Category Archives: C.diff. in the news

Clifford McDonald, MD and Alison Laufer-Halpin, Ph.D., of the CDC Discuss the Human Microbiome on C. diff. Spores and More

C Diff Foundation’s “C. diff. Spores and More Global Broadcasting Network” is honored to announce Doctors McDonald and Laufer-Halpin as our guest speakers on

Tuesday, July 25, 2017 at 10 a.m. PT / 1 p.m. ET

(www.cdiffradio.com)

These two leading topic experts will be discussing significant ways to unlock the mysteries of the human microbiome; how it affects our health, the immune system, and why it is so important to protect it.

As part of the Centers for Disease Control and Prevention (CDC) efforts to protect patients and slow antibiotic-resistance, the CDC is investing in research to discover and develop new ways to prevent antibiotic-resistant infections.

 

Learn more about C Diff Radio at: http://www.cdiffradio.com/.

C Diff Foundation Welcomes Denise Graham, Strategic Advisor

We are pleased to welcome Denise Graham
to the C Diff Foundation.

Denise Graham, Founder and President of DDG Associates, formerly the Executive Vice President to the Association for Professionals in Infection Control (APIC) and Epidemiology, led the nation’s public reporting initiative thereby enabling her to work closely with all agencies falling under the U.S. Department of Health and Human Services.  Her expertise in this arena continues by assisting clients with ongoing changes such as value-based purchasing and guidelines coming from the Centers for Disease Control and Prevention (CDC).

With greater than twenty years of experience in the healthcare industry, Denise has formed key working relationships with numerous leading experts.

Denise comes to the C Diff Foundation as Strategic Advisor to assist the organization with greater visibility and continued growth in educating and advocating for C.difficile Infection prevention, treatments, environmental safety and support worldwide.

To contact Denise:, please e-mail her at:    denise@cdifffoundation.org

Early Results From the CDC Prevention’s Emerging Infections Program shows a decline in Clostridium difficile Infections from 2011 to 2014

The early results from the CDC’s Prevention’s Emerging Infections Program show prevalence steadily increased from 2000 to 2010 but decreased from 2011 to 2014, which is around the time antimicrobial stewardship programs were being introduced because of increased awareness of the disease. For example, the VA introduced their program in 2012.

 

Clostridium difficile rates are dropping for the first time in a decade in healthcare settings, and it’s likely due to better cleaning and antibiotic prescribing policies, authorities say.

The rates for national healthcare incidence of the disease may be decreasing anywhere from 9% to 15%, a Centers for Disease Control and Prevention expert said in an NPR report.

Clostridium difficile rates are dropping for the first time in a decade in healthcare settings, and it’s likely due to better cleaning and antibiotic prescribing policies, authorities say.

The rates for national healthcare incidence of the disease may be decreasing anywhere from 9% to 15%, a Centers for Disease Control and Prevention expert said  in an NPR report.

The decreased rates may be credited to an increase in antimicrobial stewardship programs.

The programs restrict unnecessary antibiotic prescriptions, in addition to implementing stricter cleaning and infection control protocols. C. diff does not respond to conventional cleaning methods.

“It was estimated that C. diff infection was the most commonly reported infection [acquired in healthcare settings] nationally,” said Alice Guh, M.D., medical officer at the CDC. “That generated a lot of awareness.”

That’s three times what it was in 2000.

In nursing homes, 20% to 50% of residents can be colonized with the disease at a time, medical experts note.

To read article in its entirety click on the following link

http://www.mcknights.com/news/c-diff-rates-in-healthcare-settings-drop-for-first-time-in-a-decade/article/672543/

Multiple Recurring Clostridium difficile infections (mrCDI) Data From 2001-2012 Study

Article from the Lancashire Post, July 4, 2017

To read the article in its entirety, please click on the following link:

http://www.lep.co.uk/news/offbeat/cases-of-clostridium-difficile-soaring-1-8630398

 

mrCDI (multiple recurring C. difficile infections), they are the most difficult to treat and are rapidly becoming more common, say scientists.

* also referred to  as rCDI, recurring CDI

In the US between 2001 and 2012 the annual rate rose by almost 200 per cent more than four times the increase in ‘ordinary’ C. diff.

The bug, which can kill elderly patients, most commonly affects those who have recently been treated with antibiotics.

The precise reasons for the sharp rise in mrCDI’s incidence is so far unknown but adds strain to healthcare systems with an urgent need for new treatments.

FMT has shown good results in small studies in the war on C. diff but hasn’t yet been thoroughly evaluated.

Professor James Lewis, of Pennsylvania University, said: “The increasing incidence of C. difficile being treated with multiple courses of antibiotics signals rising demand for faecal microbiota transplantation in the United States.

 

“While we know faecal microbiota transplantation is generally safe and effective in the short term, we need to establish the long term safety of this procedure.”

C.diff is a bacterium that causes inflammation of the colon, a condition called colitis. Symptoms include diarrhoea, fever, loss of appetite, nausea and abdominal pain.

Recurrent C.diff, a bout within 90 days of the last, is a major problem with the risk of contracting it again at 50-60 per cent after three or more infections.

 

The bacteria are found in faeces, and people can become infected if they touch items or surfaces that are contaminated and then touch their mouths or mucous membranes.

Burden On Healthcare Systems

C. diff afflicts half a million Americans a year causing tens of thousands of deaths and costing the nation’s healthcare system an estimated $5 billion.

The study published in the Annals of Internal Medicine identified the alarming trend by analysing a nationwide health insurance database with the records of more than 40 million US patients.

Cases of C. diff were considered to have multiple recurrences when doctors treated them with at least three closely spaced courses of antibiotics.

According to the analysis, the incidence of C diff rose by about 43 percent over the study period, compared to 189 percent for mrCDI.

Older females more susceptible

The latter group were more likely to be older with an average age of 56, seven years more than the former’s 49 and were more likely to be female (64 per cent vs. 59 percent.

They were also more likely to have been exposed previously to medications such as corticosteroids, heartburn drugs known as PPIs (proton-pump inhibitors) and antibiotics.

The rapid rise in the incidence of mrCDI may be due in part to Americans’ increasing use of such drugs. But Prof Lewis said other causes are also likely.

He said: “An additional driver of this rise in incidence could be the recent emergence of new strains of C. difficile, such as NAP1, which has been shown to be a risk factor for recurrent CDI.”

C.diff is notorious for spreading among vulnerable patients within hospitals and can lead to fatal blood infections (sepsis) – especially among the elderly.

The antibiotics metronidazole, vancomycin, and fidoxamicin are commonly used to treat CDI……….

Long used in veterinary medicine, FMT is an alternative to antibiotics and involves infusions of foecal matter from healthy intestines.

The aim is to help restore a normal gut bacteria population in the patient and thereby discourage C. diff growth.

But Prof Lewis said despite such promising results more needs to be known about FMT’s long-term safety – and the fast-rising incidence of mrCDI underscores this need.

The American Gastroenterological Association recently set up a formal registry for doctors to report their results with FMT procedures.

Prof Lewis said: “It’s a way in which practitioners who are performing faecal microbiota transplantation can contribute data to help answer these critical questions.”

A small study in 2013 found a single FMT infusion cleared up diarrhoea in 81 percent of the recurrent-CDI patients who received it. On the other hand the standard antibiotic vancomycin worked for just 31 percent.

 

C diff Infection Compared Control in 6 United Kingdom Hospitals With Whole-Genome Sequencing (WGS)

David W. Eyre
Warren N. Fawley
Anu Rajgopal
Christopher Settle
Kalani Mortimer
Simon D. Goldenberg
Susan Dawson
Derrick W. Crook
Tim E. A. Peto
A. Sarah Walker

.

Clin Infect Dis cix338.
Published:
29 May 2017 

Abstract

Background Variation in Clostridium difficile infection (CDI) rates between healthcare institutions suggests overall incidence could be reduced if the lowest rates could be achieved more widely.
Methods.

We used whole-genome sequencing (WGS) of consecutive C. difficile isolates from 6 English hospitals over 1 year (2013–14) to compare infection control performance. Fecal samples with a positive initial screen for C. difficile were sequenced. Within each hospital, we estimated the proportion of cases plausibly acquired from previous cases.

Results.

Overall, 851/971 (87.6%) sequenced samples contained toxin genes, and 451 (46.4%) were fecal-toxin-positive. Of 652 potentially toxigenic isolates >90-days after the study started, 128 (20%, 95% confidence interval [CI] 17–23%) were genetically linked (within ≤2 single nucleotide polymorphisms) to a prior patient’s isolate from the previous 90 days. Hospital 2 had the fewest linked isolates, 7/105 (7%, 3–13%), hospital 1, 9/70 (13%, 6–23%), and hospitals 3–6 had similar proportions of linked isolates (22–26%) (P ≤ .002 comparing hospital-2 vs 3–6). Results were similar adjusting for locally circulating ribotypes. Adjusting for hospital, ribotype-027 had the highest proportion of linked isolates (57%, 95% CI 29–81%). Fecal-toxin-positive and toxin-negative patients were similarly likely to be a potential transmission donor, OR = 1.01 (0.68–1.49). There was no association between the estimated proportion of linked cases and testing rates.

Conclusions.

WGS can be used as a novel surveillance tool to identify varying rates of C. difficile transmission between institutions and therefore to allow targeted efforts to reduce CDI incidence.

To view the article in its entirety please click on the following link:

Preventing Clostridium difficile infection (CDI) is a priority for infection control teams, as it remains a major healthcare-associated infection; although the incidence of healthcare-associated CDI in the United Kingdom has fallen to 1.5 per 10000 inpatient bed-days [1], rates across Europe range from 0.7 to 28.7/10000 bed-days [2], and there were an estimated 293000 healthcare-associated cases in the United States in 2011 [3].

Variation in CDI incidence across countries and between healthcare institutions [4] suggests overall incidence could be reduced if the lowest rates could be achieved more widely. Surveillance programs [5] and penalties for healthcare institutions [6] have been implemented to promote reductions. However, robustly identifying the best performing institutions is challenging.

Variations in true incidence can arise from differences in patient risk factors or locally circulating strains. However, testing strategy also influences reported incidence; reported CDI incidence is associated with testing rates [2]. With low testing rates, CDI ascertainment is likely to be suboptimal. Conversely, high testing rates may lead to overdiagnosis, for example, from testing C. difficile colonized patients, who do not have CDI but may have diarrhea of another cause.

The lack of a universally accepted objective CDI case definition means that robust comparisons of infection rates between institutions should ideally also consider independent measures of which patients are being tested to assess the comparability of differing testing strategies [7].

Additionally, assessing potential sources of healthcare- attributed CDI cases [8] is complex, requiring differentiation between lapses in infection control around symptomatic cases or more generally, deviation from optimal antimicrobial stewardship, and external factors, for example, the food chain. Healthcare exposure increases the risk of C. difficile acquisition; both CDI and colonization increase during hospital stay [9]. However, despite this strong association, studies using whole-genome sequencing (WGS) [10–12] and other genotyping schemes [13–15] have shown that, in endemic settings with standard infection control, only the minority of infections are likely to have been acquired from other hospitalized CDI cases. However, the extent to which this proportion of linked cases varies between hospitals is unknown. Furthermore, such potential variance in linkage rates could identify a potentially preventable group of CDIs.

We investigated variation in the proportion of linked cases using WGS of consecutive C. difficile isolates from 6 hospitals in England and explored whether this could be used to assess their infection control effectiveness, by assessing the proportion of cases plausibly acquired from (linked to) previous cases.

METHODS

Samples and Settings

Hospitals in England are recommended to store frozen aliquots of C. difficile–positive fecal samples for 12 months [16]. Stored consecutive hospital and community diarrheal samples submitted for routine C. difficile testing at 6 hospital laboratories were studied, including a tertiary referral center and teaching hospital, and 5 district general hospitals serving a mix of urban and rural populations (see Supplement). Samples were obtained for a one-year period at each hospital between January 2013 and October 2014. Results were anonymized by assigning a computer-generated random identifier, hospital 1 to hospital 6.

Each hospital used the United Kingdom-recommended 2-stage C. difficile testing algorithm [17]. Hospital 1 used toxin gene polymerase chain reaction (PCR) as a screening test, hospital 2 both glutamate dehydrogenase (GDH) enzyme immunoassay (EIA) and toxin gene PCR as a combined screening test, and hospitals 3–6 a GDH screen. Screen-positive samples underwent confirmatory fecal-toxin EIA testing. Screen-positive, fecal-toxin-positive patients were regarded as having CDI. Toxin gene PCR was also performed as a third-line test on all GDH-positive samples at hospitals 3 and 6, and on samples from inpatients at hospital 5. PCR-positive, fecal-toxin-negative patients, with a clinical syndrome in keeping with CDI, were regarded as potential cases for treatment and infection control purposes.

All screen-positive fecal samples were sent to Leeds General Infirmary microbiology laboratory, United Kingdom (except hospital 2, which submitted isolates and excluded toxin EIA-negative/PCR-negative samples), where they underwent selective culture for C. difficile [18] and capillary electrophoresis ribotyping [19]. Individual patient consent for use of anonymized bacterial isolates was not required.

Sequencing

DNA was extracted from subculture of a single colony from each culture-positive sample and sequenced using Illumina HiSeq2500. Sequence data were processed as previously (see Supplement) [10, 20], mapping sequenced reads to the C. difficile 630 reference genome [21]. Sequences were compared using single-nucleotide polymorphisms (SNPs) between sequences obtained from maximum-likelihood phylogenies [22], corrected for recombination [23]. Potentially toxigenic strains were identified as those containing toxin genes using BLAST searches of de novo [24] assemblies.

Analysis

For each sample, only the hospital, collection date, and fecal-toxin EIA result were known; no further epidemiological data were available. Within each hospital, sequences were compared with all sequences from samples obtained in the prior 90 days. Samples from the community and hospital were included to increase the chance of identifying transmission events occurring in hospital but leading to CDI onset after discharge. From previous estimates of C. difficile evolution and within-host diversity [10, 25, 26], ≤2 SNPs are expected between isolates linked by transmission within 90 days. Therefore, where ≥1 prior sequences within ≤2 SNPs were identified, a case was considered to have been potentially acquired from another case. A 90 day threshold for linking cases was chosen assuming that cases were rapidly treated and infectiousness declined, and that subsequent cases related by direct transmission occurred within incubation periods implied by surveillance definitions [8] and previous studies [13]. As the sources of cases occurring at the start of the study may themselves have been sampled before the study started, the proportion of cases linked to a prior case was only calculated for cases occurring after the first 90 days, with cases in the first 90 days included only as potential sources for subsequent cases.

Two differing case definitions were considered. Initially, all patients with culture-positive potentially toxigenic C. difficile were considered “cases” to capture possible transmission events involving potentially toxigenic C. difficile irrespective of fecal-toxin status. The analysis was then repeated restricted only to fecal-toxin-positive CDI cases. For comparisons with previously published data, the same definition and analysis approach was applied to fecal-toxin-positive CDI cases occurring within 90 days in Oxford (September 2007 to December 2010, split by calendar year) [10] and Leeds (August 2010 to April 2012) [11].

Risk Factor Analysis

Univariate logistic regression was used to determine whether a case’s toxin status affected the risk of it being genetically related to a prior case, that is, potentially acquired from another case. Similarly, logistic regression was used to determine whether a case’s fecal-toxin status affected the risk of it being genetically linked to a subsequent case, that is, to assess the relative infectiousness of fecal-toxin-positive and toxin-negative patients.

To assess whether the locally circulating strain mix affected transmission estimates, hospital-specific estimates were adjusted for ribotype using multivariate logistic regression (see Supplement).

Simulations

To estimate the impact of missing data (as not all sampled cases were sequenced at some hospitals), we simulated transmission at a theoretical hospital. We subsampled simulated cases and calculated the change in the percentage of cases linked to a prior case as the proportion of missing samples increases (details in Supplement).

METHODS

Samples and Settings

Hospitals in England are recommended to store frozen aliquots of C. difficile–positive fecal samples for 12 months [16]. Stored consecutive hospital and community diarrheal samples submitted for routine C. difficile testing at 6 hospital laboratories were studied, including a tertiary referral center and teaching hospital, and 5 district general hospitals serving a mix of urban and rural populations (see Supplement).

Samples were obtained for a one-year period at each hospital between January 2013 and October 2014. Results were anonymized by assigning a computer-generated random identifier, hospital 1 to hospital 6.

Each hospital used the United Kingdom-recommended 2-stage C. difficile testing algorithm [17].

Hospital 1 used toxin gene polymerase chain reaction (PCR) as a screening test,

Hospital 2 both glutamate dehydrogenase (GDH) enzyme immunoassay (EIA) and toxin gene PCR as a combined screening test, and hospitals 3–6 a GDH screen.

Screen-positive samples underwent confirmatory fecal-toxin EIA testing. Screen-positive, fecal-toxin-positive patients were regarded as having CDI. Toxin gene PCR was also performed as a third-line test on all GDH-positive samples at hospitals 3 and 6, and on samples from inpatients at hospital 5. PCR-positive, fecal-toxin-negative patients, with a clinical syndrome in keeping with CDI, were regarded as potential cases for treatment and infection control purposes.

All screen-positive fecal samples were sent to Leeds General Infirmary microbiology laboratory, United Kingdom (except hospital 2, which submitted isolates and excluded toxin EIA-negative/PCR-negative samples), where they underwent selective culture for C. difficile [18] and capillary electrophoresis ribotyping [19]. Individual patient consent for use of anonymized bacterial isolates was not required.

Sequencing

DNA was extracted from subculture of a single colony from each culture-positive sample and sequenced using Illumina HiSeq2500. Sequence data were processed as previously (see Supplement) [10, 20], mapping sequenced reads to the C. difficile 630 reference genome [21]. Sequences were compared using single-nucleotide polymorphisms (SNPs) between sequences obtained from maximum-likelihood phylogenies [22], corrected for recombination [23]. Potentially toxigenic strains were identified as those containing toxin genes using BLAST searches of de novo [24] assemblies.

Analysis

For each sample, only the hospital, collection date, and fecal-toxin EIA result were known; no further epidemiological data were available. Within each hospital, sequences were compared with all sequences from samples obtained in the prior 90 days. Samples from the community and hospital were included to increase the chance of identifying transmission events occurring in hospital but leading to CDI onset after discharge. From previous estimates of C. difficile evolution and within-host diversity [10, 25, 26], ≤2 SNPs are expected between isolates linked by transmission within 90 days. Therefore, where ≥1 prior sequences within ≤2 SNPs were identified, a case was considered to have been potentially acquired from another case. A 90 day threshold for linking cases was chosen assuming that cases were rapidly treated and infectiousness declined, and that subsequent cases related by direct transmission occurred within incubation periods implied by surveillance definitions [8] and previous studies [13]. As the sources of cases occurring at the start of the study may themselves have been sampled before the study started, the proportion of cases linked to a prior case was only calculated for cases occurring after the first 90 days, with cases in the first 90 days included only as potential sources for subsequent cases.

Two differing case definitions were considered. Initially, all patients with culture-positive potentially toxigenic C. difficile were considered “cases” to capture possible transmission events involving potentially toxigenic C. difficile irrespective of fecal-toxin status. The analysis was then repeated restricted only to fecal-toxin-positive CDI cases. For comparisons with previously published data, the same definition and analysis approach was applied to fecal-toxin-positive CDI cases occurring within 90 days in Oxford (September 2007 to December 2010, split by calendar year) [10] and Leeds (August 2010 to April 2012) [11].

Risk Factor Analysis

Univariate logistic regression was used to determine whether a case’s toxin status affected the risk of it being genetically related to a prior case, that is, potentially acquired from another case. Similarly, logistic regression was used to determine whether a case’s fecal-toxin status affected the risk of it being genetically linked to a subsequent case, that is, to assess the relative infectiousness of fecal-toxin-positive and toxin-negative patients.

To assess whether the locally circulating strain mix affected transmission estimates, hospital-specific estimates were adjusted for ribotype using multivariate logistic regression (see Supplement).

Simulations

To estimate the impact of missing data (as not all sampled cases were sequenced at some hospitals), we simulated transmission at a theoretical hospital. We sub-sampled simulated cases and calculated the change in the percentage of cases linked to a prior case as the proportion of missing samples increases (details in Supplement).

RESULTS

Consecutive samples sent for C. difficile testing at 6 hospitals were studied for 12 months (Table 1). In total, 1052/1098 (96%) of GDH/toxin-PCR screen-positive samples were available: 95/98 (97%) at hospital 1, 144/178 (81%) at hospital 2, 118/127 (93%) at hospital 5 and otherwise 100%. 974/1052 (93%) available samples were confirmed as C. difficile on culture. For the 5 hospitals with available testing data, 887/21539 (4.1%) of samples submitted for testing were culture-positive (Table 1); 971/974 (99.7%) culture-positive samples were successfully sequenced. Of sequenced culture-positive samples, 451/971 (46.4%) were EIA fecal-toxin-positive, 35–71% by hospital. By contrast, 851/971 (87.6%) were potentially toxigenic, that is, had toxin genes detected via sequence data. Hence, 400/851 (47.0%) samples containing potentially toxigenic C. difficile did not have fecal-toxin detected. In the 971 sequenced isolates, the most common ribotypes identified were 014, 015, 005, 002, 020, and 078 (Table 2). Ribotype-027(NAP1/ST-1) only accounted for 16 (2%) cases.

To view graphs and tables, please click the following link:

https://academic.oup.com/cid/article/doi/10.1093/cid/cix338/3857742/Comparison-of-Control-of-Clostridium-difficile

Relatedness to Prior Cases

The proportion of cases plausibly linked to a prior case by recent transmission varied by hospital. Of 851 sequenced potentially toxigenic cases, all were considered as potential sources of infection, but only the 652 obtained after the first 90 days of sampling at each hospital were assessed for linkage to a previous case. Across the 6 hospitals, 128/652 (20%, 95% confidence interval [CI] 17–23%) potentially toxigenic cases were genetically linked to a prior case from the previous 90 days. Hospital 2 had the fewest cases linked to a prior case, 7/105 (7%, 3–13%), hospital 1 had an intermediate number, 9/70 (13%, 6–23%), and hospitals 3–6 had similar numbers of linked cases, 37/153 (24%, 18–32%), 32/134 (24%, 17–32%), 18/76 (24%, 15–35%), and 25/113 (22%, 15–31%), respectively. Hospital 2 had significantly fewer linked cases than hospitals 3–6 (P ≤ .002), with weaker evidence for lower rates in hospital 1 than hospitals 3, 4, and 5 (P = .05, .07, .09, respectively). Overall, 48/128 (38%) of potential transmission recipients were fecal-toxin-negative (11–68% across hospitals, Figure 1A). Fecal-toxin detection in a recipient was associated with increased odds of having a potential transmission donor, odds ratio 1.67 (95% CI 1.12–2.48, P = .01).

 

In total, 59/128 (46%) putative transmission recipients were only linked to ≥1 fecal-toxin-positive potential donors, 50 (39%) to only fecal-toxin-negative donors, and 19 (15%) to both toxin-positive and toxin-negative donors. Considering the 667 cases occurring in the first 270 days at each hospital, that is, the cases with an opportunity to transmit to a sampled case within the next 90 days, 120 (18%) were potential donors. Fecal-toxin-positive and -negative cases were similarly infectious: the odds ratio for a fecal-toxin- positive case, compared to a fecal-toxin-negative case, being a potential transmission donor was 1.01 (95% CI 0.68–1.49, P = .97).

When only considering transmission to and from fecal- toxin-positive cases, fewer cases were genetically linked to a previous case within 90 days, 51/335 (15%, 95% CI 12–20%). We observed a different “ranking” of hospitals compared with the above analysis of linkage rates based on potentially toxigenic isolate-positive patients: hospital 3 had the greatest proportion of fecal-toxin-positive cases genetically related to a prior fecal-toxin-positive case, 31% (22–41%), and hospital 6 the lowest, 0% (0–9%) (Figure 1B).

Results were similar to those for all potentially toxigenic C. difficile (Figure 1A) if all C. difficile sequences, nontoxigenic as well as potentially toxigenic, were considered (Figure 1C). Considering only nontoxigenic isolates, very similarly to potentially toxigenic isolates, 19/96 (20%, 95% CI 12–29%) were genetically linked to a prior patient isolate from the previous 90 days.

There was no evidence that the number of linked cases varied during the study at any hospital (Figure 1D). Because different numbers of sequences were obtained from the different hospitals, we investigated how this affected the estimated proportions of cases linked to a prior case. Estimated proportions of linked cases were relatively stable once approximately 50 cases had been sequenced (Figure 2).

Impact of Testing Frequency

The proportion of originally tested samples that were stored and then culture-positive was similar across the 5 hospitals with testing data, 3.8%–4.3% (P = .89, Table 1). In contrast, testing rates ranged from 98 to 239 samples per 10000 bed-days. There was no association between the estimated proportion of cases linked to a previous case within 90 days and testing rates (P = .19 for all potentially toxigenic cases, Figure 3A, and P = .60 for fecal-toxin-positive cases only, Figure 3B). For comparison, Figure 3B also displays rates of linked cases for previously published data from Oxford and Leeds.

Figure 2:  Proportion of potentially toxigenic cases linked to a previous potentially toxigenic case by hospital and number of sequences obtained. Abbreviation: SNP, single-nucleotide polymorphism.

Adjustment for Ribotype

After adjustment for locally circulating ribotypes, estimates of the proportion of potentially toxigenic cases related to a previous potentially toxigenic case within ≤2 SNPs and ≤90 days remained largely unchanged (Figure 4A). Using the same model, per-ribotype estimates for the proportion of related cases, adjusted for differences across hospitals, showed more variation (Figure 4B, Table 2 for unadjusted proportions). Ribotype-027 had significantly more related cases (adjusted proportion, 57%, 95% CI 29–81%, n = 12) than the comparison group of all other ribotypes (11%, 7–18%, P = .002, n = 124), as did ribotype-002 (25%, 15–38%, P = .04, n = 53), 012 (50%, 29–71%, P = .001, n = 22), and 087 (44%, 23–67%, P = .005, n = 18).

Adjustment for Completeness of Testing

As only 144/178 (81%) of GDH-positive samples at hospital 2 were retrievable for culture we assessed the likely impact of these missing samples on the estimated proportion of linked cases by simulating transmission and sampling at a theoretical hospital (Figure S1). As sampling becomes increasingly less complete, the estimated proportion of linked cases declines proportional to the probability of a case being sampled. Applying our simulation to hospital 2 provides a revised estimate of 8% of cases being linked to a prior case (see Supplement for details).

……………………….

DISCUSSION

Here, we demonstrate the value of WGS as a tool to estimate different rates of C. difficile transmission across institutions. Sequencing consecutive C. difficile isolates from routine testing over one year, we found transmission rates varied between 6 hospitals. Considering all patients with potentially toxigenic C. difficile, irrespective of fecal-toxin status, in the best performing hospital only 7% of patients’ isolates were sufficiently genetically related to a previous isolate from another patient to support transmission (8% adjusting for incomplete sampling). By contrast, approximately 3–4-fold more isolates (22–26%) were related in 4 of the other hospitals. These results remained similar after adjusting for the locally circulating strains.

Restricting to only patients with fecal-toxin-positive CDI, we confirmed previous findings that only a minority of CDI cases arise from contact with another symptomatic case: 35% in Oxford [10], 35% in Leeds [11], and 37% of ribotype-027 cases in Liverpool [12], were genetically linked to a previous case, with only a subset of these cases sharing time and space on the same hospital ward.

Applying the criteria for linking cases used in the present study to the Oxford and Leeds data sets, 38% of cases in Oxford were linked to a previous case in 2008 falling to 19% in 2010, and 30% of cases were similarly linked in Leeds. Across the 6 study hospitals, serving a range of populations, toxin-positive CDI linkage rates were all <15% with the exception of hospital 3, where 31% of cases were linked. It is likely the lower linkage rates in the current study in part reflect the falling incidence of ribotype-027 [11], associated with more onward transmission in this study, likely as a result of national fluoroquinolone restriction [27] but may also represent changes in infection prevention and control practice.

Our findings also support the recently reported role in transmission of GDH-positive patients with toxigenic C. difficile, but no detected fecal-toxin [28]. By sequencing all GDH-positive cases, we were able to compare the probability of fecal-toxin-positive and toxin-negative patients being potential sources of transmission, that is, having C. difficile genetically linked to a subsequent C. difficile isolate in another patient. Fecal-toxin-negative patients were similarly infectious to fecal-toxin-positive patients: fecal-toxin status did not affect the odds of being a potential transmission source. Strategies to identify and institute infection control measures around patients with potentially toxigenic C. difficile without detected fecal-toxin are therefore likely to reduce overall CDI incidence, although may be more costly, for example if toxin gene PCR is used as an initial screen rather than GDH EIA. Toxin-positive patients, that is, CDI cases, were more likely to have an identified potential transmission donor, than toxin-negative patients. This is in keeping with previous observations that recent C. difficile acquisition is associated with increased risk of disease, whereas long-term carriage is relatively protective [29].

It is likely that differing clinical CDI testing thresholds applied across the study hospitals, despite each being guided by national recommendations; notably, testing rates varied more than 2-fold between hospitals (98–239 tests/10000 bed-days). However, despite this variation, the overall proportion of samples tested that were C. difficile culture-positive was very similar across hospitals (~4%). These 2 findings combined resulted in varying rates of potentially toxigenic C. difficile isolation, 4.2–8.2/10000 bed-days, and varying (fecal-toxin-positive) CDI rates, 1.8–5.7/10000 bed-days. As the proportion of samples that were C. difficile culture-positive was close to reported community asymptomatic C. difficile colonization rates (~4%), and lower than reported colonization rates in asymptomatic hospital inpatients, (~10%) [30], it is possible that the higher reported CDI rates in some study hospitals may reflect overascertainment; independent assessment of which symptomatic patients are tested for CDI would be required to resolve this with certainty [7]. As designed, the study did not measure the extent of transmission involving asymptomatic patients, and therefore it is likely that not all hospital-associated transmission is captured. However, as this was the case for all hospitals, comparisons can still be made between hospitals and with previous studies investigating symptomatic patients.

Interestingly, we did not find any evidence of a relationship between rates of C. difficile testing and proportions of cases that could be linked to a previous case. Differing sampling/testing will likely mean the study populations at each hospital varied, for example with some institutions potentially more likely to include milder CDI cases than others. It should also be noted that differences in the population sampled by a particular testing strategy may affect the proportion of cases linked differently to incomplete sampling of a given population. We quantified the impact of the latter through simulation. Unfortunately, incomplete sampling could appear very similar to the impact of good infection control, as both results in low proportions of linked cases. One study limitation is that we only sequenced 81% GDH-positive samples at hospital 2. However, we demonstrate it may be possible to adjust for incomplete sampling, providing missed cases as assumed missing at random, and the number of onward transmissions from each case was random.

Both a limitation and a strength of our approach is that it relies only on sequencing laboratory samples and sampling dates. We demonstrate this allows comparative hospital surveillance with very limited, and no personal, sensitive or confidential, data. However, without ward admission and patient contact data, it is possible some genetically linked cases do not represent direct transmission from other cases. Genetic links might also arise through indirect healthcare-associated transmission via unsampled hosts or the hospital environment. Additionally, a minority of cases, without healthcare exposure in the last 90 days, may still have been genetically linked. However, there is no obvious reason why genetically related community C. difficile exposures, and therefore the proportion of such cases linked, should vary across England at a population level, even if other CDI risk factors do vary geographically, for example, antimicrobial use. Therefore, although we analyze transmission within the populations served by each hospital, as most CDI cases have recent healthcare exposure, the overall proportion of linked cases is still likely to be a reasonable combined indicator of infection control performance around cases and more generally. Without patient-level identifiers some repeat tests from the same patient may have been wrongly assigned as transmission events; however, we anticipate this was uncommon; repeat testing within 28 days is discouraged in national guidelines [17], and such samples are frequently not routinely processed.

Our method of comparing infection control performance depends on culturing C. difficile, which is not routinely undertaken, and on sequencing at least 6 months of samples, at around US$100 per sample. However, if samples are stored, as recommended in England, C. difficile could be cultured and sequenced retrospectively if increased incidence was noted and then continued prospectively to monitor the impact of any interventions. The cost-effectiveness of such an approach needs further evaluation.

In summary, here we present a novel method that enables assessment of the extent of hospital-acquired infection transmission within healthcare institutions. This approach revealed differences in CDI transmission rates across 6 English hospitals. It demonstrates the potential of whole-genome sequencing as a nationwide tool to identify institutions with excellent and also suboptimal infection control and therefore has the potential to allow targeted efforts to reduce CDI incidence.

Resources:  https://academic.oup.com/cid/article/doi/10.1093/cid/cix338/3857742/Comparison-of-Control-of-Clostridium-difficile

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Researchers Suggest a Portion Of C. diff. Cases In Europe Involve Infections Associated With Other Sources Outside of Healthcare-Associated Infections

As part of a multicenter study, investigators from the University of Oxford, the University of Leeds, Astellas Pharma Europe, and elsewhere used a combination of ribotyping, sequencing, phylogenetics, and geographic analyses to retrace the genetic diversity and potential sources of C. difficile isolates involved in infections in European hospitals.

Recent research suggests a proportion of Clostridium difficile cases in Europe involve not only hospital-acquired infections but also infections associated with other sources, such as food.

As stated in the article:

https://www.genomeweb.com/sequencing/clostridium-difficile-genetic-patterns-europe-point-possible-infection-sources-beyond?utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Mon%20PM%202017-04-24&utm_term=GW%20Daily%20News%20Bulletin

David Eyre, a clinical lecturer at the University of Oxford, was slated to present the work at the European Congress of Clinical Microbiology and Infectious Diseases annual 2017 meeting in Vienna this past weekend. The study was funded by Astellas Pharma’s Europe, Middle East, and Africa (EMEA) program.

“We don’t know much about how C. difficile might be spread in the food chain, but this research suggests it may be very widespread,” Eyre said in a statement. “If that turns out to be the case, then we need to focus on some new preventative strategies such as vaccination in humans once this is possible, or we might need to look at our use of animal fertilizers on crops.”

“This study doesn’t give us any definitive answers,” he explained, “but it does suggest other factors [than hospital infections] are at play in the spread of C. difficile and more research is urgently needed to pin them down.”

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Some of the strains clustered by locale, consistent with spread from one individual to the next, for example in a healthcare setting. But more unexpectedly, the team also saw strains smattered across seemingly unconnected sites. And because at least one of those strains had previously been linked to pig farming, the researchers speculated that some infections may have been transmitted through food sources.

 

To read the article in its entirety click on the following link:

https://www.genomeweb.com/sequencing/clostridium-difficile-genetic-patterns-europe-point-possible-infection-sources-beyond?utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Mon%20PM%202017-04-24&utm_term=GW%20Daily%20News%20Bulletin

Contagion Live Shared Interview With Belinda Ostrowsky, MD, How to Be Smarter About C. difficile Testing

 How to Be Smarter About Testing for C. difficile
APR 03, 2017

Belinda Ostrowsky, MD, MPH, Health Systems Director of Epidemiology, Antimicrobial Stewardship & Infection Prevention, Montefiore Medical Center, and Associate Professor of Clinical Medicine, Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, explains how to be more sensible when it comes to testing for Clostridium difficile.

http://www.contagionlive.com/videos/how-to-be-smarter-about-testing-for-c-difficile