Part 1: Concerns with Antibiotic Overuse
Three of the most common antibiotic-related unwanted effects seen the ED include:
- Their toxic effects
- Selection of pathogenic bacteria
- Increasing antibiotic resistance
The Magnitude of Antibiotic-Related Toxic Effects
A data-set analysis of almost 110,000 residents in 67 Ontario nursing homes demonstrated that there was a 24% increased risk of antibiotic-related adverse effects in high antibiotic-prescribing nursing homes compared to low ones (Daneman, 2015). Hypersensitivities, being amongst the common adverse reactions to antibiotics, have been responsible for as much as 10% of adverse drug reactions in other studies (Slatore, 2003), and antibiotics have been associated with up to a 5% risk of allergic reactions (Solensky, 2003).
Data from the National Injury Surveillance between 2004 and 2006 shows that 1 in 5 ED visits were due to a drug-related adverse event – representing 142,505 annual emergency visits and 79% of them were allergic reactions (Shehab, 2008).
Antibiotics and Selection of Pathogenic Bacteria
The association of antibiotics and Clostridium difficile infections is familiar to all hospital workers. Antibiotics alter the microbiota of the gut to favour an environment where pathogenic bacteria can thrive (Baulmer, 2006). Bacteria other than C. difficile have also been associated with antibiotic-related diarrhea due to this mechanism (Larcombe, 2016). At The Ottawa Hospital, our internal data shows that our rate of C. difficile infections has risen from 0.32 per 1000 patient days in 2014-15 to 0.42 per 1000 patient days in 2015-16.
Antibiotics and the Proliferation of Antibiotic Resistance
Data from Public Health Ontario (PHO, 2015) show that rates of MRSA have been steadily increasing. The jurisdiction that has witnessed the highest rise of MRSA rates corresponds to postal code “K” – our home postal code, with a rise of 66% since 2013 (PHO, 2015). Other resistant strains, such as VRE, have shown similar trends (CNSIP, 2015).
The problem of an increasing rate of antibiotic-related unwanted effects is further complicated by stagnation in the development of new antimicrobials. Since 1969, there have only been two classes of new antibiotics introduced in the market (Conly, 2005) and the number of new antibiotic applications for approval to the FDA is decreasing every year (CDC, 2013).
What is the role of the ED for antibiotic stewardship?
Recent data also demonstrates that there is significant variability in antibiotic prescribing rates across Ontario hospitals, suggesting there is ample room for improvement (Daneman, 2017). The American College of Emergency Physicians (ACEP) also has a position that “emergency departments take an active role in designing and systematically studying strategies to improve antimicrobial stewardship” (May, 2013).
Next, we present three common clinical scenarios where the role of antibiotics is unfounded or controversial.
Part 2: Three Cases where the Role of Antibiotics is Questionable
Catheter-Associated Asymptomatic Bacteriuria
Within 24 hours of Foley catheter insertion 5 % of patients will have bacterial colonization of their urinary system – this number jumps to 100 % within one month (Hooton, 2010). However, a large prospective study of 1497 patients showed that catheter-associated bacteriuria was associated with symptoms in fewer than 10 % of patients (Tambya, 200). Table 1 summarizes three of the most important studies that demonstrate antibiotics have a limited role in catheter-associated asymptomatic bacteriuria (CA-ABU).
Table 1. Major Trials for Antibiotics and Catheter-Associated Asymptomatic Bacteriuria
|Article||Cephalexin for Susceptible Bacteriuria in Afebrile, Long-term Catheterized Patients
|Bacteremia and Mortality with Urinary Catheter-Associated Bacteriuria
Infection Control and Hospital Epidemiology. Kzilbach, 2013
|A Randomized Trial of Catheter Change and Short Course of Antibiotics for Asymptomatic Bacteriuria in Catheterized ICU Patients
Intensive Care Medicine. Leone, 2007
|Population||In-patients with CA-ABU. Weekly urine samples for 43 weeks. RCT||In-patients with CA-ABU. 444 instances of CA-ABU. Followed 30 days. Retrospective cohort of 9 months||ICU patients with CA-ABU. 60 patients. RCT|
|Intervention||Cephalexin for each instance of positive bacteriuria. 17 patients||Any antibiotic treatment||3 days of antibiotics and catheter change|
|Comparison||Placebo. 18 patients||No antibiotics||No antibiotics|
|Outcome||Bacteriuria present in 98.7% of weekly urine specimens of cephalexin group, and 98.2% of placebo group
Cephalexin susceptibility of 36% in cephalexin arm and 75% in placebo arm
|Antibiotics odds-ratio of 0.7 ( CI 0.32-1.71) for bacteremia and 0.9 (CI 0.43-1.69) for mortality||Rate of bacteriuria at 15 days, urosepsis, and mortality same between both groups|
In spite of evidence showing no meaningful benefit from antibiotic treatment in CA-ABU, a recent study showed the downstream effects that antibiotic mis-prescribing can have in the ED (Kiyatkin, 2016). In their retrospective study, 59% of patients had antibiotics inappropriately initiated in the ED, and in those cases 80% of them had them inappropriately continued by the in-patient consultant.
Pulpitis is a common dental ailment resulting in over 6,000 ED visits in the Champlain LHIN (OOHA, 2017). Multiple dental societies have published recommendations and guidelines suggesting the indications for antibiotics in dental pain, which include (SDCEP, 2013):
- Worsening swelling
- Obvious signs of cellulitis
Table 2 summarizes the two most important trials questioning the role of antibiotics in uncomplicated dental pain.
Table 2. Major Trials for Antibiotics and Uncomplicated Pulpitis
|Article||Effect of Systemic Penicillin on Pain in Untreated Irreversible Pulpitis
Endodontics. Nagle, 2000
|Efficacy of Penicillin for Dental Pain without Overt Infection
Academic Emergency Medicine. Runyon, 2004
|Population||Emergency patients with irreversible pulpitis||Emergency patients with irreversible pulpitis|
|Intervention||Penicillin 500 mg po Q6H x 7 days. 20 patients||Penicillin. 98 patients (34 lost to follow up)|
|Comparison||Placebo. 20 patients||Placebo. 97 patients (27 lost to follow up)|
|Outcome||Same scores for sum pain intensity, total ibuprofen taken, and percentage of patients with vital teeth||Infection rate 6- 7 % in both groups. No difference in visual analog pain scores|
There has been a shift in the understanding of the pathophysiology of diverticulitis, whereby most frameworks emphasize the role of inflammation, gut microbiota imbalances, colon motility, and visceral hypersensitivity as crucial elements in the disease (Strate, 2012). Most expert bodies have not updated their guidelines with regards the role of antibiotics in uncomplicated diverticulitis, however the American Gastroenterology Association in 2015 downgraded the recommendation for antibiotics to one of “selective use” (Stollman, 2015).
Table 3 summarizes the two most impactful RCTs that challenge the role of antibiotics in uncomplicated diverticulitis.
Table 3. Major Trials for Antibiotics and Uncomplicated Diverticulitis
|Article||Randomized Clinical Trial of Antibiotics in Acute Uncomplicated Diverticulitis
British Journal of Surgery. Chabok, 2012
|Randomized Clinical Trial of Observational versus Antibiotic Treatment For a First Episode of CT-Proven Uncomplicated Acute Diverticulitis
British Journal of Surgery. Daniels, 2017
|Intervention||Antibiotics x 7 days (cephalosporin + flagyl, carbapenem, or pip-tazo)
311 patients (22 lost to follow up)
|Amox-clav (95 % of patients ) or cipro/flagyl (5%)
268 patients (10 lost to follow up)
|Comparison||IV fluids. 399 patients (19 lost to follow up)||IV fluids. 263 patients (6 lost to follow up)|
|Outcomes||No difference in complication rate, emergency surgeries, hospital stay, or recurrent diverticulitis|| No difference in time to recovery, proportion without recovery, readmission, complications, recurrence, or mortality
13 % of patients in observation group sent home directly
|First RCT to address this question, with a substantial sample size, showing no benefit from antibiotics
|Methodologically sound RCT with large sample size and standard antibiotic regimens
Take Home Points
- Antibiotic overuse is a growing concern – emergency departments must be leaders in antibiotic stewardship
- The role of antibiotics is questionable in:
- Catheter-associated asymptomatic bacteriuria
- Uncomplicated dental pain with no signs of cellulitis
- Acute uncomplicated first episode diverticulitis
- Solensky, R. Hypersensitivity Reactions to Beta-Lactam Antibiotics . Clinical Reviews in Allergy & Immunology. 2003; 24:221-8.
- Shehab N, Patel P, Srinivasan A, and Budnitz D. Emergency Department Visits for Antibiotic-Associated Adverse Events. Clinical Infectious Disease. 2008; 47:735-43.
- Baumler A, and Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. 2016; 535:85-93.
- Larcombe S, Hutton M, and Lyras D. Involvement of Bacteria Other Than Clostridium difficile in Antibiotic-Associated Diarrhoea. Trends in Microbiology. 2016; 24:463-76.
- Ontario Agency for Health Protection and Promotion (Public Health Ontario); Institute for Quality Management in Healthcare. Antimicrobial resistance in common hospital pathogens in Ontario: annual laboratory and hospital survey report 2015. Toronto, ON: Queen’s Printer for Ontario; 2017.
- Conly J, and Johnston B. Where are all the new antibiotics? The new antibiotic paradox. Canadian Journal of Infectious Disease and Medical Microbiology. 2005; 16:159-60.
- CDC. Antibiotic Resistant Threats in the United States, 2013.
- Public Health Agency of Canada. National Microbiology Laboratory. Canadian Antimicrobial Resistance Surveillance System – Report 2016. Ottawa ON: PHAC; 2016.
- Daneman N, Bronskill S, Gruneir A, et al. Variability in Antibiotic Use Across Nursing Homes and the Risk of Antibiotic-Related Adverse Outcomes for Individual Residents. JAMA Internal Medicine. 2015; 175:1331-39.
- May L, Cosgrove S, L’Archeveque M, et al. Antimicrobial stewardship in the emergency department and guidelines for development. Annals of Emergency Medicine. 2013; 62.
- Public Health Ontario. Antimicrobial Stewardship Strategy: Preventing treatment of non-infectious conditions. Toronto, ON: Queen’s Printer for Ontario; 2016.
- Hooton T, Bradley S, Cardenas D, et al. Diagnosis, Prevention, and Treatment of Catheter- Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clinical infectious Disease. 2010; 50:625-63.
- Tambya P, and Maki D. Catheter-associated UTI is rarely symptomatic. Archives of Internal Medicine. 2000; 160:678-82.
- Warren J, Anthony W, Hoopes J, et al. Cephalexin for susceptible bacteriuria in afebrile, long-term catheterized patients. JAMA. 1982; 248:454-8.
- Kizilbash Q, Petersen N, Chen G, et al. Bacteremia and Mortality with Urinary Catheter-Associated Bacteriruria. Infection Control and Hospital Epidemiology. 2013; 34:1153-9.
- Leone M, Perrin A, Granier I, et al. A randomized trial of catheter change and short course of antibiotics for asymptomatic bacteriuria in catheterized ICU patients. Intensive Care Medicine. 2007; 33:726-9.
- Kiyatkin D, Bessman E, and McKenzie R. Impact of Antibiotic Choices Made in the Emergency Department on Appropriateness of Antibiotic Treatment of Urinary Tract Infections in Hospitalized Patients. Journal of Hospital Medicine. 2016; 11:181-4.
- Maund J. No Access to dental care: Facts and figures on visits to emergency rooms and physicians for dental problems in Ontario. Ontario Oral Health Alliance. Source data from MOHLTC. January 2017.
- Scottish Dental Clinical Effectiveness Programme. Management of acute dental problems – Guidance for healthcare professionals. National Dental Advisory Committee. Dundee; 2013.
- Gottlieb M, and Khishfe B. Are Antibiotics Necessary for Dental Pain Without Overt Infection? Annals of Emergency Medicine. 2017; 69:128-30.
- Nagle D, Reader A, Beck M, and Weaver J. Effect of systemic penicillin on pain in untreated irreversible pulpitis. Oral Surgery, Oral Medicine, Oral Pathology. 2000; 90:636-40.
- Runyon M, Brennan M, Batts J, et al. Efficacy of penicillin for dental pain without overt infection. Academic Emergency Medicine. 2004; 11:1268-71.
- Soreide K, Boermeester M, Humes D, and Velmahos G. Acute colonic diverticulitis: modern understanding of pathomechanisms. Scandinavian Journal of Gastroenterology. 2016; 51:1416-22.
- Strate L, Modi R, Cohen E, and Spiegel B. Diverticular Disease as a Chronic Illness: Evolving Epidemiologic and Clinical Insights. The American Journal of Gastroenterology. 2012; 107:1486-93.
- Stollman N, Smalley W, Hirano I, and AGA. AGA Institute Guideline on the Management of Acute Diverticulitis. Gastroenterology. 2015; 149:1944-9.
- Chabok A, Pahlman L, Hjern F, et al. Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. British Journal of Surgery. 2012; 99:532-9.
- Daniels L, Unlu C, de Korte N, et al. Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis.. British Journal of Surgery. 2017; 104:52-61.