What to do with the results of the PROSTASHORT trial?

The PROSTASHORT trial was a randomized controlled trial, which showed that treating a febrile urinary tract infection in men for 7 days was inferior to 14 days. On the one hand, it was considered one of the most influential studies in infectious diseases of 2023 (15). On the other hand, Brad Spellberg, one of the leading infectious disease specialists behind the ‘shorter is better’ movement, described the study as follows (9):

“If you use an absurdly low dose of levofloxacin 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”.

In this blog post, let’s take a deeper look at this study.

1. What are internal flaws of the PROSTASHORT trial?

2. Which evidence came out since the start of the PROSTASHORT trial?

1. What are internal flaws of the PROSTASHORT trial?

The study population was heterogeneous.

The PROSTASHORT trial (1), as its name indicates, was intended to include community-acquired, acute prostatitis (2). This fact was confirmed by the main author during a presentation at the time that 168 patients were already recruited (3). Nevertheless, the final text never mentions acute prostatitis; instead febrile urinary tract infection (UTI) is chosen as inclusion criterion. However, this syndrome – although easily defined – covers a lot of different pathologies, among which acute bacterial prostatitis, pyelonephritis, epididymitis, and rarely cystitis or urethritis.

• A previous study about febrile UTI in men showed that 90% of participants had concomitant prostate involvement (4). In the PROSTASHORT trial by contrast, a positive digital rectal examination, the key finding of acute prostatitis (5), was merely present in less than 60% of participants (6).

• Another study that investigated febrile UTI in men and women, included acute pyelonephritis, prostatitis and urosepsis (7). This study demonstrated an increased clinical and bacteriological treatment failure in patients treated for 7 days versus 14 days, which was attributed to prostatic involvement. Nevertheless, no difference was observed in the subgroup of patients treated with ciprofloxacin for 7 days versus 14 days (7).

• In the PROSTASHORT trial, blood cultures were positive in 16.8% of cases in which they were performed. As discussed below, this subpopulation is interesting as recent evidence suggests that in these patients 7-day antibiotic treatment might be sufficient (8).

My view: Although intended as a study about acute prostatitis, the inclusion of multiple entities complicates the interpretation of the PROSTASHORT trial. Furthermore, its conclusion is inconsistent with other studies.

The dose of ofloxacin is too low.

• One of Brad Spellberg’s main points of criticism is that the ofloxacin dose of 400 mg/day, equivalent to levofloxacin 200 mg/day, is too low. Indeed, most guidelines advocate for higher doses of levofloxacin. For instance, UpToDate recommends a dose of 500 to 750 mg per day (5). Moreover, 20% of the 7-day treatment group had a BMI of more than 30 kg/m² (1), in which a dose of 750 mg a day is strongly recommended (9).

  
  

• Furthermore, most patients were initially treated with ceftriaxone or cefotaxime and only switched on day 3 or 4 to ofloxacin (6). Beta-lactams are known for their suboptimal penetration into prostatic tissue. In another study, their use was considered the main explanation for failure of short-course antibiotic therapy in men with febrile UTI (7).

The translation of the primary endpoint to clinical practice is not straightforward.

• First of all, let me clearly state there was a significant increase in clinical failure in the 7-day group compared to the 14-day group at 6 weeks after clinical presentation. In total 5 patients (4.3%) in the 7-day group developed fever related to a UTI in that period whereas no patient in the 14-day group did. The fragility index of this finding is, however, 1. Moreover, interpretation of other variables included in the primary endpoint is challenging.

  
  

• Collecting a control urine sample after discontinuation of antibiotics is an FDA-recommended practice, as they reason that continued bacteriuria might be a risk factor for early relapse (11). However, my search for studies backing this statement was unfruitful. I could only find one Danish pediatric study that concluded that follow-up urine sampling did not add value (13). Moreover, guidelines in adults don’t usually recommend follow-up urine samples after clinically successful treatment of a UTI (12,14).

  
  

• Additionally, the PROSTASHORT trial does not specify the proportion of reinfection versus relapse. Another study demonstrated that more than half of the positive urine samples in the follow-up period were due to reinfection with a different microorganism (4), which might not be prevented by prolonged antibiotic therapy. Similarly, four times as many participants in the 7-day treatment group were taking antibiotics in their follow-up period, although the indication for this therapy is unclear (6).

2. Which evidence came out since the start of the PROSTASHORT trial?

Since the PROSTASHORT trial started recruitment, several major trials have been published that may shed new light on its findings.

Studies on Antibiotic Duration in Bloodstream infections

In the past few years, four studies have examined if treating bloodstream infections with 7 days of antibiotics was inferior to 14 days (16). The largest of them, the BALANCE trial (8), included a total of 3,608 patients. In this study, 53.3% of participants were male and 42.2% had a urinary source for their bacteremia. The BALANCE trial concluded that 7-day treatment was non-inferior to 14-day in terms of mortality. Subgroup analysis by infection source confirmed this conclusion, as did a separate analysis using clinical decision rules (17). At present, another sub-study is still ongoing, which is specifically looking at bacteriological resolution of the infection using follow-up urine samples 6 to 12 weeks after completion of antimicrobial therapy (18).

Nevertheless, a meta-analysis of these four trials concluded, with 95-97% certainty, that 7 days of antibiotic therapy is non-inferior to 14 days for mortality (16). As almost 17% of the participants in the PROSTASHORT trial had positive blood cultures, this conclusion is applicable to those patients as well (1). However, mortality as sole outcome measure is never the whole story in clinical practice. One of the biggest criticisms of the BALANCE trial is that it did not evaluate suppurative or distant complications (19). In other trials, such complications were more likely with shorter therapy (19).

McAteer et al (2023)

This was a retrospective study of 1099 patients who were treated with 7, 10, or 14 days of antibiotics for complicated UTI (20). The latter was defined as UTIs that occurred in the setting of pre-existing structural or functional abnormalities of the urinary tract or any UTI in men. Overall, men accounted for 67% of the study population. Compared to the PROSTASHORT trial, patients were probably sicker, as all had concomitant bacteremia, and 27% were initially admitted to the intensive care unit. The primary outcome was relapse of the same infection. This study concluded that 7-day treatment was non-inferior to 14-day treatment as long as antibiotic therapy consisted entirely of intravenous beta-lactams or appropriately dosed oral fluoroquinolones, or trimethoprim-sulfamethoxazole.

My view: The danger of the PROSTASHORT trial is that it may prevent new guidelines from recommending shorter antibiotic therapy in febrile UTI in men. To position itself as a game changer, this study has too many flaws and substantial contradictory evidence already exists. If the BALANCE sub-study confirms that 7 days of adequately dosed antibiotic therapy is non-inferior to 14 days in treating febrile UTI, in my opinion, a new golden standard will be established.

References:

1. Lafaurie 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 Jun 16;76(12):2154-2162.

 2. Wintenberger C, Guery B, Bonnet E, et al; Recommendation Group of the SPILF. Proposal for shorter antibiotic therapies. Med Mal Infect. 2017 Mar;47(2):92-141.

 3. https://www.infectiologie.com/UserFiles/File/jni/2017/com/jni2017-prostashort-lafaurie.pdf (Accessed on June 3, 2025.).

 4. Ulleryd P, Sandberg T. Ciprofloxacin for 2 or 4 weeks in the treatment of febrile urinary tract infection in men: a randomized trial with a 1 year follow-up. Scand J Infect Dis. 2003;35(1):34-9.

 5. Meyrier M, Trautner BW, Kulkarni PA. Acute bacterial prostatitis. In: UpToDate, Connor RF (Ed), Wolters Kluwer. (Accessed on June 8, 2025.).

 6. https://www.infectiologie.com/UserFiles/File/jni/2021/com/jni2021-st15-03-lafaurie.pdf (Accessed on June 3, 2025.).

 7. 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 Med. 2017 Apr 3;15(1):70.

 8. Daneman N, Rishu A, Pinto R, et al. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med. 2025 Mar 13;392(11):1065-1078.

 9. https://www.bradspellberg.com/shorter-is-better (Accessed on December 22, 2024.).

 10. Castro-Balado A, Varela-Rey I, Mejuto B, et al. Updated antimicrobial dosing recommendations for obese patients. Antimicrob Agents Chemother 68:e01719-23.

 11. Center for Drug Evaluation and Research. Complicated urinary tract infections: developing drugs for treatment guidance for industry. Silver Spring, MD, 2018.

 12. Nederlandse Vereniging voor Urologie. Urineweginfecties (UWI) bij volwassenen. Richtlijnendatabase (Accessed June 4, 2025).

 13. Lytzen R, Kaalund-Jørgensen K, Ahmed A, et al. A follow-up urine sample has limited value after treatment for urinary tract infection in children. Dan Med J. 2015 Jan;62(1):A4989.

 14. Caron F, Galperine T, Flateau C, et al. Practice guidelines for the management of adult community-acquired urinary tract infections. Med Mal Infect. 2018 Aug;48(5):327-358.

 15. Freiberg JA, Wright PW. What's Hot This Year in Infectious Diseases Clinical Science. Clin Infect Dis. 2024 May 15;78(5):1170-1174.

16. Lee TC, Prosty CJ, Fralick M, et al. Seven vs Fourteen Days of Antibiotics for Gram-Negative Bloodstream Infection: A Systematic Review and Noninferiority Meta-Analysis. JAMA Netw Open. 2025 Mar 3;8(3):e251421.

 17. Ong SWX, Pinto R, Rishu A, et al. Identifying heterogeneity of treatment effect for antibiotic duration in bloodstream infection: an exploratory post-hoc analysis of the BALANCE randomised clinical trial. EClinicalMedicine. 2025 Apr 10;83:103195.

 18. Rogers BA, Fowler R, Harris PNA, et al. Non-inferiority trial of a shorter (7 days) compared with a longer (14 days) duration of antimicrobial therapy for the treatment of bacteraemic urinary sepsis, measured by microbiological success after the completion of therapy: a substudy protocol for the Bacteraemia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) multicentre randomised controlled trial. BMJ Open. 2023 Jun 26;13(6):e069708.

 19. Patamatamkul S. Possible reluctance to shorten antibiotic duration in Gram-negative bacteremia and limitations of mortality-based outcomes: the need to prioritize clinical-microbiologic recurrence in future trials-Insights from the "Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness" (BALANCE) Trial. IJID Reg. 2025 Mar 20;15:100639.

 20. McAteer J, Lee JH, Cosgrove SE, et al. Defining the Optimal Duration of Therapy for Hospitalized Patients With Complicated Urinary Tract Infections and Associated Bacteremia. Clin Infect Dis. 2023 May 3;76(9):1604-1612.