What is the optimal duration of antibiotics for complicated UTI in a male patient?
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Introduction
The Infectious Disease Society of America (IDSA) provides clear recommendations on the treatment duration for a urinary tract infection (UTI) in women; however, there are no recommendations on the treatment duration in men.1 UTIs in men are much less common than in females and are generally considered to be complicated, since most present as a result of a structural or neurologic abnormality.2-3 Uncomplicated infections are rare, but may occur in male patients.4 UTIs may also be classified as afebrile or febrile, with afebrile infections involving the lower urinary tract and having a lower risk of complications and febrile infections manifesting as prostatitis and pyelonephritis.5 Therefore, the optimal treatment duration in men has generally been a prolonged course of antibiotics of at least 7 to 14 days.3
Although the IDSA guidelines do not provide specific recommendations for the duration of therapy for males, the European Association of Urology guideline on urological infections recommends for males with cystitis a treatment duration of at least 7 days of trimethoprim-sulfamethoxazole (TMP-SMZ) or a fluoroquinolone in accordance with susceptibility testing.1,3 A 2023 systematic review found a lack of consensus on the definition of UTI in adult men as well as the duration of treatment among the various UTI guidelines.5 Clinical literature has also found a short course of antibiotics to be non-inferior for various bacterial infections; however, the literature is inconsistent and limited for the indication of UTI in males.6
Clinical trial efficacy data
There is limited clinical evidence on treatment of UTIs in males; however, 2 meta-analyses evaluated the clinical and microbiological cure rates of short course compared to long course of antibiotics in febrile female and male patients combined. Eliakim-Raz et al. evaluated ≤ 7 days of treatment compared to >7 days of treatment using fluoroquinolones, beta-lactams, and TMP-SMZ, and found no difference in clinical failure nor microbiological failure.7 In a subgroup of patients with >20% having urogenital abnormalities, microbiological failure was significantly lower in the longer duration treatment arm. Erba et al. evaluated ≤7 days of treatment (short course) compared to longer courses in 4 systematic reviews and 10 non-duplicated RCTs.8 Among the non-duplicated RCTs, clinical cure rate was higher for short-course antibiotic treatment compared to longer duration of therapy, but no difference in microbiological failure rates was seen.
Limited RCTs exist comparing treatment duration in male and female patients with febrile and afebrile UTI. Drekonja et al. 2021 evaluated symptom resolution after completion of ciprofloxacin or TMP-SMX for 7 days compared to 14 days in afebrile men.9 A 7-day course demonstrated non-inferiority compared to the 14-day course. Lafaurie et al. evaluated ofloxacin treatment for 7 days compared to 14 days in febrile men. Treatment success did not reach the prespecified noninferiority margin of 10%, demonstrating inferiority of the 7-day course compared to the 14-day course in this population.10 Lastly, in the RCT by van Niewukoop et al., non-inferiority was not met in a 7-day course of ciprofloxacin compared to a 14-day course in febrile men and women.11 Additionally, in a subgroup analysis of febrile men, a 14-day course of ciprofloxacin was found to be superior to a 7-day course.
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| Table 1. Overview of meta-analyses examining various durations of UTI treatment.7-8 |
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| Study design and duration | Population | Treatment Arms | Results | Limitations | Conclusions |
| Meta-analyses with febrile UTI patients |
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| Elikaim-Raz et al. 20137 Systematic review and Meta-analysis | 8 RCTs (N=2515) female and male patients with pyelonephritis and UTI with sepsis | ≤ 7 days of treatment >7 days of treatment Included studies used fluoroquinolones, beta-lactams, and TMP-SMZ | Primary At end of treatment, clinical failure was not significantly different between groups (RR, 0.63; 95% CI, 0.33 to 1.18; n=1076). Secondary Clinical failure for per protocol population at end of follow-up (range, 22 to 63 days) did not differ between treatment arms (RR, 0.79; 95% CI, 0.56 to 1.12; n=1398). Microbiologic failure at end of follow-up did not differ between the 2 arms (RR, 1.16; 95% CI, 0.83 to 1.62; n=1402). Microbiologic failure in subgroup of patients with >20% having urogenital abnormalities was significantly lower in the long-treatment arm (RR, 1.78; 95% CI, 1.02 to 3.10; n=287). Safety Reported adverse events were not significantly different between groups (RR, 0.93; 95% CI, 0.73 to 1.18; n=2127). | Including 5 RCTS with men and women and 3 RCTs without men in the study population makes it difficult to assess impact of short versus long duration therapy on only men with UTIs, especially without sub-group analyses assessed in the review. Microbiologic follow-up varied amongst the RCTs. Some studies had follow-up as 10 days after completion and some listed 6 weeks after completion. Lack of standardization challenges the ability to assess recurrence of UTI with varied follow-up windows. Two Swedish trials utilized antibiotics that are not appropriate therapy, pivampicillin and ampicillin. There were differences in treatment comparisons allowed in the study. There were 3 trials that compared different antibiotics, either fluoroquinolones, β-lactams, or TMP-SMZ and 5 that compared the same antibiotics to each other. There are difficulties in comparing different antibiotics when they are used for different durations. Using studies more than 10 years old can be a limitation due to changes in susceptibility patterns, follow-up window recommendations, and common treatment algorithms at different institutions or practices. | There is no difference between the 7 days or longer treatment for clinical or microbiological failure. |
| Erba 20218 Systematic review | 4 systematic reviews and 10 non-duplicated RCTs (N=1536) with female and male patients with pyelonephritis | Most studies compared ≤7 days of treatment (short course) with longer courses | Primary The clinical cure rate was higher for short-course antibiotic treatment compared to longer duration of therapy, among non-duplicated RCTs (RR, 0.70; 95% CI, 0.53 to 0.94). Secondary No significant difference was found in microbiological failure rates, among non-duplicated RCTs (RR, 1.06; 95% CI, 0.75 to 1.49). Safety Safety data was not assessed. | This study did not include primary studies and relied on the findings of systematic reviews and guidelines. This approach may not have captured all evidence in the topic and may have limited the study scope. There was high heterogeneity of 55% for microbiological failure. Some studies in the course varied on defining 14 days as short versus long course, posing inconsistencies on what is considered short or long by the authors. Not assessing safety in the review is a limitation as adverse effects may guide clinical decision making for either short or longer courses. Similar to Eliakim-Raz, the use of studies more than 10 years old can be limiting due to changes in in susceptibility patterns, follow-up window recommendations, and common treatment algorithms at different institutions or practices. | For uncomplicated pyelonephritis, a short course of antibiotics is associated with a higher cure rate and no difference in microbiological failure rate than with a longer duration of treatment. |
| Abbreviations: CI, confidence interval; RCT, randomized controlled trial; RR, relative risk; TMP-SMX, trimethoprim-sulfamethoxazole; UTI, urinary tract infection. |
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| Table 2. Overview of RCTs examining various durations of UTI treatment.9-11 | ||||||
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| Study design and duration | Subjects | Interventions | Inclusion and Exclusion Criteria | Results | Limitations | Conclusions |
| Afebrile UTI patients |
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| Drekonja et al. 20219 DB, PC, MC, non-inferiority RCT | N=272 outpatient adult male US veterans with afebrile symptomatic UTI | Ciprofloxacin or TMP-SMX for 7 or 14 days (dosing not described) | Inclusion Males 18 years old and above with new onset of at least either dysuria, frequent or urgent urination, hematuria, CVA tenderness, pain in the perineal, flank, or suprapubic areas, primarily outpatient care, max of 24 hours of inpatient observation. Exclusion Documented fever with a temperature of 38º C or at least 100.4º F, treatment for a UTI within the last 14 days, and requiring treatment with antibiotics other than ciprofloxacin or TMP-SMX after urine growth culture results. Urine culture was not required for enrollment but encouraged based on institution practices. | Primary In the as-treated population (modified per protocol), UTI symptoms resolved by day 14 after completion of antibiotic treatment in 93.1% of the 7-day cohort and in 90.2% of the 14-day cohort (difference, 2.9%; 1-sided 97.5% CI, −5.2% to not captured; noninferiority margin of -10%) Secondary In the as-treated population, UTI symptoms returned within 28 days of stopping medication was 9.9% in the 7-day cohort and 12.9% in the 14-day cohort (difference, −3.0%; 2-sided 95% CI, −10.8% to 6.2%; p=0.70). Safety Adverse events were reported by 19.8% of the 7-day group and by 23.6% of the 14-day group, and most included diarrhea. | The long enrollment period (April 2014 through December 2019) poses a challenge as there could have been institutional changes in recommendations of antibiotics for treatment and for antibiotic susceptibilities during this period. Ciprofloxacin contains boxed warnings and may be less appropriate as a treatment option compared to alternative agents. The study did not enroll the needed 290 participants to detect a difference with 85% power. Urine cultures were encouraged, but not required based on the institution, and this potentially introduces patients without bacteriuric UTIs into the study. Patients without pre-treatment urine culture were 12.1% of the study participants. The average patient in the study was a 70-year-old white male who experienced an E. coli related UTI, limiting generalizability. | In afebrile men with suspected and symptomatic UTI, a 7-day course of either ciprofloxacin or TMP-SMX demonstrated noninferiority to the 14-day treatment. |
| Febrile UTI patients |
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| Lafaurie et al. 202310 DB, PC, MC, non-inferiority RCT | N=240 adult French men with febrile, symptomatic UTI | Day 1 to 3: treated empirically while awaiting culture results with ofloxacin 200 mg twice daily (oral or IV), ceftriaxone 1000 mg once daily (IV or IM), or cefotaxime 1000 mg 3 times daily (IV or IM). Day 3 to 7: all patients received oral ofloxacin 200 mg twice daily. Day 8 to 14: randomized to continue oral ofloxacin or placebo. | Inclusion Adult males with fever (≥38° C or <36° C) and new onset of at least either pain in the perineal, flank, or suprapubic areas, hematuria, pain during prostatic or rectal examination, significant leukocyturia in urinalysis, or culture showing a single pathogen with susceptibilities to third generation cephalosporins, fluoroquinolones, or nalidixic acid. Exclusion UTI occurring 48 hours after hospital admission, sepsis, or urosepsis, treatment for a UTI with antibiotics in the past 12 months, indwelling urinary catheter, use of fluoroquinolone or aminoglycoside within 72 hours of starting the study antibiotic, allergies to fluoroquinolones, or fluoroquinolone-related tendinopathy. | Primary In the ITT population, treatment success at week 6 (defined as no UTI-related fever at and negative urine cultures) was reported by 55.7% of patients in the 7-day group and 77.6% of patients in the 14-day group (risk difference, -21.9; 95% CI, -33.3 to -10.1). This did not meet the prespecified noninferiority margin of -10%, demonstrating inferiority of 7-day treatment duration compared to 14-day. Secondary The recurrence of UTI between weeks 6 to 12 occurred for 2 patients in the 7-day group and 5 patients in the 14-day group (p=0.45). Between weeks 6 through 12, there was no difference between the 7-day and 14-day group in persistence or new acquisition of treatment-resistant organisms, based off rectal swab results. Safety By week 6, there were no differences between drug related AEs in either group (p=0.54). No grade 4 events occurred in either group. The AEs reported included osteoarticular pain, diarrhea, skin rash, and headache. | The study did not recruit the prespecified 284 patients required to meet 80% power, increasing the risk of Type II error. The investigators had stringent limitations on when treatment was deemed successful: the primary endpoint was assessed at 6 weeks instead of 2 weeks as other comparable UTI studies. This was due to prior French practice that has since changed from study initiation that required a negative urine culture at 4 to 6 weeks after completion of therapy. | In febrile and symptomatic men, a 7-day course of ofloxacin was considered inferior to the 14-day treatment. |
| van Niewukoop et al. 201711 DB, PC, MC, non-inferiority RCT | N=200 adult Dutch men and women with febrile UTI | All patients received ciprofloxacin 500 mg twice daily for 7 days (OL). Patients were randomized to receive an additional 7 days of therapy or placebo (DB). | Inclusion Men and women at last 18 years or older, with presumed UTI. Criteria for inclusion included fever ≥38.2º C or feeling fever-associated rigors in prior 24 hours, at least 1 UTI symptom (frequency urgency, dysuria, pain in perineal, suprapubic, or flank regions, CVA tenderness), and positive nitrate test or pyuria. Exclusion Isolation of ciprofloxacin-resistance uropathogen, metastatic infectious loci, allergies to fluoroquinolones, polycystic kidney disease, permanent renal replacement therapy, kidney transplantation, pregnancy, and inability to speak Dutch. | Primary The clinical cure rate (defined as absence of fever and resolution of UTI symptoms without additional antimicrobial therapy) at 10 to 18 days after treatment for the ITT population was 90% for the 7-day group vs 95% for the 14-day group (difference, -4.5%; 90% CI, -10.7 to 1.7; Pnon-inferiority = 0.072). Non-inferiority was not met, as the CI exceeded the prespecified 10% noninferiority margin. In men, the cure rate was 86% for the 7-day group and 98% for the 14-day group (difference, -11.2%; 90% CI, -20.6 to -1.8; Pnon-inferiority = 0.417; Psuperiority=0.05), demonstrating inferiority with the 7-day regimen. Secondary The bacteriologic cure rate at 10 to 18 days after last treatment dose for ITT population was 93% for the 7-day group and 97% for the 14-day group (difference, -4.3%; 90% CI, -9.7 to 1.2; Pnon-inferiority =0.041) The long-term clinical cure rate defined as 70 to 84 days after last dose in the ITT population was 93% in the 7-day group and 91% In the 14-day group (difference, 1.1%; 90% CI, -5.5 to 7.6; Pnon-inferiority = 0.005). Similar non-inferiority was demonstrated in male subgroup analysis. Safety General AEs were similar between the 7-day and 14-day arm with the most common being myalgia (10% and 12%, respectively), dizziness (10% and 9%), and headache (16% and 4%). | This study included both men and women. Although subgroup analyses were assessed by sex, the study was not powered to make conclusions for male patients alone. Rationale was not provided in the study why the durations were chosen for short-term and long-term clinical cure rates. Similar to the Drekonja et al. study, urine culture was not an inclusion criterion nor was diagnosis confirmed by a culture. This can potentially introduce patients without a true UTI into the study. All patients could receive empiric antibiotics at physician discretion prior to ciprofloxacin. Additional subgroup analysis would be useful to see if different empiric therapy impacted outcomes, as no formal empiric therapy protocol was provided to physicians. | In the ITT population, non-inferiority was not met with a 7-day course of ciprofloxacin compared to a 14-day course. |
| Abbreviations: AE, adverse event; CI, confidence interval; CVA, costovertebral angle; DB, double-blind; E. coli, Escherichia coli; IM, intramuscular; ITT, intention-to-treat; IV, intravenous; MC, multicenter; OL, open label; PC, placebo-controlled; PP, per protocol; RCT, randomized controlled trial; TMP-SMX, trimethoprim-sulfamethoxazole; US, United States; UTI, urinary tract infection. |
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Conclusion
There is currently not enough clinical evidence to recommend the use of a short course of antibiotics compared to a long course in male patients with UTI. Additionally, some data suggest that a short course of antibiotics is inferior compared to a long course in men. UTIs in males are less common than in female and are typically characterized as complicated due to involvement with the prostate. Further research is warranted to establish if there is efficacy in a short course of antibiotics in male patients; however, each patient should be clinically assessed, and treatment decisions made on an individual basis.
References
- 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-e120. doi:10.1093/cid/ciq257
- Fernandez JM, Coyle EA. Urinary Tract Infections. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s pharmacotherapy: a pathophysiologic approach, 12th Edition. McGraw Hill; 2023. Accessed May 25, 2023. https://accesspharmacy-mhmedical-com.proxy.cc.uic.edu/content.aspx?bookid=3097§ionid=266108683
- Bonkat G, Bartoletti R, Bruyere F, et al. EUA guidelines on urological infections. EAU Guidelines. 2022.
- Gupta K. Acute simple cystitis in adult males. UpToDate; 2022. Accessed May 26, 2023. https://www-uptodate-com.proxy.cc.uic.edu/contents/acute-simple-cystitis-in-adult-males?search=uti%20male&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Soudais B, Ribeaucoup F, Schuers M. Guidelines for the management of male urinary tract infections in primary care: a lack of international consensus-a systematic review of the literature. Fam Pract. 2023;40(1):152-175. doi:10.1093/fampra/cmac068
- Lee RA, Stripling JT, Spellberg B, Centor RM. Short-course antibiotics for common infections: what do we know and where do we go from here?. Clin Microbiol Infect. 2023;29(2):150-159. doi:10.1016/j.cmi.2022.08.024
- 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):2183-2191. doi:10.1093/jac/dkt177
- Erba L, Furlan L, Monti, A. et al. Short vs long-course antibiotic therapy in pyelonephritis: a comparison of systematic reviews and guidelines for the SIMI choosing wisely campaign. Intern Emerg Med 16, 313–323 (2021). https://doi.org/10.1007/s11739-020-02401-4
- 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):324-331. doi:10.1001/jama.2021.9899
- 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 [published online ahead of print, 2023 Feb 14]. Clin Infect Dis. 2023;ciad070. doi:10.1093/cid/ciad070
- 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;15(1):70. Published 2017 Apr 3. doi:10.1186/s12916-017-0835-3
Prepared by:
Hamna Khan
PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy
Justyna Fydrych, PharmD, BCPS
PGY2 Drug Information Pharmacy Resident
Patricia Hartke, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
June 2023
The information presented is current as May 26, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.