Common Food Additive Promoting C. diff?

Trehalose, in the food supply since 2000, may play a role in the increased prevalence and toxicity of Clostridium difficile, according to a new study appearing in the journal Nature. In this 150-Second analysis, F. Perry Wilson, MD, examines the data, and speculates on the future of this common additive.

An article appearing in Nature made waves last week when it suggested that a common food additive known as trehalose might be responsible for the current Clostridium difficile epidemic.

Food additives? Infectious diarrhea? This one merits a closer look.

First a bit of background.

These are the infection rates per hospital stay for C. diff over time in the U.S. You’ll note a bit of an uptick starting around the year 2000.

 C. diff, like all bacteria, has several strains, and if there’s one to worry about it’s ribotype 027 – a “hypervirulent” strain that emerged in 1985 but has been outcompeting other C. diff strains over the past 20 years. What gives 027 its competitive edge?

The Nature paper shows us that one thing 027 can do is a bit special – it can metabolize trehalose, a common food additive that the FDA labeled “safe” in the year 2000 – right when 027 starts to really take off.

So what is trehalose? Chemically, it’s two glucose molecules linked by a glucoside bond.

It is the primary blood sugar in flying insects like bees which is of no human interest but is fun to discuss at cocktail parties.

Trehalose is not calorie-free and it’s a bit sweet but it’s mostly a stabilizing agent used in all sorts of processed foods and products – toothpastes, ice cream, breads, hand lotion, gum.

The Nature paper shows us that two of the most virulent strains of C. diff, including 027, can metabolize even trace amounts of trehalose. They go on to show that when strains are mixed together, low concentrations of trehalose can lead to natural selection for the 027 strain – it can simply outcompete the less virulent strains by metabolizing this scarce resource.

I asked lead author Dr. Robert Britton about competition with other bacteria.

He wrote: “We don’t know about competition with other bacteria but many do have the machinery to eat trehalose (and to actually make it).”

Of course, C. diff usually rises to prominence when other gut bacteria have been killed by antibiotics, meaning competition with other bacteria is limited.

The paper also suggests that the virulence of the 027 strain may be linked to trehalose directly. When infected mice were given trehalose, they were much more likely to die, as you can see from this Kaplan-Meier curve.

Now, this study is not going to lead to a cure for C. diff. If we were to eliminate dietary trehalose I have no doubt that certain strains would evolve to exploit any other energy-containing molecule we put in our bodies. And to be fair, I should mention some studies suggest that trehalose has a protective role in reducing the rate of fatty liver disease.

 But this study reminds us that while we may be able to easily determine if a compound is toxic to a human cell, determining how a compound will affect the complex interplay of the human system with the thousands and millions of symbiont species within and around us, is exceedingly difficult. So eat with care.

Is Antibiotic Prescribing by Dentists an Overlooked Problem?

When looking for a potential cause of community-acquired Clostridium difficileinfection (CDI), dental prescribing is often a large and overlooked blind spot, according to a recent report.

A report done in partnership between the Emerging Infections Program at the Centers for Disease Control and Prevention and state health departments found that upward of 15% of patients with community-acquired CDI who reported taking antibiotics were prescribed the drugs by their dentist within the 12 weeks before illness.

The report also noted that dentists routinely prescribe antibiotics to their patients without follow-up. In 2013, dentists wrote prescriptions for a staggering 24.5 million courses of antibiotics, or 77.5 prescriptions per 1000 people. This accounts for approximately 10% of all antibiotic prescriptions in the outpatient setting.

Dentists often give their patients antibiotics to manage oral infections and for prophylaxis before dental visits for patients meeting certain clinical criteria. Recent guidance on who should receive antibiotic prophylaxis before dental visits has changed since then, but it’s unknown whether dentists have changed their prescribing habits as a result.

Question 1 of 3

In an average month, how many of your patients report receiving antibiotic prescriptions from their dentists?


1 to 10

11 to 20

21 to 30

More than 30


Question 2 of 3

How often do you coordinate antibiotic prescribing with patients’ dentists?





Question 3 of 3

Have you ever asked a dentist to prescribe antibiotics before a dental procedure for a patient who has had a joint replacement, congenital heart disease, or some other potential risk factor?



Rapid Antibiotic Testing Comes of Age


Phoenix—In recent years, there has been an explosion of FDA-approved rapid diagnostic testing methodologies for infectious diseases. During an education session at the 2017 annual meeting of the American College of Clinical Pharmacy, pharmacists discussed some of the excitement surrounding the recent advances in treating the most worrisome bugs.

“Rapid diagnostic tests represents one of the few bright spots in the changing world of escalating antimicrobial resistance and stewardship,” said Katherine Perez, PharmD, BCPS-AQ ID, an infectious disease clinical specialist at Houston Methodist.

Dr. Perez pointed out that rapid identification of microorganisms and resistance is critical for targeted treatment in serious infections caused by multidrug-resistant gram-negative bacteria (GNB). Research efforts have focused on pathogens associated with increased morbidity, mortality and excessive health care costs, including influenza virus, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species, Clostridium difficile, extended-spectrum beta-lactamase (ESBL)-producing Klebsiella species, carbapenemases, Mycobacterium tuberculosis and Candida species.


Current conventional culture-based methods to isolate and identify a pathogen, followed by susceptibility testing, can take 72 hours or more. This is concerning, Dr. Perez noted, because delaying administration of appropriate antimicrobials is associated with increased mortality rates for patients with gram-negative septicemia and septic shock (Clin Infect Dis 2013;57:S139-S170). Having the ability to detect the presence of resistant bacteria in a clinical sample in less than one hour, Dr. Perez noted, helps improve the effectiveness of antimicrobial stewardship programs.

In an ideal world, antimicrobial treatment would be prompt; appropriate; administered at an adequate dose and interval, guided by pharmacokinetic/pharmacodynamic principles; and discontinued appropriately, based on clinical response and microbiological data. All of this, Dr. Perez noted, is contingent on accurately determining a pathogen’s identification and antimicrobial susceptibility.

Various Methodologies

Emerging rapid detection methods of pathogens include a variety of technologies that vary greatly in complexity, price, speed and ability to identify single or multiple pathogens. Dr. Perez highlighted a number of rapid infectious disease diagnostics using different methodologies, including the polymerase chain reaction (PCR)-based FilmArray Blood Culture Identification panel (BioFire Diagnostics LLC). The panel tests for 24 pathogens and three antibiotic resistance genes associated with bloodstream infections. The test can accurately identify pathogens in more than nine of 10 positive blood cultures in about an hour, with only two minutes of hands-on time, she said (J Clin Microbiol 2016;54:687-698).


The advantages of PCR-based testing, she noted, include rapid results, low detection limits, specific organism detection and subtyping, not requiring growth on media, high throughput and, generally, short hands-on time for laboratory staff. Disadvantages include susceptibility to contamination, the need for dedicated laboratory space for instruments, and dependence on quality of products used, and most require initiation from positive cultures/single colonies. PCR cannot indicate viability of the pathogen detected and comes with practical limitations that can affect turnaround time.

Targeting Worrisome Bugs

Ryan Shields, PharmD, MS, associate professor of medicine in the Division of Infectious Diseases at the University of Pittsburgh, said carbapenem-resistant bugs top the list of most worrisome bugs. Carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae (CRE) are listed as critical priorities for research and development of new antibiotics by the World Health Organization. The CDC lists multidrug-resistant A. baumannii and P. aeruginosa as serious threats, and CRE as an urgent threat.


Carbapenem-resistant pathogens, Dr. Shields said, are associated with loss of our last line of defense against resistant pathogens and cross-resistance to other antibiotic classes. They are also associated with increased lengths of stay, health care expenditures and increased mortality rates among patients. “Carbapenem resistance is a major threat to public health,” he said.

A recent study concluded that antibiotic stewardship and infection prevention and control have been unable to prevent the rapid spread of resistant GNB, particularly carbapenem-resistant P. aeruginosa and other nonfermenting GNB, ESBL-producing and CRE (Intensive Care Med 2017 Jul 21. [Epub ahead of print]). Carbapenem-resistant Klebsiella pneumoniae, Dr. Perez said, is an emerging nosocomial pathogen associated with considerable mortality.

Rapid tests should detect all carbapenem-resistant organisms and distinguish carbapenemase-producing organisms from isolates that are resistant to carbapenems because of other mechanisms, Dr. Perez noted. The organisms have diverse enzyme types and considerable variation in levels of phenotypic carbapenem resistance (e.g., minimum inhibitory concentration evaluation). Non–carbapenemase-mediated carbapenem resistance complicates things.

The Rapidec Carba NP biochemical test (bioMérieux) detects any type of carbapenemase activity by monitoring the color change of a pH indicator according to hydrolysis of the substrate, imipenem. The tests are rapid, easy to read and handle, and cost-effective, and have a turnaround time of approximately one hour. They can be used for first-line screening in the absence of molecular typing, Dr. Perez said.

Table. Integrating Rapid Diagnostics Into Practice
Beta-Lactamase Bacteria Recommended Therapy
CTX-M (ESBL) Enterobacteriaceae Ertapenem (Invanz, Merck)
KPC Klebsiella pneumoniae and other enteric gram-negative organisms Colistin + tigecycline/aminoglycoside/carbapenem; ceftazidime-avibactam (Avycaz, Allergan)
NDM carbapenemases K. pneumoniae and other enteric gram-negative organisms Colistin + tigecycline; aztreonam (Azactam, Bristol-Myers Squibb) + ceftazidime-avibactam
VIM or IMP carbapenemase Pseudomonas aeruginosa Colistin + aztreonam/aminoglycoside/tigecycline
OXA beta-lactamases P. aeruginosa Colistin + high-dose carbapenem
Acinetobacter baumannii Colistin + minocycline; high-dose carbapenem
ESBL, extended-spectrum beta-lactamase Source: Katherine Perez, PharmD, BCPS-AQ ID.

Integrating Into Practice

Dr. Perez noted that the Infectious Diseases Society of America, CDC and National Quality Forum have recognized the emerging role of rapid diagnostics and biomarkers in antimicrobial stewardship programs. Molecular biology and testing can be used to improve antimicrobial stewardship interventions, assist in anti-infective escalation and de-escalation efforts, and improve clinical outcomes.

Implementation of rapid diagnostic tests may be cost-neutral or even constitute a cost savings when stewardship efforts streamline care. “Rapid diagnostic tests can reduce total hospital costs by decreasing length of stay,” Dr. Perez said.

Multiple stakeholders, including infectious disease physicians, microbiologists and laboratory pharmacists, need to create guidance for clinicians up front regarding the use of rapid infectious disease diagnostics, Dr. Perez noted. “There is a need to connect the dots among antimicrobial stewardship, rapid diagnostics and improved outcomes to make this case,” she said. “Who gets notified when an organism and a resistance marker are identified by rapid diagnostics?”

Providing Guidance

Stewardship pharmacists can provide guidance to clinicians to positively affect patient care. Some stewardship programs use automated alerts for positive blood cultures coupled with antimicrobial stewardship interventions, to ensure that a patient is prescribed effective antibiotics sooner, Dr. Perez said. Selective antibiogram reports for blood culture isolates are helpful for driving empirical choices and may be useful particularly for multidrug-resistant organisms.

“Advances in testing provide new opportunities for stewardship programs to streamline care for patients with serious infections,” she added. “Rapid diagnostic tests are game-changing for patient care moving forward.”

Donor-patient compatibility may play important role in stool transplant

A study published in Science shows new strains of microbes from the donor were more likely to colonize the patient’s intestines if that particular species exists in the patient’s gut.

The finding suggests that by matching donors to patients, the success of faecal microbiota transplant can be considerably increased. Moreover, focusing on bacterial strands instead of species could also improve the effectiveness of the novel therapy in conditions where it’s currently not effective.

The bulk of the population has Escherichia coli in their intestines but different people have different strains of the species; some strains can cause health issues. By differentiating between the strains, the researchers could track if the microbes in a patient’s gut after a stool transplant were their own or came from the donor.

Using this approach we can examine if, for instance, an antibiotic-resistant strain is replaced by a non-resistant one, said lead researcher Professor Willem de Vos, of the Wageningen University, Netherlands. It could then aid in designing stool transplants for other conditions besides recurrentClostridium difficile infections.

The study is part of a clinical trial on the use of stool transplants as a treatment modality for metabolic syndrome. The data is collected from only 10 participants but there are strong indications that donor-patient compatibility plays a bigger role than previously thought; transplants from one donor led to very different outcomes in three individual patients.

For Superbugs, Fight Fire With Fire: Non-Toxic C. Diff Bacteria Ward Off Antibiotic-Resistant Strain

If you haven’t heard of Clostridium difficile, better known as C. difficile or C. Diff, you will soon. It’s one of the fastest growing superbugs, rivaling MRSA in both frequency and severity. Due to antibiotic resistance, a cure for C. difficile  has been elusive, but a recent study suggests that we’ve been looking in the wrong places and the only thing strong enough to fight off C. difficileis actually more C. difficile.

bacteria culture

According to a report published in the Journal of the American Medical Association, trials on 173 individuals with C. difficile infections showed that introducing a non-toxigenic C. difficile strain helped to dramatically cut the odds of repeat infections and is a promising start to finally getting an upper hand on this potentially fatal superbug.

In the study, conducted by researchers at Loyola University Health System in Illinois, patients with C. difficile infections were given spores of a non-toxin producing strain of C. difficile. Around 69 percent of the time the “friendlier” strain was able to occupy areas in the gut where the toxic C. difficile strain normally thrived. This inhibited the severe C. difficile from returning and only one in 50 of the patients experienced a recurrent C. difficile infection.

The research is still in its earliest stages, but the researchers are excited about the results. Although the patient remains infected with C. difficile, more importantly, the symptoms cease. The eventual goal of the research is to develop a treatment involving the digestion of “friendly” C. difficile spores to indefinitely prevent a patient once again falling ill from the infection.

“What we’re doing is establishing competition with the original, toxic strain,” Dr. Dale Gerding, one of the researchers involved in the study explained, as reported by the BBC. “I’m excited about this and looking forward to a phase-three [larger] trial. We think it’ll go a long way to reduce C. diff recurrence.”

C. difficile infections are almost exclusive to hospital settings, clinics, nursing homes and other health care facilities. The reason for this is that the bacteria take hold in individuals whose normal fauna of bacteria is disrupted due to antibiotic courses. Without the normal healthy bacteria standing in the way, the drug-resistant C. difficile can take hold and cause inflammation in the patient’s colon. According to the Centers for Disease Control and PreventionC. difficile infections are widespread and each year it’s linked to about 29,000 deaths in the United States.

Symptoms of C. difficile infections include frequent diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness. These infections are commonly treated with antibiotics, but due to the bacteria’s evolved resistance to treatment the infection returns in around 20 percent of cases. Currently fecal transplants are the most effective way to treat repeat C. difficile infections, but the recent study suggests an equally effective and far less invasive approach to the condition.

Scientists develop ‘electronic nose’ for rapid detection of C. diff infection

A fast-sensitive “electronic-nose” for sniffing the highly infectious bacteria C. diff, that causes diarrhoea, temperature and stomach cramps, has been developed by a team at the University of Leicester.

Using a mass spectrometer, the research team has demonstrated that it is possible to identify the unique ‘smell’ of C. diff which would lead to rapid diagnosis of the condition.

What is more, the Leicester team say it could be possible to identify different of the disease simply from their smell – a chemical fingerprint – helping medics to target the particular condition.

The research is published on-line in the journal Metabolomics.

Professor Paul Monks, from the Department of Chemistry, said: “The and identification of the bug Clostridium difficile (often known as C. diff) is a primary concern in healthcare facilities. Rapid and accurate diagnoses are important to reduce Clostridum difficile infections, as well as to provide the right treatment to infected patients.

“Delayed treatment and inappropriate antibiotics not only cause high morbidity and mortality, but also add costs to the healthcare system through lost bed days.

Different strains of C. difficile can cause different symptoms and may need to be treated differently so a test that could determine not only an infection, but what type of infection could lead to new treatment options.”

The new published research from the University of Leicester has shown that is possible to ‘sniff’ the infection for rapid detection of Clostridium difficile. The team have measured the Volatile Organic Compounds (VOCs) given out by different of strains of Clostridium difficile and have shown that many of them have a unique “smell”. In particular, different strains show different chemical fingerprints which are detected by a .

The work was a collaboration between University chemists who developed the “electronic-nose” for sniffing volatiles and a colleague in microbiology who has a large collection of well characterised strains of Clostridium difficile.

The work suggests that the detection of the chemical fingerprint may allow for a rapid means of identifying C. difficile infection, as well as providing markers for the way the different strains grow.

Professor Monks added: “Our approach may lead to a rapid clinical diagnostic test based on the VOCs released from faecal samples of patients infected with C. difficile. We do not underestimate the challenges in sampling and attributing C. difficile VOCs from faecal samples.”

Dr Martha Clokie, from the Department of Microbiology and Immunology, added: “Current tests for C. difficile don’t generally give strain information – this test could allow doctors to see what strain was causing the illness and allow doctors to tailor their treatment.”

Professor Andy Ellis, from the Department of Chemistry, said: “This work shows great promise. The different strains of C. diff have significantly different chemical fingerprints and with further research we would hope to be able to develop a reliable and almost instantaneous tool for detecting a specific strain, even if present in very small quantities.

C difficile: Obesity Linked to Community-Onset Infections.

Obesity may be a risk factor for Clostridium difficile infection (CDI), according to results from a retrospective cohort study of 132 cases seen at a tertiary care medical center.

After potential confounders were taken into account, patients with simple community-onset infections were more than 4 times as likely to be obese as patients who had community-onset infections that came shortly after an exposure to a healthcare facility, according to data reported in an article published in the November issue ofEmerging Infectious Diseases.

“Obesity may be associated with CDI, independent of antibacterial drug or health care exposures,” write the researchers, led by Jason Leung, MD, from the University of Michigan Hospital in Ann Arbor. Such an association could help explain the uptick of community-onset cases in individuals having low levels of traditional risk factors.

The authors propose that obesity may perturb the intestinal microbiome in ways similar to those seen with inflammatory bowel disease and use of antibiotics, both of which are known risk factors for CDI.

“Translational research could help elaborate the dimensions of the interaction of the intestinal microbiota with C. difficile in obese patients,” the researchers maintain. They also suggest that an investigation of a dose–response relationship between body mass index and infection risk might be informative.

“[I]t is critical to establish whether obesity is a risk factor for high rates of C. difficile colonization, as is [inflammatory bowel disease]; if that risk factor is established, prospective observations would improve understanding of whether obesity plays a role in the acquisition of CDI, or alters severity of disease and risk for recurrence,” they write.

As for the patients with community-onset infections after healthcare exposure, the study’s findings highlight “the importance of increased infection control at ancillary health care facilities and surveillance for targeting high-risk patients who were recently hospitalized.”

In the study, the researchers reviewed the microbiology results and medical records of all patients who had laboratory-proven, nonrecurrent CDI at Boston Medical Center in Massachusetts during a 6-month period.

When the patients were classified according to the setting of disease onset, 43% had infections that began in the community without recent exposure to a healthcare facility, 30% had infections that began in a healthcare facility, and 23% had infections that began in the community within 30 days of exposure to a healthcare facility (most often a hospital or long-term care facility).

The prevalence of obesity, defined as a body mass index exceeding 30 kg/m2, was 34% in the group with community-onset infections compared with 23% in the general population (odds ratio, 1.7; 95% confidence interval [CI], 1.02 – 2.99). The value stood at 13% in the group with community-onset healthcare-associated infections and 32% in the group with healthcare-onset infections.

In multivariate analyses, patients with simple community-onset infections were significantly less likely to be older than 65 years (odds ratio, 0.35; 95% CI, 0.13 – 0.92; P < .05) and more likely to be obese (odds ratio, 4.06; 95% CI, 1.15 – 14.36; P < .05) than patients with community-onset healthcare-associated infections.

In addition, patients with simple community-onset infections were significantly less likely to have prior antibiotic exposure (odds ratio, 0.29; 95% CI, 0.11 – 0.76; P < .05) than patients with healthcare-onset infections. There was also a trend whereby they were much more likely to have inflammatory bowel disease (odds ratio, 6.40; 95% CI, 0.73 – 56.17; P < .10).

Finally, patients with community-onset healthcare-associated infections were dramatically less likely to have had prior antibiotic exposure than patients with healthcare-onset infections (odds ratio, 0.08; 95% CI, 0.02 – 0.28; P < .05).

Antibiotics for All but Very Mild C difficile.

On October 29, the European Society of Clinical Microbiology and Infection (ESCMID) issued updated guidelines for Clostridium difficile infection (CDI), reviewing treatment options of antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, and fecal or bacterial intestinal transplantation. The new recommendations, published online October 5 in Clinical Microbiology and Infection, advise antibiotic treatment for all but very mild cases of CDI.

CDI, which is potentially fatal, is now the leading cause of healthcare-acquired infections in hospitals, having surpassed methicillin-resistant Staphylococcus aureus.

“[A]fter the recent development of new alternative drugs for the treatment of CDI (e.g. fidaxomicin) in US and Europe, there has been an increasing need for an update on the comparative effectiveness of the currently available antibiotic agents in the treatment of CDI, thereby providing evidence-based recommendations on this issue,” write Sylvia B. Debast, from the Centre for Infectious Diseases, Leiden University Medical Center The Netherlands, and colleagues from the ESCMID Committee.

The new guideline, which updates the 2009 ESCMID recommendations now used widely in clinical practice, summarizes currently available CDI treatment options and offers updated treatment recommendations on the basis of a literature search of randomized and nonrandomized trials.

The ESCMID and an international team of experts from 11 European countries developed recommendations for different patient subgroups, including initial nonsevere disease, severe CDI, first recurrence or risk for recurrent disease, multiple recurrences, and treatment of CDI when patients cannot receive oral antibiotics.

Antibiotic Recommended in Most Cases

Specific recommendations include the following:

·         For nonepidemic, nonsevere CDI clearly induced by antibiotic use, with no signs of severe colitis, it may be acceptable to stop the inducing antibiotic and observe the clinical response for 48 hours. However, patients must be monitored very closely and treated immediately for any signs of clinical deterioration.

·         Antibiotic treatment is recommended for all cases of CDI except for very mild CDI, which is actually triggered by antibiotic use. Suitable antibiotics include metronidazole, vancomycin, and fidaxomicin, a newer antibiotic that can be given by mouth.

·         For mild/moderate disease, metronidazole is recommended as oral antibiotic treatment of initial CDI (500 mg 3 times daily for 10 days).

·         Fidaxomicin may be used in all CDI patients for whom oral antibiotic treatment is appropriate. Specific indications for fidaxomicin may include first-line treatment in patients with first CDI recurrence or at risk for recurrent disease, in patients with multiple recurrences of CDI, and in patients with severe disease and nonsevere CDI.

These recommendations were based on 2 large phase 3 clinical studies that compared 400 mg/day oral fidaxomicin with 500 mg/day oral vancomycin, the standard of care. The rate of CDI recurrence was lower with fidaxomicin, but the cure rate was similar for both treatments.

·         For severe CDI, suitable oral antibiotic regimens are vancomycin 125 mg 4 times daily (may be increased to 500 mg 4 times daily) for 10 days, or fidaxomicin 200 mg twice daily for 10 days.

·         In life-threatening CDI, there is no evidence supporting the use of fidaxomicin.

·         In severe CDI or life-threatening disease, the use of oral metronidazole is strongly discouraged.

·         For multiple recurrent CDI, fecal transplantation is strongly recommended.

·         Total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended for CDI with colonic perforation and/or systemic inflammation and deteriorating clinical condition despite antibiotic treatment.

·         Additional measures for CDI management include discontinuing unnecessary antimicrobial therapy, adequate fluid and electrolyte replacement, avoiding antimotility medications, and reviewing proton pump inhibitor use.

Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing.


It has been thought that Clostridium difficile infection is transmitted predominantly within health care settings. However, endemic spread has hampered identification of precise sources of infection and the assessment of the efficacy of interventions.


From September 2007 through March 2011, we performed whole-genome sequencing on isolates obtained from all symptomatic patients with C. difficile infection identified in health care settings or in the community in Oxfordshire, United Kingdom. We compared single-nucleotide variants (SNVs) between the isolates, using C. difficileevolution rates estimated on the basis of the first and last samples obtained from each of 145 patients, with 0 to 2 SNVs expected between transmitted isolates obtained less than 124 days apart, on the basis of a 95% prediction interval. We then identified plausible epidemiologic links among genetically related cases from data on hospital admissions and community location.


Of 1250 C. difficile cases that were evaluated, 1223 (98%) were successfully sequenced. In a comparison of 957 samples obtained from April 2008 through March 2011 with those obtained from September 2007 onward, a total of 333 isolates (35%) had no more than 2 SNVs from at least 1 earlier case, and 428 isolates (45%) had more than 10 SNVs from all previous cases. Reductions in incidence over time were similar in the two groups, a finding that suggests an effect of interventions targeting the transition from exposure to disease. Of the 333 patients with no more than 2 SNVs (consistent with transmission), 126 patients (38%) had close hospital contact with another patient, and 120 patients (36%) had no hospital or community contact with another patient. Distinct subtypes of infection continued to be identified throughout the study, which suggests a considerable reservoir of C. difficile.


Over a 3-year period, 45% of C. difficile cases in Oxfordshire were genetically distinct from all previous cases. Genetically diverse sources, in addition to symptomatic patients, play a major part in C. difficiletransmission.

Source: NEJM


Probiotics Do Not Reduce Diarrhea Risk in Large Trial.

Probiotic supplements did not prevent antibiotic-associated diarrhea (AAD) or Clostridium difficile diarrhea (CDD) in a large randomized, double-blind, placebo-controlled trial.

Stephen J. Allen, MD, from Swansea University, United Kingdom, and colleagues reported the results in an article published onlineAugust 8 in the Lancet.

The researchers recruited patients 65 years or older to the Probiotic lactobacilli and bifidobacteria in antibiotic-associated diarrhoea andClostridium difficile diarrhoea in the elderly (PLACIDE) trial if they were exposed to 1 or more oral or parenteral antibiotics in the preceding 7 days or were about to begin antibiotic therapy. Participants were enrolled from 5 hospitals between December 1, 2008, and February 28, 2012, and were excluded if there were existing diarrhea or CDD in the previous 3 months, significant immune system compromise, any illness requiring intensive care, prosthetic heart valve, or underlying gastrointestinal disease. The primary study outcomes were the occurrence of AAD within 8 weeks of recruitment and CDD within 12 weeks of recruitment.

Overall, 1493 patients were randomly assigned to the microbial preparation group and 1488 to the placebo group. Of those, the researchers included 1470 and 1471, respectively, in the primary-endpoint analyses. Antibiotic exposure was similar between the 2 groups. The probiotic preparation consisted of a capsule containing 2 strains of Lactobacillus acidophilus and 2 strains of bifidobacterium.

The researchers found no difference between the groups in the incidence of ADD (including CDD). In the probiotics group,159 (10.8%) patients developed ADD compared with 153 (10.4%) patients in the placebo group (relative risk [RR], 1.04; 95% confidence interval [CI], 0.84 – 1.28; P = 0.71).

The study authors also found that CDD was an uncommon cause of ADD, occurring in only 12 (0.8%) participants in the microbial preparation group and 17 (1.2%) participants in the placebo group (RR, 0.71; 95% CI, 0.34-1.47; P = 0.35).

“Our trial suggests that properties common to many so-called probiotic bacteria, such as the production of lactic acid, are not effective against AAD in older inpatients,” write Dr. Allen and colleagues.

Although the authors note that this “is the largest trial so far for this problem,” they acknowledge study weaknesses such as low ethnic diversity and lack of participation by eligible patients resulting from an unwillingness to take an additional preparation.

“Our findings do not provide statistical evidence to support recommendations for the routine use of microbial preparations for the prevention of AAD and CDD,” conclude the study authors.

In an accompanying editorial, Nick Daneman, MD, FRCPC, from the University of Toronto, Ontario, Canada, points out that recent meta-analyses have shown large positive effects with the use of probiotic supplements. He also notes that statistical variations such as a low event rate in the current study and overlapping confidence intervals between this study and the meta-analysis may account for the differing results.

However, the size of the current study “dwarfs” previous studies, most of which, he says, were small single institution efforts. “PLACIDE is a large and rigorous negative study, and we must judge whether it can tip the balance of probiotic evidence,” he writes.

“At the very least, the low absolute risk reductions in PLACIDE question the cost-effectiveness of probiotics,” writes Dr. Daneman. In addition, “lactobacilli and bifidobacteria are only two types of non­pathogenic bacteria, and we must consider whether they can really tip the balance of a diverse gut ecosystem,” he concludes.

Funding for this study was provided by the Health Technology Assessment program of the National Institute for Health Research, with additional funding provided by the County Durham and Tees Valley, National Institute for Health Research Comprehensive Local Research Network. Dr. Allen has done research in probiotics supported by Cultech, UK; has been an invited guest at the Yakult Probiotic Symposium; and has received research funding from Yakult, UK. The other authors and the editorialist have disclosed no relevant financial relationships.

Source: Lancet.