In this article shorter is better with antibiotics is discussed, with highlights of lessons and resources.
Authored by: Mira Maximos, PharmD, MSc, ACPR, BScPhm, BHSc
Shorter is better with antibiotics refers to shortening the number of days an antibiotic course is given to treat an infection while not increasing risk for treatment failure. When this can be done safely (and there are many instances where it can be), it can offer benefits such as reducing the risk to the patient since less drug exposure results in less chance for toxicity or Clostridioides difficile infection.
Recently a Twitter chat was held with the central focus of shortening the antibiotic course. Numerous individuals engaged in the event and many relevant readings and considerations were shared by the participants. Pulling from this, the following was developed. Here are some lessons and resources on shorter is better with antibiotics.
1. A shorter antibiotic course can sometimes be as effective at treating a bacterial infection as compared to a longer course
Antibiotics are used frequently in healthcare. In the inpatient setting one study approximated that 50% of hospitalized patients receive at least one antibiotic during their hospitalization with 20-30% of this population receiving unnecessary therapy . In another study, 78% of long-term care (LTC) residents were found to receive at least 1 course of antimicrobial therapy over the course of a year with 63% of those prescribed courses lasting greater than 10 days .
Historically antibiotic durations often appear arbitrary or based on unclear evidence. At its origins, the antibiotic course duration of 7 to 14 days is based on the fact that a week has 7 days as described by Dr. Rice in 2008  and Dr. Spellberg in a 2019 . Multiple eloquently written articles by Dr. Spellberg Antibiotics: 5 Myths Debunked and Shorter is Better show that randomized trials comparing longer to shorter courses of antibiotics for multiple acute bacterial infections including cellulitis, community acquired pneumonia (CAP), urinary tract infection (UTI), and intra-abdominal infections have found shorter course therapies to be just as effective [4-7].
A systematic review published in 2017 to compare the evidence supporting short versus long-course oral antibiotics in treatment of outpatients infections including UTIs, CAP and multiple pediatric infections found that short course antibiotics appeared to have no difference in clinical cure rate when compared to longer courses . Shorter course antimicrobials have been supported for infections in hospitalized patients in another systematic review and meta-analysis of RCTs for common infections including pneumonia, UTIs and intra-abdominal infections .
Furthermore, a systematic review published in 2019 supports the evidence that shorter courses of antibiotics can be just as effective as prolonged courses, this time with a focus on bacteremia due to Enterobacteriaceae . Studies of interest for this review included patients receiving antibiotic treatment for ≤10 days and >10 days. The short- and long-course antibiotic treatments did not differ in 30-day all-cause mortality, clinical cure or relapse at 90 days. Furthermore, in Enterobacteriaceae bacteremia, the short- and long-course antibiotic treatments did not differ significantly in terms of clinical outcomes.
Resources to help guide shortening antibiotic duration in the LTC population have been growing steadily with a fantastic repository of information for education and summaries on shortening the antibiotic course in LTC inspired by work from Brad Langford and colleagues at Public Health Ontario (PHO) can be found in the ASP section of the PHO web page. These resources focus on common infections in LTCs including cystitis, cellulitis and pneumonia [11,12].
2. Shorter courses of antibiotics have been associated with less adverse drug events
Antibiotic use has be associated with a myriad of adverse drug events including drug reactions, end-organ damage, and secondary infections with possibly resistant organisms and Closterium difficile infections . In a multitude of randomized controlled trials (RCTs) published for different diseases, short-course therapy of antibiotics was often as effective as longer courses with better point estimates of clinical success and fewer adverse events .
A retrospective cohort trial of adult inpatients admitted to the medicine ward at an academic centre in the US included review of 1488 medical records for patients for 30 days after antibiotic initiation. The investigators looked for development of the following adverse antibiotic effects: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac and neurologic and at 90 days for Closterium difficile . In their manuscripts, they noted that every additional 10 days of antibiotic therapy conferred a 3% increased risk of an adverse drug event of which the most common were gastrointestinal (42%), renal (24%) and hematologic (15%) abnormalities.
Furthermore, antibiotic use in the hospital setting must be balanced against risks associated with acute illness  which may be associated with increased risk of adverse drug events…
- Many patients admitted to hospital may present with acute renal failure that can increase the risk of antibiotic associated nephrotoxicity
- IV antibiotics, which are often administered at high doses may have different adverse effect profiles that PO antibiotics that are most commonly prescribed in the outpatient setting
- Hospitalized patients are often administered multiple medications together, which can increase the risk of adverse drug events
- Hospitalized patients are often elderly and/or have multiple chronic conditions and thus may have impaired metabolism and clearance of medications
3. Shorter courses of antibiotics have been associated with less bacterial resistance to antimicrobials
The notion that “finishing an antibiotic course to prevent resistance” has been challenged and in fact, the evidence suggests that taking antibiotics longer than necessary increases resistance rather than prevent it, argue folks like Dr. Llewelyn .
Before discussing evidence around antibiotic duration and bacterial resistance, it is first important to note that resistance is not always simply associated with antibiotic exposure. The Maxwell Finland Lecture by Dr. Rice notes that resistance is not only multifactorial but differs in complexity based on the pathogen involved . Dr Rice discusses points at which antimicrobial selective pressure can be affected:
- Before therapy begins
- During treatment of those truly infected
- By avoiding use of combinations
- By treating only for as long as is required to cure the infection
- Note that curing an infection does not always mean microbiological eradication
In 2010 a systematic review and meta-analysis of observational and experimental studies in primary care were reviewed to assess the effect of antibiotic prescribing on antibiotic resistance in individual patients . The authors noted that individuals prescribed antibiotics in primary care for CAP or UTIs had a higher odds ration (OR) of developing resistance to the antibiotic. The authors provide a pooled analysis of 5 studies on UTIs showing an OR for resistance of 2.5 (95% confidence interval 2.1 to 2.9) within 2 months of antibiotic treatment and 1.33 (1.2 to 1.5) within 12 months. Another 7 studies of CAP treatment pooled analysis showed an OR of 2.4 (1.4 to 3.9) and 2.4 (1.3 to 4.5) for the same periods, respectively.
Antibiotic resistance appears to be inevitable and infections will always occur despite preventative efforts . Although antibiotic resistance is multifactorial as described above, it appears that there is evidence of increased resistance with recurrent antibiotic courses therefore judicious use and optimized antibiotic courses may help to curb resistance rates. However, the use of antibiotics in the animal industry affects increasing rise of resistance through environmental exposure to large quantities of antibiotics that result in selective pressure . Overtreating patients with antibiotics can also increase selective pressure that drives antibiotic resistance in society . Dr. Rice notes that the most viable strategy for reducing antimicrobial selective pressure is to treat an infection for only as long as necessary .
4. There are many available resources and frameworks to help promote rational antibiotic prescribing, including avoiding unnecessarily long courses
A multitude of resources exist to help change practice around antibiotic prescribing. Below are frameworks that approach the topic from different perceptions: the 4 moments of antibiotic decision making, behaviour change interventions in general, and LTC as well as earlier Infectious Diseases (ID) consult to lower mortality risk.
The 4 Moments of Antibiotic Decision Making
ASPs can successfully improve antibiotic use but often require external motivators to influence prescribing practices. An article discussing “the 4 moments of antibiotic decision making”  reviews key times when antibiotic use can be affected and may therefore be times when intervention by ASP teams may be better received:
- Does the patient have an infection that requires antibiotics?
- Have appropriate cultures been ordered before starting antibiotics? What is being used empirically?
- Can antibiotics be stopped, narrowed or stepped down from IV to PO after time has passed?
- What duration of antibiotic therapy is needed for this patient’s diagnosed infection?
Behaviour Change Models
Factors that generally help to improve understanding and motivate practice change include examples such as :
- Peer comparison by audit and feedback
- Accountable justification
- Creation of expected practices
A combination of factors is likely to be more successful at improving prescribing practices associated with duration of antibiotic use. Some frameworks that can be combined include:
- Antimicrobial stewardship knowledge with educational programs being targeted at students and early learners as part of core curricula for medical, pharmacy and postgraduate students 
- Audit and feedback interventions that involve assessment of antimicrobial therapy by trained ASP teams of physicians and/or pharmacists that make recommendations to the prescribing service in real time 
- Care standards developed by broad coalitions of primary and speciality care providers approved by specialists, stakeholder committees and leadership that can help shift the sense of medical-legal responsibility from the provider to the institution and provide psychological reassurance when standards change 
A behavior change analysis published in 2019 by Langford and colleagues looked to determine what factors influence duration of antibiotic use in LTC and found the following key themes :
- Environmental context and resources
- Beliefs and consequences
- Social influencers
- Behavior regulations
Earlier Infectious Diseases (ID) Consultation:
Another point of evidence that may support optimal antimicrobial use is a study of adult ED patients with Severe Sepsis or Septic Shock who completed the 3-hour sepsis treatment bundle involving ID consultation within 12 hours of ED triage compared to standard of care for outcomes of in-hospital mortality, 30-day readmission, length of stay (LOS) and antibiotic management . The authors found that:
- In-hospital mortality was lower in early ID consult group
- There was no significant difference in 30-day readmission or mean LOS
- There was a trend towards shorter time to antibiotic-escalation in early ID group
5. Although shortening the antibiotic course has many benefits, there are some situations where it may not be appropriate
In considering to use a shorter courses of antibiotics, it is important identify that it is not always appropriate and could lead to harm if done incorrectly. Let’s use the example of blood stream infections, which are unfortunately common amongst hospitalized critically ill patients and appear to occur with increasing incidence due to highly invasive care, immunosuppressive therapies and multiple comorbidities . Bloodstream infections demand prompt initiation of adequate antimicrobial therapy as an important predictor of survival . Cutting therapy short for a severe infection of this nature without the necessary evidence to support it could serve disastrous.
Many indications that call for prolonged courses of antimicrobial therapy involve complex pathology and often require discussion between the prescriber and patient for tailored approach and plan to care. Examples include [19,20]:
- Staphylococcus aureus and Pseudomonas species bacteremia
- Critical illness with complex etiology
- Lack of sufficient control of the infection source
A retrospective cohort study of critically ill patients with bloodstream infections assessed the impact of patient, pathogen, and infectious syndrome characteristics associated with shorter (<10 days) or longer >10 days) of antimicrobial treatment . Among the 100 critically ill patients reviewed in this study, the median duration of antibiotic treatment was 11 days with predictors of longer course treatment being (1) foci with established requirement for prolonged treatment, (2) underlying respiratory foci and (3) infections with Staphylococcus aureus or Pseudomonas species .
On the other side of this argument, the STOP-IT trial retrospectively evaluated risk factors that are often assumed to require prolonged courses of antimicrobials in intra-abdominal infections (IAI) and found that those with corticosteroid use, higher scores of Acute Physiology and Chronic Health Evaluation II, those with hospital-acquired infections and colonic source of IAI were significant factors for treatment failure . When authors controlled for randomization groups, the presence and number of risk factors were independently associated with treatment failure but antimicrobial duration was not. This may support the notion that time to source control is paramount to treatment success and may have better clinical relevance for patient oriented outcomes, such as mortality, than duration of antimicrobial therapy which has been supported in other literature as well .
Therefore, although longer antibiotic duration does have areas of evidence where it is essential and there are situations where longer antibiotic courses are more reasonable based on prescriber expertise, with source control being paramount.
REFERENCES & READINGS
1. Tamma PD, Avdic E, Li DX, Dzintars K, Cosgrove SE. Association of adverse events with antibiotic use in hospitalized patients. JAMA Intern Med. 2017;177(9):1308-1315. doi:10.1001/jamainternmed.2017.1938
3. Rice LB. The Maxwell Finland Lecture: For the Duration— Rational Antibiotic Administration in an Era of Antimicrobial Resistance and Clostridium difficile. Clin Infect Dis. 2008;46(4):491-496. doi:10.1086/526535
7. el Moussaoui R, de Borgie CAJM, van den Broek P, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ. 2006;332(7554):1355. doi:10.1136/bmj.332.7554.1355
8. Dawson-Hahn EE, Mickan S, Onakpoya I, et al. Short-course versus long-course oral antibiotic treatment for infections treated in outpatient settings: a review of systematic reviews. Fam Pract. 2017;34(5):511-519. doi:10.1093/fampra/cmx037
9. Royer S, DeMerle KM, Dickson RP, Prescott HC. Shorter Versus Longer Courses of Antibiotics for Infection in Hospitalized Patients: A Systematic Review and Meta-Analysis. J Hosp Med. 2018;13(5):336-342. doi:10.12788/jhm.2905
10. Tansarli GS, Andreatos N, Pliakos EE, Mylonakis E. A Systematic Review and Meta-analysis of Antibiotic Treatment Duration for Bacteremia Due to Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63(5):e02495-18. doi:10.1128/AAC.02495-18
13. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ. 2010;340:c2096. doi:10.1136/bmj.c2096
15. Tamma PD, Miller MA, Cosgrove SE. Rethinking How Antibiotics Are Prescribed: Incorporating the 4 Moments of Antibiotic Decision Making Into Clinical Practice. JAMA. 2019;321(2):139-140. doi:10.1001/jama.2018.19509
17. Langford BJ, Quirk J, Carey S, Daneman N, Garber GE. Influencing duration of antibiotic therapy: A behavior change analysis in long-term care. Am J Infect Control. 2019;47(12):1409-1414. doi:10.1016/j.ajic.2019.05.020
18. Madaline T, Wadskier Montagne F, Eisenberg R, et al. Early Infectious Disease Consultation Is Associated With Lower Mortality in Patients With Severe Sepsis or Septic Shock Who Complete the 3-Hour Sepsis Treatment Bundle. Open Forum Infect Dis. 2019;6(10). doi:10.1093/ofid/ofz408
19. Havey TC, Fowler RA, Pinto R, Elligsen M, Daneman N. Duration of antibiotic therapy for critically ill patients with bloodstream infections: A retrospective cohort study. Can J Infect Dis Med Microbiol. 2013;24(3):129-137. doi:10.1155/2013/141989
20. Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children. Clin Infect Dis. 2011;52(3):e18-e55. doi:10.1093/cid/ciq146
21. Hassinger TE, Guidry CA, Rotstein OD, et al. Longer-Duration Antimicrobial Therapy Does Not Prevent Treatment Failure in High-Risk Patients with Complicated Intra-Abdominal Infections. Surg Infect (Larchmt). 2017;18(6):659-663. doi:10.1089/sur.2017.084
22. Bloos F, Thomas-Rüddel D, Rüddel H, et al. Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study. Crit Care. 2014;18(2):R42. doi:10.1186/cc13755
ABOUT THE AUTHOR
Mira Maximos, PharmD, MSc, ACPR, BScPhm, BHSc is a hospital pharmacist practicing in Ontario, Canada at Woodstock Hospital, a small and amazing community hospital. She is the Antimicrobial Stewardship Pharmacist and also covers General Medicine and Inpatient Rehabilitation.
She completed a BScPhm, PharmD and MSc at the University of Waterloo, Hospital Residency at London Health Sciences Centre and Honors Spec in Health Sciences with a Major in Physiology BHSc at Western University. She has guest lectured at both her alma maters.
Joyfully skipping down the path of lifelong learning, she lives for journal clubs (an escape from parenting two amazing and animated kiddos), playing Magic the Gathering (geek and nerd), holds the highest scrabble score in her household (n=2 adults), and is interested in research/education around medication taking behaviours, knowledge translation and patient safety.
You can find her on twitter @MiraMaximos
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