Case Studies Encrusted Cystitis Secondary to Corynebacterium glucuronolyticum in a 57-Year-Old Man Without Predisposing Factors Chelsea R. Curry, DO, MBA,1 Karan Saluja, MD,1* Sanchita Das, MD,1 Beenu Thakral, MD,1 Pankaj Dangle, MD,2 Thomas C Keeler, MD,2 William G Watkin, MD1 Lab Med Spring 2015;46:136-139 DOI: 10.1309/LMXQP557EINXBXIF
ABSTRACT Encrusted cystitis is a rare condition characterized by encrustation of the bladder mucosa with associated chronic inflammation induced by urea-splitting bacterial infection—most commonly, Corynebacterium urealyticum. Moreover, it usually occurs in immunocompromised patients, especially recipients of renal transplants or patients with a history of previous urological procedures. Due to the rarity of the entity and the slow growth of Corynebacterium species, appropriate treatment is often delayed due to difficulties in diagnosis and resistance to numerous antibiotics. We report a case of encrusted
Encrusted cystitis is a rare condition in which infection by urea-splitting bacteria, most commonly Corynebacterium urealyticum, can lead to extensive bladder calcification. This bacterium can form biofilms and may persist if calcifications are not completely removed. C. urealyticum is a common skin colonizer, seen in up to 30% of hospitalized elderly individuals who are receiving broadspectrum antibiotics. This opportunistic pathogen mainly causes acute cystitis, pyelonephritis, encrusted cystitis, and encrusted pyelitis.1,2 Infections are more common in
Abbreviations: CT, computed tomography; PCR, polymerase chain reaction; CFU, colony-forming units; MIC, minimal inhibitory concentration; rRNA, ribosomal RNA; MEGA, Molecular Evolutionary Genetics Analysis; NCBI, National Center for Biotechnology Information; BLAST, Basic Local Alignment Search Tool Department of Pathology and Laboratory Medicine, and 2Division of Urology, University of Chicago Pritzker School of Medicine, Chicago, Illinois and NorthShore University HealthSystem, Evanston, Illinois 1
*To whom correspondence should be addressed.
[email protected]
136 Lab Medicine
Spring 2015 | Volume 46, Number 2
cystitis caused by Corynebacterium glucuronolyticum, another ureasplitting microbe, in a 57-year-old previously healthy Caucasian man with no known predisposing factors. The timely diagnosis and management in this otherwise healthy patient was facilitated by characteristic imaging, cystoscopy, and histologic findings confirmed by results of prolonged urine cultures and 16S ribosomal RNA (rRNA) gene sequencing of the microbe. Keywords: encrusted cystitis, Corynebacterium glucuronolyticum, urea-splitting bacterial infection, cystoscopy, sequencing, 16S rRNA
men. Corynebacterium species grow slowly and are often missed in rapid urine cultures, especially if the bacterial load is low, and thus present a potential diagnostic challenge. Thus, there can be a delay in diagnosis and treatment if this entity is not considered in a patient with dysuria and hematuria, especially in a post–renal transplantation scenario, post-urinary tract surgery, or instrumentation.3 However, the diagnosis should be considered based on sterile pyuria, alkaline urinary pH, and characteristic calcifications of the urinary excretory system, as observed via computed tomography (CT) scan, and then confirmed by prolonged culture, supplemented with DNA–polymerase chain reaction (PCR) sequencing if available.4,5 Successful treatment includes a combination of antibiotics, urine acidification, and endoscopic removal of encrustations.6 In all reported cases, to our knowledge, patients had predisposing factors, such as a previous urological procedures, prolonged catheterization, long-term hospitalization with broad-spectrum antibiotic therapy, or immunosuppressive therapy after renal transplantation or for systemic inflammation.7 Herein, we report a rare case of encrusted cystitis caused by another urea-splitting
www.labmedicine.com
Case Studies
Image 1 Radiographic features of the bladder of the patient, a previously healthy 57-year-old Caucasian man with no predisposing factors. A, Axial computed tomography (CT) image showing thickened bladder wall (arrow). B, Cystoscopy shows diffuse and complete involvement of the bladder wall by multiple yellow-tan to tan-white, necrotic-appearing lesions.
microbe, which we characterized by gene sequencing as Corynebacterium glucuronolyticum, in a 57-year-old previously healthy man with no known predisposing factors.
Case Presentation and Follow-up A 57-year-old Caucasian man with no significant past medical or surgical history, including any urologic procedures, had dysuria and urinary urgency of 2 weeks’ duration. Empirical antibiotic treatment with ciprofloxacin did not improve his symptoms. Urinalysis results revealed hematuria, pyuria, and proteinuria; however, the results of the urinary culture were negative. Empiric clindamycin therapy was started; also, a CT scan was obtained, which demonstrated marked thickening and edema of the bladder wall with several areas of calcification that we believed represented an infection or a neoplasm (Image 1A). Results of a subsequent cystoscopic examination showed a diffusely inflamed bladder with multiple yellowtan to tan-white, easily crumbled, necrotic-appearing lesions (Image 1B). The histological examination of the bladder biopsies showed mucosal ulceration, acute inflammation, and extensive calcified necrotic debris replacing the bladder mucosa (Image 2A and 2B). We also observed chronic inflammation (including eosinophils)
www.labmedicine.com
in the lamina propria, along with marked reactive vascular proliferation in the submucosa. We noted no granulomas or eggs. The results of a Brown and Hopps tissue Gram stain were negative. After the histologic diagnosis of encrusted cystitis was made, a subsequent urine specimen collected for culture grew Corynebacterium species after an extended incubation period (>7 days). The results of a Gram-stained smear of the urine remained negative. Results of a culture performed on blood agar (Thermo Fisher Scientific Inc., Waltham, MA) in air supplemented with 5% CO2 and incubated at 37ºC showed a white-yellow circular convex colony (1000 colony-forming units [CFU]/mL) which, on Gram staining, demonstrated Gram-positive coryneform rods. The microbe was sensitive to ceftriaxone (minimal inhibitory concentration [MIC], 1.0 μg/mL), penicillin G (MIC ≤0.03 mcg/mL), trimethoprim/sulfamethoxazole (MIC, 1/19 μg/mL), and vancomycin (MIC, 0.5 μg/mL), and resistant to clindamycin (MIC > 0.5 μg/mL), erythromycin (MIC > 0.5 μg/mL), and tetracycline (MIC > 4 μg/mL). We used 16S ribosomal RNA (rRNA) gene sequencing to characterize the organism further. Bacterial DNA was extracted using the MasterPure DNA purification kit (Epicentre Biotechnologies, Madison, WI). The 16S rRNA gene was amplified by PCR using universal primers 4F and 534R.8,9 The PCR products were purified using ExoSAP-IT (Affymetrix Inc., Santa Clara, CA); the purified products were sequenced using the BigDye Terminator
Spring 2015 | Volume 46, Number 2 Lab Medicine
137
Case Studies
A
B
Image 2 Microscopic features of the bladder of the patient, a previously healthy 57-year-old Caucasian man with no predisposing factors. A, Low power view showing extensive mucosal ulceration and increased vascularity of the lamina propria (original magnification ×40). B, High power view showing bladder mucosa replaced by an acute and chronic inflammatory infiltrate and exuberant dystrophic calcification (original magnification ×100).
Cycle Sequencing Kit v1.1 (Thermo Fisher Scientific Inc.)
characteristic urease activity hydrolyzes urea, releasing
on the 3500XL genetic analyzer (Thermo Fisher Scientific
ammonia which alkalinizes the urine and damages the
Inc.). We analyzed sequences using MEGA (Molecular
glycosaminoglycan layer of the bladder mucosa. This
Evolutionary Genetics Analysis) software10 and compared
facilitates bacterial adherence, tissue inflammation, and
the results with all available 16S rRNA sequences available
precipitation of struvite (phosphate salts of ammonium,
in the National Center for Biotechnology Information
magnesium, and calcium). Precipitation of these crystals
(NCBI) GenBank database using the BLAST (Basic Local
leads to the bladder-wall encrustations that characterize
Alignment Search Tool) program. The isolate produced a
this condition. Various other organisms, such as
98% match with Corynebacterium glucuronolyticum.
streptococcus, staphylococcus, Proteus, and Escherichia coli, also may this condition.3
Subsequent bladder biopsies obtained 1 and 3 months following initial presentation still demonstrated ulcerated
The differential diagnosis of urinary-bladder-wall
mucosa and dystrophic calcifications. The patient
encrustation includes schistosomiasis, tuberculosis,
continued to display symptoms after prolonged oral
urea-splitting bacterial infections (Corynebacterium or
vancomycin treatment and cystoscopies. Thereafter, we
Proteus), necrotic urothelial carcinoma, and malakoplakia.
initiated intravenous vancomycin therapy, which resulted
This condition can also occur after intravesical infusion of
in improvement of his symptoms. The patient has been
cyclophosphamide or mitomycin.12
asymptomatic for 1 year after therapy. Previously reported cases of encrusted cystitis have occurred in patients with predisposing factors. Previous urological procedures, prolonged catheterization, or long-
Discussion
term hospitalization with broad-spectrum antibiotic therapy have most commonly been reported as causative factors.13
Encrusted cystitis, first described in 1914, is usually
Encrusted cystitis has been observed in immunosuppressed
caused by Corynebacterium urealyticum, a Gram-positive,
patients, including recipients of renal transplants, and in
slow-growing, lipophilic, asaccharolytic, and usually
patients being treated for cancer or a systemic autoimmune
multidrug-resistant organism with strong urease activity,
disorders such as rheumatoid arthritis, systemic lupus
which can infect the upper and lower urinary tract. The
erythematosus, or vasculitis.7,14 Rarely reported predisposing
11
138 Lab Medicine
Spring 2015 | Volume 46, Number 2
www.labmedicine.com
Case Studies
factors include neurologic bladder dysfunction and ectopic kidney (the latter in a child).15 More than 40 urea-splitting bacteria have been identified as causing urinary tract infections.11 Herein, we report a rare case of encrusted cystitis caused by C. glucuronolyticum in a patient without predisposing factors. This particular type of bacteria has been isolated from the genitourinary tract of humans, predominantly men, as shown in a recently reported rare case of nongonococcal urethritis caused by C. glucuronolyticum but with no evidence of encrusted cystitis.16,17 Currently, we do not fully understand why this type of bacterial infection occurs in patients with no risk factors. Patients with encrusted cystitis often have persistent symptoms of dysuria, urethral discomfort, suprapubic and/or lumbar pain, and gross hematuria. Appropriate treatment is often delayed due to misdiagnosis and resistance to many antibiotics. Treatment includes appropriate antimicrobial therapy, urine acidification, and surgical removal of encrustations. Corynebacterium is typically sensitive to glycopeptides, including vancomycin and teicoplanin. Acidification of the urine has a synergistic effect with antibiotics by dissolving the calcified encrustations and preventing the formation of additional encrustations. Urine is acidified with oral or topical acidic preparations. Application of a topical acidic solution through a catheter or nephrostomy tube is usually needed, especially at the start of treatment. Finally, surgical resection of encrustations via cystoscopy is usually necessary and often requires multiple procedures. Left untreated, encrusted cystitis and pyelitis can eventually lead to renal failure.18 Thus, precise diagnosis of encrusted cystitis and prompt implementation of appropriate medical and surgical treatment are essential to prevent detrimental sequelae. LM
4. Favre G, García-Marchiñena P, Bergero M, et al. Diagnosis and treatment of the encrusted cystitis [article in Spanish]. Actas Urol Esp. 2010;34(5):477-478. 5. Zheng J, Wang G, He W, Jiang N, Jiang H. Imaging characteristics of alkaline-encrusted cystitis. Urol Int. 2010;85(3):364-367. 6. Lieten S, Schelfaut D, Wissing KM, Geers C, Tielemans C. Alkalineencrusted pyelitis and cystitis: an easily missed and life-threatening urinary infection. BMJ Case Rep. 2011;2011. doi: 10.1136/ bcr.12.2010.3613. 7. Soriano F, Tauch A. Microbiological and clinical features of Corynebacterium urealyticum: urinary tract stones and genomics as the Rosetta Stone. Clinical MicrobiolInfect. 2008;14(7):632-643. 8. Clarridge JE, 3rd. Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin Microbiol Rev. 2004;17(4):840-862. 9. Simoons-Smit AM, Savelkoul PH, Newling DW, VandenbrouckeGrauls CM. Chronic cystitis caused by Corynebacterium urealyticum detected by polymerase chain reaction. Eur J Clin Microbiol Infect Dis. 2000;19(12):949-952. 10. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. 2011;28(10):2731-2739. 11. Meria P, Desgrippes A, Arfi C, Le Duc A. Encrusted cystitis and pyelitis. J Urol. 1998;160(1):3-9. 12. Pollack HM, Banner MP, Martinez LO, Hodson CJ. Diagnostic considerations in urinary bladder wall calcification. AJR Am J Roentgenol. 1981;136(4):791-797. 13. Del Prete D, Polverino B, Ceol M, et al. Encrusted cystitis by Corynebacterium urealyticum: a case report with novel insights into bladder lesions. Nephrol Dial Transplant. 2008;23(8):2685-2687. 14. Pagnoux C, Bérezné A, Damade R, et al. Encrusting cystitis due to Corynebacterium urealyticum in a patient with ANCA-associated vasculitis: case report and review of the literature. Semin Arthritis Rheum. 2011;41(2):297-300. 15. Guimarães LC, Soares SC, Albersmeier A, et al. Complete genome sequence of Corynebacterium urealyticum strain DSM 7111, isolated from a 9-year-old patient with alkaline-encrusted cystitis. Genome Announc. 2013;1(3):e00264-13. doi: 10.1128/genomeA.00264-13. 16. Devriese LA, Riegel P, Hommez J, Vaneechoutte M, de Baere T, Haesebrouck F. Identification of Corynebacterium glucuronolyticum strains from the urogenital tract of humans and pigs. J Clin Microbiol. 2000;38(12):4657-4659. 17. Galan-Sanchez F, Aznar-Marin P, Marin-Casanova P, GarciaMartos P, Rodriguez-Iglesias M. Urethritis due to Corynebacterium glucuronolyticum. J Infect Chemother. 2011;17(5):720-721. 18. Tanaka T, Yamashita S, Mitsuzuka K, et al. Encrusted cystitis causing postrenal failure. Journal Infect Chemother. 2013;19(6):1193-1195.
References 1. Anagnostou N, Siddins M, Gordon DL. Encrusted cystitis and pyelitis. Intern Med J. 2012;42(5):596-597. 2. Chung SY, Davies BJ, O’Donnell WF. Mortality from grossly encrusted bilateral pyelitis, ureteritis, and cystitis by Corynebacterium group D2. Urology. 2003;61(2):463. 3. Khan FR, Katmawi-Sabbagh S, England R, Al-Sudani M, Khan SZ. Alkaline cystitis - a delayed presentation post transurethral resection of prostate. A case discussion and literature review. Cent European J Urol. 2012;65(1):43-44.
www.labmedicine.com
To read this article online, scan the QR code, http://labmed. ascpjournals.org/content/46/2/143. full.pdf+html
Spring 2015 | Volume 46, Number 2 Lab Medicine
139
