School’s out forever?

Colleagues from the University of Edinburgh did a really nice job exploring the impact of individual public health interventions on the SARS-CoV-2 reproduction number (R) across 131 countries. Their work fueled the discussion on whether schools should be closed to control transmission. Rightfully so? Read Patricia Bruijning-Verhagens’ take on this study.

For their analyses they used the real-life interventions as they were implemented when the pandemic started and subsequently lifted this summer, inevitably with differences in timing and sequences between countries. Yet, this variation allowed them to explore how each intervention influenced the effective R-value (Reff) over time in each country. A few reflections on the study:

First, we need to understand how comparisons were made; for each country they cut the observation period into time fragments based on the non-pharmaceutical public health interventions (NPIs) that were used. A change in NPI – implemented or lifted – starts a new fragment, which can last from days to months.  For each day in a fragment, they took the Reff from the available country data, and compared the Reff from the last day of a fragment to the Reff on the first day of the new fragment, and subsequently to the Reff values of all subsequent days in that fragment. The result is a daily ratio of old versus new Reff values following a change in NPI.

Next, all Reff ratios were entered in a multivariate model to determine associations between Reff ratios and implementation or lifting of individual NPI. Results can be interpreted as; what is the relative effect of implementing intervention A on Reff, while keeping measures B, C, D, etc. constant.  Importantly, effects are quantified in terms of  RELATIVE reduction/increase in Reff. ABSOLUTE effects of NPI will depend on the Reff at the start of intervention. For example; The Reff ratio for a ban on public gatherings is 0.76 (minus 24%) when we compare the Reff at day 28 after implementation to a situation without bans. Then, if Reff was 3 before implementation, the ban on public gatherings will reduce the Reff to 0.76*3=2.28 at day 28, yielding an absolute reduction in Reff of 0.72. Yet, if Reff was 1.2 at the start, then the absolute reduction will be 0.29 (0.76%*1.2=0.91).

The results of the multivariate model highlight another effect that needs to be considered; whith multiple NPIs implemented/lifted at the same time, their joint effect is smaller than the sum of their individual effects. This is estimated as interaction parameters Z1 and Z2. For instance, closing schools has an Reff ratio of 0.86 on day 14 following closure and the Reff ratio for banning public gatherings is 0.83. The Reff ratio for interaction on day 14 is approximately 1.17 as you can see in the figure below.

So, the interaction eliminates the effect of one of both interventions. The same happens when lifting two interventions at the same time; the joint increase in Reff is less than would be expected on the Reff ratios from each NPI separately. The effect of an NPI may thus differ, depending on the context (i.e. other NPIs in place). An alternative explanation is that the model overestimates the single intervention Reff ratios, because of collinearity in the data. Ideally, one would estimate interaction effects separately for each possible combination of two NPIs, but this requires inclusion of many more parameters in the multivariate model, which were not available. This interaction effect also becomes apparent when we look at the four scenarios of composite NPIs; Moving from scenario candidate 3 to 4, the Reff ratio for day 28 changes by 0.10 only, although two more interventions were added (school closure and stay at home requirements).

An important limitation of the data is that many interventions were implemented or released shortly after one another, seriously limiting the number of informative datapoints and precluding quantification of individual effects of interventions. This is reflected by the wide confidence intervals for many estimates. For instance, schools were already closed at the start of the observation period in 64 of 131 countries and only 25 countries lifted school closure at some point. Moreover, school closure was followed by other interventions within a week in 75% of countries, leaving only 16 countries with more than 7 days to quantify effects of school closure as separate intervention. Furthermore, differences across countries add to heterogeneity in the data and, thus, to imprecision in estimates.

To conclude, this study provides some insight in the effectiveness of some NPIs, but precise effects of individual interventions remains uncertain and will highly depend on the prevailing Reff at the time of implementation/lifting, and other interventions implemented, lifted or maintained. The authors acknowledge some of these limitations and caution that ‘ the impact on R by future reintroduction and re-relaxation of interventions might be substantially different’. Obviously, many readers that claimed major effects of NPI, in particular of school closure, didn’t make it till this stage of the manuscript.

Patricia Bruijning-Verhagen, MD, PhD, is pediatrican and epidemiologist at the Julius Center for Health Sciences and Primary Care, at the UMC Utrecht

WHO IPC Core Components

While I had seen the WHO IPC Core Components, I have totally missed the great video they made.  Thus, with no further comment, here the link to this well-made video.

Just in case that the link via the picture doesn’t work, copy and paste the following link into your browser:

Candida auris part III. Are you prepared?

Schermafbeelding 2017-05-20 om 13.28.23

MMWR just published on the ongoing transmission of Candida auris in the US, while at the same time PLOS Pathogens came with an excellent review on the topic.

By now I had the debatable pleasure to be around for the birth of a few “superbugs”, but this one is clearly putting a lot of effort into reaching the top of the list. I believe (classical pessimist) that many institutions still ignore this new adversary (or are even unaware), and most certainly have no game-plan to prevent its introduction and consequent spread.  In the MMWR publication the current recommendations for C. auris–colonized or infected patients were repeated, with only one change from previous recommendations, namely that a more effective (sporicidal) disinfectant is needed, but I seriously wonder who follows this guidance.

Thus, here it comes, another 30-seconds-questionaire.  Why?  Because I hope that you will prove me wrong and that we – the infection control people at the frontline – act on threat, instead of re-act once we are overrun.

Link to questions


Notes from the Field: Ongoing Transmission of Candida auris in Health Care Facilities — United States, June 2016–May 2017. Weekly / May 19, 2017 / 66(19);514–515

Chowdhary A, Sharma C, Meis J. Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLOS Pathogens May 18, 2017

We need to work together to reduce CRE and other pathogens

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!

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Tubular Bells

Picture courtesy of Justin Cellini

Bells have a certain resonance for me. When they toll, people listen as they are normally of significance. I have just heard one. I have been waiting from this paper to come out since I heard the authors speak about progress at last year’s Infection Prevention Society meeting in Glasgow. Decision-making prior to passing a urinary catheter is something close to my heart, since we need to know why people do things if we are to modify practice. For me, telling people that a list of specific indications for an intervention exists merely makes the decision-maker pick which one on the list fits their desire or perceived need to catheterise most.

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A postcard from Portugal: “Some days we don’t have any needles on the ICU”

portugal stamp

Most of us know that Portugal is facing a dual threat: high rates of antibiotic-resistant bacteria and financial difficulties. This results in a vicious cycle: there’s no money to address antibiotic resistance, so transmission continues unabated and the antibiotic resistance problem gets worse. You can understand the dilemma from the hospital administrators’ viewpoint: I met an intensivist who confessed that “some days we don’t have any needles”. In this situation, is it better to buy some needles or invest in another infection preventionist?

I recently attended a national infection control meeting in Portugal, where I participated in a forum on “International experiences with HCAI”. You can download my slides here.

MRSA first emerged as a problem in the 1980s in Europe. It became a major problem in many European countries in the 1990s and 2000s so that recent data from ECDC shows high rates of meticillin resistance in S. aureus invasive isolates, especially in some southern European countries; the contrast between the rate of MRSA in the UK and Portugal is stark. In the early 2000s, the rate of MRSA was higher in the UK than in Portugal whereas now, it is much lower in the UK (Figure 1).

Figure 1: Rates of meticillin-resistance in invasive S. aureus in the UK and Portugal. Data from EARS-Net.mrsa uk vs portugal earsnet

Greece, Italy and Portugal are especially affected, with 25 to >50% of invasive S. aureus isolates resistant to methicillin. In the UK, a national strategy has yielded a dramatic reduction in the number of MRSA bloodstream isolates reported to the government in a mandatory reporting scheme (Figure 2).

Figure 2: Dramatic reductions in MRSA bacteraemia in England. But what has made the difference? mrsa bacteraemia whats made the differecnce

Since the national intervention in England was multifactorial, it is not clear what made the most impact, and it seems likely that more than one intervention contributed to the decline. Interventions included increased attention to intravenous line care, cleaning and disinfection of the environment, improved diagnostics (including the introduction of chromeagar and rapid PCR) and a national hand hygiene campaign. Perhaps the single most important intervention was the introduction of MRSA reduction targets, which were very controversial at the time, but put the issue of MRSA higher on the priority list for the hospital administration.

And this issue is not restricted to MRSA. In fact, the threat of the resistant Gram-negatives is even greater than MRSA in many ways. Carbapenem-resistant Enterobacteriaceae are rare currently in Portugal, accounting for 1-5% of invasive K. pneumoniae isolates. However, you get the feeling that it’s only a matter of time: carbapenem-resistant Acinetobacter baumannii are now endemic on many Portugese ICUs, and carbapenem use in Portugal is some of the highest in Europe, with >45% of patients on an antibiotic and >5% of patients on a carbapenem according to the ECDC point prevalence survey. Indeed, there has been a disturbing increase in multidrug-resistant K. pneumoniae in Portugal in recent years (Figure 3).

Figure 3: Disturbing emergence of multidrug-resistant Klebsiella pneumoniae in Portugal. Data from EARS-Net.

mdr kleb uk vs portugal ears net

The reason for these differences between the UK and Portugal is not clear, but may include infection control staffing, antibiotic usage and lower prioritisation by hospitals. Some progress is being made in Portugal with the recent launch of a national strategy to control healthcare-associated infection. However, the financial climate and somewhat fragmented healthcare system (compared with the NHS) will make implementation challenging. But at least it’s a start.

Image: Portugal stamp.

Universal vs. targeted interventions in infection prevention and control: the case for a targeted strategy

Today, I participated in a debate with Professor Ian Gould on universal vs. targeted interventions for infection prevention and control at Infection Prevention 2014. I was arguing for a targeted approach, and you can download my slides here, and you can listen to a recording of the talks here.

Universal interventions are appealing: they make no discrimination between patients, there’s a clear message for staff, and you have no way of knowing reliably who is colonized anyway! However, for me to get behind a universal intervention, it would have to demonstrate short-term, long-term and cost-effectiveness.

Before getting into the details of my argument, it is worth defining what we mean by ‘universal’ or ‘targeted’ interventions (see Table 1, below). It’s important to note that an intervention can be targeted either to an individual (e.g. chlorhexidine given to decolonize the skin of a patient known to be colonized with MRSA) or targeted to a population (e.g. chlorhexidine given to all patients in high risk settings, such as the ICU). Screening is an interesting one. It’s easy to mistake screening as a universal strategy when it’s applied to all patients (as is common in the NHS), but it’s fundamentally a targeted strategy to identify patients for an intervention (such as isolation and / or decolonization). A truly universal strategy has no need of screening.

Table 1: defining universal and targeted interventions.universal vs. targeted definitions_cropped

Short-term effectiveness

Short-term effectiveness can be difficult to measure. What is the standard for demonstrating short-term effectiveness? Most common interventions lack accepted standards for demonstrating short-term effectiveness, and the results may well be different as setting and pathogen varies. However, there are some universal approaches that have effectively failed at the first hurdle and not demonstrated even short-term effectiveness. For example, ‘selective’ digestive decontamination has been applied to try to decolonize carriers of resistant Gram-negatives. Although this clearly has some impact, and reduces colonization, it seems to temporarily suppress the level of resistant bacteria in the gut flora, not decolonize the patient. Similarly, the use of universal gloves and gowns failed to meet the primary endpoint in a cluster randomized controlled study (the BUGG study).

Long-term effectiveness

A number of universal strategies that have demonstrated some level of short-term effectiveness fail in terms of long-term effectiveness due to the promotion of bacterial resistance (or reduced susceptibility). For example, selective digestive decontamination on a group of patients resulted in a sharp increase in gentamicin resistance, and perhaps more worryingly an increase in colistin resistance. Furthermore, a microbiomic analysis of a patient undergoing selective digestive decontamination identified a seven-fold increase in the abundance of aminoglycoside resistance genes in the ‘resistome’.

Another way in which universal strategies that are effective in the short-term may fail in the long-term is due to reliance on human beings to maintain compliance with protocols. This is relatively easy during studies, where staff have both support and scrutiny to drive performance. When the spotlight is off and they’re on their own, performance is less impressive. We can see this type of “reverse Hawthorne effect” in compliance with contact precautions, and in hand and environmental hygiene.

Cost effectiveness

Once a strategy has demonstrated both short-term and long-term effectiveness, it must demonstrate cost effectiveness before widespread adoption. Even if you disagree with me and consider screening to be a universal strategy for MRSA when applied to all patients at the time of admission, it has failed to demonstrate cost-effectiveness in almost all scenarios. Economic analysis using the standard threshold of £30,000 per Quality Adjusted Life Year (QALY) has shown that screening all admissions for MRSA is not effective for teaching or acute hospitals at current, high or low prevalence. Universal screening was only cost-effective for specialist hospitals (the vast minority), and then only at some levels of MRSA prevalence. For this reason, the Department of Health is going to reverse its recommendation for universal screening of all hospital admissions.


I can’t think of a single universal intervention that has demonstrated short-term, long-term and cost effectiveness (see Table 2). Decolonization using chlorhexidine comes close, but almost all studies of this intervention have been performed in an ICU setting, where this intervention is applied to a targeted population. I would be uncomfortable about using chlorhexidine for daily bathing of all hospital patients due to the risk of promoting reduced bacterial susceptibility.

Table 2: short-term, long-term and cost-effectiveness of universal interventions.universal vs targeted debate summary_cropped

Targeted interventions have been shown to be effective in reducing transmission, preserve the activity of our precious antimicrobial agents, require less modification of human behaviour, and are cheaper and less resource-intensive. So, on balance, I favour targeted interventions for infection prevention and control.