Five Medication-Related Interventions Every Pharmacist Should Know About Clostridium Difficile

Clostridium difficile is arguably the most important pathogenic organism to cause infection in United States hospitals today. Here, an infectious diseases pharmacist identifies five medication-related interventions every pharmacist should know about Clostridium difficile.

Authored By: Erin McCreary, Pharm.D., BCPS

[Last updated 24 April 2017]

Clostridium difficile infection (CDI aka “C diff” aka “The Diff”) is the most common healthcare-associated infection caused by bacteria in the United States. The Centers for Disease Control and Prevention (CDC) designated CDI an urgent drug-resistant threat in 2013 [1]. According to the CDC, nearly half a million patients were diagnosed with CDI in 2011 [2]. This resulted in 29,000 associated deaths, of which 15,000 were directly attributable to CDI. That’s more than carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa, multidrug-resistant Acinetobacter spp. and methicillin-resistant Staphylococcus aureus (MRSA) combined [2]! With statistics like this, CDI is a pandemic all healthcare professionals should take very seriously (and this is before considering the financial implications of CDI, which results in over $4 billion in excess medical costs). Additionally, hospitals with high CDI rates lose significant amounts of money, making this a hot topic throughout health care.

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. 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:

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.

REFERENCES

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.