Tikkinen KAO. et al., 2025: A Multicentre Randomized Controlled Trial of Antimicrobial Prophylaxis to Prevent Urinary Tract Infections after Shockwave Lithotripsy for Urolithiasis: The APPEAL Trial.

Kari A O Tikkinen, Borna Tadayon Najafabadi, Sakineh Hajebrahimi
Eur Urol. 2025 Sep 24:S0302-2838(25)00506-8. doi: 10.1016/j.eururo.2025.08.019

Abstract

Background and objective: Shockwave lithotripsy (SWL) carries a risk of postprocedural infection. Use of antibiotic prophylaxis by clinicians is variable and international guidelines provide conflicting recommendations, reflecting low-certainty evidence. We investigated whether antibiotic prophylaxis reduces bacteriuria and post-SWL urinary tract infections (UTIs).

Methods: APPEAL, an international multicenter, blinded trial, randomized adults undergoing SWL for urolithiasis to a single dose of ciprofloxacin or placebo. The primary outcome was the incidence of a composite of bacteriuria or symptomatic UTI after SWL. Other outcomes included the incidence of pyelonephritis or urosepsis.

Key findings and limitations: Of the 1722 randomized patients, 28 underwent postrandomization exclusions (mainly nonvisualizable stones). Among the analysis population (n = 1694; median age 50 yr; 30% female), 74% had kidney stones and 26% had ureteral stones. Bacteriuria (without symptoms) or symptomatic UTI occurred in 20 patients (2.7%) in the ciprofloxacin arm and 30 (3.9%) in the placebo arm (risk ratio [RR] 0.68, 95% confidence interval [CI] 0.41-1.15). Symptomatic UTI occurred in ten patients (1.3%) in the ciprofloxacin arm and 21 (2.7%) in the placebo arm (RR 0.49, 95% CI 0.19-1.23). No patients in the ciprofloxacin arm and nine (1.2%) in the placebo arm developed pyelonephritis (RR 0.05, 95% CI 0.003-0.93). No patients developed urosepsis and no serious adverse events occurred.

Conclusions and clinical implications: A single dose of ciprofloxacin reduced the risk of post-SWL pyelonephritis, with a modest absolute benefit. The patient importance of this reduction depends on individual preferences in weighing a small absolute reduction in risk against the potential harms and resistance-related implications of antibiotic use. Results from the APPEAL trial will inform global practice and support evidence-based decision-making for patients undergoing SWL.

Comment Peter Alken

I am surprised to see that this study was done and is published in European Urology in 2025.
Concerning the indication for prophylactic antibiotic the authors state:
“ … international guidelines generally do not support antibiotic prophylaxis in SWL” (1)
The ClinicalTrials.gov ID is NCT03692715 and the Study Registration Dates show a first submission on 21.08.2018. The actual study start was 27.09.2018. The informed consent form list the ciprofloxacin risks as: “Side effects specific to the study antibiotic(ciprofloxacin) are rare but may include nausea, headache, insomnia, constipation, dizziness, abdominal pain, and tendon rupture and allergic reaction (itching, skin rash, fever, difficulty breathing).”
Concerning prophylaxis with ciprofloxacin the authors have stated in 2024 in European Urology focus (2): “In 2019, the European Commission issued a legally binding decision (referred to as (3)) restricting the use of quinolone antibiotics, including ciprofloxacin, across all EU countries, primarily because of adverse effects associated with prolonged use [5]. This decision has influenced opinions on suitable antibiotic prophylaxis strategies, particularly in the context of urinary procedures for which quinolones were commonly used. In spite of this, we believed that continuation of recruitment for APPEAL was ethical because (1) evidence has shown that the adverse effects of quinolones are overwhelmingly associated with long-term use, and (2) ciprofloxacin remains one of the prophylactic antibiotics most often used in urology.”

European Medicines Agency (EMA) published In November 2018 a referral procedure (EMA/H/A-31/1452) under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data concluded that serious adverse reactions including tendon, muscle and joint disorders, neurologic and psychiatric disorders listed in the product information of different (fluoro)quinolones could in rare cases become long-lasting, disabling and potentially even irreversible and substantially disrupt patients’ daily activities. To maintain a favourable benefit-risk balance for all (fluoro)quinolone containing medicinal products for systemic use, revised indications, warnings, and other changes to the product information, including direct healthcare professional communication (DHPC) were implemented in EU Member States including recommendations for cessation of prescribing for milder, non-severe or self-limiting infections, and restrictions for other indications (4)
My impression is that publication of the study will lead to further continuation of quinolone subscriptions.
1 Tikkinen KAO, Tadayon Najafabadi B, Hajebrahimi S, et al.; A Multicentre Randomized Controlled Trial of Antimicrobial Prophylaxis to Prevent Urinary Tract Infections after Shockwave Lithotripsy for Urolithiasis: The APPEAL Trial. Eur Urol. 2025 Sep 24:S0302-2838(25)00506-8. doi: 10.1016/j.eururo.2025.08.019. Epub ahead of print. PMID: 40998628.
2 Tikkinen KAO, Tornberg SV, Ruotsalainen J, et al. Update on APPEAL, an International Randomized Controlled Trial Evaluating Ciprofloxacin Versus Placebo in Patients Undergoing Shockwave Lithotripsy for Urolithiasis. Eur Urol Focus. 2024 Sep;10(5):697-699. doi: 10.1016/j.euf.2024.07.011. Epub 2024 Aug 6. PMID: 39112135.
3 European Medicines Agency. Quinolone- and fluoroquinolone containing medicinal products. Amsterdam, The Netherlands: European Medicines Agency; 2019. http://www.ema.europa.eu/ en/documents/referral/quinolone-fluoroquinolone-article-31- referral-annex-iii_fi.pdf.


Peter Alken