N4-acetyl-sulfamethoxazole stone in a patient on chronic trimethoprim/sulfamethoxazole therapy: a case report and literature review.

Am J Clin Exp Urol 2024;12(5):296-300 www.ajceu.us /ISSN:2330-1910/AJCEU0159430 Case Report N4-acetyl-sulfamethoxazole stone in a patient on chronic trimethoprim/sulfamethoxazole therapy: a case report and literature review Kevin Morgan1, William Donelan1, Mitsu Andre1, Jennifer Janelle2, Benjamin Canales1, Vincent G Bird1 Department of Urology, University of Florida, Gainesville, FL 32610, USA; 2Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, USA 1 Received July 24, 2024; Accepted October 15, 2024; Epub October 15, 2024; Published October 30, 2024 Abstract: Though early antibiotic sulfonamides had poor urine solubility and resulted in urine crystalluria and urolithiasis, sulfamethoxazole urolithiasis is a rare phenomenon. In our case report, we describe a patient with N4acetyl-sulfamethoxazole (metabolite of sulfamethoxazole) urolithiasis that developed after prolonged exposure to trimethoprim/sulfamethoxazole (TMP-SMX). Prior to stone formation, our patient had a total colectomy and end ileostomy created after an episode of toxic megacolon secondary Clostridium difficile. He also had benign prostatic hypertrophy and chronic urinary retention. These specific metabolic conditions, including dehydration leading to higher urinary concentration, urinary stasis, and low urinary pH may have predisposed our patient to this rare condition. Our patient’s stones were then imaged under light microscopy and scanning electron microscopy (SEM). It was found to be comprised of rectangular shaped crystals. To our knowledge, this is the first time these stone crystals have been imaged with SEM. Keywords: Kidney stone, urolithiasis, sulfamethoxazole, trimethoprim Introduction Sulfamethoxazole in combination with trimethoprim has been a mainstay of antibiotic therapy since the 1970s. Both substrates target bacterial biosynthesis of folic acid [1] to inhibit bacterial growth. It is mostly available as an oral antibiotic and used to treat common bacterial infections of the urinary tract, respiratory tract, and skin. Early antibiotic sulfonamides developed in the 1930s had poor urine solubility and resulted in urine crystalluria and urolithiasis, which were well known complications of sulfonamide therapy at that time [2, 3]. Subsequently, sulfonamides with higher urine solubility have been developed and sulfa-drug induced crystalluria now occurs rarely [3-7]. Here we describe our case of a patient with N4-acetyl-sulfamethoxazole urolithiasis which developed after prolonged exposure to trimethoprim/sulfamethoxazole (TMP-SMX). Materials and methods Our patient was a 72-year-old male who initially underwent L1-2, L2-3, L3-4, and L4-5 laminec- tomy surgery with hardware placed in February of 2020 (3 years prior) for lumbar spinal stenosis. His postoperative course was complicated by Serratia marcescens and Candida parapsilosis surgical site infections requiring multiple revision surgeries and antibiotic courses. In December of 2020, he developed fulminant Clostridium difficile colitis with toxic megacolon, ultimately requiring total colectomy and end ileostomy. Following this, he was placed on TMP-SMX and fluconazole indefinitely for suppression of his chronic spinal hardware infection. An abdominopelvic computed tomography (CT) scan in June of 2022 was normal, as part of routine preoperative imaging prior to ileostomy reversal. On the day of his planned ileostomy reversal in September 2022, Urology performed ureteral catheterization and bilateral retrograde pyelography to assist with intraabdominal ureteral identification. On left retrograde pyelography, he was found to have severe left sided hydroureteronephrosis. An indwelling ureteral stent was left, and the Ileostomy reversal was aborted. A CT scan was performed in October of 2022 and showed a 1 cm left lower https://doi.org/10.62347/PIXS5642 Sulfamethoxazole-derived stones in patient on chronic TMP-SMX therapy Figure 1. A. Computed tomography (CT) of the abdomen demonstrates no stone in the left kidney. B. CT of the abdomen demonstrates a left lower pole (red arrow) stone 4 months later. C. Left lower pole stone measures 321 Hounsfield units (HU). pole stone (mean Hounsfield units (HU) 321; Figure 1). This was treated with ureteroscopy/ stone extraction. A stone analysis was not performed at that time, as there was not an adequate specimen. No anatomic anomaly of the left ureter was identified, and the hydronephrosis resolved. Despite complete stone clearance, he developed a new 13 mm left lower pole stone (mean HU 206) and two small right renal stones in the span of 1 month (Figure 2). He also developed bladder stones during this 297 time. He had a history of BPH, TURP, urethral stricture disease with prior dilation, and bladder dysfunction with significant bladder trabeculations. He elected for surveillance at that time. He notably passed multiple stones in the ensuing months. He brought these stones in during his follow up visit in May of 2023, and stone analysis (infrared spectroscopy, Quest Diagnostics©, Secaucus, NJ) revealed N4-Acetyl-Sulfamethoxazole (Figure 3). At that point, antimicrobial therapy was discontinued Am J Clin Exp Urol 2024;12(5):296-300 Sulfamethoxazole-derived stones in patient on chronic TMP-SMX therapy Figure 2. A. CT of the abdomen and pelvis demonstrates new stone growth (red arrow) in the left kidney 1 month after treatment. B. Left kidney stone averages 206 HU. C. The same CT study demonstrates a bladder stone (yellow arrow). D. The bladder stone averages 232 HU. due to risk of ongoing therapy outweighing potential benefits. He last passed a stone shortly after stopping trimethoprim/sulfamethoxazole in June 2023. Surveillance renal/ bladder ultrasounds in July 2023 and March 2024 did not show any evidence of stone, and he has had no recurrence of infection symptoms related to his spine. Discussion Early sulfonamides were commonly implicated in urolithiasis formation, dating back to the 1940s [8]. Specifically, acetylated metabolites had a tendency to precipitate and crystalize in renal tubules, causing oliguria or anuria, or in the collecting system resulting in stone formation [9]. The development of sulfonamides with greater solubility has decreased the incidence of sulfonamide-induced urolithiasis substantially. Sulfamethoxazole was introduced in 1961, and now, in combination with trime298 thoprim, is on the World Health Organization Model List of Essential Medicines [10]. Urolithiasis derived from sulfamethoxazole is rare despite widespread use of sulfamethoxazole throughout the world. Sulfamethoxazole and N4-acetyl-sulfamethoxazole have losangic shaped crystals, which may contribute to low lithogenic potential [8]. Factors that may predispose patients to sulfonamide crystallization include urine concentration, degree of acetylation, urinary stasis, urine pH (acidic), and urine temperature [11]. We know the degre (...truncated)