by Alexandra McGhie, Megan Campbell and Nick Graves to highlight a new AHRQ Report as it relates to an NHMRC (Australia) Partnership Grant led by Queensland University of Technology (QUT) & The Wesley-St. Andrew’s Research Institute (WSARI) called REACH.

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New report calls for further research examining the impact of environmental cleaning interventions on Healthcare Associated Infection (HAI) rates

A new report by the US Agency for Healthcare Research and Quality (AHRQ) calls for further studies on emerging strategies for environmental cleaning and their impact on healthcare associated infection rates.

The report, Environmental Cleaning for the Prevention of Healthcare-Associated Infections (Technical Brief Number 22) details a systematic review of 80 studies that aimed to  determine the evidence base and comparative effectiveness of environmental cleaning methods and monitoring strategies of frequent touch surfaces in hospital rooms. The report concluded there was a lack of studies directly comparing cleaning methods and monitoring strategies, and calls upon the research community to undertake further research that:

·       Examines and compares emerging strategies (including ATP and UV light technologies).

·       Includes patient colonisation and infection rates as outcome measures.

·       Identifies surfaces in hospital rooms posing the greatest risk of pathogen transmission.

·       Examines factors that affect the real-world implementation of cleaning interventions (organizational culture, training, feedback).

An obvious omission to the report is that the value for money of any change to practice is not considered. Current health spending growth will not continue as it has. And infection prevention communities must think about the returns per dollar spent on new programmes.

Both effectiveness and cost-effectiveness evidence for a new ‘bundle’ approach to hospital cleaning will be generated by the REACH project. The effect on the transmission of healthcare associated infections (HAIs) in eleven Australian hospitals will be estimated and the value for money assessed.

The randomised controlled trial funded by the an NHMRC Partnership grant (GNT1076006) is led by QUT and The Wesley-St. Andrew’s Research Institute (WSARI) in conjunction with industry, policy and professional partners.

For more information about the REACH Project, please visit:  http://reach.cre-rhai.org.au/

The post originally appeared on the AusHSI Blog.

Safety and efficacy of nontoxigenic C. difficile spores in preventing recurrent CDI

Lead Author: Dr. Dale Gerding

We have written and spoken often on the efficacy of fecal transplants in treating recurrent C. difficile infections. Wouldn't it be great if there was a way to prevent recurrent CDI in the first place? What if "good" C. difficile strains that lack toxin production genes could be used to out compete bad strains and prevent recurrent CDI?

There is a new study just published in JAMA that evaluates the safety and efficacy of a nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) in preventing recurrent CDI in those patients initially treated with metronidazole and/or oral vancomycin. In the four-arms of the phase 2, double-blind placebo-controlled trial they compared patients given oral liquid formulation of NTCD-M3, 10^4 spores/day for 7 days (n = 43), 10^7 spores/day for 7 days (n = 44), or 10^7 spores/day for 14 days (n = 42), or placebo for 14 days (n = 44).

Recurrent CDI occurred in 13/43 (30%) of placebo patients and only 14/125 (11%) of patients treated with NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006). Fecal colonization with the NTCD-M3 strain was reported in 69% of treated patients and was associated with lower recurrence: 2/86 (2%) recurrence if colonized vs. 12/39 (31%) recurrence in treated but uncolonized patients (OR, 0.01; 95% CI, 0.00-0.05). Side effects such as abdominal pain, diarrhea and serious side effects were actually higher in the placebo groups. If this smaller study's findings are confirmed in larger trials, we may just have a new treatment for the prevention of recurrent CDI. Very cool.

Check out the video interview with lead author Dr. Dale Gerding, another related video and the JAMA Associate Editor's podcast covering this article and other important studies.

Ebola vaccine - do we really need a placebo-controlled RCT?

The last time that I waded into the world of vaccine effectiveness, it maybe didn't go as well as planned. Though I've learned that I get knocked down, but I get up again just as Chumbawamba tells me to do every morning.

There are several candidate Ebola vaccines in various stages of evaluation. Recently, in response to the huge increase in cases, there have been calls to speed the evaluation, manufacture and distribution of vaccines to help control the outbreak. Science, NPR and even Gizmodo had recent posts describing the urgent need to rush vaccines to the field and the barriers to widespread testing and distribution of novel vaccines. Mike Osterholm has a sobering article in Politico where he outlines the public health crisis and strongly argues for the production of 500,000,000 vaccines. He reminds us that this effort "will require mobilizing people and resources on a massive scale (and) it has to be the international community’s top priority."

Scientists, companies and governments met at WHO this week to establish ways to speed up the development and testing of the candidate vaccines. Major barriers include paperwork (agreements) and things like insurance coverage for possible vaccine side-effects. Thus, most barriers are not scientific in nature, which is encouraging.

However there may be another barrier to the testing of novel Ebola vaccines: the individual randomized double-blind placebo controlled trial. Now, we all understand that this study design is the gold standard for internal validity; however, sometimes ethical or logistical concerns may outweigh internal validity. This Ebola outbreak may be one of those times. But let me explain.

In several of the articles, Dr. Anthony Fauci, Director of NIAID, and several others have stated their preference for the placebo-controlled RCT. On NPR Dr. Fauci said "Some scientists think moving forward without a control group of people who don't get the vaccine isn't worth the risk - if you did it in the way where you never could tell whether it worked well, worked a little, didn't work at all, or actually made people worse ... you could actually propagate a disaster." In the Science article Dr. Fauci was said to believe "that a randomized, controlled trial, in which people receive either the actual Ebola vaccine or an unrelated shot such as the hepatitis B vaccine, will be needed and if you are going to deploy a vaccine widely within a country, you better be sure it’s effective." I agree with most of what Dr. Fauci is suggesting, although I think placebo controls and individual (vs cluster) RCT have significant limitations in this outbreak.

For example, I don't think placebos are acceptable during the 2014 pandemic in Africa. There is no practical way to administer Hepatitis B vaccine as a placebo in this desperate situation - I suspect there might be riots. Additionally, a placebo controlled RCT is not the only study design with strong internal validity. One option is the cluster-randomized trial (cluster-RCT) where vaccine is administered to some communities and not others. Given that there will initially be limited vaccine supplies, this distribution pattern could be more practical. For example, some towns in each country could receive vaccine and others won't (no placebo - just no vaccine) and infection rates could be compared in both groups.

To get a litter more technical, Ebola vaccine cluster-RCTs could follow a stepped wedge design. Stepped wedged designs are used when ethical, financial, or logistical (e.g. geographic) constraints prevent the use of individually randomized or parallel cluster-RCT (i.e. treatment and control groups enrolled at the same time). In this design, vaccine would be rolled out randomly to communities as it became available (purple boxes in the figure above from Brown and Lilford), so that after one community is vaccinated then the next community would be vaccinated and then the next. Eventually every community is vaccinated. In this design, time-periods before the community is vaccinated serve as controls (white boxes in the figure). The stepped wedge cluster-randomized design has been used effectively in numerous settings including HIV and other infectious diseases.

This post is already too long. For those still interested in stepped wedge designs, please read the Brown/Lilford study or the Hussey/Hughes review. I'm sure scientists and political officials are considering numerous options for testing the safety and efficacy of candidate vaccines while simultaneously delivery potentially life-saving immunity to the millions at risk. Given that an estimated 21,000 people have already been infected and that 1.4 million may be infected by January 2015, I hope that vaccine trials aren't delayed because some insist on an individual RCT. The really good internal validity of the stepped wedge cluster RCT is not far from the excellent internal validity of the individual RCT. Really good is good enough.

10/1 Update: WHO considering a stepped wedge design. Good news.

10/10 Update: new Lancet Editorial Adebamowo et al. discussing the ethics and practical issues of the individual randomized trial h/t @HelenBranswell

More antibiotics NOT more better in sepsis

There is a meme in antibiotic therapy for all infectious disease clinical syndromes that earlier and more antibiotics lead to lower mortality. I'm not sure that this meme is supported by data from good studies, but it has been so effectively spread through the establishment that its very existence goes unnoticed (check this abstract's first sentence). I think this unproven belief threatens effective antimicrobial stewardship and is partially responsible for the emergence of antimicrobial resistant organisms, but I digress...

Published online in JAMA this week is a randomized trial of dual antibiotic vs monotherapy in sepsis funded through the German Sepsis Research Network (SepNet). The 2.5 year study in 44 German ICUs compared meropenem monotherapy (n=298) with meropenem+moxifloxacin (n=278) in patients with sepsis or septic shock. Patients were treated for 7 to 14 days or until discharge or death and duration was informed by a procalcitonin-guided treatment protocol on study days 7 and 10. The primary outcome was mean of daily total Sequential Organ Failure Assessment (SOFA) scores over 14-days with similar scores in both monotherapy (7.9 points) and dual therapy (8.3 points) patients, p=0.36. 28-day mortality was 22% in the mero and 24% in mero+moxi patients (p=0.58) and 90-day mortality was 32% in the mero and 35% in the mero+moxi patients (p=0.43).

Groups were similar and infections were predominately pneumonia, intra-abdominal and GU. Blood cultures were positive in 33% of patients with Escherichia coli and MSSA being the most commonly isolated, while 18 had MRSA from any source. 100% of cultures tested were susceptible to the mero+moxi combination while 94% of specimens were susceptible to meropenem monotherapy.

This is an important study and one that should make us question current empiric therapy dogma. However, it doesn't answer the question whether antibiotics overall made a difference and whether other therapeutic options including source control might be more important.  It's nice to see clinical ID slowly emerge into the modern evidence-based medicine era even if so few studies are completed in the US.

image source: http://abacaxihortela.blogspot.com/2011/09/only-1.html

Best news ever! A Norovirus vaccine that works!

As a parent or two young kids, I dread the slightest hint of nausea. Now, perhaps, I might have one less pathogen to fear and perhaps in old age, I can even take a cruise.

In the recent NEJM there is a report of an RCT assessing the safety, immunogenicity, and efficacy of an intranasal norovirus viruslike particle (VLP) vaccine. The study was conducted in adults aged 18 to 50. They received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus during an inpatient challenge with 10 times the infectious dose and monitored for infection and gastroenteritis symptoms for a minimum of 4 days. (No way I'd ever volunteer for this study)

The study included 98 patients with 90 completing both injections. A Norwalk virus–specific IgA seroresponse was found in 70% of vaccine recipients. This level of response is  similar to my old Maryland colleague Samer El Kamary's 2010 JID paper that showed a 79% response rate. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo and 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo and 61% of vaccine recipients, P=0.05). Not perfect, but still a great result.

Note: These data were also presented at earlier IDSA (2010) and ICAAC (2011) meetings.

Source: RL Atmar et al. NEJM Dec 8, 2011

Update: This news is pretty good too. (Massive drop in in-hospital deaths...in Canada)

Oseltamivir+Zanamivir combination therapy vs monotherapy for seasonal influenza

A Combination Lock

In infectious diseases, there is always the trade-off between treating the individual patient and the population effects of antimicrobial resistance.  One way to counteract the development of resistance might be combination therapy (eg HIV ART) but this would only apply if the combination provided an added benefit to the individual patient with minimal side effects.  To answer this question for influenza, researchers in France in fall 2009 (85% H3N2 virus) conducted an RCT comparing oral oseltamivir 75 mg twice daily plus zanamivir 10 mg by inhalation twice daily to oral oseltamivir monotherapy or inhaled zanamivir monotherapy. The primary outcome was the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2. They also tracked symptom resolution out to day 14 among other outcomes.

The researchers planned to enroll 900 patients with ILI<36 hours and a positive rapid influenza A test, however the RCT was halted after only 541 (447 with confirmed virus) were enrolled.  In the intention to treat analysis, 46% in the O+Z group reached RCT-PCR<200, while this was achieved in 59% of the oseltamivir monotherapy and 34% of the zanamivir monotherapy groups.  Nausea and/or vomiting was more frequent in the combination arm.  Thus, the trial was ended early. The authors concluded: "Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice."

Duval et al. PLoS Medicine November 2, 2010

Alcohol hand rubs in the workplace: A Randomized Trial

Just a quick post because I've got to get the kids to bed.  Researchers in Germany randomized 134 administrative employees at the Ernst-Moritz-Arndt University Greifswald to alcohol hand rub or nothing (n=67 in each group).  Subjects were to use >3ml of hand rub at least 5x/day especially after using the bathroom, blowing their nose, before eating and after contact with an ill person. The study lasted from March 2005 to April 2006.  People who used hand disinfects prior to the study were excluded.  They found significant reductions in common cold symptoms, fever, cough, and fewer days of illness with each symptom. A thing to note is that 111 of the 134 subjects were female, although it is hard to figure how this would hurt the generalizability. Alright, story time...

BMC Infectious Disease article by Hubner et al.