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References for Shorter Is Better Table

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Community Acquired Pneumonia: 14 RCTs (total N = 8,732 patients)

1. Dunbar LM, Khashab MM, Kahn JB, Zadeikis N, Xiang JX, Tennenberg AM. Efficacy of 750-mg, 5-day levofloxacin in the treatment of community-acquired pneumonia caused by atypical pathogens. Current medical research and opinion 2004; 20(4): 555-63.

2. Zhao X, Wu JF, Xiu QY, et al. A randomized controlled clinical trial of levofloxacin 750 mg versus 500 mg intravenous infusion in the treatment of community-acquired pneumonia. Diagn Microbiol Infect Dis 2014; 80(2): 141-7.

3. Pakistan Multicentre Amoxycillin Short Course Therapy pneumonia study g. Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind trial. Lancet 2002; 360(9336): 835-41.

4. Greenberg D, Givon-Lavi N, Sadaka Y, Ben-Shimol S, Bar-Ziv J, Dagan R. Short-course antibiotic treatment for community-acquired alveolar pneumonia in ambulatory children: a double-blind, randomized, placebo-controlled trial. The Pediatric infectious disease journal 2014; 33(2): 136-42.

5. el Moussaoui R, de Borgie CA, 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.

6. Uranga A, Espana PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA internal medicine 2016; 176(9): 1257-65.

7. Dinh A, Davido B, Bouchand F, Duran C, Ropers J, Cremieux AC. Honey, I shrunk the antibiotic therapy. Clin Infect Dis 2018; 66(12):1981-2.

8. Harris JA, Kolokathis A, Campbell M, Cassell GH, Hammerschlag MR. Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children. The Pediatric infectious disease journal 1998; 17(10): 865-71.

9. Ginsburg AS, Mvalo T, Nkwopara E. et al. Amoxicillin for 3 or 5 Days for Chest-Indrawing Pneumonia in Malawian Children. NEJM.  2020 383: 13-23.

10. Pernica JM, Harman S, Kam AJ, et al. Short-Course Antimicrobial Therapy for Pediatric Community-Acquired Pneumonia. JAMA Pediatrics, 2021; DOI: 10.1001/jamapediatrics.2020.6735.

11. 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 397:1195-1203.

12. Bielicki J, Stohr W, Barratt S, et al.  Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia.  The CAP-IT Randomized Clinical Trial.  JAMA.  2021;326(17):1713-1724.

13. Williams DJ, Creech CB, Walter EB, et al.  Short- vs. Standard-Course Outpatient Antibiotic Therapy for Community-Acquired Pneumonia in Children.  JAMA Pediatrics.  2022.  176(3):253-261.

14. McCallum G, Fong S, Grimwood K, et al. Extended Versus Standard Antibiotic Course Duration in Children <5 Years of Age Hospitalized With Community-acquired Pneumonia in High-risk Settings: Four-week Outcomes of a Multicenter, Double-blind, Parallel, Superiority Randomized Controlled Trial.  Ped Infect Dis J. 2022. 41(7):549-555.

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Atypical Community Acquired Pneumonia: 1 RCT (total N = 100 patients)

1. Schonwald S, Kuzman I, Oresković K, et al. Azithromycin: single 1.5 g dose in the treatment of patients with atypical pneumonia syndrome--a randomized study. Infection 1999; 22(3):198-202.

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Possible ICU Pneumonia: 1 RCT (total N = 81 patients)

Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162(2 Pt 1): 505-11.--Note, this study randomized patients with a new infiltrate on CXR, but a low Clinical Pulmonary Infection Score (6 or less) in ICU to 3 vs. 14-21 days of abx. The intent was to randomize patients who had a low probability of true pneumonia (low CPIS score) but who were going to get antibiotics anyway. 58% of patients were ventilated and may have had possible VAP (unclear if the infiltrates happened after 48 hours of ventilation or within the first 48 hours), and 42% were not ventilated and either had hospital onset pneumonia in the ICU, or possibly had infiltrates within the first 48 hours of hospitalization.  So the study population likely includes low probability CAP, HAP, and VAP.  However, 3 very important points of this study: 1) It was the first ever RCT of duration of abx therapy for serious infection; 2) Patients who likely don't have infections don't need long courses of abx; and 3) They demonstrated reduced emergence of resistance to abx at the site of infection with short course .

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Ventilator Associated Pneumonia: 3 RCTs (total N = 1086 patients)

1. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA : the journal of the American Medical Association 2003; 290(19): 2588-98.

2. Capellier G, Mockly H, Charpentier C, et al. Early-onset ventilator-associated pneumonia in adults randomized clinical trial: comparison of 8 versus 15 days of antibiotic treatment. PLoS One 2012; 7(8): e41290.

3. Mo Y, Booraphun S, Li AY, et al.  Individualised, short-course antibiotic treatment versus usual long-course treatment for ventilator-associated pneumonia (REGARD-VAP): a multicentre, individually randomised, open-label, non-inferiority trial.  Lancet Resp Med.  2024.  ePub.

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Honorable mention:  4 RCTs with limits that prevent their inclusion in the table.

Kollef M, Chastre J, Clavel M et al. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia. Critical Care. 2012. 16:R218.--doripenem was not non inferior to imipenem, but the failure was likely due to the concerns about doripenem as a therapeutic for this disease (including dosing/pK concerns), not the difference in duration (again, if 8 is non inferior to 15 in 2 RCTs, how can 7 be less effective than 10, and doripenem had problems in 2 other RCTs of VAP in which the same duration of therapy was used in both arms, see Kollef et al. Doripenem for treating nosocomial pneumonia and ventilator-associated pneumonia – Authors' reply. Lancet. 20:20-21.

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Hassen MF, Ayed S, Ben Sik Ali H, et al. [Duration of antibiotic therapy for ventilator-associated pneumonia: comparison of 7 and 10 days. A pilot study]. Ann Fr Anesth Reanim. 2009. 28:16-23.--30 patient study, found no difference in outcomes for 7 vs. 10 days. Small study. We know 8 non inferior to 15, not clear 7 vs. 10 adds to this.

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Bougle A, Tuffet S, Federici S, et al. Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial. 2022. Intensive Care Medicine. 48(7):841-849.--Underenrolled study due to slow enrollment, trend to more relapse in 8 day vs. 15 day arm, wide confidence interval, difficult to interpret.

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Medina J, Perez Protto S, Paciel D, Pontet J, Saldun P, Berro M. Antibiotic
treatment for the ventilator-associated pneumonia: 8 vs. 12 days randomized trial
preliminary data.  ICAAC annaul meeting 2007.  Abstract 36J.--A meeting abstract, never underwent peer review or published, "preliminary data", and again, if we know 8 is non inferior to 15 from 2 larger RCTs, its intuitive that it would be non-inferior to 12.

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Cystic Fibrosis Exacerbation: 1 RCT (total N = 919 patients)

1. Goss CH, Heltshe SL, West NW, et al. A Randomized Clinical Trial of Antimicrobial Duration for Cystic Fibrosis Pulmonary Exacerbation Treatment. Am J Resp Crit Care Med. 2021 204:1295-1305.

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Empyemas/Complicated Parapneumonic Effusions: 2 RCTs (total N = 103 patients)*

1. Hassan M, Gad-Allah M, El-Shaarawy B, et al. The Short versus Long Antibiotic Course for Pleural Infection Management (SLIM) randomised controlled open-label trial. ERJ Open Res. 2023 Apr 11;9(2):00635-2022.

2. Porcel JM, Ferreiro L, Rumi L, et al. Two vs. three weeks of treatment with amoxicillin-clavulanate for stabilized community-acquired complicated parapneumonic effusions. A preliminary non-inferiority, double-blind, randomized, controlled trial. Pleura Peritoneum. 2020 Feb 26;5(1):20190027.

*While durations of 2 and 3 weeks were equal to 3 and 5-6 weeks in these studies, it is possible if not likely that 1 week post source control is adequate, and merits study. That is what I personally do.  In both of these studies, source control was acheived with chest tubes.

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Complicated UTI/Pyelonephritis: 11 RCTs (total N = 2,630 patients)

1. Jernelius H, Zbornik J, Bauer CA. One or three weeks' treatment of acute pyelonephritis? A double-blind comparison, using a fixed combination of pivampicillin plus pivmecillinam. Acta Med Scand 1988; 223(5): 469-77.

2. de Gier R, Karperien A, Bouter K, et al. A sequential study of intravenous and oral Fleroxacin for 7 or 14 days in the treatment of complicated urinary tract infections. Int J Antimicrob Agents 1995; 6(1): 27-30.

3. Talan DA, Stamm WE, Hooton TM, et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA : the journal of the American Medical Association 2000; 283(12): 1583-90.

4. Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 2012; 380(9840): 484-90.

5. Peterson J, Kaul S, Khashab M, Fisher AC, Kahn JB. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology 2008; 71(1): 17-22.

6. Klausner HA, Brown P, Peterson J, et al. A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis. Current medical research and opinion 2007; 23(11): 2637-45.

7. Dinh A, Davido B, Etienne M, et al.  Is 5 days of oral fluoroquinolone enough for acute uncomplicated pyelonephritis? The DTP randomized trial.  Eur J Clin Microbiol Infect Dis.  2017; 36:1443-8.

8. van Nieuwkoop C, van der Starre WE, Stalenhoef JE, et al.  Treatment duration of febrile urinary tract infection: a pragmatic randomized, double-blind, placebo-controlled non-inferiority trial in men and women.  BMC Medicine.  2017; 15:70-8.

9. Drekonja DM, Trautner B, Amundson C, et al.  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):324-331.

10. Zaoutis T, Shaikh N, Fisher BT, et al.  Short-Course Therapy for Urinary Tract Infections in Children: The SCOUT Randomized Clinical Trial.  JAMA Pediatr. 2023;177(8):782-789.--Note in this study, patients who were improving at day 5 were randomized to 5 more days of placebo vs. Abx, yet there were more failures between day 6 and 14 (4.2% vs. 0.6%; during which placebo vs. abx was being given), but NOT after day 14 (4% vs. 3.7%), in the 5 day arm. The failure rate was low either way, and the authors conclude short course is reasonable.

11. Montini G, Tessitore A, Console K, et al.  Short Oral Antibiotic Therapy for Pediatric Febrile Urinary Tract Infections: A Randomized Trial.  Pediatrics (2024) 153 (1): e2023062598.--In this study, children with UTIs randomized to 5 vs. 10 days of abx had significantly FEWER 30 day relapses in the 5 day arm (2.8% vs. 14.3%).

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Confusing trial that people should think carefully about before interpreting

Lafaurie M, Chevret S, Fontaine JP.  Antimicrobial for 7 or 14 days for febrile urinary tract infection in men: a multicenter noninferiority double blind placebo-controlled, randomized clinical trial.  Clin Infect Dis. 2023; ePub.--Study purports to show inferiority of 7 days of therapy for febrile UTI in men. It does not show this. Couple of key points. The name PROSTASHORT is an unfortunate acronym for the trial because the trial did not enroll prostatitis and they say in the methods they tried to exclude prostatic infections. It was true febrile UTIs in men. The primary endpoint was the long-controversial FDA success endpoint for cUTI trials: clinical success, no relapse, and negative urine culture irrespective of symptoms at follow up. Clinically we do not check urine cultures in asymptomatic patients, nor should we, so this endpoint is problematic. Furthermore, the drug studied was ofloxacin dosed at 200 BID, which is the licensed UTI dose. But levofloxacin is the L entantiomer of oflox, and has all the antimicrobial activity (R entantiomer is not active). So an oflox dose of 200 BID = 100 BID of levoflox.  The standard dose of levoflox in the real world is 750 once daily (some people might choose 500, but most prefer 750 for PK reasons). This is an absurdly low dose of drug. Despite this absurdly low dose, 96% of patients treated with 7 days of oflox achieved clinical success/symptom resolution, and there was no difference in relapse between 7 and 14 days.  The driver of clinical failures was a higher rate of asymptomatic bacteriuria on long-term follow up urine cultures in 7 day than 14 day arms. So, the conclusion of the study is that if you use an absurdly low dose of levoflox equivalent for 7 days, your patients will be cured, but may have a higher rate of asymptomatic bacteriuria should you get a follow up urine culture for no reason, and this higher rate of asymptomatic bacteriuria will not increase risk of relapse. Take away is this: 7 days works just fine--use a real dose of drug.

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Honorable mention: 2 weeks vs. 4 weeks (long vs. really long)--no difference in clinical cure

Ulleryd and Sandberg.  Ciprofloxacin for 2 or 4 weeks in the treatment of febrile UTI in men: a randomizsed trial with a 1 year follow-up.  Scan J Infect Dis.  2003; 35:34-39.  

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Complicated Intra-Abdominal Infections: 3 RCTs (total N = 886 patients)

1. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med 2015; 372(21): 1996-2005.

2. Montravers P, Tubach F, Lescot T, et al. Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. Intensive Care Med 2018; 44(3):300-310.

3. Srinu D, Shah J, Jena A, et al. Conventional vs short duration of antibiotics in patients with moderate or severe cholangitis: Non-inferiority randomized trial. Am J Gastroenterol 2023. ePub.

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Complex Appendicitis (appendicitis with necrosis, perforation, or abscess): 2 RCTs     (total N = 1,085 patients)

1. de Wijkerslooth E, Boerma EJG, van Rossem CC, et al. 2 days versus 5 days of postoperative antibiotics for complex appendicitis: a pragmatic, open-label, multicentre, noninferiority randomised trial. Lancet.  2023.  ePub.--No difference in clinical failures or mortality, significantly lower drug adverse events in short arm (9% vs. 22%), significantly shorter hospital length of stay in short arm, but higher readmission rate in short arm (12% vs. 6%) (harder to be readmitted when you stay in the hospital longer).

2. Saar S, Mihnovits V, Lustenberger T, et al. Twenty-four hour versus extended antibiotic administration after surgery in complicated appendicitis: A randomized controlled trial. J Trauma Acute Care Surg. 2019. 86:36-42.--Complication rate 18% vs. 29% (short vs. long, p = 0.3), significantly shorter hospital length of stay for short arm, no difference in readmissions. 

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GNB Bacteremia: 3 RCTs (total N = 1,186 patients; not including multiple cUTI/cIAI pts in above trials who were also bacteremic)

1. Yahav D, Franceschini E, Koppel F, et al. Seven versus fourteen Days of Antibiotic Therapy for uncomplicated Gram-negative Bacteremia: a Non-inferiority Randomized Controlled Trial. Clin Infect Dis 2019 69:1091-8.

2. von Dach E, Albrich WC, Brunel AS, 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. 323:2160-9.

3. Molina J, Montero-Matos E, Praena-Segovia J, et al. Seven versus 14-days course of antibiotics for the treatment of bloodstream infections by Enterobacterales. A randomized, controlled trial.  Clin Microbiol Infect. 2022. 28(4):550-557.

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​​Acute Bacterial Skin and Skin Structure Infections: 4 RCTs (3 non-inferior, total N = 1,412 patients; 1 trial, N = 151 of low dose oral fluclox which is poorly absorbed had excess relapses at 90 d)

1. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004; 164(15): 1669-74.

2. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA : the journal of the American Medical Association 2013; 309(6): 559-69.

3. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2014; 14(8): 696-705.

4. Cranendonk et al.  Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomised, double-blind, placebo-controlled, non-inferiority trial.  Clin Microbiol Infect 2019; 26(5):606-612.

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Soft Tissue Non Osteomyelitis Diabetic Foot Infection: 1 RCT (total N = 66 patients)

1. Pham T-T, Gariani K, Richard J-C, et al. Moderate to Severe Soft Tissue Diabetic Foot Infections: A Randomized, Controlled, Pilot Trial of Post-Debridement Antibiotic Treatment for 10 versus 20 days. Annals of Surgery 2022.  276(2):233-238.

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Osteomyelitis Not Surgically Treated 6 vs. 12 weeks: 2 RCTs (total N = 391 patients)

1. Bernard L, Dinh A, Ghout I, et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet 2015.  385:875-82.​

2. Tone A, et a. Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study. Diabetes Care 2015;38:302-307.

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Osteomyelitis with Removed Orthopedic Implant: 1 RCT (total N = 123 patients, including 39 pts with 2-stage exchanged PJI)

1. Benkabouche M, Racloz G, Spechbach H, et al. Four versus six weeks of antibiotic therapy for osteoarticular infections after implant removal: a randomized trial. J Antimicrobial Chemother 2019.  74:2394-2399.

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Diabetic Foot Osteomyelitis with Debridement or Total Bone Resection: 2 RCTs (total N = 130 patients)

1. Lazaro-Martinez J, Aragon-Sanchez J, Garcia-Martinez E, et al. Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial. Diabetes Care 2014;37:789-95.

2. Gariani K, Pham T-T, Kressman B, et al. Three versus six weeks of antibiotic therapy for diabetic foot osteomyelitis: A prospective, randomized, non-inferiority pilot trial. Clin Infect Dis 2021.  73(7):e1539-e1545.

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Honorable Mention: Acute Hematogenous Osteomyelitis in Children: 1 RCTs (total N = 131 patients)

1. Peltola H, Paakkonen M, Kallio P, et al. Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. 2010. Pediatric Infect Dis J. 29(12):1123-8.--honorable mention because the durations was 20 days vs. 30 days, no difference.

2. Gariani K, Pham T-T, Kressman B, et al. Three versus six weeks of antibiotic therapy for diabetic foot osteomyelitis: A prospective, randomized, non-inferiority pilot trial. Clin Infect Dis 2021.  73(7):e1539-e1545.

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Septic Arthritis: 2 RCTs (total N = 284 patients)

1. Peltola H, et al. Prospective, randomized trial of 10 days versus 30 days of antimicrobial treatment, including a short-term course of parenteral therapy, for childhood septic arthritis. Clin Infect Dis. 2009. 48(9):1201-10.

2. Gjika E, et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial. Ann Rheum Dis 2019; 78:1114–1121.

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Bacterial Meningitis in Children: 6 RCT (total N = 1,387 patients)

1. Molyneux E, et al. 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study. Clin Infect Dis. 2011.  377: 1837–45. (1004 pt RCT)

2. Karageorgopoulos DE, et al. Short versus long duration of antibiotic therapy for bacterial meningitis: a meta-analysis of randomised controlled trials in children.  Arch Dis Children. 94(8):607-14.--meta-analysis of 5 RCTs, 384 pts.

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Honorable mention: Nathan N et al. Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study. Lancet. 2005. 366(9482):308-13.--1 dose ceftriaxone was as effective as a "long acting" formulation of chloramphenicol, primary endpoint was outcome at 72 h, but also no difference in survival.

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Acute Exacerbation Chronic Bronchitis/COPD: >20 RCTs (total N = 11,008 patients)

1. El Moussaoui R, Roede BM, Speelman P, Bresser P, Prins JM, Bossuyt PM. Short-course antibiotic treatment in acute exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies. Thorax 2008; 63(5):415-22.

2. Messous S, Trabelsi I, Bel Haj Ali K, et al.  Two-day versus seven-day course of levofloxacin in acute COPD exacerbation: a randomized controlled trial.  Ther Advanc Resp Dis.  2022.  16:175. 

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Acute Bacterial Sinusitis: 6 RCTs (total N = 2,423 patients)

1. Henry DC, Riffer E, Sokol WN, Chaudry NI, Swanson RN. Randomized double-blind study comparing 3- and 6-day regimens of azithromycin with a 10-day amoxicillin-clavulanate regimen for treatment of acute bacterial sinusitis. Antimicrob Agents Chemother. 2003;47(9):2770-2774.

2. Ferguson BJ, Anon J, Poole MD, et al. Short treatment durations for acute bacterial rhinosinusitis: Five days of gemifloxacin versus 7 days of gemifloxacin. Otolaryngol Head Neck Surg. 2002;127(1):1-6.

3. Sher LD, McAdoo MA, Bettis RB, Turner MA, Li NF, Pierce PF. A multicenter, randomized, investigator-blinded study of 5- and 10-day gatifloxacin versus 10-day amoxicillin/clavulanate in patients with acute bacterial sinusitis. Clin Ther. 2002;24(2):269-281.

4. Roos K, Brunswig-Pitschner C, Kostrica R, et al. Efficacy and tolerability of once-daily therapy with telithromycin for 5 or 10 days for the treatment of acute maxillary sinusitis. Chemotherapy. 2002;48(2):100-108.

5. Williams JW Jr, Holleman DR Jr, Samsa GP, Simel DL. Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole for acute maxillary sinusitis. JAMA. 1995;273(13):1015-1021.

6. Klapan I, Culig J, Oresković K, Matrapazovski M, Radosević S. Azithromycin versus amoxicillin/clavulanate in the treatment of acute sinusitis. Am J Otolaryngol. 1999;20(1):7-11.

 (special thanks to Dr. Fernando Dominguez @FDominguezID for identifying the ABS trials!)​

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Variceal Bleeding: 2 RCT (total N = 171 patients)

1. Lee TH, Huang CT, Lin CC, et al. Similar rebleeding rate in 3-day and 7-day
   intravenous ceftriaxone prophylaxis for patients with acute variceal bleeding. J Formosan Medical Association 2016; 115: 547-52.

2. Lo G-H, Yeh J-H, Tseng C-H, et al. A non-inferiority trial comparing 2 days vs. 5 days of terlipressin and ceftriaxone in terms of 5-day rebleeding for patients with acute gastro-esophageal variceal hemorrhage. Am J Gastroenterol 2024; ePub.

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Neutropenic Fever: 2 RCTs (total N = 438 patients)

1. Aguilar-Guisado M, Espigado I, Martin-Pena A, et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol 2017; 4(12): e573-e83.

2. de Jonge NA, Sikkens JJ, Zweegman S, et al. Short versus extended treatment with a carbapenem in patients with high risk fever of unknown origin during neutropenia: a non-inferiority, open label, multicentre, randomised trial. 2022; 9:E563-72.

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Post-Operative Prophylaxis (total N = 21,190 patients)

1. de Jonge SW, Boldingh QJJ, Solomkin JS, et al. Effect of postoperative continuation of antibiotic prophylaxis on the incidence of surgical site infection: a systematic review and meta-analysis.  Lancet Infect Dis. 2020; 20:1182-1192.  Meta-analysis of 52 RCTs, found lower infection rates with contnuation of prophylaxis only in a subset of studies in which non antibiotic perioperative care standards were not followed, and not in studies with standard of care peri-operative care standards.

2. Berry PS, Rosenberger LH, Guidry CA, et al.  Intraoperative Versus Extended Antibiotic Prophylaxis in Liver Transplant Surgery: A Randomized Controlled Pilot Trial. Liver Transplant. 2019; 25(7):1043-1053.  (Courtesy of Dr. Josh Osowicki, thanks buddy!)

3. The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) Investigators. Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized Clinical Trial. JAMA Oncology; 8(3):345-353. (Courtesy of Dr. Bernardo Pimental, obrigado amigo!)

4. Nagata K, Yamada, K, Shinozaki T, et al.  Effect of Antimicrobial Prophylaxis Duration on Health Care–Associated Infections After Clean Orthopedic Surgery: A Cluster Randomized Trial. JAMA Network Open.  2022;5(4):e226095.

5. Gahm J, Konstantinidou AL, Lagergren J, et al.  Effectiveness of Single vs Multiple Doses of Prophylactic Intravenous Antibiotics in Implant-Based Breast Reconstruction: A Randomized Clinical Trial. JAMA Network Open. 2022;5(9):e2231583.

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Erythema Migrans (Lyme Disease): 3 RCTs (total N = 523 patients)

1. Steere AC, Hutchinson GJ, Rahn DW, et al. Treatment of the Early Manifestations of Lyme Disease. Annals of Internal Medicine. 1983. 99:22-26. (substudy in this paper)

2. Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 2003.  138(9):697-704.

3. Stupica D, Collinet-Adler S, Blagus R, et al. Treatment of erythema migrans with doxycycline for 7 days versus 14 days in Solvenia: a randomised open-label non-inferiority trial. Lancet Infectious Diseases 2019; 394(10202):929-938.

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​​P. vivax Malaria: 1 RCTs (total N = 1,872 patients)

1. Taylor W, et al. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial. Lancet 2019; 394(10202):929-938.

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Other Honorable Mentions

1. Anunnatsiri S, Chaowagul W, Teparrukkul P, et al. A Comparison Between 12 Versus 20 Weeks of Trimethoprim-sulfamethoxazole as Oral Eradication Treatment for Melioidosis: An Open-label, Pragmatic, Multicenter, Non-inferiority, Randomized Controlled Trial.  Clinical Infectious Diseases 2021; 73:e3627–e3633.--Conclusion was that 12 weeks was not non-inferior on relapse to 20 weeks, but was significantly superior on mortality.  But 12 weeks isn't that short, so this is honorable mention.--Thanks to Dr. Noah Wald-Dickler for finding this study!

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References for Shorter Is Better: TB Is Complex

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Latent TB: 8 RCTs (total N = 21,140 patients)

1. Sterling TR, Scott NA, Miro JM, et al. Tuberculosis Trials Consortium, the AIDS Clinical Trials Group for the PREVENT TB Trial (TBTC Study 26ACTG 5259).  Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS 2016;30:1607–15.

2. Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011;365:11–20.

3. Sterling TR, Villarino ME, Borisov AS, et al. TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155–66.

4. Villarino ME, Scott NA, Weis SE, et al. International Maternal Pediatric and Adolescents AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr 2015;169:247–55.

5. Diallo T, Adjobimey M, Ruslami R, et al. Safety and side e􀃗ffects of rifampin versus isoniazid in children. N Engl J Med 2018;379:454–63.

6. Menzies D, Adjobimey M, Ruslami R, et al. Four months of rifampin or nine months of isoniazid for latent tuberculosis in adults. N Engl J Med 2018;379:440–53.

7. Menzies D, Dion MJ, Rabinovitch B, Mannix S, Brassard P, Schwartzman K. Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months. Am J Respir Crit Care Med 2004;170:445–9.

8. Swindells , Ramchandani R, Gupta A, et al.  One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis. New Eng J Med. 2019;380:1001-1011.

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Active Pulmonary Tuberculosis: 6 mo vs. 18 mo: 1 RCT (total N = 860 patients)

Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second report. Lancet. 1973; 1(7816):1331-8.

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Active Pulmonary Tuberculosis: 4 mo RIPE vs. 6 mo: 1 RCT (total N = 330 patients)

Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council. Am Rev Respir Dis. 1986; 133:779-83.

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Active Pulmonary Tuberculosis: 4 mo Rifapentine-Moxi-INH vs. 6 mo RIPE: 1 RCT (total N = 2343 patients)

Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. New Eng J Medicine. 2021; 384:1705-1718.--Study demonstrated statistical non-inferiority of rifapentine + INH + moxifloxacin (but not rifapentine + INH), but with a trend in the wrong direction, including for the Per Protocol population more failures (+3% (95% CI +1-5%)).

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Active Pediatric Pulmonary Tuberculosis: 4 mo RIP(E) vs. 6 mo RIP(E): 1 RCT (total N = 1204 patients)

Turkova A, Wills GH, Wobudeya E, et al. Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. New Eng J Medicine. 2022: 386:911-22.

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Active Pulmonary Tuberculosis: 2-3 mo BDQ/LZD/INH/PZA/EMB vs. 6 mo RIPE: 1 RCT (total N = 370 patients got control or BDQ regimen, 300 got other regimens)

Paton NI, Cousins C, Suresh C, et al. Treatment Strategy for Rifampin-Susceptible Tuberculosis. New Eng J Medicine. 2023: ePub.

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MDR-TB (INH/rifampin resistance but not FQ or AG resistance): 6 mo levofloxacin, bedaquiline and linezolid vs. >9 mo WHO-approved injectible regimen: 1 RCT (total N = 93 patients)

Esmail A, Oelofse S, Lombard C, et al. An All-Oral 6-Month Regimen for Multidrug-Resistant TB (the NExT Study): A Multicenter, Randomized Controlled Trial. Am J Resp Crit Care Med. 2022: 205(10):1214-1227.

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Rifampin Resistant TB: 24 week bedaquiline, pretomanid, linezolid, moxifloxacin vs. 9-20 mo standard care regimen: 1 RCT (total N = 303 patients)

Nyang'wa BT, Berry C, Kazounis E, et al. A 24-Week, Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial. Lancet. 2023. ePub. (24 wk bedaquiline+pretomanid+linezolid+moxifloxacin resulted in superior clinicial outcomes, superior safety, and faster micro clearance than traditional 9-20 week regimens that include injectables.  In a substudy, a randomized arm without moxifloxacin was also non-inferior to traditional regimens).

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Active Abdominal Tuberculosis: 6 mo vs. 12 mo: 1 RCT (total N = 193 patients)

Balasubramanian R, Nagarajan M, Balambal R, et al. Randomised controlled clinical trial of short course chemotherapy in abdominal tuberculosis: a five-year report. Int J Tuberc Lung Dis. 1997; 1:44-51.

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Active Lymph Node Tuberculosis: 6-9 mo vs. 18 mo: 2 RCT (total N = 351 patients)

1. Short course chemotherapy for tuberculosis of lymph nodes: a controlled trial. British Thoracic Society Research Committee. Brit Med J. 1985; 290:1106-8.

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2. Campbell IA, Ormerod LP, Friend JA, et al.  Six months versus nine months chemotherapy for tuberculosis of lymph nodes: final results. British Thoracic Society Research Committee. Respir Med. 1993; 87:621-3. 

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Active Spinal Tuberculosis: 6 mo vs. 9 mo vs. 18 mo: 1 RCT (total N = 436 patients)

Five-year assessment of controlled trials of short-course chemotherapy regimens of 6, 9 or 18 months' duration for spinal tuberculosis in patients ambulatory from the start or undergoing radical surgery. Fourteenth report of the Medical Research Council Working Party on Tuberculosis of the Spine. Int Orthop. 1999; 23:73-81.
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References for Shorter Is Better Exceptions

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Prosthetic Joint Infections:

Combined DAIR, 1-, and 2-Stage Exchanges 

1 RCT (total N = 410 patients)

Bernard L, Arvieux C, Brunschweiler B, et al. Antibiotic Therapy for 6 or 12 Weeks for Prosthetic Joint Infection. New Eng J Medicine 2021; ePub.--6 weeks clearly inferior overall, and particularly for hte DAIR cohort

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DAIR Only: Early Infection Onset (< 1 month After Implant) 

1 RCT (total N = 63 patients)

Lora-Tamayo J, Euba G, Cobo J, et al. Short- versus long-duration levofloxacin plus rifampicin for acute staphylococcal prosthetic joint infection managed with implant retention: a randomised clinical trial. Int J Antimicrob Agents 2016;48:310-6.

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Febrile cUTI in Men: 1 RCT (total N = 520 patients)

Laufarie M, Chevret S, Fontaine JP, et al. Antimicrobial for 7 or 14 days for febrile urinary tract infection in men: a multicenter noninferiority double blind placebo-controlled, randomized clinical trial. Clin Infect Dis. 2023; ePub.--NOTE, failure was driven primarily by large difference in microbiological success rate at 6 weeks after end of therapy. This is of unclear relevance given that there was not a difference in clinical relapse/recurrence of infection. The clinical cure rate was an amazing 95.6% in the 7 day arm, which was statistically worse than the almost unheard of 100% in the 14 day arm, but still 95.6% is an amazingly good/unusual clinical success rate for a cUTI study. Furthermore, ofloxacin at a dose of 200 mg BID was used, which while the licensed dose of this older FQ, is far below the standard daily dose of the active enantiomer levofloxacin (750 mg daily). Overall, this study gives high confidence that FQ at normal dose is highly clinically effective at treating febrile cUTIs in males, despite the statistical inferiority.

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Otitis Media < 2 Years Old: 1 RCT (total N = 520 patients)

Hoberman A, Paradise JL, Rockette HE, et al. Shortened Antimicrobial Therapy for Otitis Media in Young Children. New Eng J Medicine. 2016; 375:2446-2456.

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Otitis Media > 2 Years Old: Meta-Analysis of 49 Trials

Kozyrskyj A, Klassen TP, Moffatt M, and Harvey K. Short-course antibiotics for acute otitis media. Cochrane Database Syst Rev 2010 Issue 9 Pages CD001095.

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Strep Throat:

See systematic review: Holm AE, Carl Llor LB, Cordoba G.  Short- vs. Long-Course Antibiotic Treatment for Acute Streptococcal Pharyngitis: Systematic Review and Meta-Analysis of Randomized Controlled Trials.  Antibiotics.  2020;9:733.  Summarizing 5 RCTs of PCN 3-5 d vs. 7-10 d showing shorter course resulted in more short term clinical failures; and summarizing >20 RCTs of 3-5 d of numerous other antibiotics (cephalosporins, macrolides, clindamycin)  vs. 10 d PCN generally showing similar outcomes of shot vs. long therapy.

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1 recent RCT: Stahlgren GS, Tyrstrup M, Edlund C, et al.  Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study.  BMJ.  2019;367:l5337., showing similar cure rate of the shorter course, more frequent regimen, with fewer new episodes of tonsillitis and fewer adverse events in the short course arm, but a small decrease in eradication of colonization (80% vs. 90%).

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Chronic Pulmonary Aspergillosis:

Seghal IS, Dhooria S, Muthu V, et al.  Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India.  Lancet Infectious Diseases.  2022. 22(7):1052-1061.

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