Duration of antimicrobial therapy for common infections in primary care

Authors:

Kevin Afra, MD, MHA, FRCPC (biography, no disclosures)

Maggie Wong, PharmD, ACPR (biography, no disclosures)

Tim T.Y. Lau, PharmD, ACPR, FCSHP (biography, no disclosures)

Victor Leung, MD, FRCPC (biography and disclosures). Disclosures: Member of advisory boards for GSK, Merck, and Biomerieux. Mitigating potential bias: Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements.

What we have noticed

Appropriate use of antimicrobials is a key strategy to avert the looming threat of antimicrobial resistance. In the absence of significant societal change, antimicrobial resistance will kill more people than cancer by the year 2050.¹ Healthcare providers are increasingly aware of the importance of using antimicrobials wisely. The Choosing Wisely Canada campaign has excellent and practical recommendations for syndromes that do not require routine antibiotic prescription (e.g. upper respiratory tract infections and acute bronchitis).²

Nevertheless, many infections seen in routine practice are bacterial in etiology and benefit from antibiotic therapy. We often see antibiotics prescribed for 7 to 14 days for routine, community-acquired infections. These treatment durations are based on historical practice and dogma. As specialists in Infectious Diseases and Antimicrobial Stewardship, we are regularly asked how long to treat various common infections.

Antibiotic treatment duration decision making is fundamentally a balance of expected benefit and harm. Anchoring our expectations of benefit and harm with the most current literature can better inform clinical decision-making. The harms of antibiotics are often underappreciated.

First, more prolonged courses of antibiotics are associated with increased risk of C. difficile infection.^3,4 This risk has been identified as early as 48 hours into antibiotic treatment and increases in a duration-dependent manner. Second, more prolonged courses of antibiotics are associated with an increase in antibiotic-associated adverse events.⁵ Third, duration of antibiotic exposure is associated with acquiring antimicrobial resistant organisms in a duration-dependent manner.^6,7

All these potential harms are important to consider when determining treatment duration. Antibiotics should only be prescribed for the duration needed to cure infection – optimizing benefit – and no longer.⁸ We will now summarize the evidence for optimal treatment duration in three common infections seen in primary care.

Data that answer these questions

Community-acquired pneumonia (CAP)

A 2018 meta-analysis of 21 studies involving 4861 patients demonstrated that short course therapy (≤6 days) was equally as effective as longer course therapy in CAP.⁹ Clinical practice guidelines from the American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) in 2019 recommended that antibiotics be continued until patients achieve clinical stability and for no less than 5 days.¹⁰ Patients are considered to be clinically stable if they are afebrile for 48 hours AND do not have more than one of the following: heart rate >100 beats/minute, respiratory rate >24 breaths/minute, systolic blood pressure <90 mmHg, or arterial oxygen saturation <90% on room air.

These clinical stability criteria were validated in a 2016 Spanish randomized clinical trial of hospitalized CAP.¹¹ Patients were randomized at day 5 to intervention group, where antibiotics were stopped upon reaching ATS/IDSA clinical stability criteria, or to control group, where duration was determined by physicians per usual practice. Median duration of therapy was 5 days in the intervention versus 10 days in the control group. Clinical success at day 30 was similar between the two groups.

A more recent French randomized, placebo-controlled, clinical trial published in 2021 demonstrated that 3 days of therapy was non-inferior to 8 days of therapy in non-intensive care unit (non-ICU) patients with moderately severe CAP.¹² Patients who achieved clinical stability after 3 days of β-lactams were then randomized to placebo or amoxicillin plus clavulanate for 5 additional days. Clinical cure by day 15 was similar between the placebo and treatment group, and there was no difference in 30-day mortality rate. An older but smaller randomized, placebo-controlled trial in hospitalized CAP similarly showed equivalent outcomes between 3 days compared to 8 days of therapy.¹³

While much of the evidence supporting 3-5 days of β-lactam therapy in CAP comes from trials in hospitalized patients, we believe this is applicable to outpatients treated with β-lactams who generally have less severe illness and better outcomes than hospitalized patients with CAP.

Cellulitis

A meta-analysis of randomized and observational trials in 2020 assessed duration of therapy in cellulitis.¹⁴ No differences were found between short course therapy (3-6 days) and long course therapy. However, there are several limitations to the applicability of these trial data. First, several older trials evaluated azithromycin in short course therapy, which has a notably longer half-life than comparator drugs, and is not routinely used in practice for soft tissue infections. Second, a more recent trial found similar outcomes at short-term follow-up but potentially increased risk of relapse at 90 days with short-course therapy.¹⁵ Unfortunately, the trial was stopped before the planned sample size was reached due to slow recruitment. Nevertheless, the majority of patients in published trials to date achieve clinical success regardless of the duration of therapy.

While select patients with cellulitis may require prolonged therapy, the evidence suggests that 5-6 days of β-lactam therapy is appropriate for most cases of outpatient cellulitis. Erythema classically worsens in the first 1-2 days of therapy; so long as the patient is improving systemically and remains non-toxic, appropriate empiric therapy does not require modification. Patients should be reassessed prior to completion of therapy to ensure there is clinical improvement prior to stopping antibiotics. Systemic features like fevers and chills should be resolved, and erythema on an improving trajectory, before stopping antibiotics. However, erythema from cellulitis can persist for some time even after cellulitis is adequately treated. Patients with complicated cellulitis (e.g., undrained abscess or underlying osteomyelitis) may require longer durations of therapy.

Complicated urinary tract infection

Short durations of therapy have been well established for female cystitis.¹⁶ Duration of therapy for complicated urinary tract infection (UTI), including pyelonephritis and male cystitis, has previously been less clear.

A 2021 US randomized, placebo-controlled trial of male patients with afebrile UTI found equivalent outcomes for 7 days versus 14 days of therapy.¹⁷ Patients were treated with either ciprofloxacin or trimethoprim-sulfamethoxazole – it’s unclear whether these results can be extrapolated to oral β-lactams or nitrofurantoin.

A meta-analysis in 2013 of pyelonephritis and septic UTI found equivalent outcomes between shorter duration (<7 days) and longer duration therapy.¹⁸ Multiple recent randomized clinical trials of gram-negative bacteremia, predominantly from a UTI source, have found equivalent outcomes between 7 days and 14 days of therapy.^19–21 Males comprised approximately one-third of all patients. Importantly, patients with source control issues (e.g., untreated obstruction or undrained abscesses) and males with prostatitis were excluded from these trials.

Therefore, in addition to established short course therapy for uncomplicated female cystitis, 7 days of therapy is sufficient in pyelonephritis and male cystitis.

What we recommend (practice tip)

Shorter treatment durations are just as effective as longer durations for a wide range of common infections. Prolonging antibiotic treatment to reduce the risk of bacterial resistance is an outdated dogma; the longer an individual is exposed to antibiotics, the greater the risk of acquiring antimicrobial resistant organisms.²² Longer durations of therapy also increase the risk of adverse events and C. difficile infection.

We recommend the following, evidence-based treatment durations for three common infections in primary care:

1. Mild-to-moderate community-acquired pneumonia can be treated with 3 days of therapy, so long as patients are clinically stable before stopping therapy.
2. Uncomplicated cellulitis can be treated with 5-6 days of therapy.
3. Complicated urinary tract infection, including pyelonephritis and male cystitis, can be treated with 7 days of therapy.

Additional Reading

Wong M, Lau TTY, Leung V, Afra K. Is shorter better? Duration of therapy for common bacterial infections in adults. British Columbia Medical Journal. 2022 Jun;64(5):208-212. (View)

References

1. Review on Antimicrobial Resistance. Antimicrobial resistance: tackling a crisis for the health and wealth of nations [Internet]. London: Review on Antimicrobial Resistance; 2014 [cited 2022 Apr 5]. (View)
2. Choosing Wisely Canada. Using antibiotics wisely in primary care [Internet]. Toronto: Choosing Wisely Canada; [n.d.] [cited 2022 Apr 5]. (View)
3. Stevens V, Dumyati G, Fine LS, Fisher SG, van Wijngaarden E. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011;53(1):42–8. (View)
4. Branch-Elliman W, O’Brien W, Strymish J, Itani K, Wyatt C, Gupta K. Association of duration and type of surgical prophylaxis With antimicrobial-associated adverse events. JAMA Surg 2019;154(7):590–8. (View)
5. Vaughn VM, Flanders SA, Snyder A, et al. Excess antibiotic treatment duration and adverse events in patients hospitalized with pneumonia: a multihospital cohort study. Ann Intern Med 2019;171(3):153–63. (Request with CPSBC or view with UBC)
6. Armand-Lefèvre L, Angebault C, Barbier F, et al. Emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients. Antimicrob Agents Chemother 2013;57(3):1488–95. (View)
7. Teshome BF, Vouri SM, Hampton N, Kollef MH, Micek ST. Duration of exposure to antipseudomonal β-lactam antibiotics in the critically ill and development of new resistance. Pharmacotherapy 2019;39(3):261–70. (View)
8. Grant J, Saux NL. Duration of antibiotic therapy for common infections. Official Journal of the Association of Medical Microbiology and Infectious Disease Canada 2021;6(3):181–97.  (View)
9. Tansarli GS, Mylonakis E. Systematic review and meta-analysis of the efficacy of short-course antibiotic treatments for community-acquired pneumonia in adults. Antimicrob Agents Chemother 2018;62(9):e00635-18. (View)
10. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019;200(7):e45–67. (View)
11. Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med 2016;176(9):1257–65. (Request with CPSBC or view with UBC)
12. Dinh A, Ropers J, Duran C, et al. Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial. Lancet 2021;397(10280):1195–203. (View with CPSBC or UBC)
13. 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. (View)
14. Cross ELA, Jordan H, Godfrey R, et al. Route and duration of antibiotic therapy in acute cellulitis: A systematic review and meta-analysis of the effectiveness and harms of antibiotic treatment. J Infect 2020;81(4):521–31. (View with CPSBC or UBC)
15. Cranendonk DR, Opmeer BC, van Agtmael MA, et al. Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial. Clin Microbiol Infect 2020;26(5):606–12. (View)
16. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52(5):e103-20. (View)
17. Drekonja DM, Trautner B, Amundson C, Kuskowski M, Johnson JR. Effect of 7 vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial. JAMA 2021;326(4):324–31. (View)
18. Eliakim-Raz N, Yahav D, Paul M, Leibovici L. Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2013;68(10):2183–91. (View)
19. Yahav D, Franceschini E, Koppel F, et al. Seven versus 14 days of antibiotic therapy for uncomplicated Gram-negative bacteremia: a noninferiority randomized controlled trial. Clin Infect Dis 2019;69(7):1091–8. (View)
20. von Dach E, Albrich WC, Brunel A-S, et al. Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated Gram-negative bacteremia: a randomized clinical trial. JAMA 2020;323(21):2160–9. (View)
21. Molina J, Montero-Mateos E, Praena-Segovia J, et al. Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial. Clin Microbiol Infect 2022;28(4):550–7. (Request with CPSBC or find via WorldCat)
22. Llewelyn MJ, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ 2017;358:j3418. (View with CPSBC or UBC)

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Duration of antimicrobial therapy for common infections in primary care

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