WHO have just released some guidelines for the prevention and control of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aerugionsa. This guideline builds on the excellent WHO core components for IPC guidelines.
Some fascinating modelling from the CDC Vital Signs programme suggests that a co-ordinated, multi-facilitiy approach will be much more effective than each hospital doing its own prevention interventions.
The team first estimated the burden of key infections in the US: CRE, multi-resistant P. aeruginosa, invasive MRSA and CDI combined were responsible for 310,000 infections in 2011, which would increase 10% to 340,000 over 5 years. However, with an ‘aggressive’ national intervention, this could be reduced to below 200,000 by 2019. It would be a huge undertaking to implement and co-ordinate a national campaign in the US, where there is so much heterogeneity in the way that hospitals are structured and funded. But if anybody can do it, the CDC can!
I was privileged to be asked to speak at the inaugural Healthcare Infection Society Middle East Summit in Dubai this week on ‘European approaches to MDR-GNR prevention and control’. You can download my slides here.
I began with a (probably too lengthy) preamble outlining some overall points:
- CRE is a big deal in Europe, especially in the UK, and has prompted unprecedented action on a national level in the form of a Toolkit, a Patient Safety Alert and a letter to all CEOs requesting (demanding?) an action plan. The political picture is similar elsewhere in Europe and in the USA. Although this level of government scrutiny can be challenging, on the whole I think it’s beneficial, and is probably a sizeable factor in the successes achieved with MRSA and CDI.
- Do we go universal or targeted? There’s been much discussion recently about abandoning traditional targeted (aka vertical) approaches in favour of universal (aka horizontal). Interesting, all guidelines that I could lay my hands on favoured a targeted approach for MDR-GNR, centred around screening and isolation of carriers.
- Where is the evidence? We are hamstrung by the lack of high quality studies telling us with any certainty what works to control MDR-GNR. Pretty much all studies to date are either performed in an outbreak setting (regression to the mean…) or include multiple interventions (which worked?), or both. The few studies that evaluated a single intervention in an endemic setting are underpowered to deliver a meaningful conclusion. So, we need bigger and better studies!
- How do you produce good guidelines – who is on the guideline writing dream team, and what are the key pitfalls to avoid. Plus, importantly, how to good guidelines translate through a good policy into good practice?
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.
During Alexander Fleming’s Nobel Lecture on December 11th 1945 he said ‘It is not difficult to make microbes resistant to penicllin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.’ Almost 70 years later, we find ourselves towards the end of antibiotics. In honour of ‘European Antibiotic Awareness Day’, I thought I’d compare several attempts to outline approaches to curb antibiotic resistance:
- A report from a Lancet Infectious Diseases Commission chaired by Prof Otto Cars examining the need for global solutions, which was published yesterday.
- The 2013 G8 Summit, which had a strong focus on antibiotic resistance.
- Dr Brad Spellberg gave an inspiring lecture at ID Week 2013 based on some high-profile recent publications in the New England Journal of Medicine and Clinical Infectious Diseases.
I’ve listed the common themes that emerged in my order of priority (see Table above):
- Prevention is better than cure. We have a reasonably good understanding of what works to prevent the spread of many hospital pathogens, so we need to implement effective strategies. However, there are still important questions about what works to prevent transmission, particularly outside of hospitals, so this area should be prioritised for research. It seems to me there’s an imbalance in the Lancet ID Commission report between prevention and treatment, with a disappointing lack of focus on prevention.
- Reduce antibiotic use. Stop selling antibiotics at the cost of Smarties. Otherwise they will be consumed like Smarties.
- Improve diagnostics. Targeted use of the right antibiotic will help to reduce inappropriate and empiric antibiotic use. The proposed universal use of antibiotics does not fit well with this.
- Implement effective surveillance for action. I very much like the idea of a global antibiotic resistance surveillance network proposed by the Lancet ID Commission, and, in the mean time, a US national ‘EARS-Net’-like network.
- Embrace novel approaches. Table 1 in this open-access NEJM article outlines the key novel approaches available, and their current status in terms of research.
- Highlight the financial burden of resistance. This comes low down the list for me, not because it’s unimportant, but because the burden of resistance is now pretty well characterised.
- Facilitate the development of new antibiotics. Perhaps somewhat controversially, I’ve listed the development of new antibiotics at the bottom of the list. Most bacterial targets have now been covered and even if we do succeed in bringing truly novel antibiotics to market, resistance will emerge eventually.
The noises coming from the global opinion leading healthcare authorities, such as ECDC, CDC and national Departments of Health give me some confidence that the problem of antibiotic resistance is at least now firmly on the agenda. Furthermore, the fact that the solutions mooted by the G8 politicians align closely with those proposed by the expert academics is encouraging. However, the challenges of antibiotic resistance will only grow is left unchecked. We are facing a complex, multifaceted problems, which demands a complex, multifaceted solution. In the pre-antibiotic era, prevention was all we had and we may be there again before too long.
Drs Tara Palmore and David Henderson have written an engaging ‘view from the trenches’ in CID reflecting on their efforts to control an ongoing outbreak of CRE at the NIH Clinical Center, beginning in 2011.
The review outlines their interventions, including:
- aggressive active surveillance (including regular house-wide surveys);
- rapid identification and characterization of resistant organisms and resistance mechanisms (a mixture of conventional culture-based microbiology, mass-spec and mass spec);
- whole-genome sequencing of outbreak isolates (which allowed the identified of counterintuitive transmission patterns);
- enhanced contact precautions for all infected or colonized patients (patients only to leave room for medical reasons, visitors to wear gloves and gowns, staff not to touch personal electronic devices, preferable use of single-use equipment and enhanced terminal disinfection);
- geographic and personnel cohorting;
- daily chlorhexidine gluconate baths;
- dedicating equipment for cohorted patients and aggressive decontamination of equipment that had to be reused on uncohorted patients;
- monitoring adherence to infection control precautions, including unwavering attention to adherence to appropriate hand hygiene procedures (included the use of observing ‘enforcers’ to make sure staff complied with the basics);
- enhanced environmental decontamination (including double bleach wipe daily disinfection, hydrogen peroxide vapor for terminal disinfection and careful management of drains);
- engagement of all stakeholders involved in care of at-risk patients;
- and detailed, frequent communication with hospital staff about issues relating to the outbreak.
The authors discuss the problem of determining which of these interventions worked, since they were implemented more or less simultaneously; the so-called “kitchen sink” approach (Figure). A recent systematic review performed by ECDC identified this problem in virtually all studies evaluating control interventions for CRE.
There’s an interesting section on the ‘unintended consequences’ of publishing in report, including the inevitable scaremongering in some parts of the lay-press. It wasn’t all bad though; this is an unusually detailed article based on the original NIH outbreak report in the Washingtonian.
Some reflections from me:
- This all started with the transfer of a colonized patient from New York. Recognizing and containing colonized patients that are transferred from other hospitals is going one of the most important fronts in the battle against CRE. Worth noting that ECDC are recommending a rectal screen of all cross-border transfers of hospital patients in Europe.
- Mortality was especially high in the NIH outbreak (albeit in patients with serious underlying illness), illustrating the clinical ‘teeth’ that this issue bares.
- The outbreak reignited from an unidentified reservoir after apparently being brought under control; we have a limited understanding of the challenging epidemiology of these organisms.
- It’s sad, though not surprising, that the high hand hygiene compliance achieved during the outbreak could not be sustained following the outbreak.
- As you would expect, relying on clinical cultures only is looking at the tip of the iceberg. Active surveillance is a must.
- One unique aspect of their enhanced contact precautions was an instruction for staff to avoid touching personal electronic items. This makes a lot of sense, and should be considered for inclusion in regular contact precautions.
- There are some telling insights on the practical challenges of cohorting staff, not least the fact that there were not enough physicians to feasibly cohort!
- The initial isolation measures failed, and NIH (commendably) went to extraordinary lengths to bring the outbreak under control. ‘Aggressive’ is used to describe several aspect of their strategy, which seems apt. Israel is another success story of extraordinary CRE control measures. Greece and Italy are examples of where extraordinary measures have not been undertaken and CRE have quickly become endemic.