Clostridium difficile

Probiotics Fail to Reduce Antibiotic-Related Diarrhea.

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High-dose probiotics do not prevent diarrhea in older hospitalized patients, according to a large study in the Lancet.

Nearly 3000 inpatients aged 65 and older who were on antibiotic therapy were randomized to 21 days of a placebo capsule or a capsule containing lactobacilli and bifidobacteria, taken once daily. After 8 weeks, the incidence of antibiotic-associated diarrhea or Clostridium difficile diarrhea did not differ significantly between the groups.

The authors conclude: “Our findings do not provide statistical evidence to support recommendations for the routine use of microbial preparations for the prevention” of diarrhea.

Source: Lancet 

Does adding routine antibiotics to animal feed pose a serious risk to human health?

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As fears rise over resistance, some countries have banned routine use of antibiotics in animal feed. David Wallinga says a ban is possible without damaging food productivity, but David G S Burch argues that the drugs used in agriculture are not those causing problems with resistance in humans

Yes—David Wallinga

You cannot dispute the warning of England’s chief medical officer, Sally Davies, that antibiotic resistance is one of modern health’s greatest threats. Also beyond dispute is her analysis of its causes—the lack of new drugs combined with massive overuse of existing antibiotics. What physicians and policy makers generally overlook, however, is the critical role played by the ongoing overuse of antibiotics in livestock and poultry production. Enforceable measures to reduce this overuse must be core to any effort to avert the coming catastrophe. Because meat production is global in nature, these measures must be implemented nationally and supranationally.

Cost of resistance

Resistant infections generally cause more morbidity, mortality, and longer periods in hospital. In the United States alone, associated treatment costs add as much as $26bn (£17bn; €20bn) to the nation’s annual hospital bill; in 2012 dollars, the figure could be nearly $35bn, closer to $70bn if lost work and other societal costs are included.1 2

It will get worse. Ten times more cases of meticillin resistant Staphylococcus aureusoccurred in US children’s hospitals in 2008 than a decade earlier.3 From 2000 to 2009, admissions to hospital associated with Clostridium difficile doubled to 336 000,4 while deaths have tripled. Infections by deadly extended spectrum β-lactamase producing Enterobacteriaceae (especially Escherichia coli) are on the rise, in hospital and in communities.5 The World Health Organization states that bacteria – including antimicrobial resistant bacteria—commonly transferring from food animals to people comprise Salmonella, Campylobacter, E coli, and Enterococcus species. Emerging evidence shows that S aureas, including MRSA and C difficile, “also occur in food animals [those we eat] and can later be found in food products and environments shared with humans.”6

Interest in creating a pipeline of new antibiotics is understandable. But we cannot be sure that drug companies will succeed, regardless of the size of the financial incentives extended to them. Even if they do, some bacteria are likely to acquire resistance to the new drugs in a fraction of the time spent developing them. Meanwhile, how affordable will these new patented drugs be?

Ecological challenge

An ecological approach frames the problem of antibiotic resistance differently. Like Darwin, an ecologist asks what characteristics of the microbial ecosystem drive bacteria to evolve, acquire, and then expend the fitness cost to retain resistance genes in the first place. The answer is the selection pressure provided by our enormous use of antibiotics. This use creates environmental reservoirs of resistance genes (other genetic “determinants” of resistance, like plasmids) and resistant bacteria. These reservoirs now exist throughout the bacterial ecosystem: in the gut flora of human and food animals; in sewage plants, rivers, and farms; as well as in households and hospitals. By itself the development and use of new antibiotics will only add to this selection pressure. To decrease that pressure, overall reductions in antibiotic use—which is unpopular with drug companies—should come first.

That is where antibiotic overuse in animal agriculture becomes relevant. Data for drugs sold in the US in 2009-11, collected by the US Food and Drug Administration, show that antimicrobials added to animal feed or drinking water comprise 72% of all US sales of antimicrobials, over 13 000 tonnes a year.7 Most, though not all, antimicrobials routinely fed to US animals are medically important, including penicillins, tetracyclines, aminoglycosides, streptogramins, macrolides, and sulfas.

These are not single injections for sick animals. They are additives in feed given routinely, without a prescription, at lower than therapeutic concentrations, for purposes such as growth promotion and controlling disease in otherwise healthy animals being raised in crowded and often unhygienic conditions that can promote disease.

The US is not exceptional. Frank Aarestrup, head of the World Health Organization’s collaborating centre for antimicrobial resistance in foodborne pathogens and of Denmark’s National Food Institute, found that before Denmark phased out antibiotics for growth promotion, which it completed in 2000, about two thirds of antimicrobial use in pork and 90% in poultry production was for promoting growth and most of these were human antibiotics.8

Selection for resistant bacteria can occur at antibiotic concentrations hundreds of times lower than those previously thought9; the lower concentrations of antibiotics put into animal feed compared with injections for sick animals therefore offer little basis for complacency. New research also indicates that antibiotics in feed can spur the spread of resistance by promoting new genetic mutations10 as well as by promoting the transfer among gut bacteria of resistance genes (including, potentially, antibiotic resistance genes) through phages.11 Transfer of resistance between pathogenic and commensal bacteria, Gram negative and Gram positive bacteria species, and between bacteria in farm and human settings have all been observed, not surprisingly. All inhabit the same microbial ecosystem.

An essential and typically overlooked point is that antibiotic resistance, often including resistance to a dozen or more antimicrobials of different classes, is often physically linked on single strands of DNA. The physical linkage means that cross selection can and does occur. In other words, exposure to just one of the antimicrobial agents represented on that genetic “cassette” can provide the selection pressure for a previously susceptible bacteria to acquire resistance to all the antimicrobials physically linked on that cassette. The fact of cross selection means that regulatory agencies’ typical approach of assessing the risk of single bug-drug combinations is at odds with the actual threat of resistance that exists in the microbial ecosystem.

Routine antibiotics are not necessary

Contrary to claims by some in the livestock and drug industries, routine antibiotics are not necessary for animal health. Pasture based production was the norm before antibiotics. Industrial style meat production, in which animals are confined in close quarters and fattened on soy and maize based feeds, also is possible without routine antibiotics, as Denmark has shown. Writing last year in Nature, Aarestrup compared Denmark, where antibiotic use is now 50 mg/kg of meat produced, with the US, where it is 300 mg/kg.8 Denmark has reduced antimicrobial use in livestock production by 60% while increasing pork production by half since 1994.

Almost every European and North American public health authority agrees: routine antibiotic use in animal food production likely worsens the epidemic of resistance. Hundreds of studies, recently summarised, comprise the ever growing body of evidence.12 Less certain is the political will to act on that information.

No—David G S Burch

When antibiotics are used, whether in humans or animals, there is a risk of selection for resistance. This applies not only to the target bacteria but also to commensal bacteria such as Escherichia coli and Enterococcus species that exist in the gut and may also be exposed to the antibiotic. Resistant infections have become increasingly problematic in hospitals and care homes, hence the concern about the extent of antibiotic use. However, adding antimicrobial products to the feed of animals in the European Union is unlikely to affect development of critical drug resistance in humans and pose a serious risk to human health.

How resistance develops

Treatment with oral antibiotics exposes the gut microflora to the drug and even some injectable products are excreted through bile into the gut. The drugs may kill susceptible bacteria and leave resistant ones, or resistant mutants may develop through a natural competitive response, with genes for resistance then passed from one bacterium to another, often by plasmids. Resistant strains are therefore just as likely to occur from human treatment as from adding an antimicrobial substance to the feed of an animal.

Veterinary medicine often involves treating large numbers of animals. Medicated feed is a common approach in the United Kingdom and other countries such as the US, especially in pigs, but less so in poultry where water medication is often preferred. More than half of antimicrobial use in the UK is in feed.13 Some countries want to reduce antibiotic use in animals because of fears about resistance, and the Netherlands has stopped the routine use of these drugs in feed. The main concerns in the Netherlands were an increase in meticillin resistant Staphylococcus aureus (MRSA), which had spread throughout the European Union pig herd, but not in the UK; increasing identification of extended spectrum β-lactamase producing bacteria, especially in poultry; and increasing fluoroquinolone resistance in E coli, again, especially in poultry.14

Different antibiotics

So was use of antibiotics in feed associated with this increased resistance? It was not. No meticillin or related products (which directly select for MRSA), third or fourth generation cephalosporins (which select for extended spectrum β-lactamase producing bacteria), or fluoroquinolones are approved for use in feed in the EU. In the UK the antibiotics licensed for use in feed under veterinary prescription only are mainly older classes such as tetracyclines, macrolides (tylosin, tilmicosin, and tylvalosin), lincosamides (lincomycin), pleuromutilins (tiamulin, valnemulin), diaminopyrimidine-sulfonamide combinations (trimethoprim-sulfadiazine), β-lactams (penicillin V, amoxicillin), aminoglycoside-aminocyclitols (neomycin, apramycin, and spectinomycin), and amphenicols (florfenicol).

Since the complete ban of antibiotic growth promoters in the EU, completed in 2006, the glycopeptide, avoparcin (human use: vancomycin, teicoplanin) and the streptogramin, virginiamycin (human use: quinupristin, dalfopristin) are no longer used in feed, although virginiamycin is still used in the US. Oxazolidinones (linezolid), carbapenems (meropenem, imipenem), and glycylcyclines (tigecycline) are not used at all in feed or licensed for veterinary use. A current controversy is colistin, which is approved for use in feed in some EU countries but not in the UK and is being considered for use in humans as a last resort, despite its toxicity.

Low risk of transmission to humans

How bacteria that might carry resistance genes are transmitted to humans must be considered. Farmers and workers in close contact with animals are likely to be exposed to infections from animals. The transmission of MRSA from infected pigs to farmers is common,15 but transmission to the general public is rare, reported at 0.003% of the population in Denmark.16

The main potential route of transmission to the public is through contaminated food products. Zoonotic infections, such as Salmonella enterica Enteritidis has been shown to be transmitted through eggs and poultry meat. The reported incidence of S Enteritidis infection in the EU fell by 41% between 2006 and 2009 because of the vaccination of laying and breeder flocks.17 Campylobacter is still a major contaminant of chicken carcasses, and the EU needs to tackle this. Pig meat and beef seem to be very low campylobacter carriers in comparison, but they are associated with S Typhimurium, with reported cases affecting 0.0045% of the UK human population.18 It is difficult to quantify Escherichia coli and enterococci carriage and spread by food to humans, but if campylobacter and salmonella are used as models, their contamination rate and survival after consumption are also likely to be relatively low. If the meat is cooked properly and there is good hygiene in the kitchen, the risk is extremely low—almost zero.

Environmental transmission is another possible route, through faecal and slurry spreading on fields, but normal mains water processing seems to be highly effective in managing this risk. Regulatory authorities assess the environmental risk of manure and the safety of antimicrobial residues in edible tissues before use is approved, unlike in human medicine.

Given that the critical antimicrobials in human medicine are not used in animal feed, that regulatory authorities conduct thorough assessments of the risk of resistance from use of antimicrobial substances, and that the environmental effect and the effects of residues in edible tissues are also assessed, it is highly unlikely that adding antibiotics to feed poses a serious risk to humans, especially compared with the extensive use of antibiotics directly in humans.

Source: BMJ

 

C difficile: 10% of Patients Are Carriers at Hospitalization.

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One in 10 (9.7%) patients has asymptomatic Clostridium difficile(CD) colonization at the time of hospitalization, according to a new study. The 3 main risk factors for colonization are recent hospitalization (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.02 – 5.84), chronic dialysis (OR, 8.12; 95% CI, 1.80 – 36.65), and corticosteroid use (OR, 3.09; 95% CI, 1.24 – 7.73).

Surbhi Leekha, MBBS, MPH, from the Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, and colleagues present their analysis of adults admitted to a tertiary care hospital in an article published in the May issue of the American Journal of Infection Control. Approximately half of admissions were enrolled in the study, but only 22% of admitted patients provided stool samples (n = 320).

Colonization rates were determined by polymerase chain reaction analysis of formed stool. This approach circumvented the problems associated with anaerobic cultures.

The data are consistent with a previous large, multicenter study in Canada, which demonstrated that recent hospitalization is a risk factor for CD colonization. A previous study has also demonstrated that individuals receiving chronic dialysis are at risk for CD infection. This is the first study, however, to demonstrate that corticosteroid use is a risk factor for CD colonization.

The authors note that although CD epidemiology has changed during the past decades, the risk factors for infection appear to be unchanged.

“We propose that elucidation of risk factors for CD colonization could help identify asymptomatic individuals for targeted surveillance in selected hospital settings such as high endemicity despite the use of other control measures or epidemic situations. Potential infection prevention measures to prevent CD transmission from asymptomatically colonized patients include contact precautions, hand hygiene with soap and water, and environmental cleaning with a sporicidal agent. In our population, by targeting those with identified risk factors, we would need to screen approximately half of those patients with anticipated stays >24 hours, to identify three-fourths of those colonized with C difficile,” the authors write.

Source: medscape.com

 

 

Novel Strategy for Preventing CDI.

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Antigermination therapy prevented disease in mice challenged with massive inocula of C. difficile spores.

Spore germination is necessary for the development of symptomatic Clostridium difficile infection (CDI). Recent investigations have yielded novel nonantibiotic agents that inhibit spore germination mediated by taurocholate, a bile salt. To determine whether CamSA — a taurocholate analog that inhibits germination in vitro — might prevent CDIs, researchers conducted experiments using a mouse model.

Mice received an antibiotic “cocktail” in their drinking water for 3 days, and then a single dose of intraperitoneally administered clindamycin on day 4. The animals, in groups of five, each received 0 mg/kg, 5 mg/kg, 25 mg/kg, or 50 mg/kg of CamSA by oral gavage, followed on day 5 by gavage challenge with a massive dose of C. difficile spores and additional doses of CamSA 1 and 24 hours thereafter. The mice were then monitored for clinical evidence of CDI, and disease signs were scored. Some animals in each group were sacrificed and underwent postmortem examination of the gastrointestinal tract.

All animals that received 0 mg/kg of CamSA developed severe CDI within 48 hours of spore inoculation. In contrast, those that received 50 mg/kg showed no clinical or histopathologic evidence of CDI. Animals that received either 5 mg/kg or 25 mg/kg had a delayed onset of CDI and a reduction in disease severity. The excretion of cells and spores in feces also correlated with CamSA dose: Vegetative cells predominated in animals in the untreated (0-mg/kg) and 5-mg/kg groups, whereas spores predominated in those in the 25-mg/kg and 50-mg/kg groups.

Although CamSA (3 doses at 50 mg/kg) was protective in mice challenged with spores, it was ineffective in preventing CDI in animals challenged with vegetative cells.

Comment: These findings in a murine model deserve special attention. The novel, nonantibiotic strategy studied could be a “game changer” as we consider potential approaches for CDI management. As the authors note, patients determined to be at risk for CDI could receive CamSA before initiating antibiotics, then additional doses as needed until the intestinal microbiota has recovered.

Source: Journal Watch Infectious Diseases

 

Probiotics to Prevent Clostridium difficile–Associated Diarrhea.

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Probiotic prophylaxis lowered the incidence of CDAD by 66%.

Antibiotic treatment disturbs the normal gastrointestinal flora and raises risk for Clostridium difficile–associated diarrhea (CDAD). To evaluate the effectiveness and safety of probiotics for preventing CDAD, researchers performed a systematic review and meta-analysis. CDAD was defined as an episode of diarrhea associated with a positive C. difficile culture or toxin assay.

Twenty randomized, controlled trials that involved 3818 adults and children were included in the analysis; 18 studies were placebo controlled. Information on antibiotic regimens was not provided. Probiotics used in the trials included Bifidobacterium, Lactobacillus, Saccharomyces, and Streptococcus species.

Probiotics lowered the incidence of CDAD by approximately 66%. The incidence of adverse events, including abdominal cramping, nausea, fever and flatulence, was higher among controls than among probiotic recipients (12.6% vs. 9.3%); no serious adverse events were attributed to probiotics. The results were similar among children and adults, with lower and higher doses of probiotics, and across the different probiotic species.

Comment: The authors believe that their meta-analysis provides moderate-quality evidence to support a clinically significant protective effect of probiotics in preventing C. difficile–associated diarrhea. As with any meta-analysis, the quality of individual studies varied; the grading methodology used in this analysis required a larger sample size for the evidence to be considered high quality. Nevertheless, given the lack of serious adverse events, we might reasonably encourage use of probiotics, particularly for susceptible patients, such as those who are receiving broad-spectrum antibiotics.

Source:Journal Watch General Medicine

In Emergency Situations, a Fecal Transplant May Be a Lifesaving Option .

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Probiotics, i.e. beneficial gut bacteria have been heavily featured in the media lately, and for good reason. Researchers are increasingly realizing just how essential your intestinal microflora really is to your health.

The easiest way to improve the makeup of bacteria in your gut is to include traditionally fermented foods in your diet, but in an emergency situation, a novel procedure called fecal microbiota transplant may be the difference between life and death.

Who Knew a Fecal Transplant Could Be a Life Saving Procedure?

Such was the case with Kaitlin Hunter, a California woman who developed a potentially lethal bacterial infection in her colon after spending a month in the hospital recuperating from a serious car accident.

As reported by CNN Health:1

“In the hospital after her accident, doctors followed standard care and put Hunter on antibiotics to prevent an infection. In spite of the antibiotics – or possibly because of them – Clostrium difficile (C. diff) infected her colon, causing severe stomach pain, diarrhea and vomiting…

It’s believed that antibiotics, which kill harmful infection-causing bacteria, also weaken the beneficial, healthy bacteria percolating in the colon. With the colon’s defenses down, C. diff grows rampant, releasing a toxin and inflaming the colon.

C. diff infections kill about 14,000 people in the United States every year, according to the Centers for Disease Control and Prevention, and the number and severity of total cases have increased dramatically over the past decade.”

A fecal microbiota transplant (FMT) involves taking donor feces (the donor is typically a spouse or relative; in the Kaitlin’s case, it was her mother) and transferring it to the patient during a colonoscopy. In this way, the patient receives a transplanted population of healthy bacteria that can combat the overgrowth of pathogenic bacteria.

Recent research has shown the procedure to be very effective against recurrent Clostridium difficile infections. In a study2 published earlier this summer, FMT had a 91 percent primary cure rate, meaning resolution of symptoms without recurrence within 90 days of FMT. The secondary cure rate was 98 percent. Here, resolution of symptoms occurred after one additional course of vanomycin either with or without probiotics and/or a repeat FMT.

Antibiotics Without Probiotics Can Be a Dangerous Proposition

Kaitlin had received nine rounds of antibiotics, so it’s no wonder such a dangerous infection could get foothold in her colon. In this particular case, the fecal transplant likely saved her life.

However, I would dissuade you from thinking this procedure is a magical route to fix less than life threatening conditions. Furthermore, it’s important to understand that you have the power to prevent such a dangerous condition from occurring in the first place. It would certainly be nice if more doctors understood the importance of reseeding the gut with probiotics during and after a course of antibiotics, to reduce the health risks to their patients. However, as in so many other instances, many doctors still overlook this critical step, and this is where knowledge and self-responsibility comes into play.

Any time you take an antibiotic, it is important to take probiotics to repopulate the beneficial bacteria in your gut that are killed by the antibiotic along with the pathogenic bacteria. And you certainly don’t need a doctor’s prescription or permission for this.

If you’re in a hospital setting, you’re not likely to be served fermented foods, but you could have a family member or friend bring some in, or ask your doctor to sign off on a probiotics supplement. Outside a hospital setting, your best bet is to incorporate traditionally fermented foods in your diet, so you’re constantly maintaining a healthy bacterial balance.

Other Infections that Can Be Treated with Probiotics

Clostridium difficile infections are very serious, and since the cure rate with beneficial bacteria is so high for this type of infection, it can give you an idea of the power of probiotics for other, far less lethal ailments. For example, another type of infection that is far more common than C. diff. is Candida albicans.

An overgrowth of Candida, a type of yeast, can cause a variety of chronic health problems in both men and women. Under normal circumstances Candida albicans is a harmless part of your skin, intestines, and for women, your vagina. But Candida cells develop rapidly, and if your system is out of balance from eating unhealthy foods, taking certain prescription drugs, or fighting an illness for example, Candida can quickly grow out of control.

Vaginal yeast infections tend to occur when the normal acidity of a woman’s vagina changes, allowing the yeast to multiply. It’s estimated that up to 75 percent of women have had at least one vaginal yeast infection in their lifetime, which typically is accompanied by intense itching, burning with urination and sometimes a thick, white discharge. Up to 80 million Americans – 70 percent of them women – suffer from yeast-related problems, and if you suffer from yeast infections (especially if they’re recurrent) you should also be on the watch for other symptoms of Candida overgrowth, such as:

Chronic fatigue Weight gain
Food allergies Irritable bowel syndrome
Migraines PMS

 

As with all yeast-related problems, the infection occurs because your system has become run down or out of balance, allowing the Candida that already exists in your body to multiply out of control, causing illness. You may also fall into the trap of treating the infection with an over-the-counter anti-fungal cream, and then assuming that when the symptoms disappear the problem is cured. However, these creams only treat the symptoms and do nothing about the underlying yeast overgrowth that caused the problem to begin with.

How to Harness Your Gut Bacteria for Better Health

Do you suffer from gas and bloating? Constipation or diarrhea? Fatigue? Headaches? Sugar cravings? All of these are signs that unhealthy bacteria of one type or another have taken over too much real estate in your gut, which is actually quite common considering how vulnerable your gut bacteria are to environmental insults. It’s important to realize that your lifestyle can and does influence your gut flora on a daily basis. Therefore, to protect your microflora, you’ll want to avoid:

Poor diet is another enemy to healthy gut bacteria. Sugar is enemy number one, as it actually nourishes the bad or pathogenic bacteria, yeast, and fungi in your gut. Hence, dramatically limiting or eliminating sugar and fructose is an essential step to optimize your gut health. Processed foods also promote bad bacteria – partly due to the high fructose content in most processed foods, but also because of the processing, which essentially “kills” the food.

One of the major side benefits of eating a healthy diet like the one described in my nutrition plan is that it helps your beneficial gut bacteria to flourish. A critical part of a healthful diet is fermented foods, as they will actively “reseed” your body with good bacteria, and can do so far more effectively and inexpensively than a probiotic supplement. It’s unusual to find a probiotic supplement containing more than 10 billion colony-forming units.

But when my team tested fermented vegetables produced by probiotic starter cultures, they had 10 trillion colony-forming units of bacteria. Literally, one serving of vegetables was equal to an entire bottle of a high potency probiotic! So clearly, you’re far better off using fermented foods. Again, when choosing fermented foods, steer clear of pasteurized versions, as pasteurization will destroy many of the naturally-occurring probiotics. Examples of traditionally fermented foods include:

  • Fermented vegetables
  • Lassi (an Indian yoghurt drink, traditionally enjoyed before dinner)
  • Fermented milk, such as kefir (like fermented vegetables, a quart of unpasteurized kefir also has far more active bacteria than you can get from a probiotic supplement)
  • Natto (fermented soy)

Learn to Make Your Own Fermented Vegetables

Fermented vegetables are my favorite as they’re both easy to make, and one of the tastiest types of fermented food. To learn how to inexpensively make your own, review the following interview with Caroline Barringer, a Nutritional Therapy Practitioner (NTP) and an expert in the preparation of the foods prescribed in Dr. Natasha Campbell-McBride’s Gut and Psychology Syndrome (GAPS) Nutritional Program. In addition to the wealth of information shared in this interview, I highly recommend getting the book Gut and Psychology Syndrome, which provides all the necessary details for Dr. McBride’s GAPS protocol.

Although you can use the native bacteria on cabbage and other vegetables, it is typically easier to get consistent results by using a starter culture. Caroline prepares hundreds of quarts of fermented vegetables a week and has found that she gets great results by using three to four high quality probiotic capsules to jump start the fermentation process. If you’re not quite ready to make your own, Caroline also prepares the vegetables commercially. I used hers for a month before I started making my own batches. You can find her products on www.CulturedVegetables.net or www.CulturedNutrition.com.

How to Reduce Chances of “Healing Crisis”

There is one precaution that needs to be discussed here, and that is the potential for a so-called “healing crisis,” provoked by the massive die-off of pathogenic bacteria, viruses, fungi, and other harmful pathogens by the reintroduction of massive quantities of probiotics. It can significantly worsen whatever health problem you’re experiencing, before you get better.

The reason for this is because when the probiotics kill off the pathogens, those pathogenic microbes release toxins. These toxins are what’s causing your problem to begin with; be it depression, panic attacks, rheumatoid arthritis, multiple sclerosis, or any other symptom. When a large amount of toxin is suddenly released, your symptoms will also suddenly increase. So, if you’ve never had fermented foods before, you need to introduce them very gradually.

Dr. Campbell-McBride recommends starting off with just ONE TEASPOON of fermented vegetable, such as sauerkraut, with ONE of your meals, and then wait for a couple of days to see how you react. If it’s manageable, you can have another helping, and gradually increase your portion. If you feel worse, stop. Let the side effects subside, and then have just a tiny amount again. Some may even need to start with just a teaspoon of the juice ferment to start. Then move on to two teaspoons per day, and so on.

It’s important to realize that besides containing massive amounts of beneficial bacteria, fermented foods also contain many active enzymes, which act as extremely potent detoxifiers. As Dr. Cambell-McBride explains:

“Healing goes through two steps forward, one step back, two steps forward, and one step back. But you will find that the next layer is smaller. The die off and the detox will not last as long as the previous one… We live in a toxic world, and many of us have accumulated layers and layers of toxicity in our bodies. The body will clean them out, but you will find that each layer will last shorter and not be as severe… Eventually, you will come to complete, radiant health. You will feel 100 percent healthy, no matter how ill you were before.”

Source: Dr. Mercola

 

 

 

 

Antibiotic Stewardship Program Reduces C. difficile Infection Rates.

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Restricted cephalosporin, fluoroquinolone, and clindamycin use was associated with reduced antibiotic consumption and a decline in the incidence trend of Clostridium difficile infection.

Use of cephalosporins, fluoroquinolones, and clindamycin has repeatedly been associated with increased risk for Clostridium difficile infection (CDI). However, little is known about how CDI rates are affected by antibiotic stewardship programs aimed at decreasing the administration of such “high-risk” antibiotics.

Researchers recently described their experience with a restriction policy for second- and third-generation cephalosporins, fluoroquinolones, and clindamycin at a hospital in Northern Ireland that became effective in January 2008, after a major CDI outbreak in other, affiliated institutions. The policy was devised based on a time-series analysis involving one of these affiliated institutions for the period February 2002 through March 2007, which suggested that treatment of 14 patients with second-generation cephalosporins or 8 with third-generation cephalosporins — versus 94 with amoxicillin/clavulanic acid or 78 with macrolides — would result in one CDI case (Antimicrob Agents Chemother 2009; 53:2082).

Cephalosporins, quinolones, and clindamycin were prescribed significantly less frequently during the study period following implementation of the restriction policy (January 2008–June 2010) than during the 4-year preimplementation period; the use of other antibiotics remained unchanged. The intervention resulted in an overall reduction in antibiotic use and a reversal of the increasing trend for antibiotic consumption. These changes were associated with a significant decline in the incidence trend for CDI (rate decrease, 0.047/1000 bed-days per month). Variations in CDI incidence were affected by the Charlson patient comorbidity index, with a lag of 1 month.

Comment: This report on a successful antibiotic stewardship intervention is a nice example of the cause–effect relationship between antibiotic use and the occurrence of potentially serious nosocomial infections. The authors note that an antimicrobial-management team’s close surveillance of prescribing was key to successful implementation of the restriction policy.

Sourc: Journal Watch Infectious Disease.

 

Bacterial infections in end-stage liver disease: current challenges and future directions.

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Introduction

Bacterial infections continue to be a leading cause of mortality andacute-on-chronic liver failure in end-stage liver disease (ESLD). The consequences of infection include prolonged hospitalisation, acute kidney injury (AKI), death, de-listing from liver transplant and susceptibility to further infections. The diagnosis of infections in cirrhosis is fraught due to the background of a partial systemic inflammatory response syndrome (SIRS) state and negative cultures in 30-50% of patients. Furthermore, the lack of multi-center studies limits the generalisability of currently available results. The modulation of infections by the underlying immune state, gut barrier function and super-imposed medications such as beta-blockers, proton pump inhibitors and antibiotics is required. A rational approach to the diagnosis and prevention of AKI associated with infection, withjudicious use of crystalloids and albumin, is also needed. Changes in bacteriology including emergence of multi-resistant organisms and Clostridium difficile have also recently changed the approach for prophylaxis and therapy of infections. Effective strategies for the prevention, diagnosis, and management of infections in ESLD form a large unmet need. A systematic approach to study the epidemiology, bacteriology, resistance patterns, and procedure and medication utilisation specific to ESLD is needed to improve outcomes.

Bacterial infections in patients with end-stage liver disease affect candidacy for liver transplantation. Up to one-third of all hospitalised patients with cirrhosis are infected.1–5 With sepsis, mortality increases to more than 50% and is associated with significant costs.6 A recent systematic review demonstrated a fourfold increased risk of death in infected cirrhotic patients compared with their non-infected counterparts.7 More importantly, intensive care unit (ICU) mortality of patients with cirrhosis has remained unchanged over 50 years, unlike disease states such as cardiac failure where mortality has decreased.8 Therefore the prevention, diagnosis and management of infections in patients with end-stage liver disease form a large unmet need. This commentary briefly reviews infections in patients with cirrhosis, and outlines specific areas that need to be addressed in such patients hospitalised with infections.

Scope of the problem

The magnitude of the problem of infections in cirrhosis is not quantifiable for many reasons. Infections are often difficult to recognise in patients with cirrhosis because 30–50% of infections, such as spontaneous bacterial peritonitis (SBP), can remain culture negative.9 Conventional risk-scoring strategies, such as the systemic inflammatory response syndrome (SIRS) criteria, cannot reliably differentiate sepsis (SIRS plus infection) from non-infectious SIRS.10 This is important because a partial SIRS-like state is present in most patients with decompensated end-stage liver disease and therefore in itself cannot be used to differentiate between infected and uninfected patients. There are also difficulties diagnosing the presence of infections, especially in hospitalised cirrhotic patients.5 Strategies such as measuring C-reactive protein and procalcitonin may be helpful in selected patients, but a specific differentiator is still needed.11 ,12 Time-appropriate strategies are needed to suspect infections and send cultures early so as to initiate appropriate antimicrobial therapy. Also a heightened suspicion of potentially resistant organisms is required in order to change therapy as needed.2 In addition, most current studies are single centre, and there are limited data on the emergence of multiresistant strains and healthcare-associated (which develop <48 h after admission in patients with previous exposure to healthcare services in the preceding 90 or 180 days) and nosocomial (which develop >48 h after admission) infections.

Some idea of the magnitude of the problem may be obtained from the US nationwide inpatient sample (NIS), which analyses data from 20% of acute care hospitals and includes 8 million discharge records from 38 states. The NIS identified 65 072 patients in 2006 with a discharge diagnosis of cirrhosis. The total costs incurred were approximately US$14 billion per year. Of the hospitalised patients, 26 300 had presumed infection and required ICU support, as identified by mechanical ventilation and invasive cardiovascular monitoring. The in-house mortality of the hospitalised cirrhotic patients was 53%, or 13 800 deaths a year nationwide. The mean length of hospitalisation was 13.8 days. The total costs associated with ICU admissions in cirrhotic patients with presumed infection were US$3 billion, with mean costs of US$116 200 per admission and average daily costs of US$16 589 in non-survivors.

Another study from the NIS showed that Clostridium difficile infection in patients with cirrhosis was associated with a significantly higher mortality, length of stay and total costs compared with patients admitted with cirrhosis without C difficile and patients with C difficile without cirrhosis. This is striking because the mean age of the patients with C difficile without cirrhosis was significantly higher than that of patients with C difficile and cirrhosis.13 In the Korean National database, patients with cirrhosis and bacteraemia were significantly more likely to die than those without cirrhosis.14 Bacteraemia in cirrhotic patients was more likely to be due to intra-abdominal infections and Klebsiella pneumoniae, and less likely to be due to coagulase-negative Staphylococcus. Multivariate analysis confirmed cirrhosis as an independent risk factor for mortality (HR 2.11, 95% CI 1.43 to 3.13).14

The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) currently includes 12 centres throughout North America focused on determining outcomes after infections in patients with cirrhosis.15 Preliminary data from the NACSELD study noted that, in 176 patients from nine sites, the majority of infections were SBP and urinary tract infection (UTI), followed by spontaneous bacteraemia, skin, respiratory and C difficile infections. Gram-positive (36%) organisms were the most common, followed by Gram-negative (30%) organisms. The remainder were either fungal (4%) in origin or infections without an isolated organism. The death rate was highest for respiratory (44%), bacteraemia (38%) and C difficile (41%) infections, and lowest for urinary (21%) and skin (29%) infections or SBP (17%). The index infections were healthcare-associated (56%) or nosocomial (20%), and, importantly, 28% of patients developed a second infection during hospitalisation. The overall mortality was 25%, and patients who died had a higher Model for End-Stage Liver Disease (MELD) score at admission (25±8 vs 19±7, p<0.001) and were more likely to have hepatic encephalopathy (HE), hepatorenal syndrome (HRS), mechanical ventilation and ICU stay during hospitalisation (all p<0.0001). There was a higher incidence of second infections during hospitalisation in patients who died than in patients who survived (53% vs 20%, p=0.0001). Patients who developed a second infection were more likely to have a Gram-negative first infection, an ICU stay, lower albumin, greater length of hospitalisation and higher MELD score. Multivariate analysis showed that only second infection (p=0.0009) and MELD score (p<0.0001) were associated with death. Therefore there is a need to develop early diagnostic and prognostic markers, including biomarkers, for a better understanding of infections so as to improve outcomes.

Contribution of drugs such as antibiotics, proton pump inhibitors (PPIs) and ß blockers to infections and underlying immune status

Changes in gut bacteria in cirrhosis can lead to bacterial overgrowth with subsequent enhanced bacterial translocation from the gut to the systemic circulation and ascites, identified by bacterial DNA or by isolating bacteria in systemic biofluids. Bacterial translocation is the major pathogenetic factor for infections.5 ,16–18 Bacterial translocation can be silent or can result in florid infections.19 Even in the absence of infection, bacterial translocation can increase mortality.20 ,21 It is also a process that is facilitated by acid suppression22 ,23 and increased intestinal permeability in cirrhosis, specifically with advanced disease. Sepsis as a result of bacterial translocation and small-bowel bacterial overgrowth is a key component of the natural history of infections.20 However, one of the key modulators of outcomes of infections is the underlying immune status, which is negatively affected at multiple levels in cirrhosis. Specifically, the neutrophil burst, phagocytosis and opsonisation are impaired.21 Recent evidence has also indicated that antimicrobial peptides and NOD2 genetic variants are altered in patients with cirrhosis.24 ,25 A deeper understanding of the bacterial–immune interface either at the intestinal wall or within the ascitic fluid or mesenteric lymph nodes is important for developing biomarkers that would predict development of infection with an overall view to prevention.26

Single-centre studies have associated the use of PPIs with SBP and C difficile.13 ,27 This is an important observation, as PPIs are some of the most overprescribed drugs for cirrhosis.28 An appropriate indication for PPI use exists in fewer than half of the patients.29 PPIs predispose to bacterial overgrowth and adversely affect immune function.30 Another seemingly contradictory association is the effect of non-selective ß blockers (NSBBs) on the negative outcomes in cirrhosis. While a meta-analysis showed a reduced development of SBP in previous studies, a recent non-randomised study demonstrated a worse survival in the subset with refractory ascites.31 ,32 The effect of NSBBs on cirrhosis outcomes has led to the formulation of a ‘window hypothesis’, which suggests that NSBBs only improve outcomes in a narrow window of the cirrhosis natural history between those who have medium to large varices before the development of end-stage liver disease.33 Therefore the clinical role of NSBBs in cirrhosis needs to be elucidated further.

The role of non-absorbable antibiotics, such as rifaximin, in the modulation of infections in cirrhosis is also emerging. Whereas the pivotal HE trial did not show a significant difference in the rate of infections between groups, subsequent small studies reported a protective role of rifaximin against endotoxaemia and SBP.34–36 Outpatient prophylaxis using fluoroquinolones or sulfamethoxazole/trimethoprim in patients with previous SBP has been clearly shown to reduce subsequent episodes of SBP, but not survival.37 It is not completely clear whether these agents can improve outcomes in subgroups of patients with ascites fluid albumin <1.0 g/dl. SBP prophylaxis has been associated with the development of C difficile in a single-centre study.13 The study of SBP prophylaxis becomes more nuanced, especially when the emergence of multiresistant strains is considered.2 Further studies into the use of antibiotics are required to determine their role in reducing infections and mortality.

Thus several lines of evidence suggest the influence of outpatient medication on infection risk. Considering the small sample size and retrospective nature of most of these studies, further evaluation of drugs such as PPIs, non-absorbable antibiotics (such as rifaximin) and NSBBs is needed to determine their role in infections.

Prognosis and management in the ICU

Several precipitating factors are associated with deterioration in cirrhosis leading to multiple organ failure. These include infection, gastrointestinal bleeding, alcoholic hepatitis, superimposed viral hepatitis, drug-induced hepatotoxicity, and surgery. The response to infection in patients with cirrhosis is often exaggerated, leading to ICU admission because of sepsis, severe sepsis and septic shock.38 MELD score has been validated as a predictor of mortality in cirrhotic patients in the ICU and may have better prognostic capacity than the Child–Turcotte–Pugh score and the Simplified Acute Physiology Score II. The Acute Physiology and Chronic Health Evaluation III score is another predictor of early ICU mortality. The Sequential Organ Failure Assessment score correlates with mortality: failure of two organ systems is associated with a mortality of 55%, and failure of three or more organs with almost 100% mortality.39 Even when supportive measures are introduced, the underlying immune dysfunction state (immune paralysis following the first infection which contributes to secondary infections), poor nutrition, ongoing portal hypertension-related systemic haemodynamic changes, HE and gastrointestinal bleeding prevent recovery in these patients. Liver transplantation is ultimately an effective form of therapy for these patients, and worsening liver and renal function increase the MELD score, but ongoing infection and multiorgan system dysfunction make them generally poor candidates.

The ‘sepsis bundle’ has been accepted as the standard of care in patients with severe sepsis in the ICU.40 It is not clear whether these recommendations apply to patients with cirrhosis and severe sepsis. For example, arterial lines and central venous catheters are recommended for monitoring of mean arterial pressure and central venous pressure in severe sepsis. However, in critically ill cirrhotic patients, such vascular access may be associated with a significantly increased risk of bleeding. Red blood cell transfusions are recommended to increase central venous oxygen saturation. However, red blood cell transfusions in cirrhotic patients may be associated with an increased risk of variceal bleeding. Thus the role of the sepsis bundle in cirrhosis needs validation.

The key areas of need in the management of cirrhotic patients in the ICU is the prevention of nosocomial and second infections, reduction of unnecessary instrumentation, judicious use of antibiotic and antifungal agents, and validation of prognostic scores that take into account the underlying liver disease severity. Additional areas that need to be addressed are whether albumin is the preferred volume expander, how coagulopathy should be corrected, the optimal vasopressor support, the methodology for determining adrenal insufficiency, and the situations in which steroids should be given and the doses that should be used.6 Finally, the role of artificial and bioartificial liver support devices needs to be determined in this population.41

Prevention and treatment of acute kidney injury (AKI) in infected patients with cirrhosis

A critical need is to prevent and adequately treat renal dysfunction in infected cirrhotic patients. This is because renal dysfunction with AKI has emerged as a major determinant of mortality in patients with cirrhosis.42 ,43 AKI, including HRS, is associated with a markedly shorter survival. In patients with decompensated cirrhosis admitted to hospital, increased creatinine concentration within 24 h of admission is associated with poorer survival. Even more profound is the requirement of renal replacement therapy, which is associated with 94% in-hospital mortality.44 While most cases of functional renal impairment respond to volume challenge, with return of renal function to baseline levels, approximately one-third of patients are not volume responsive; these include patients with HRS or acute tubular necrosis.45 Therefore the first line of management of AKI in hospitalised cirrhotic patients is volume expansion, the response to which can determine the prognosis and subsequent management—for example, the use of vasoconstrictors would be indicated for volume-unresponsive cases of AKI such as HRS. Acute or type 1 HRS is defined as renal failure, which is characterised by a doubling of the initial serum creatinine to a level of >2.5 mg/dl in <2 weeks, which has been reported in about 10% of cirrhotic inpatients. Chronic or type 2 HRS is characterised by moderate renal failure, with serum creatinine between 1.5 and 2.5 mg/dl.45 Whereas type 2 HRS is usually associated with refractory ascites and follows a steady declining course, type 1 HRS is usually precipitated by an acute event and is often part of multiorgan system failure.46 The most common precipitating factor of type 1 HRS is bacterial infection,47 ,48 and this may occur despite clearance of the bacterial infection. The inflammatory response to bacterial infections increases systemic arterial vasodilatation, with further reduction of the effective arterial blood volume and further renal vasoconstriction, leading to renal failure.

SBP was the first bacterial infection recognised to be associated with a high incidence of renal failure in cirrhosis. This occurs in approximately one-third of patients despite resolution of the infection,48 ,49 and is associated with an in-hospital mortality of 42–67%.49 ,50 However, it was soon recognised that any bacterial infection could precipitate renal failure in cirrhosis.51 Patients who develop renal failure with bacterial infection have a higher MELD score and lower mean arterial pressure.47 Biliary or gastrointestinal tract infections are more likely to be associated with the development of renal failure, followed by SBP and UTI, although other infections such as pneumonia or even skin infections are associated with the development of renal failure. Once renal failure develops, it can be transient, resolving with the clearance of the infection, or it can persist, or even progress despite the clearance of infection.51 Biliary or gastrointestinal infection-induced renal failure is most likely to progress, followed by SBP- and UTI-related renal failure.47 Once renal failure sets in, the probability of survival at 3 months is only 31%, and decreases with higher MELD scores.52

Prevention of renal failure in the setting of infections remains a challenge. With SBP, patients given albumin have a lower incidence of renal failure, associated with improved survival.53 Underlying liver and renal function determine the risk of developing renal dysfunction associated with SBP. In one study, using the definition of high risk as plasma urea ≥60 mg/dl and serum bilirubin ≥4 mg/dl, almost 30% of patients who presented with SBP could be regarded as low risk for the development of renal failure and therefore were not given albumin. Renal failure only developed in 4.7% of the low-risk group, which had a 3.1% mortality. In contrast, 40% of the patients with SBP in the high-risk group (70% of the entire cohort) already had renal failure at the time of SBP diagnosis, while an additional 26% developed renal failure before SBP resolution.54 Those in the high-risk group treated with albumin had a significantly improved 90-day survival (p=0.01). The number of patients needed to treat in the high-risk group to avoid one death was 5.5. Similar findings were also reported by Sigal et al55 and Terg et al. 56 Thus the need for universal administration of albumin for the treatment of SBP needs to be re-evaluated. The need for albumin to prevent the development of renal failure in other bacterial infections also needs to be examined.

A small study assessed the effects of 2 mg/day terlipressin (a systemic vasoconstrictor) in addition to ceftriaxone (1 g every 12 h) on systemic haemodynamics and clinical outcome in patients with SBP.57 This regimen improved the hyperdynamic circulation compared with ceftriaxone alone. There was a significant increase in SBP reversal and a reduction in mortality with terlipressin at 48 h. Therefore the use of a vasoconstrictor should be investigated as a potential alternative, or additive, to albumin in the prevention of renal impairment in SBP.

Renal dysfunction, especially HRS type 1, is treated with vasoconstrictors and albumin infusion. The choice of vasoconstrictor depends on local availability: midodrine in North America in combination with octreotide, and terlipressin for most other parts of the world.45 Given the poor survival of patients with cirrhosis, bacterial infections and established renal failure,47 there is now a trend towards treating renal impairment at an earlier stage than defined type 1 HRS. One challenge has been to define an early stage of renal dysfunction, as serum creatinine is an inaccurate measure of renal function.58 ,59

A new definition of AKI in cirrhosis has been proposed,60 which is an increase in serum creatinine of 0.3 mg/dl in <48 h (table 1).61 The exact prevalence of AKI according to this new definition is unknown, but is an important question because it appears that such small increases in serum creatinine in patients with cirrhosis may negatively affect survival.

View this table:

Table 1

Proposed definition of kidney disease in cirrhosis60

Several newer concepts are helping to shape treatment strategies. These include the understanding that both the acute deterioration in renal function and the background chronic renal dysfunction can be functional or structural in nature, and the recent recognition that the inflammatory response to bacterial infection may be partly responsible for the development of renal failure.

Measures for prevention, surveillance and identification of healthcare-associated and nosocomial infections and multiresistant bacteria and C difficile

The emergence of multiresistant species and the looming spectre of nosocomial and healthcare-associated infections are concerning. Nosocomial infections in the general population are estimated to affect 1.7 million persons a year, cost at least US$5 billion annually, and are the sixth leading cause of death in the USA.62–65 Although healthcare-associated and nosocomial infections are different, they both increase length of stay, cost and mortality, and occur more commonly in ‘sicker’ patients following procedures such as surgery or in those who need mechanical ventilation or vascular or urinary catheters.66 The organisms responsible are often resistant to the ‘first line’ antibiotics often given for similar community-acquired infections, making empiric antibiotic treatment decisions more challenging and expensive.2 ,67–69

Nosocomial infections in non-cirrhotic patients are usually broken down into four categories62 ,66–68 as shown in table 2. However, there has been little published on nosocomial infections in patients with cirrhosis. Fernandez et al studied multiresistant organisms and nosocomial infections occurring in a single centre over three time periods: 1998–2002 (n=572), 2005–2007 (n=507) and 2010–2011 (n=162).2 ,3 Infection was present in one-third of hospital admissions: 25–32% healthcare associated and 36–45% nosocomial. Community-acquired infections were most commonly SBP (35%) and cellulitis (19%), healthcare-associated infections were most commonly SBP (28%) and UTIs (24%), and nosocomial infections were dominated by UTIs (31%).2 C difficile was not studied. Overall, multidrug-resistant (MDR) organisms caused 4% of community-acquired, 14% of healthcare-associated and 35% of nosocomial infections (p<0.001).2 This high risk of MDR organisms decreased the efficacy of their ‘standard of care’ antibiotic regimens to 40% in nosocomial infections, and doubled mortality in patients infected with MDR organisms. In another European single-centre study, Merli and colleagues found that one-third of 150 hospitalised patients with cirrhosis experienced at least one infection; 78% were healthcare-associated or nosocomial infections.4 UTIs were most common, and 64% were caused by MDR organisms. MDR organisms were predominantly Gram-negative isolates in SBP, such as Escherichia coli and K pneumoniae with extended spectrum β lactamase activity. The change in bacteriology also reflects an emergence of Gram-positive pathogens. A disturbing trend is the increased isolation of methicillin-resistant Staphylococcus aureus.70 Enterococcus faecalis and Enterococcus faecium have been isolated in 10–24% of infections in the setting of cirrhosis and are associated with a mortality of 25%. Focusing on specific infections, it has been found that SBP is an important cause of both community-acquired and nosocomial infections in patients with cirrhosis.71 ,72 Whereas community-acquired SBP is more commonly caused by Gram-negative rods, nosocomial SBP has an increased prevalence of Gram-positive cocci. In addition, nosocomial acquisition increases the risk of resistance to cephalosporin and fluoroquinolone and significantly increases mortality. Although previous reports on nosocomial infections did not include C difficile infection, it was a common nosocomial infection found in the NACSELD study and had the highest risk of mortality (28%).15 This is similar to the previous C difficile National Database study in cirrhosis in which length of stay doubled, mortality markedly increased, and cost increased by US$43 665/infected admission.13

View this table:

Table 2

Categories of nosocomial infections in the non-cirrhotic population66

We propose, on the basis of our and other previous work in this area, that healthcare-associated and nosocomial infections in cirrhosis be broken down into six categories: spontaneous bloodstream infections unrelated to interventions or infections at other sites, UTIs, pulmonary infections, SBP, C difficile and intervention-related infections (table 3). Although up to one-third of all nosocomial infections should be preventable,73 ‘success in curbing their emergence remains elusive.’74 It should be emphasised that the data available on healthcare-associated and nosocomial infections in cirrhosis are largely limited to single centres, although smaller multicentre studies exist.1–4 ,13 ,71 ,72 ,75–80

View this table:

Table 3

Proposed categories of nosocomial infections in cirrhosis

Summary

Because of the high morbidity and mortality in patients with cirrhosis who become infected (many of whom may be denied liver transplantation because of multiple organ failure) and the paucity of data in this field, we propose the studies outlined in table 4. Only through systematic study of epidemiology, bacteriology, resistance patterns, and procedure and medication utilisation specific to patients with cirrhosis will we discover how to routinely accomplish this in the most cost-effective way.

View this table:

Table 4

Challenges and future directions of bacterial infection management in cirrhosis

Footnotes

  • Funding This was partly funded by the NIH grant NIDDK RO1DK087913 and partly from an educational grant from Grifols Pharmaceuticals.
  • Competing interests None.
  • Provenance and peer review Not commissioned; externally peer reviewed.

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Source: BMJ/Gut

 

 

 

 

 

Proton-Pump Inhibitors Raise Risk for C. difficile Infections.

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In two meta-analyses, PPI use was associated with a 1.7-fold higher risk for Clostridium difficile infection.

In February 2012, the FDA issued a safety alert regarding an association between proton-pump inhibitors (PPIs) and Clostridium difficile infection. In new meta-analyses, two groups of researchers used slightly different criteria to select studies in which this association could be evaluated; all included studies (23 and 42, respectively) were observational (cohort or case-control). Each meta-analysis involved roughly 300,000 patients.

In both meta-analyses, risk for C. difficile infection was significantly higher in PPI users than in nonusers (risk ratio, about 1.7). Although results across individual studies were heterogeneous, nearly all trended toward higher risk. Most of the included studies were adjusted for confounding variables, including antibiotic use. Concomitant use of both PPIs and antibiotics — examined in one meta-analysis — was associated with greater risk for C. difficile infection than was use of PPIs alone or antibiotics alone. Risk for C. difficile infection was higher with histamine (H)2-receptor antagonists than with no acid-suppressive therapy, but lower with H2-receptor antagonists than with PPIs.

Comment: The opportunity for residual confounding in these studies is substantial, because sicker patients are more likely both to receive PPIs and to be vulnerable to C. difficile infection. Still, these worrisome findings should remind clinicians to initiate PPIs only for valid indications and to stop PPIs in patients who take them for unclear reasons.

Source:Journal Watch General Medicine

Clostridium difficile — But from Where?

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An investigation of Clostridium difficile transmission within hospital wards identified the transmission route in less than 25% of cases.

Clostridium difficile is a leading cause of both healthcare-associated diarrhea and hospital-acquired infection. With today’s more-virulent strains, such illness causes considerable morbidity and mortality. Although C. difficile infection (CDI) is almost universally preceded by antibiotic therapy, which may have ended weeks or months before symptom onset (JW Infect Dis Feb 29 2012), the source and transmission route of such infection often cannot be identified.

Now, investigators have published the results of an extensive investigation of C. difficile transmission dynamics in Oxfordshire, U.K. From September 2007 through March 2010, 29,299 unformed stool samples from 14,858 individuals (inpatients and outpatients) were tested by enzyme immunoassay for C. difficile toxins; samples that tested positive were cultured. A total of 1276 C. difficile isolates were subjected to multilocus sequence typing, which revealed 69 distinct strains.

Analysis of hospital admissions and ward-movement data for each patient with CDI, assuming an 8-week maximum infection period and a 12-week maximum incubation period, showed that 66% of cases were not linked to known cases, and only 23% had a credible ward-based source. When the analysis was adjusted for chance meetings of patients within the hospital, only 16% of cases were linked by probable transmission events.

Comment: The results of this sophisticated epidemiologic study contrast with the current view of hospitals as C. difficile transmission “hotspots.” Editorialists note that the authors did not consider several potential sources and routes of C. difficile transmission in hospitals, such as intervention suites, other wards, and asymptomatic carriers. Nonetheless, there appear to be additional, as-yet-unidentified reservoirs of infectivity and routes of C. difficile transmission in the community.

Source: Journal Watch Infectious Diseases