Tag Archives: C. diff. treatments

The Latest Developments in C. diff Research and Treatment






The Program Podcast is Now Available —

Listen at your leisure as our guest, Dr Mary Beth Dorr, PhD, Clinical Director, Clinical Research, Infectious Diseases, and he product development team lead for bezlotoxumab, Merck & Co., Inc.  provided us with an overview of a C. diff. infection, the challenges of recurrence, the latest clinical research overview, current treatment landscape, and pending new C. diff infection treatment guidelines from the Infectious Diseases Society of America (IDSA) that are anticipated to be released fall of 2017.

Click on the C. diff. Spores and More Logo to be connected to the podcast

Two UK Researchers, Prof.Alistair Leanord and Dr. David Enoch, Present CDI Data At the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Repeated infection with the bacterium Clostridium difficile (C. difficile, C.diff.), which causes abdominal pain, fever, diarrhea is linked to higher death rates, as well as having a significant impact on health services in terms of cost and hospital beds occupied.

In the first of two presentations at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (tomorrow (Saturday), Professor Alistair Leanord, from Glasgow University, UK, will say that in Scotland the extra impact on the health service from C. difficile infections amounted to 10,600 bed days a year. “This is the equivalent to a 30-bed hospital ward being fully occupied all year,” he will say.

He will tell the congress that the (median) average cost of a patient with C. difficile infection was £7,500 (€8,600 approximately) compared to £2,800 (€3,200 approx) for patients with other medical conditions. In Scotland over a one year period, from October 2015 to October 2016, there were 1,150 cases of C. difficile infection in patients aged 15 and over. This cost the National Health Service (NHS) in Scotland a total of £8,650,000. Out of this amount, the additional costs of treating C. difficile infection, over and above the basic cost of a hospital bed and normal medical care, was £1,955,000. The calculations were carried out at Strathclyde University, which is part of the Scottish Healthcare Associated Infection Prevention Institute (SHAIPI) research consortium.

Until now, little has been known about the impact on health service resources from C. difficile infections, and on patients in terms of recurrence of infection, readmission to hospital, length of stay and death rates.

Prof. Leanord and his colleagues in Scotland identified 3,304 patients with C. difficile in Scottish hospitals between 2010 and 2013 and matched them with 9,516 patients who did not have the infection (the control group). Approximately two-thirds of the C. difficile patients acquired the infection in hospital.

They found that patients with C. difficile infection had more than double the risk of dying from any cause within two months of being admitted to hospital; nearly a third of all C. difficile cases (29%) died within two months compared to 14% of patients in the control group. Patients with C. difficile stayed in hospital a (median) average 9.7 days longer than the patients without the infection. Of the 1,712 C. difficile patients who were discharged from hospital within 30 days of the first episode of infection, 59% were readmitted within six months; of the 626 cases discharged more than 30 days after the first episode 53% were readmitted within six months. Few of these re-admissions were directly related to C. difficile infection.

“However, nearly a sixth of patients (14%) who were cured of the initial infection recurred within three months, and nearly one third of them (29%) had a second recurrence within a year,” says Prof. Leanord.

Older people were more vulnerable to a recurrence. Among the patients with C. difficile infection, 22% were aged 85 or over, and patients aged 75 and over had approximately double the risk of a recurrence of the infection compared to those aged under 65. Patients aged between 65-74 had 1.5 times the risk of recurrence compared to younger patients.

Prof. Leanord will conclude: “Having a clear understanding of the nature of C. difficile infections in Scotland will allow the Scottish government to target resources at the most appropriate patients to try to reduce the overall burden of the disease on the health service. Our findings are very likely to be applicable to the rest of the UK and other countries as well.”


In a second presentation on Saturday, Dr David Enoch, a consultant microbiologist and infection control doctor at the National Infection Service, Public Health England, Cambridge (UK), will report the outcomes of 6,874 patients who had acquired C. difficile infection in hospital between 2002 and 2013 in England. Of these, 1,141 (16.6%) had recurrences of the infection.

“We found that 49% of hospital patients who suffer a recurrent episode of C. difficile infection die within a year, compared to 38% of those who suffer an initial infection only,” he will say. “In addition, 21% of patients with a recurrence suffered other complications as well, such as dehydration, malnourished and sometimes even perforation of the bowel, compared to 18% of patients who did not have a recurrence.”

Dr Enoch estimates that there are approximately 125,000 cases of C. difficile infection in Europe each year, and between 15-30% of these recur. “Cases in the UK have been coming down since 2008, which is most probably due to improvements in antibiotic prescribing and cleaning regimens in hospitals. This is encouraging but more still needs to be done.”

The average age of the patients was 77 and the average length of stay in hospital was 38 days.

“The main risk factor for developing C. difficile infection is prior antibiotic use. These patients are often already ill from some other underlying illness, which explains why they needed antibiotics in the first place. Older people are at greater risk of C. difficile infection as they are often sicker, have other illnesses or conditions, and so need more antibiotics,” he will say.

Dr Enoch continues: “Although much has been done, particularly in the UK, to try to prevent C. difficile infection, strict adherence to antibiotic guidelines by clinicians and thorough cleaning of the hospital environment are crucial in ensuring that patients don’t develop C. difficile infection in the first place. Treatment with a new drug called fidaxomicin has also been shown to reduce the risk of recurrence in patients who are unfortunate enough to develop an infection. However, we still have a lot to learn, particularly about how C. difficile infection occurs in the community, and how best to treat it.”

Treatments for recurrences of C. difficile infection  —–  include stopping the antibiotic that made the patient susceptible to the infection and starting a different antibiotic that is effective against C. difficile infection. These antibiotics include metronidazole, vancomycin and fidaxomicin. Supportive therapy, such as extra fluids, and surgery in serious or life-threatening cases may also be necessary. Faecal transplantation is emerging as a promising option; this is a process in which the good bacteria that the gut needs but which has been killed off by antibiotics is transplanted into the patient from a healthy donor.

(CDF:  Consider contacting an organization conducting Clinical Trials to Treat and Prevent.  Click on the following link for more information :  https://cdifffoundation.org/clinical-trials-2/


Abstract no: #1672, presented by Prof. Alistair Leanord in the “Clostridium difficile infections: epidemiology and outcome” oral session, 16.30-18.30 hrs, Saturday 22 April, Hall A.

Abstract no: #883, presented by Dr Enoch in the “Clostridium difficile: guts and glory” e-poster mini-oral session, 15.30-16.30 hrs, Saturday 22 April, ePoster Arena 4.


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


An Article Written By A Pharmacist: There Are Ways Pharmacists Can Have a Positive Impact On Patient Care When It Comes To A Clostridium difficile Infection (CDI)

There are a myriad ways pharmacists can have a positive impact on patient care and show their value within healthcare institutions when it comes to CDI.




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


First, pharmacists should lead by example on patient care rounds by always wearing personal protective equipment (including gloves) when entering a room and washing their hands after leaving a room. You know how hand sanitizers claim to kill 99% of germs?

With CDI, welcome to the 1%. It takes good old-fashioned soap and water to remove CDI spores for your skin and prevent you from passing the pathogen to a colleague or patient.

That’s the crazy (or is it sad?) thing about CDI – we cause it with antibiotics, and we spread it amongst each other.

It is important for infection control specialists and antimicrobial stewardship (AMS) teams to work together to decrease CDI rates.

Pharmacists are pivotal members of AMS teams, but even those without a formal role in AMS can (and should) consider all medication-related problems surrounding CDI.

They can recommend appropriate treatment for CDI, leverage their knowledge of medications to help prevent CDI primary infection and recurrence, and think beyond CDI in patients presenting with diarrhea by considering non-medication and medication-related causes.

This peer-reviewed blog post only highlights five of the many interventions pharmacists can make to improve patient care. There is an abundance of other issues surrounding CDI that are not addressed below.

Notably, the role of probiotics for primary and secondary prevention and the role of fidaxomicin and/or fecal transplantation in a CDI treatment algorithm will be saved for another day.

This post also does not address the new FDA-approved monoclonal antibody, bezlotoxumab, which works by binding and neutralizing CDI toxin B. This novel medication demonstrated promising results in phase 3 trials and was associated with a significantly lower CDI recurrence rate than placebo. However, this drug cashes in around $5,000 per dose for a 70 kg patient (without a non-industry sponsored cost-effectiveness analysis in sight). The role in therapy for bezlotoxumab will be an exciting conversation in the ID community this year, so stay tuned!

In the meantime, here are five medication-related interventions that are easy to learn and easy to implement in order for pharmacists to make a huge difference for patients with CDI.

1. When in doubt, don’t pick metronidazole

I recently attended a conference where a speaker presenting on CDI asked the audience this question: “Would you give your mom metronidazole?” This resonated with me as I realized the answer was… probably not.

The 2010 Infectious Diseases Society of America (IDSA) guidelines for CDI in adults recommend the use of metronidazole for mild-to-moderate disease and oral vancomycin for severe disease.

Patients should be treated for 10-14 days regardless of disease severity [3]. For patients who experience a first recurrence, it is recommended to treat based on severity of illness, regardless of the previous therapy the patient received. If a patient experiences a second CDI recurrence, the guidelines recommend avoiding metronidazole not for efficacy concerns, but for drug toxicity and safety concerns associated with prolonged use.

The problem with these recommendations is that CDI severity varies widely and there is no universally accepted determinant of “severe” disease. Additionally, enhanced data on phenotypic and genotypic resistance mechanisms in C. difficile noting reduced susceptibility to metronidazole and pharmacokinetic data explaining the poor fecal concentrations of metronidazole leave us questioning if there is any patient population for whom metronidazole is appropriate empiric therapy.

Historically, the decision to use metronidazole over vancomycin has been driven by cost (metronidazole is much cheaper than oral vancomycin). There is also concern that use of oral vancomycin will drive emergence of vancomycin-resistant enterococci and other multidrug-resistant organisms by causing greater disruption of the intestinal microbiota, which appears to be the case in murine models but has not been demonstrated in humans [4,5].

As enhanced diagnostic testing is developed (including polymerase chain reaction [PCR] ribotyping for detection of the hypervirulent NAP1/BI/027 strain of Clostridium difficile), it should be easier to determine patients with severe or hypervirulent disease. In the absence of this testing, however, clinical presentation and laboratory parameters including white blood cell count > 15 x 103/mm3, albumin < 2.5 g/dL, and/or serum creatinine ≥1.5 times baseline drive decisions regarding disease severity.

A recent Veterans Affairs (VA) study of more than 10,000 patients with CDI found that patients who received oral vancomycin had a lower risk of mortality across all severities of illness [6]. The authors note this difference was largely driven by patients with severe disease, where patients were approximately 20% less likely to die of any cause within 30 days if they were treated with vancomycin over metronidazole. There were no differences in mortality found in patients with mild-to-moderate disease or in CDI recurrence between treatment options irrespective of disease severity. These findings corroborate previous studies, which demonstrated superiority of vancomycin for clinical cure in severe disease. While not statistically significant, a numerically greater percentage of patients achieved clinical success with vancomycin and a lower percentage of patients experienced disease recurrence versus those treated with metronidazole, regardless of disease severity [7,8].

In the aforementioned VA study conducted by Stevens and colleagues, 42% of patients presented with severe disease, yet only 4% to 6% received initial vancomycin therapy [6]. Hopefully, antimicrobial susceptibility testing and ribotyping will become more widely available to help clinicians tailor CDI therapy to the infective strain. Until then, pharmacists can ensure that patients with severe disease or disease recurrence (regardless of severity at the time of recurrence) receive oral vancomycin therapy to enhance the likelihood of clinical success and to attenuate the chance of additional recurrence. It may be reasonable to start patients with mild-to-moderate disease and experiencing their first CDI on metronidazole, but they should be monitored closely and switched to oral vancomycin if they do not have adequate response to therapy.

2. Forget about fluoroquinolones

It is no secret that the number one risk factor for developing CDI is antibiotic exposure, but not all antibiotics were created equally when it comes to this risk. Fluoroquinolones have the highest odds ratio of CDI (2-12.7), trumping cephalosporins (1.6-5.4), clindamycin (1.8-4.8) and beta lactam/beta-lactamase inhibitor combinations (1.9); although recent literature suggests that carbapenems and clindamycin are associated with more CDIs than penicillins, carbapenems, and fluoroquinolones [9,10].

Fluoroquinolone-resistant strains of Clostridium difficile are correlated with the rising prevalence and spread of the hypervirulent NAP1/BI/027 strain. A recent study conducted in England found that national infection control efforts and antimicrobial restriction led to a significant decline in incidence of CDI [11]. While clindamycin, broad-spectrum cephalosporins, and fluoroquinolones all had restrictions during the study period, the authors attribute moving the needle on CDI rates to fluoroquinolones based on genome sequencing and fluoroquinolone susceptibility patterns. Commentary on this study points out the retrospective, quasi-experimental study design and states results should be interpreted cautiously. As mentioned above in regard to choosing appropriate empiric therapy for CDI, the author writes how molecular typing and susceptibility testing are crucial for providers to truly understand CDI and enable us to implement antimicrobial stewardship interventions that will make an impact.

When you combine the CDI data with recent FDA warnings about fluoroquinolone safety and the impact fluoroquinolone overuse has on organism nonsusceptibility (also known as antibiotic “collateral damage”), it is reasonable to avoid fluoroquinolones whenever possible when selecting antibiotic therapy. My institution piloted a fluoroquinolone restriction in our MICU, SICU and abdominal solid organ transplant units last summer and expanded this initiative housewide last month. It can be done!

Suggested additional reading:

  1. Sarma JB, Marshall B, Cleeve V, Tate D, Oswald T, Woolfrey S. Effects of fluoroquinolone restriction (from 2007-2012) on Clostridium difficile infections: interrupted time-series analysis. J Hosp Infect. 2015;91:74-80.
  2. Kallen AJ, Thompson A, Ristaino P, et al. Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital. Infect Control Hosp Epidemiol. 2009;30:264-72.

3. Less is more (and antimicrobial stewardship is the best)

First, as good antibiotic stewards we should ensure patients receive antibiotics only when they have a true infection (we won’t even talk about asymptomatic bacteriuria). After the patient is deemed clinically infected, it is our responsibility to ensure the right drug is administered at the right dosage for the right duration. Limiting days of therapy to the shortest appropriate duration is crucial to limiting antibiotic exposure and improving patient outcomes. Cumulative antibiotic exposure is particularly hazardous for CDI risk, and this risk can persist for up to 6 months after exposure to any antibiotic [12]! Have I mentioned yet how important antimicrobial stewardship is?

For example, consider a patient with a pneumonia diagnosis. It is a fairly common occurrence for patients to receive approximately 72 hours of vancomycin and piperacillin-tazobactam empiric therapy, and then be prescribed an additional 7-10 days of definitive therapy. Healthcare teams forget that the days of vancomycin and piperacillin-tazobactam count and with clinical improvement most patients should not require more than 7 days of total antibiotic therapy for this infection. Defining day 1 of therapy will vary based on the patient’s clinical status, culture data, and source control. Having the conversation early and often with providers, though, can help the entire team come to an agreement on day 1 and think about defining duration. Pro tip: If you are working on a Thursday or Friday and an antibiotic course is near anticipated completion, ask for those stop dates early to avoid the antibiotics carrying through the weekend. Those extra couple of days or doses do make a difference!

The world would be simpler if this were just an inpatient issue. Community-acquired CDI is just as serious as hospital-acquired CDI, and prevalence in the community is rising. Pharmacists can review discharge prescriptions from inpatient settings or the emergency department at the point of discharge, or once the patient arrives at a community pharmacy. If the duration or quantity seems excessive, it probably is. Do not hesitate to contact providers and ask for clarification on treatment duration to help limit antibiotic exposure and decrease the risk of CDI!

4. Ask why when it comes to the PPI

Antibiotic use is the most prominent risk factor for CDI, but other medication classes should also be watched vigilantly. Acid suppressive therapy (including proton pump inhibitors [PPI] and H2-receptor antagonists [H2RA]), has been associated with primary CDI [13]. Gastric acid protects humans by inhibiting bacterial overgrowth and preserving the normal microbiota of the gastrointestinal tract. While there is conflicting literature historically, more recent literature supports how decreased gastric acidity due to PPI therapy predisposes patients to CDI.

Kwok and colleagues found a significant association between PPI use and risk of developing CDI versus non-users in a pooled analysis of 39 studies (OR 1.74, 95% CI 1.47-2.85) [14]. The risk was increased when PPIs were combined with antibiotic therapy (OR 1.96, 95% CI 1.03-3.70). PPI use alone was associated with recurrent CDI (OR 2.51, 95% CI 1.16-5.44). This group found that H2RA use was associated with a lower risk of CDI than PPI use (OR 0.71, 95% CI 0.53-0.97). While it has also been reported that PPI use does not increase risk of CDI recurrence, more recent literature suggests recurrence does occur more frequently in patients on PPI therapy (OR 1.66, 95% CI 1.18-2.34) [15,16]. When this group evaluated all acid suppressive therapy (PPI and H2RA), there was not a significant association with recurrent CDI, implying the degree of acid suppression does make a difference in terms of overall infection risk. Extended duration of PPI therapy has also been associated with an increased risk of developing CDI [17].

Pharmacists should strongly encourage PPI cessation in patients on antimicrobial therapy, especially if the patient has a history of CDI. If the patient requires acid-suppressive for a valid indication (e.g., mechanical ventilation, severe coagulopathy, recent gastrointestinal bleed), then pharmacists can facilitate switching PPIs to H2RA’s when appropriate. The risks and benefits of acid-suppressive therapy should also be critically evaluated in patients with additional risk factors for CDI including age greater than 65, immunocompromised, serious illness, long length of stay, or previous gastrointestinal surgery or manipulation.

Pharmacists can help the health care team and patient tremendously by investigating why patients are on acid suppressive therapy and discuss stopping these medications with the patients and providers, if indicated. Multiple studies have indicated that more then 50% of patients on PPI’s do not have an evidence-based indication for therapy, meaning there is a lot of room for intervention and optimization with these medications [18.19]. One place to start is by reconciling orders from patients as they transition to the floor from the ICU; if their risk for stress ulcers has resolved and they were not on an acid suppressive agent at home, recommend discontinuation prior to transfer.

5. Drugs can cause diarrhea [20,21]

Finally, in a world where CDI is such a significant player in the hospital setting, it is important for providers to step back and consider hospitalized patients may have a cause of diarrhea that is not CDI.

The differential diagnosis for diarrhea is sometimes overlooked due to fear of CDI, and diagnostic testing is sent without ruling out other possible causes. The PCR testing for CDI is exquisitely sensitive, meaning it will result positive for nearly all Clostridium difficile, including colonization. Therefore, it is possible for a patient with a positive PCR to receive unnecessary treatment for colonization and be at risk for undertreatment of the true cause of his or her diarrhea. If a patient is complaining of diarrhea or multiple loose bowel movements, pharmacists have a great opportunity to evaluate the necessity of some medications. Streamline bowel regimens by discontinuing multiple agents and recommend transition from scheduled to as needed laxatives when appropriate.

Pharmacists can educate health care teams about medication-related causes of diarrhea. More than 700 drugs have diarrhea listed as an adverse reaction, but there are a few medications in particular that are very likely to cause diarrhea. The ones I commit to memory include:

Sorbitol-containing products * Metformin
Colchicine Digoxin
Lithium Chemotherapy
Itraconazole Magnesium
Laxatives Mycophenolate
Acid-suppressants Dicyclomine
NSAIDS Amitriptyline
Alendronate Hyoscyamine

*You can look up inactive ingredients for medications here: https://dailymed.nlm.nih.gov/dailymed/index.cfm

Final thoughts

To combat such a deadly and prevalent infection, all healthcare workers need to work together, not just infectious diseases specialists. With these quick and easy medication-related tips, pharmacists can help connect antimicrobial stewardship, infection control, primary medical teams, infectious diseases consult services, and the patient together to optimize diagnosis and treatment of CDI.


1. Antibiotic Resistance Threats in the United States. Centers for Disease Control and Prevention website. http://www.cdc.gov/ drugresistance/pdf/ar-threats-2013-508.pdf. Published 2013. Accessed April 2, 2017.

2. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-834

3. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010 May;31(5):431-55.

4. Lewis BB, et al. Loss of microbiota-mediated colonization resistance to clostridium difficile infection with oral vancomycin compared with metronidazole. J Infect Dis. 2015;212:1656-65.

5. Deshpande A, et al. Effect of fidaxomicin versus vancomycin on susceptibility to intestinal colonization with vancomycin-resistant enterococci and klebsiella pneumoniae in mice. Antimicrob Agents Chemother. 2016;60:3988-93.

6. Stevens VW, Nelson RE, Schwab-Daugherty EM, et al. Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection. JAMA Intern Med. 2017;177:546-553.

7. Zar FA, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-7.

8. Johnson S, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59:345-54.

9. Owens RC, Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antimicrobial-associated risk factors for Clostridium difficile infection. Clin Infect Dis. 2008;46 Suppl 1:S19-31.

10. Vardakas KZ, Trigkidis KK, Boukouvala E, Falagas ME. Clostridium difficile infection following systemic antibiotic administration in randomised controlled trilas: a systematic review and meta-analysis. Int J Antimicrob Agents. 2016;48:1-10.

11. Dingle KE, Didelot X, Quan TP, et al. Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect Dis. 2017;17(4):411-421.

12. Kavanagh K, Pan J, Marwick C, et al. Cumulative and temporal associations between antimicrobial prescribing and community-associated Clostridium difficile infection: population-based case-control study using administrative data. J Antimicrob Chemother. 2017;1193-1201.

13. Kyne L, Sougioultzis S, McFarland LV, Kelly CP. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol. 2002;23(11):653-9.

14. Kwok CS, Arthur AK, Anibueza CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107(7):1011-1019.

15. Freedberg DE, Salmasian H, Friedman C, Abrams JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol 2013; 108:1794.

16. Tariq R, Singh S, Gupta A, et al. Association of gastric acid suppression with Clostridium difficile infection: A systematic review and meta-analysis. JAMA Intern Med. 2017 [EPub ahead of print].

17. Barletta JF, El-Ibiary SY, Davis LE, et al. Proton Pump Inhibitors and the Risk for Hospital-Acquired Clostridium difficile Infection. Mayo Clin Proc 2013; 88:1085.

18. Choudhry MN, Soran H, Ziglam HM. Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile-associated disease. QJM. 2008;101:445-8.

19. Mcdonald EG, Milligan J, Frenette C, Lee TC. Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. JAMA Intern Med. 2015;175(5):784-91.

20. Chassany O, Michaux A, Bergmann JF. Drug-induced diarrhoea. Drug Saf. 2000;22:53-72.

21. Philip NA, Ahmed N, Pitchumoni CS. Spectrum of Drug-induced Chronic Diarrhea. J Clin Gastroenterol. 2017 Feb;51(2):111-117.



Severe Cases of C.diff. Infection (CDI)Study Suggests the Most Routinely Prescribed Antibiotic Is Not the Best Treatment

Over the past two decades there has been a sharp rise in the number and severity of infections caused by the bacteria Clostridium difficile  (C. diff ) now the most common healthcare-acquired infection in the United States.


As published – to view the article in its entirety please click on the link below to be redirected:


But a new study suggests that the most routinely prescribed antibiotic is not the best treatment for severe cases. Scientists at the VA Salt Lake City Health Care System and University of Utah report that patients with a severe C. diff infection (CDI) were less likely to die when treated with the antibiotic vancomycin compared to the standard treatment of metronidazole.

The findings will be published online on Feb. 6, 2017 on the Journal of the American Medical Association (JAMA) Internal Medicine website.

C. diff does not cause illness outright. The bacterium produces two chemicals that are toxic to the human body. These toxins work in concert to irritate the cells of the Large intestinal lining producing the symptoms associated with the illness. Symptoms of CDI include watery diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness. Severe cases are associated with inflammation of the colon.

Current guidelines primarily recommend two antibiotics metronidazole or vancomycin to treat CDI. While vancomycin was the original treatment, the medical community has favored metronidazole for the past few decades, because it is less expensive and will limit vancomycin resistance in other hospital-acquired infections. The guidelines are based on small clinical trials carried out about 30 years ago.

“For many years the two antibiotics were considered to be equivalent in their ability to cure C. diff and prevent recurrent disease,” says Stevens. “Our work and several other studies show that this isn’t always the case.” In the current issue of JAMA Internal Medicine, the research team looked at the effectiveness of the two drugs by comparing the risk of mortality after treatment with these two antibiotics.

The investigators conducted the largest study to date by examining the data from more than 10,000 patients treated for CDI through the US Department of Veterans Affairs healthcare system from 2005 to 2012. A severe case of CDI was defined as a patient with an elevated white blood cell count or serum creatinine within four days of the CDI diagnosis. A mild to moderate case of CDI was defined as a patient with normal white blood cell counts and creatinine levels. About 35 percent of cases in this study were considered severe.

Patients with a severe case of CDI had lower mortality rates when treated with vancomycin compared to metronidazole (15.3 percent versus 19.8 percent). The scientists calculated that only 25 patients with severe CDI would need to be treated with vancomycin to prevent one death. “That is a powerful, positive outcome for our patient’s well-being,” explains Stevens. She cautions that the researchers still do not understand how the choice of antibiotic affects mortality rates.

“Although antibiotics are one of the greatest miracles of modern medicine, there are still tremendous gaps in our knowledge about when and how to use them to give our patients the best health outcomes,” explains Michael Rubin, M.D., Ph.D., an associate professor in internal medicine and an investigator at the VA Salt Lake City Health Care System.

“This research shows that if providers choose vancomycin over metronidazole to treat patients with severe CDI, it should result in a lower risk of death for those critically ill patients,” said Rubin. This study showed that less than 15 percent of CDI patients, including severe cases, received vancomycin.

The study results did not show a difference in the rate of the illness returning following either antibiotic treatment whether the initial illness was mild to moderate or severe. Nor did it show a difference for the rate of death following either antibiotic treatment for mild to moderate CDI cases.

Stevens cautions that the study was observational in nature and does not prove cause and effect of the drug. In addition, the study focused on patients that were primarily men; however, past studies show that the C. diff treatment outcomes for men and women were similar.

According to Stevens, future work should balance the targeted application of vancomycin treatment, especially for severe CDI cases, with economic considerations and the consequences of antibiotic resistance. “The optimal way to move forward is to do decision analysis that allows us to weigh the pros and cons of the various treatment strategies,” she says.


The research was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development.

In addition to Stevens and Rubin, co-authors include Richard Nelson, Karim Khader, Makoto Jones, Lindsay Croft and Matthew Samore (University of Utah and the VA Salt Lake City Health Care System), Elyse Schwab-Daugherty and Kevin A. Brown (Public Health Ontario and University of Toronto), Tom Greene (University of Utah), Melinda Neuhauser (VA Pharmacy Benefits Management Services) and Peter Glassman and Matthew Bidwell Goetz (VA Greater Los Angeles Healthcare System).

Clostridium difficile (C.diff.) Infection (CDI) Rates In the United States and Across the Globe Have Increased In the Last Decade, Along With Associated Morbidity and Mortality



Early Diagnosis, Prevention, and Treatment of Clostridium difficile: Update

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
5600 Fishers Lane
Rockville, MD 20857
March 2016


Clostridium difficile is a gram-positive, anaerobic bacterium generally associated through ingestion. Various strains of the bacteria may produce disease generating toxins
and TedA and TedB, as well as the lesser understood binary toxin.

Our use of the term indicates this review’s focus is the presence of clinical disease rather than asymptomatic carriage of C. difficile CDI symptoms can range from mild diarrhea to severe cases including pseudomembranous colitis and toxic megacolon and death.

Estimated U.S. health care associated CDI incidence in 2011 was 95.3 per 100,000, or about
293,000 cases nationally. Incidence is higher among females, whites, and persons 65 years of
age or older. (1)

About one third to one half of health-care onset CDI cases begin in long term care,thus residents in these facilities are at high risk.  Incidence rates may increase by four or five-fold during outbreaks.

Community associated CDI, where CDI occurs outside the institutional setting,
is also on the rise, though still generally lower than institution associated rates and may be in part due to increased surveillance. Estimated community associated CDI was 51.9 per 100,000, or   159,700 cases in 2011.  (1)

Community-associated CDI complicates measuring the effectiveness of  prevention within an institutional setting. 3  Additionally, the pathogenesis of CDI is complex and not
completely understood, and onset may occur as late as several months after hospitalization or antibiotic use

The estimated mortality rate for health -care associated CDI ranged from 2.4 to 8.9 deaths per

100,000 population in 2011.(1) For individuals ≥65 years of age, the mortality rate
was 55.1 deaths per 100,000; (1)

CDI was the 17th leading cause of death in this age group (4)
Hypervirulent C. difficile  strains have emerged since 2000 . These affect a wider population

that includes children, pregnant women, and other healthy
adults, many of whom lack standard risk profiles such as previous hospitalization or antibiotic use.(5)

The hypervirulent strains  account for 51 percent of CDI, compared to only 17 percent
of historical isolates. (6)

Time from symptom development to septic shock may be reduced in the hypervirulent strains, making quick diagnosis and proactive treatment regimens critical for positive outcomes.



Early Diagnosis, Prevention, and Treatment of Clostridium difficile: Update

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
5600 Fishers Lane
Rockville, MD 20857
March 2016



1Appendix J. References for Appendixes
1.Alcala L, Reigadas E, Marin M, et al.
Comparison of GenomEra C. difficile and Xpert
C. difficile as confirmatory tests in a multistep
algorithm for diagnosis of Clostridium difficile
J Clin Microbiol 2015 Jan;53(1):332
5. PMID: 25392360.
2.Barkin JA, Nandi N, Miller N, et al.
Super iority
of the DNA amplification assay for the
diagnosis of C. difficile infection: a clinical
comparison of fecal tests.
Dig Dis Sci 2012Oct;57(10):2592-
9. PMID: 22576711.
3.Bruins MJ, Verbeek E, Wallinga JA, et al.
Evaluation of three enzyme immunoassay
s and a loo mediated isothermal amplification test
for the laboratory diagnosis of Clostridium
difficile infection. Eur J Clin Microbiol Infect
Dis 2012 Nov;31(11):3035 9. PMID:
4.Buchan BW, Mackey TL, Daly JA, et al.
Multicenter clinical evalu
ation of the portrait
toxigenic C. difficile assay for detection of
toxigenic Clostridium difficile strains in clinical
stool specimens. J Clin Microbiol 2012
6. PMID: 23015667.
5.Calderaro A, Buttrini M, Martinelli M, et al.
Comparative analysis of different methods to
detect Clostridium difficile infection. New
Microbiol 2013 Jan;36(1):57-
63. PMID:
6.Carroll KC, Buchan BW, Tan S, et al.
Multicenter evaluation of the Verigene
Clostridium difficile nucleic acid assay.
J ClinMicrobiol 2013 Dec;51(12):4120-
5. PMID:24088862