ESCMID MDR-GNR guidelines

ESCMID experts recently released comprehensive guidelines for the control of MDR-GNR. Working with a limited evidence base, the experts managed to compile a coherent set of guidelines with graded recommendations. Given the important differences in the epidemiology of the various species and resistance patterns of MDR-GNR, this is really a 6-for-the-price-of-one set of guidelines, with separate recommendations for: ESBL-producing Enterobacteriaceae, MDR K. pneumoniae, MDR A. baumannnii, MDR P. aeruginosa, Burkholderia cepacia and Stenotrophmonas maltophilia.

Five key interventions are identified: hand hygiene measures, active screening cultures, contact precautions, environmental cleaning, and antimicrobial stewardship. ‘Selective’ decontamination using antibiotics, topical ‘source control’ using chlorhexidine, and infrastructure / education are also reviewed. Which of these is most important? Most studies included multiple interventions simultaneously, so it’s difficult to tell and it will probably depend on species and setting.

MDR-GNR controlFigure: The cornerstones of MDR-GNR control (but we don’t have enough data to say which is most important, and which are redundant).

A few points for discussion:

  • We still don’t really know what works to control MDR-GNR. Reflecting on my recent blog on influenza transmission, where the relative importance of various transmission routes varies by context, this also seems likely for MDR-GNR. The relative importance of say, environment vs. hands, is likely to vary by setting for a given MDR-GNR species. This makes definitive guidelines difficult to write!
  • The guidelines begin with a useful review of the differing transmission routes for the various MDR-GNR species. This shows that person-to-person spread of Klebsiella species and some other Enterobacteriaceae (such as Enterobacter species and Serratia species) seems to be more important than for E. coli. The non-fermenters A. baumannii and P. aeruginosa have some fundamental differences with one another and with the Enterobacteriace in terms of transmission routes. If I had to rate the importance of patient-to-patient spread vs. other routes for the various MDR-GNR I would say A. baumannii > Klebsiella species > other Enterobacteriaceae > P. aeruginosa > E. coli. But don’t hold me to it!
  • It seems odd that all of the recommendations are ‘strong’ but the evidence is graded mainly as ‘moderate’, ‘low’ or ‘very low’. Perhaps more ‘conditional’ recommendations would be a better fit with the quality of the evidence?
  • The recommendations are stratified by organism-group and setting (endemic or outbreak), which is a workable approach. What you’d do in an outbreak does probably differ from what you’d do in an endemic setting.
  • There’s a useful recommendation for the identification of a new CRE case to prompt contact tracing and enhanced local surveillance, in line with PHE and CDC recommendations.
  • There’s a little fence sitting when it comes to a recommendation for active surveillance cultures in the endemic setting: ‘the implementation of ASC [active surveillance cultures] should be suggested only as an additional measure and not included in the basic measures to control the spread of MDR-GNB in the endemic setting.’ Still not clear whether this is a recommendation for or against ASC in the endemic setting!
  • I was surprised not to see a recommendation to use a disinfectant to help bring A. baumannii outbreaks under control. I appreciate that there is little evidence in endemic settings, but controlling the environmental reservoir does seem to be important in controlling A. baumannii outbreaks.
  • The remit of the guidelines is for adult patients, but what to do on neonatal units and in paediatrics?
  • The guidelines are restricted to hospitalized patients, but what about long-term acute care facilities (that are riddled with CRE in some parts of the world) and long-term care facilities (that have an unknown but probably sizable burden of resistance)?
  • The searches were restricted to MDR bacteria according to ECDC criteria, but what about all those literature on preventing the transmission of resistant (but not multiresistant) and sensitive GNR? If something works to control GNR, there’s no reason why it shouldn’t work to control MDR-GNR (except, perhaps, for antibiotic stewardship).
  • Finally, if all else fails (and only then), consider closing the ward!

In summary, these guidelines are very well written and will provide useful guidance for those on the front line try to deal with endemic and epidemic MDR-GNR. However, above all else, they highlight the need for high-quality studies telling us what works to control MDR-GNR.

Article citation: Tacconelli E, Cataldo MA, Dancer SJ et al. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients. Clin Microbiol Infect 2014; 20 Suppl 1: 1-55.

Highlights from APIC 2014

APIC 2014I couldn’t make it to APIC this year, but I have picked out a few highlights. More than 300 abstracts were presented so I can only scratch the surface here, but the good news is that they’re all available in an AJIC supplement.

Multidrug-resistant Gram-negative rods

One of the oral presentations was on controlling CRE in Texas (Cifelli et al). The interventions comprised improvements in lab identification and patient electronic tagging, and front-line infection prevention and control practices (dedicated rooms, equipment and staff etc). It’s difficult to know which of these approaches (if any!) made the difference: we still don’t know what works to control CRE.

A group from Louisville explored transmission of CRE in an LTAC (Kelley et al). LTACs have previously been shown to be a hotbed for CRE transmission in some parts of the USA. They found that almost half of patients that acquired CRE were admitted to beds that had been previously occupied by a CRE patient, which brings a new meaning to ‘hotbed!’ This links in with previous studies showing that admission to a room previously occupied by a patient with MDROs is a risk factor for acquisition. It also shows that CRE (K. pneumoniae at least) can survive for long enough on surface to bring indirect transmission via environmental contamination into play.

Definitions and terminology surrounding CRE and MDR-GNR in general are in a state of confusion. Both require urgent clarification. A survey of 79 hospitals by Jadin et al for their definitions of MDR-GNR yielded virtually 79 different definitions! This makes it challenging for facilities to communicate clearly about MDR-GNR, since what qualifies as MDR-GNR may not make the cut in another hospital. And this is not even accounting for variations in lab diagnostics!

A small prevalence survey of CRE carriage in Michigan by Berriel-Cass et al found that 2 (3.8%) of 53 patients were colonized. Neither patient had history of CRE, but one who did have a history of CRE screened negative! It’s difficult to know who is at high risk for CRE carriage, and even more difficult to know how long they will carry it for. However, we probably know enough to conclude that “once positive always positive” is a sensible (if somewhat conservative) approach.

The rest

A fascinating study from Arizona by Sifuentes et al evaluated a hygiene intervention in a LTCF. A number of bacteriophages were used as markers for pathogenic virus transmission and inoculated onto hands and surfaces. The viruses spread rapidly throughout the faculty over a short time period (measured in hours), and a hygiene intervention significantly reduced the level of contamination of hands and surfaces. Most similar work has been performed in the acute setting, so some data from the non-acute setting is particularly welcome. This study illustrates the dynamic interplay between hand and surface contamination. In a way, hands are just another highly mobile fomite that are not disinfected frequently enough!

Jinadatha et al performed a very timely study exploring whether serial passage of bacteria with sub-lethal UV exposure prompts reduced susceptibility to UV. The study demonstrates that 25 serial exposures to UV did not affect bacterial UV susceptibility. However, the study did not explore whether other useful mutations may have occurred in the “survivors”; perhaps this is a job for whole genome sequencing in a follow-up study?

Faecal microbiota transplantation (FMT) is quickly becoming the standard of care for recurrent CDI. A study by Greig et al tells the story of implementing a FMT programme. The literature for FMT are impressive, but the ‘nuts and bolts’ of implementation are challenging. Where do you get the donor stool form? How do you screen the donors? Who performs the procedure? Who pays? Will it work here? Are just some of the questions that need to be negotiated for successfully implementing an FMT programme. The message from this study: it’s worth it – 83% of patients with recurrent CDI had resolved within 30 days.

Finally, I remain rather skeptical that “CA-CDI” is really on the rise. I may have to revise my opinion based on this abstract by Rogers and Rosacker, showing that a community-based educational intervention reduced the rate of CA-CDI!

Perspectives from ECCMID 2014: the box set

eccmid 2014

I’ve published a few ‘Perspectives from ECCMID’ on the blog over the last few days, so thought it would be useful to post a summary:

You may also be interested in some other updates from ECCMID elsewhere in the blogosphere:

Perspective from ECCMID 2014 Part II: What to do about MDR-GNR?

 gram neg

I was hoping that the ECCMID 2014 session on ‘Outbreaks of MDR Gram-negative bacteria: what works and what does not work?’ would bring some answers from large, controlled studies to improve the evidence base for MDR-GNR control. I’m sorry to report that most of what was presented only served to highlight the limitations of the evidence base! There’s a bit of a Catch 22 here: in most settings, the problem lies in outbreaks, but the answers lie in large, adequately controlled cluster randomized studies in endemic settings.

  • Dr Weterings from NL provided a rather bleak start to the session, reporting an outbreak of carbapenem-resistant K. pneumoniae in a hospital and nursing home. Environmental cultures regularly grew the outbreak strain (including a shared glucose meter) and the control measures that were effective in the hospital were more challenging to implement in the nuring home.
  • Dr Gonzalez-Galan found a bundle of interventions dramatically effective to reduce the rate of endemic MDR A. baumannii. The bundle comprised surveillance, hand hygiene audit, and a checklist for environmental cleaning and contact precautions compliance. But which element of the bundle worked, and were any elements redundant?
  • Dr Cohen reported an MDR A. baumannii outbreak in Israel affecting 70% of ventilated patients at its peak, which forced colistin as the empiric VAP therapy. Proper disinfection of the ventilators brought the problem under control. Similarly, an endoscoy-associated ESBL K. pneumoniae outbreak in Norway (reminescient of the NDM outbreak in Chigago) was controlled by implementing proper endoscope disinfection.
  • Probably the most useful presentation of the session was from Dr Cataldo preseting a systematic review of interventions for MDR-GNR. Most studies (78% of the 86 included) were in outbreak settings, and plagued by low quality. Nonetheless, bundles were 2x more effective than single interventions (45% vs. 28%). The study struggled to determine convincingly which element of the bundles was most effective, but hand hygiene, contact precations and education came through as the pillars of effective bundles.
  • Dr Dettenkofer showed that an educational intervention improved compliance with standard precautions (especially hand hygiene and to a lesser extent the inappropriate use of examination gloves for some procedures). However, ‘standard precations’ are far from standard, and it seems that you need to go further than standard precautions to control MDR-GNR.
  • Dr Hussein showed that standing over healthcare workers and telling them to wash their hands improved compliance (unsurprisingly!). I venture that hospitals would only take this measure in extreme circumstances, although hand hygiene “enforcers” are not without precedent.
  • Dr Perencevich reported that the Hawthrone effect tends to strike after 15 mins of observation, so hand hygiene observations should be kept short and sweet. (Incidentally, hand hygiene compliance was higher among doctors than nurses in this study; I think it’s the first time I’ve ever seen it this way around!)
  • Dr Hansen presented data from the PROHIBIT collaborative, who found that alcohol based hand rub usage tracks the prevalence of antimicrobial resistance across Europe. However, the rate of red and yellow cards in the Euro 2008 football championships also correlates with antimicrobial resistance rates across Europe, and national consumption of chocolate correlates with the national rate of Nobel laureates: collelation doesn’t necessarily mean causation!
  • Finally, Dr Langelar reported that the Dutch national healthcare inspectorate visits were effective in raising standards. But was this papering the cracks or effecting culture change?
  • I am sure there were lots of good posters on this topic too, but I didn’t get very far with those. Perhaps somebody else did and would like to provide some additional information?

Dr Evelina Tacconnelli gave a thoughtful talk comparing the various international guidelines for MDR-GNR, reflecting on the recently published ESCMID version. The subject is broad, specifically in terms of which MDR-GNR, and in which setting. Guidelines for CRE in a general hospital population would look quite different to guidelines for CRAB in the ICU. Dr Tacconnelli focused on the areas of controvosy: isolation for ESBL carriers, how to prioritise limited side rooms (see useful ‘Lewisham’ isolation prioritization tool in Appendix 6 of these Irish guildelines), selective digestive decontamination, and the need for bundles. Finally, Dr Tacconnelli referenced a neat model for the effectiveness of various infection control interventions for controlling the spread CRKP. This is a clever study, and probably useful, but much like Berta (showing my age), incorrect inputs result in meaningless (or worse, misleading) outputs.

Dr Anna-Pelagia Magiarakos discussed some of the challenges of implementing guidelines, reminiscent of Dr Evonne Curren’s recent talk on a similar subject. One important point is to have some guidelines to implement! Countries lacking guidelines for the control of MDR-GNR tend to have higher rates (ECDC and PROHIBIT data). Once you have some guidelines, barriers to implementation need to be overcome: time, culture, resources, lack of understanding or belief that they will work, competence, habit, routines and “ivory tower” guidelines written by those detacted from the coal-face, to name but a few!

So are we any closer to knowing what works to control MDR-GNR following ECCMID 2014? Bundles are more effective than single interventions, but we still don’t know which elements of the bundle are most important, and this will vary by pathogen and setting. We need more studies like the commendable but complex MOSAR Lancet ID study.

You can view some other ‘Perspectives from ECCMID’ here.

Image credit: Iqbal Osman.

What does lab diagnosis of MDR-GNR have to do with SURFing?

I met the Service Users Research Forum (SURF) yesterday, and they asked me to give a presentation on the emergence and detection of multidrug-resistant Gram-negative bacteria (you can download my slides here). I found these slides by Dr Katie Hopkins (PHE) useful in preparing mine. It was my first interaction with a patient-led research group and I enjoyed the meeting very much. I found the SURF members and their academic support team from the University of West London to be engaged, engaging, knowledgeable and thirsty for knowledge. Their questions were insightful and their suggestions were thought-provoking. Informal discussions on a current research proposal (for enhanced surveillance of carbapenem-resistant Gram-negatives) gave me some useful ideas; researchers can easily lose sight of the patient perspective. I can see why funders such as NIHR now insist on seeing patient involvement in the development of research proposals and I am sure I will be SURFing again in the near future!

I put together the flow chart below to try and summarise the diagnostic approach to the lab detection of MDR-GNR. I would appreciate any thoughts you have on this flow chart…

surf mdrgrn

ICHE special edition on CRE and MDROs

CRE medium

Infection Control and Hospital Epidemiology have once again excelled themselves in putting together a fine special edition on CRE and MDROs. Around this time last year I posted an article on the ICHE special edition on the role of the environment, and this special edition is equally important. I strongly recommend that you read the special edition from cover to cover, but I’ve picked out a few of my personal highlights below:

  • A thoughtful editorial by Drs Lautenbach and Perencevich sets the scene. They reflect on our ‘woeful unpreparedness’ to address both current and future MDROs.
  • A number of articles provide updates on surveillance and prevalence. Brennan et al. report findings from a 6-month CRE point-prevalence survey based on voluntary reporting in the state of Michigan, finding a crude rate of 1.07 cases per 10,000 patient days. Interestingly, this rate was almost 3 cases per 10,000 patient days in long-term acute care facilities. Isolates were not collected and analyzed, so carbapenemase genes were not confirmed; the fact that close to 10% of isolates were susceptible to meropenem suggests that a good number of the CRE were not carbapenemase producers. Indeed, another state-level point-prevalence survey (Pfeiffer et al., from Oregon) found that only 3 of the 60 CRE isolates reported were carbapenemase producers. Another state-level survey of CRE (Johnson et al., from Michigan) identified regional clustering of CRE colonization of mechanically ventilated patients in the central region of the state.
  • Analysis through the SHEA Research Network found that contact isolation policies for multidrug-resistant Gram-negative rods (MDR-GNR) are surprisingly variable. Worryingly, almost 20% of facilities surveyed did not isolate patients infected or colonized with MDR Pseudomonas or Acinetobacter, and 6% do not isolate patients with CRE. Policies for de-escalation of contact precautions were equally variable. Contact isolation policies seem to be even more lax in long-term care facilities based on data from Pfeiffer et al., reporting that only half of patients colonized with MDROs are placed on contact precautions.
  • A number of studies evaluated risk factors for CRE. For example, Bhargava et al. identified high acute morbidity score, immunosuppression, presence of indwelling medical devices and prior antimicrobial exposures to be consistent risk factors for CRE in the various patient populations they evaluated.
  • A survey of the kitchen in a Swiss hospital identified ESBL-producing Enterobacteriaceae in 92% of raw chicken and 6% of rectal samples from food handlers.
  • The efficacy of chlorhexidine bathing for MDR-GNR has been questioned, so data from Lin et al. on this issue are particularly welcomed. In a study of 62 patients in a long-term acute care facility, daily chlorhexidine gluconate (CHG) bathing halved the chances of culturing CRE from the body sites analyzed. However, it’s worth noting that the measured CHG skin concentration (15-312 mg/L before the daily bath and 78-1250 mg/L after the daily bath) was much lower than the applied CHG concentration (10,000 mg/L). This potentially brings the subtly reduced susceptibility to CHG reported in MRSA into play.
  • Several studies evaluated the potential for environmental contamination with MDR-GNR. Rosa et al. found that exposure to surfaces contaminated with MDR A. baumannii increased the risk of acquisition by almost 3-fold. Although the design of the study was fundamentally different, it is interesting to note that the increased risk from admission to a room previously occupied by a patient with MDR A. baumannii was also around 3-fold in a previous study. Havill et al. reported that the survival time for CRE (including K. pneumoniae) on dry surfaces is measured in weeks not days. Rock et al. carefully observed 220 unique interactions between healthcare workers (HCW) and patients with KPC or non-KPC producing K. pneumoniae, finding that HCW gloves or gowns became contaminated during 14% of the 220 interactions, and 26% of 43 environmental samples were positive. There was no significant difference between HCW or environmental contamination rates for KPC vs. non-KPC producing K. pneumoniae.
  • There was not much on therapy for CRE – perhaps because there is little to say for pan-drug resistant CRE! An article discussing the challenges of managing CRE infections by Drekonja et al. through surveying the CDC funded Emerging Infections Network highlighted the common problems due to toxicity from using “last-line” antimicrobials colistin and tigecycline.

It seems that the prevalence of CRE is patchy in the USA at present, and that long-term care, and long-term acute facilities are an integral part of the story. Given the limited evidence base, interventions need to cover all bases: active surveillance, rapid and accurate diagnostics, environmental (and perhaps food) hygiene, contact isolation and perhaps antiseptic decolonization, all combined with facility-wide education and communication initiatives. The most effective – and cost-effective – interventions to prevent and control the spread of CRE and other MDR-GNR are controversial so to this end I am looking forward to the SHEA ‘From MRSA to CRE: Controversies in MDROs’ and joint HIS / IPS ‘What’s that coming over the hill: rising to the challenge of resistant Gram-negative rods’ Spring meetings next month!

Photo credit: Enterobacter cloacae NDM-1 growing on Oxoid Brilliance CRE Agar by Nathan Reading.