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Genitourinary infections caused by nontuberculous mycobacteria at a university hospital in Taiwan, 1996–2008
ORIGINAL ARTICLE
INFECTIOUS DISEASES
Genitourinary infections caused by nontuberculous mycobacteria at a university hospital in Taiwan, 1996–2008 C.-T. Huang1, C.-Y. Chen1, H.-Y. Chen1, C.-H. Chou1, S.-Y. Ruan1, C.-C. Lai2 and P.-R. Hsueh3 1) Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, 2) Department of Internal Medicine, Cardinal Tien Hospital, Taipei country and 3) Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
Abstract Genitourinary infections caused by nontuberculous mycobacteria (NTM) are rarely reported. The medical records of all patients with genitourinary NTM infections treated at National Taiwan University Hospital from 1996–2008 were retrospectively reviewed. Fifteen patients were identified, of whom 10 (67%) were male. More than two-thirds of patients had underlying conditions, the most common of which was chronic renal disease. Only one patient had AIDS. Acid-fast smears of urine were negative in all patients. Eleven isolates were available for further confirmation by sequencing of the 16S rRNA gene. Mycobacterium avium complex was the most common (n = 5, 33%), followed by both Mycobacterium abscessus (n = 2; 13%) and Mycobacterium fortuitum (n = 2; 13%). Of the 12 patients receiving anti-NTM treatment, only four received adequate prescribed regimens and none died of NTM infections. Two patients died of refractory urosepsis before the urinary NTM infections were diagnosed. The clinical characteristics of the 15 patients were also compared with 43 previously reported patients with genitourinary tuberculosis. Patients with genitourinary NTM infections were more likely to report constitutional symptoms, seek medical help within 1 month after the onset of symptoms and develop leukocytosis. Patients with genitourinary tuberculosis were more likely to have ureteral strictures and abnormal chest radiographs associated with active or inactive tuberculosis. Although rare, genitourinary NTM infections pose a significant threat to life and should be considered in the differential diagnosis of genitourinary infections, especially when patients are unresponsive to conventional antibiotic treatment. Keywords: Genitourinary infection, nontuberculous mycobacteria, outcomes, tuberculosis Original Submission: 10 November 2009; Revised Submission: 4 January 2010; Accepted: 14 January 2010 Editor: M. Drancourt Article published online: 2 February 2010 Clin Microbiol Infect 2010; 16: 1585–1590 10.1111/j.1469-0691.2010.03180.x Corresponding author: P.-R. Hsueh, Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan E-mail: [email protected]
Introduction Nontuberculous mycobacteria (NTM) are ubiquitous organisms in the environment and are commonly isolated from soil, spring and tap water; domestic and wild animals; and foods [1]. More than 120 species of NTM have been identified, approximately half of which are recognized as potential human pathogens [2]. A wide variety of infections are caused by NTM, including keratitis and lymphadenitis, as well as abdominal, pulmonary, skin and soft-tissue and disseminated infections [3]. Throughout the world, these organisms have been implicated in an increasing number of
infections in both immunocompetent and immunocompromised hosts [4,5]. After lymph node involvement, genitourinary tuberculosis (TB) is the most common manifestation of extrapulmonary TB worldwide, accounting for 27% of cases [6]. However, genitourinary infections caused by NTM are quite rare and only a few cases have been reported [7–9]. Thus, data on the natural history and optimal therapy for this disease entity are very limited. Furthermore, given that most NTM strains are resistant to traditional antituberculous agents, it is important to correctly differentiate genitourinary infections caused by NTM from genitourinary TB. The present study aimed to analyze the clinical manifestations, mycobacteriology, imaging features and outcomes of patients with genitourinary NTM infections. Clinical data of patients with genitourinary TB were also retrieved and compared with those with NTM infections.
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Materials and Methods
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outcomes. Anti-NTM treatment was considered adequate if the regimen was prescribed according to the guidelines of the American Thoracic Society [3].
Study design and study population
The present study included patients treated in a 2000-bed, university-affiliated hospital in Taiwan. We retrospectively searched the records of the Mycobacteriology Laboratory from May 1996 to April 2008 for patients with positive NTM cultures from genitourinary specimens. Genitourinary NTM infections were further defined as: (i) symptoms of genitourinary infection; (ii) absence of other genitourinary pathogens; (iii) endoscopic or radiologic evidence of genitourinary infection; and (iv) histopathology showing granulomatous inflammation with or without demonstrable acid-fast bacilli. Only patients meeting all these diagnostic criteria were included in the study. For comparison, patients with culture-positive genitourinary TB treated at the same hospital from 1999– 2007 were also included.
Statistical analysis
Because of the retrospective nature of the present study and the limited number of cases, descriptive statistics are presented, including continuous variables as a mean and range and categorical variables as a number and percentage. Comparisons of characteristics between patients with genitourinary infections caused by Mycobacterium tuberculosis and NTM were performed using Student’s t-test, a chi-square test, or Fisher’s exact test as appropriate. p <0.05 (twotailed) was considered statistically significant.
Results Baseline characteristics
Bacterial isolates
Different clinical specimens were processed for mycobacterial culture according to recommended guidelines [10]. Cultures of urine specimens were performed by inoculating the specimens onto Middlebrook 7H11 selective agar with antimicrobials (BBL, Becton Dickinson, Sparks, MD, USA) and by the fluorometric BACTEC technique [BACTEC Mycobacterium Growth Indicator Tube (MGIT) 960 system; BectonDickinson Diagnostic Instrument Systems, Sparks, MD, USA] [11]. NTM were identified to the species level using conventional biochemical methods [10].
There were 15 patients with genitourinary NTM infections included in the present study. All patients were adults; twothirds of them were male and the mean age was 64 years. More than two-thirds of the patients had underlying diseases. The most common underlying condition was chronic renal disease, followed by type 2 diabetes mellitus (Table 1). Only one patient had AIDS. Two patients had previously been
TABLE 1. Comparison underlying
diseases
of and
demographic clinical
characteristics,
manifestations
of
15
patients with genitourinary nontuberculous mycobacterial infections and 43 patients with genitourinary tuberculosis
Sequencing of the 16S rRNA gene
Eleven of the 15 isolates were stored and available for further confirmation by sequencing of the 16S rRNA gene (1464 bp) using two primers (primers 8FPL and 1492) as described previously [11]. The amplification products obtained by PCR were sequenced, and the sequences were compared with known 16S rRNA gene sequences in the GenBank database of the National Center for Biotechnology Information using the BLAST algorithm (http://www.ncbi. nlm.nih.gov/blast). Data collection
The clinical charts of patients were reviewed by two boardcertified physicians. If discordant results were found, a conclusion was reached after further review by another physician who was blinded to the discordant results. Variables abstracted included the baseline clinical characteristics: symptoms and signs and their duration, laboratory results, radiographic findings, microbiological results, treatment and
Characteristics
Age (year) Mean (range) ‡65 Male Underlying disease Chronic renal disease Type 2 diabetes Malignancy Old pulmonary tuberculosis Liver cirrhosis Use of corticosteroid AIDS Signs and symptoms Fever Dysuria, frequency or urgency Anorexia Flank pain Scrotal nodule, pain or swelling Gross haematuria Duration of signs and symptoms £1 month >1–3 months >3 months
NTM (n = 15)
Tuberculosis (n = 43)
64 8 10 11 7 4 3 2 1 1 1
(22–91) (53) (67) (73) (47) (27) (20) (13) (7) (7) (7)
59 19 25 22 9 8 5 2 2 2 1
(23–91) (44) (58) (51) (21) (19) (12) (5) (5) (5) (2)
0.37 0.54 0.56 0.14
10 9 4 3 3 1
(67) (60) (27) (20) (20) (7)
11 23 3 8 6 8
(26) (53) (7) (19) (14) (19)
0.004 0.66 0.07 0.99 0.68 0.42
20 (47) 13 (30) 10 (23)
0.002 0.09 0.05
14 (93) 1 (7) –
Data are number (%), unless otherwise indicated. NTM, nontuberculous mycobacteria.
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treated for pulmonary tuberculosis, but none had active pulmonary tuberculosis.
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TABLE 2. Comparison of laboratory data and image findings of 15 patients with genitourinary infections caused by nontuberculous mycobacteria and 43 patients with genitourinary tuberculosis
Clinical features
Characteristic symptoms of urinary tract inflammation were noted in 12 (80%) of the 15 patients with genitourinary NTM infections. These symptoms included dysuria, frequency, urgency, flank pain and gross haematuria (Table 1). Fever was common and noted in two-thirds of the patients. Three (20%) patients presented with scrotal nodules, pain or swelling. Genitourinary involvement was part of the manifestations of disseminated NTM infections in two of the 15 patients, both of whom had fever at initial presentation. No evidence of extragenitourinary disease was found in other patients. The duration from onset of symptoms to seeking medical help was <1 month in all but one of the patients (Table 1). Genital NTM infections were found in three patients, all of whom underwent transurethral resection of the prostate 3–6 months before symptom onset. NTM involvement of the urinary tract was noted in 12 patients, but none of these patients had a history of urinary instrumentation. No patient had both genital and urinary tract NTM infection. Laboratory evaluation
The average leukocyte count in was 13 323/mm3 (range 5 230–25 400/mm3); leukocytosis (range 11 180–25 400/ mm3) was found in eight (53%) patients. Anaemia was found in seven patients, and hypoalbuminaemia in eight (Table 2). An abnormal urinalysis was found in 14 (93%) patients, and pyuria (87%) was the most prevalent finding. Microscopic haematuria was detected in nine (60%) patients and proteinuria in seven (7/15, 47%). Serum prostate-specific antigen (PSA) data were available for only two patients, both of whom had prostatic NTM infections and markedly elevated PSA levels (20.5 and 27.5 ng/mL). Mycobacteriology
Acid-fast smears (AFS) of urine were negative in all patients. M. avium complex (MAC) (accession number EU815938.1, maximal identity 99%) was the most common cause of genitourinary NTM infections and was isolated from five (33%) patients. Rapidly growing mycobacteria (RGM) were isolated from four (27%) patients and included two Mycobacterium abscessus (accession numbers DQ866776.1 and CU458896.1, maximal identity both 99%) and two Mycobacterium fortuitum (accession number AY457068.1, maximal identity 99%). Two patients had Mycobacterium gordonae (accession number AY215258.1, maximal identity 99%). Four Mycobacterium species isolates were not available for further 16S rRNA gene analysis.
Characteristics
Laboratory data Blood White blood cell count (/mm3) >11 000 £11 000 Haemoglobin (g/dL) <12 ‡12 Albumin (g/L) <3.5 ‡3.5 Urine Pyuria Microscopic haematuria Proteinuria Positive acid-fast smear Chest X-ray Suggesting active or inactivetuberculosis Suggesting active tuberculosis Suggesting inactive tuberculosis Radiologic findings Hydronephrosis Multiloculated renal cysts Hypoattenuated renal nodule Uneven caliectasis Renal papillary necrosis Ureteral stricture Bladder shrinkage or wall thickening Prostatic abscess Epididymal swelling Scrotal tumuor
NTM (n = 15)
Tuberculosis (n = 43)
p
8 (53) 7 (47)
7 (16) 36 (84)
0.013
7 (47) 8 (53)
24 (56) 19 (44)
0.54
8 (53) 4 (27)
19 (44) 11 (26)
0.99
32 20 13 11
0.48 0.37 0.25 0.05
13 9 7 0
(87) (60) (47) (0)
(74) (47) (30) (26)
4 (27) 2 (13) 2 (13)
26 (60) 9 (21) 17 (39)
0.024
5 4 2 2 1 1 2 2 2 0
23 4 3 1 2 16 7 1 1 3
0.18 0.19 0.59 0.16 0.99 0.045 0.99 0.16 0.16 0.56
(33) (27) (13) (13) (7) (7) (13) (13) (13) (0)
(53) (9) (7) (2) (5) (37) (16) (2) (2) (7)
Data are number (%), unless otherwise indicated. NTM, nontuberculous mycobacteria.
Radiographic findings
Chest radiographs demonstrated either active or inactive tuberculosis in four (27%) patients (Table 2). Among them, two were found to have NTM pulmonary disease, but neither had a diagnosis of pulmonary tuberculosis. Radiological findings in patients with genital NTM infections included prostatic abscess (n = 2) and epididymal swelling (n = 2) (Table 2) but all of these patients had a normal chest radiograph. The most common finding in patients with urinary tract infections was hydronephrosis, followed by multiloculated renal cysts. Treatment and outcome
Twelve (80%) of the patients had been prescribed anti-NTM treatment, but only four of these regimens were adequate (Table 3). Other regimens included clarithromycin or ciprofloxacin monotherapy and clarithromycin plus ciprofloxacin. Three of the 12 patients had surgical intervention, including nephrectomy for suspected renal cancer in one with genitourinary MAC infection and surgical drainage of prostatic abscess in two with genitourinary M. abscessus infections.
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Recovered
Recovered
Recovered Recovered Recovered Died of urosepsis Recovered Recovered Died of urosepsis Died of lung cancer Died of pneumonia Recovered Recovered Died of pneumonia Recovered
Clarithromycin, ethambutol, rifampin and amikacin
Clinical differences between genitourinary NTM infections and tuberculosis
NA, not available (four Mycobacterium species isolates were not available for 16S rRNA gene analysis.); NTM, nontuberculous mycobacteria.
Mycobacterium avium complex 43/M 15
AIDS
Mycobacterium avium complex
Clarithromycin, imipenem-cilastatin, amikacin Mycobacterium abscessus No 74/M 14
gordonae fortuitum
Mycobacterium abscessus
avium complex avium complex abscessus
avium complex
fortuitum avium complex
54/F 35/M 59/F 65/F 86/M 81/F 63/F 76/M 79/M 72/M 22/M 91/M 63/M 1 2 3 4 5 6 7 8 9 10 11 12 13
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The PSA levels returned to normal after the end of antiNTM treatment in two patients with prostatic abscess. Death occurred during treatment in three of 12 patients; the causes of death in these patients were bacterial pneumonia in two with genitourinary MAC infections and lung cancer in one. All other patients received complete anti-NTM treatment and had a good recovery. One patient who underwent epididymectomy alone for epididymitis also made a good recovery. Two patients died of refractory urosepsis before urinary NTM infections could be diagnosed: one of them had diabetes and liver cirrhosis and the other received chemotherapy for advanced gastric cancer.
No Epididymectomy No No No No No No No No Nephrectomy No Drainage of prostatic abscess Drainage of prostatic abscess No Ciprofloxacin No Ciprofloxacin No Ciprofloxacin and clarithromycin Ciprofloxacin No Ciprofloxacin Clarithromycin, ethambutol and rifampin Clarithromycin Ciprofloxacin and clarithromycin Ciprofloxacin and clarithromycin Clarithromycin, imipenem-cilastatin, amikacin Mycobacterium NA Mycobacterium Mycobacterium NA Mycobacterium Mycobacterium NA Mycobacterium NA Mycobacterium Mycobacterium Mycobacterium Mycobacterium gordonae Mycobacterium species Mycobacterium fortuitum Mycobacterium avium complex Mycobacterium species Mycobacterium gordonae Mycobacterium fortuitum Mycobacterium species Mycobacterium avium complex Mycobacterium species Mycobacterium avium complex Mycobacterium avium complex Mycobacterium abscessus Chronic renal disease, diabetes No Corticosteroid use Gastric cancer Chronic renal disease Chronic renal disease, diabetes Liver cirrhosis, diabetes Lung cancer, chronic renal disease No Chronic renal disease, diabetes No Rectal cancer, chronic renal disease Chronic renal disease
Age/ gender Case number
gordonae
Identification by sequencing of 16S rRNA Identification by conventional methods Underlying disease(s)
Anti-NTM therapy
Surgical management
Outcome
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TABLE 3. Summary of 15 patients with genitourinary infections caused by nontuberculous mycobacteria who were treated at the National Taiwan University Hospital
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Demographic characteristics and underlying diseases were not significantly different between patients with genitourinary NTM infections and those with genitourinary tuberculosis (Table 1). Patients with NTM infections were more likely to report constitutional symptoms, particularly fever, and to seek medical help within 1 month after the onset of symptoms than patients with tuberculosis. Leukocytosis was more frequent in patients with NTM infections (Table 2). AFS of urine was positive in 11 (26%) patients with tuberculosis, but in none of the patients with NTM infections. A comparison of the radiographic findings revealed that patients with tuberculosis were more likely to have ureteral strictures and chest radiographic evidence of active or inactive tuberculosis. Double-J ureteral stents were placed to relieve ureteral strictures in 15 (35%) patients with tuberculosis but none of the patients with NTM infection needed stenting.
Discussion The present series of 15 patients with genitourinary NTM infections over a 12-year period represents the largest single institutional experience of such infections reported to date. In accordance with the epidemiology of NTM infections in Taiwan, MAC and RGM were the most common NTM species involved in genitourinary infections [12]. Over the previous two decades, only 12 cases of genitourinary infection caused by NTM have been reported in the literature [7–9,13–20], and MAC, M. abscessus–chelonae complex and M. fortuitum were also the most commonly isolated NTM species in these cases [7,9,13,14,17,19,20]. Although the present study identified some features that might be useful for differentiating genitourinary NTM infections and tuberculosis, none of them was pathognomonic.
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Patients with NTM infections were more likely than tuberculosis patients to manifest signs and symptoms similar to conventional bacterial genitourinary infections, such as fever, leukocytosis and a short duration of symptoms. This may explain why only one patient with NTM infection had a ureteral stricture as a result of the limited time frame for contracture and scarring of the ureters to occur. Previous studies demonstrated that the presence of constitutional symptoms in patients with genitourinary tuberculosis is suggestive of active tuberculosis in other organs [21,22]; however this is not the case for NTM infections. Extragenitourinary disease was found in only two (20%) of the 10 patients presenting with fever. Chest imaging was useful for distinguishing NTM infection from tuberculosis. In the present study chest radiographs showed evidence of tuberculosis in 60% of patients with genitourinary tuberculosis, which is similar to the 50–75% reported in the literature [21,22]. By contrast, only 27% of patients with genitourinary NTM infections in this series had chest radiographic findings suggesting mycobacterial infection. Genitourinary tuberculosis is the result of haematogenous spread from the pulmonary site of primary infection; however, the pathogenesis of genitourinary NTM is poorly understood. The clinical manifestations of our patients suggest that there may be differences in pathogenesis between genital and urinary NTM infections. All of our patients with genital NTM infections had a normal chest radiograph and a history of previous instrumentation, supporting a previous hypothesis that NTM infections of the genital tract occur after surgical intervention with subsequent contamination [3,14]. On the other hand, none of the patients with urinary NTM infections had a history of urinary tract manipulation, whereas one-third had an abnormal chest radiograph. This indicates that the lungs are probably the portal of entry for these urinary tract infections. These patients likely had NTM pulmonary infections with subsequent dissemination [3]. Genitourinary NTM infections present a major management difficulty because of their resistance to commonly used antibiotics and antituberculous therapy. Experience in the treatment of NTM infections has mostly come from the management of pulmonary infections, which constitute threequarters of the reported NTM cases [3]. In this series, none of the patients who received either medical therapy, surgical intervention alone, or combined medical and surgical treatment, died of NTM infection. Although regimens against M. gordonae have not yet been defined [3], two patients with genitourinary M. gordonae infections responded well to ciprofloxacin monotherapy. Surgical debridement remains an important adjunct to the management of patients with RGM infections, especially in those with abscess, extensive disease
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or necrosis [23]. Two patients with M. abscessus prostatic abscess received treatment with surgical drainage combined with anti-NTM medications and recovered well. However, the anti-NTM treatment regimes were decided by treating physicians and were not standardized. More clinical experience is needed to determine the optimal therapy in this condition. Several limitations of the present study should be considered when interpreting its findings. First, the small number of cases limits the significance of some of the findings. Second, as a result of the retrospective design, the number of patients with genitourinary NTM infections during the study period may have been underestimated because mycobacterial cultures were not performed for all genitourinary specimens. Third, the data were collected from an urban, tertiary care centre, which might represent a high risk patient group with more comorbidities compared to other care settings and the results may not be generalizable to a community-based setting. In summary, although rare, genitourinary NTM infections are significant and potentially life-threatening and should be considered in the differential diagnosis of genitourinary infections, especially those unresponsive to conventional antibiotic treatment. Optimal treatment regimens remain unclear and each patient requires a judicious, individualized approach.
Transparency Declaration All authors have no conflict of interests.
References 1. Falkinham JO, III. Epidemiology of infection by nontuberculous mycobacteria. Clin Microbiol Rev 1996; 9: 177–215. 2. Jarzembowski JA, Young MB. Nontuberculous mycobacterial infections. Arch Pathol Lab Med 2008; 132: 1333–1341. 3. Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175: 367– 416. 4. Henry MT, Inamdar L, O’Riordain D, Schweiger M, Watson JP. Nontuberculous mycobacteria in non-HIV patients: epidemiology, treatment and response. Eur Respir J 2004; 23: 741–746. 5. Kennedy MP, O’Connor TM, Ryan C, Sheehan S, Cryan B, Bredin C. Nontuberculous mycobacteria: incidence in Southwest Ireland from 1987 to 2000. Respir Med 2003; 97: 257–263. 6. Golden MP, Vikram HR. Extrapulmonary tuberculosis: an overview. Am Fam Physician 2005; 72: 1761–1768. 7. Serra C, Loi G, Saddi B, Pautasso M, Manzin A. Unusual clinical presentation of Mycobacterium fortuitum infection in an immunocompetent woman. J Clin Microbiol 2007; 45: 1663–1665.
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8. Keller M, Mak A, Thibert L, Rene P, Klein MB. Mycobacterium haemophilum epididymal abscess in a renal transplant patient. J Clin Microbiol 2008; 46: 2459–2460. 9. Fox R, Mears J. Female genital tract Mycobacterium chelonae infection. J Obstet Gynaecol 2004; 24: 326. 10. Pfyffer GE, Brown-Elliott BA, Wallace RJJ. Mycobacterium. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH, eds, Manual of clinical microbiology, 6th edn. Washington, DC: American Society for Microbiology, 2005. 11. Yang SC, Hsueh PR, Lai HC et al. High prevalence of antimicrobial resistance in rapidly growing mycobacteria in Taiwan. Antimicrob Agents Chemother 2003; 47: 958–962. 12. Ding LW, Lai CC, Lee LN, Hsueh PR. Disease caused by non-tuberculous mycobacteria in a university hospital in Taiwan, 1997-2003. Epidemiol Infect 2006; 134: 1060–1067. 13. Mikolich DJ, Mates SM. Granulomatous prostatitis due to Mycobacterium avium complex. Clin Infect Dis 1992; 14: 589–591. 14. Clark R, Cardona L, Valainis G, Hanna B. Genitourinary infections caused by mycobacteria other than Mycobacterium tuberculosis. Tubercle 1989; 70: 297–300. 15. Indudhara R, Das K, Sharma M, Vaidyanathan S. Seminal vesiculitis due to Mycobacterium gastri leading to male infertility. Urol Int 1991; 46: 99–100.
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16. Jarikre LN. Mycobacterium gordonae genitourinary disease. Genitourin Med 1992; 68: 45–46. 17. Ben-Chaim J, Leibowitch I, Raviv G, Mor Y, Goldwasser B. Persistent vasocutaneous fistula associated with chronic urinary Mycobacterium chelonei infection. J Urol 1993; 149: 140–141. 18. Dahl DM, Klein D, Morgentaler A. Penile mass caused by the newly described organism Mycobacterium celatum. Urology 1996; 47: 266–268. 19. Tattevin P, Fischer EA, Ronco PM, Rossert JA, Vasseur E, Mougenot B. Granulomatous nephritis in an AIDS patient treated with combination antiretroviral therapy and infection with Mycobacterium avium. Am J Med 1999; 107: 642–643. 20. Ersoz G, Kaya A, Cayan S et al. Urinary Mycobacterium fortuitum infection in an HIV-infected patient. AIDS 2000; 14: 2802–2803. 21. Simon HB, Weinstein AJ, Pasternak MS, Swartz MN, Kunz LJ. Genitourinary tuberculosis. Clinical features in a general hospital population. Am J Med 1977; 63: 410–420. 22. Christensen WI. Genitourinary tuberculosis: review of 102 cases. Medicine (Baltimore) 1974; 53: 377–390. 23. Villanueva A, Calderon RV, Vargas BA et al. Report on an outbreak of postinjection abscesses due to Mycobacterium abscessus, including management with surgery and clarithromycin therapy and comparison of strains by random amplified polymorphic DNA polymerase chain reaction. Clin Infect Dis 1997; 24: 1147–1153.
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INFECTIOUS DISEASES
Genitourinary infections caused by nontuberculous mycobacteria at a university hospital in Taiwan, 1996–2008 C.-T. Huang1, C.-Y. Chen1, H.-Y. Chen1, C.-H. Chou1, S.-Y. Ruan1, C.-C. Lai2 and P.-R. Hsueh3 1) Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, 2) Department of Internal Medicine, Cardinal Tien Hospital, Taipei country and 3) Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
Abstract Genitourinary infections caused by nontuberculous mycobacteria (NTM) are rarely reported. The medical records of all patients with genitourinary NTM infections treated at National Taiwan University Hospital from 1996–2008 were retrospectively reviewed. Fifteen patients were identified, of whom 10 (67%) were male. More than two-thirds of patients had underlying conditions, the most common of which was chronic renal disease. Only one patient had AIDS. Acid-fast smears of urine were negative in all patients. Eleven isolates were available for further confirmation by sequencing of the 16S rRNA gene. Mycobacterium avium complex was the most common (n = 5, 33%), followed by both Mycobacterium abscessus (n = 2; 13%) and Mycobacterium fortuitum (n = 2; 13%). Of the 12 patients receiving anti-NTM treatment, only four received adequate prescribed regimens and none died of NTM infections. Two patients died of refractory urosepsis before the urinary NTM infections were diagnosed. The clinical characteristics of the 15 patients were also compared with 43 previously reported patients with genitourinary tuberculosis. Patients with genitourinary NTM infections were more likely to report constitutional symptoms, seek medical help within 1 month after the onset of symptoms and develop leukocytosis. Patients with genitourinary tuberculosis were more likely to have ureteral strictures and abnormal chest radiographs associated with active or inactive tuberculosis. Although rare, genitourinary NTM infections pose a significant threat to life and should be considered in the differential diagnosis of genitourinary infections, especially when patients are unresponsive to conventional antibiotic treatment. Keywords: Genitourinary infection, nontuberculous mycobacteria, outcomes, tuberculosis Original Submission: 10 November 2009; Revised Submission: 4 January 2010; Accepted: 14 January 2010 Editor: M. Drancourt Article published online: 2 February 2010 Clin Microbiol Infect 2010; 16: 1585–1590 10.1111/j.1469-0691.2010.03180.x Corresponding author: P.-R. Hsueh, Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan E-mail: [email protected]
Introduction Nontuberculous mycobacteria (NTM) are ubiquitous organisms in the environment and are commonly isolated from soil, spring and tap water; domestic and wild animals; and foods [1]. More than 120 species of NTM have been identified, approximately half of which are recognized as potential human pathogens [2]. A wide variety of infections are caused by NTM, including keratitis and lymphadenitis, as well as abdominal, pulmonary, skin and soft-tissue and disseminated infections [3]. Throughout the world, these organisms have been implicated in an increasing number of
infections in both immunocompetent and immunocompromised hosts [4,5]. After lymph node involvement, genitourinary tuberculosis (TB) is the most common manifestation of extrapulmonary TB worldwide, accounting for 27% of cases [6]. However, genitourinary infections caused by NTM are quite rare and only a few cases have been reported [7–9]. Thus, data on the natural history and optimal therapy for this disease entity are very limited. Furthermore, given that most NTM strains are resistant to traditional antituberculous agents, it is important to correctly differentiate genitourinary infections caused by NTM from genitourinary TB. The present study aimed to analyze the clinical manifestations, mycobacteriology, imaging features and outcomes of patients with genitourinary NTM infections. Clinical data of patients with genitourinary TB were also retrieved and compared with those with NTM infections.
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Materials and Methods
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outcomes. Anti-NTM treatment was considered adequate if the regimen was prescribed according to the guidelines of the American Thoracic Society [3].
Study design and study population
The present study included patients treated in a 2000-bed, university-affiliated hospital in Taiwan. We retrospectively searched the records of the Mycobacteriology Laboratory from May 1996 to April 2008 for patients with positive NTM cultures from genitourinary specimens. Genitourinary NTM infections were further defined as: (i) symptoms of genitourinary infection; (ii) absence of other genitourinary pathogens; (iii) endoscopic or radiologic evidence of genitourinary infection; and (iv) histopathology showing granulomatous inflammation with or without demonstrable acid-fast bacilli. Only patients meeting all these diagnostic criteria were included in the study. For comparison, patients with culture-positive genitourinary TB treated at the same hospital from 1999– 2007 were also included.
Statistical analysis
Because of the retrospective nature of the present study and the limited number of cases, descriptive statistics are presented, including continuous variables as a mean and range and categorical variables as a number and percentage. Comparisons of characteristics between patients with genitourinary infections caused by Mycobacterium tuberculosis and NTM were performed using Student’s t-test, a chi-square test, or Fisher’s exact test as appropriate. p <0.05 (twotailed) was considered statistically significant.
Results Baseline characteristics
Bacterial isolates
Different clinical specimens were processed for mycobacterial culture according to recommended guidelines [10]. Cultures of urine specimens were performed by inoculating the specimens onto Middlebrook 7H11 selective agar with antimicrobials (BBL, Becton Dickinson, Sparks, MD, USA) and by the fluorometric BACTEC technique [BACTEC Mycobacterium Growth Indicator Tube (MGIT) 960 system; BectonDickinson Diagnostic Instrument Systems, Sparks, MD, USA] [11]. NTM were identified to the species level using conventional biochemical methods [10].
There were 15 patients with genitourinary NTM infections included in the present study. All patients were adults; twothirds of them were male and the mean age was 64 years. More than two-thirds of the patients had underlying diseases. The most common underlying condition was chronic renal disease, followed by type 2 diabetes mellitus (Table 1). Only one patient had AIDS. Two patients had previously been
TABLE 1. Comparison underlying
diseases
of and
demographic clinical
characteristics,
manifestations
of
15
patients with genitourinary nontuberculous mycobacterial infections and 43 patients with genitourinary tuberculosis
Sequencing of the 16S rRNA gene
Eleven of the 15 isolates were stored and available for further confirmation by sequencing of the 16S rRNA gene (1464 bp) using two primers (primers 8FPL and 1492) as described previously [11]. The amplification products obtained by PCR were sequenced, and the sequences were compared with known 16S rRNA gene sequences in the GenBank database of the National Center for Biotechnology Information using the BLAST algorithm (http://www.ncbi. nlm.nih.gov/blast). Data collection
The clinical charts of patients were reviewed by two boardcertified physicians. If discordant results were found, a conclusion was reached after further review by another physician who was blinded to the discordant results. Variables abstracted included the baseline clinical characteristics: symptoms and signs and their duration, laboratory results, radiographic findings, microbiological results, treatment and
Characteristics
Age (year) Mean (range) ‡65 Male Underlying disease Chronic renal disease Type 2 diabetes Malignancy Old pulmonary tuberculosis Liver cirrhosis Use of corticosteroid AIDS Signs and symptoms Fever Dysuria, frequency or urgency Anorexia Flank pain Scrotal nodule, pain or swelling Gross haematuria Duration of signs and symptoms £1 month >1–3 months >3 months
NTM (n = 15)
Tuberculosis (n = 43)
64 8 10 11 7 4 3 2 1 1 1
(22–91) (53) (67) (73) (47) (27) (20) (13) (7) (7) (7)
59 19 25 22 9 8 5 2 2 2 1
(23–91) (44) (58) (51) (21) (19) (12) (5) (5) (5) (2)
0.37 0.54 0.56 0.14
10 9 4 3 3 1
(67) (60) (27) (20) (20) (7)
11 23 3 8 6 8
(26) (53) (7) (19) (14) (19)
0.004 0.66 0.07 0.99 0.68 0.42
20 (47) 13 (30) 10 (23)
0.002 0.09 0.05
14 (93) 1 (7) –
Data are number (%), unless otherwise indicated. NTM, nontuberculous mycobacteria.
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treated for pulmonary tuberculosis, but none had active pulmonary tuberculosis.
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TABLE 2. Comparison of laboratory data and image findings of 15 patients with genitourinary infections caused by nontuberculous mycobacteria and 43 patients with genitourinary tuberculosis
Clinical features
Characteristic symptoms of urinary tract inflammation were noted in 12 (80%) of the 15 patients with genitourinary NTM infections. These symptoms included dysuria, frequency, urgency, flank pain and gross haematuria (Table 1). Fever was common and noted in two-thirds of the patients. Three (20%) patients presented with scrotal nodules, pain or swelling. Genitourinary involvement was part of the manifestations of disseminated NTM infections in two of the 15 patients, both of whom had fever at initial presentation. No evidence of extragenitourinary disease was found in other patients. The duration from onset of symptoms to seeking medical help was <1 month in all but one of the patients (Table 1). Genital NTM infections were found in three patients, all of whom underwent transurethral resection of the prostate 3–6 months before symptom onset. NTM involvement of the urinary tract was noted in 12 patients, but none of these patients had a history of urinary instrumentation. No patient had both genital and urinary tract NTM infection. Laboratory evaluation
The average leukocyte count in was 13 323/mm3 (range 5 230–25 400/mm3); leukocytosis (range 11 180–25 400/ mm3) was found in eight (53%) patients. Anaemia was found in seven patients, and hypoalbuminaemia in eight (Table 2). An abnormal urinalysis was found in 14 (93%) patients, and pyuria (87%) was the most prevalent finding. Microscopic haematuria was detected in nine (60%) patients and proteinuria in seven (7/15, 47%). Serum prostate-specific antigen (PSA) data were available for only two patients, both of whom had prostatic NTM infections and markedly elevated PSA levels (20.5 and 27.5 ng/mL). Mycobacteriology
Acid-fast smears (AFS) of urine were negative in all patients. M. avium complex (MAC) (accession number EU815938.1, maximal identity 99%) was the most common cause of genitourinary NTM infections and was isolated from five (33%) patients. Rapidly growing mycobacteria (RGM) were isolated from four (27%) patients and included two Mycobacterium abscessus (accession numbers DQ866776.1 and CU458896.1, maximal identity both 99%) and two Mycobacterium fortuitum (accession number AY457068.1, maximal identity 99%). Two patients had Mycobacterium gordonae (accession number AY215258.1, maximal identity 99%). Four Mycobacterium species isolates were not available for further 16S rRNA gene analysis.
Characteristics
Laboratory data Blood White blood cell count (/mm3) >11 000 £11 000 Haemoglobin (g/dL) <12 ‡12 Albumin (g/L) <3.5 ‡3.5 Urine Pyuria Microscopic haematuria Proteinuria Positive acid-fast smear Chest X-ray Suggesting active or inactivetuberculosis Suggesting active tuberculosis Suggesting inactive tuberculosis Radiologic findings Hydronephrosis Multiloculated renal cysts Hypoattenuated renal nodule Uneven caliectasis Renal papillary necrosis Ureteral stricture Bladder shrinkage or wall thickening Prostatic abscess Epididymal swelling Scrotal tumuor
NTM (n = 15)
Tuberculosis (n = 43)
p
8 (53) 7 (47)
7 (16) 36 (84)
0.013
7 (47) 8 (53)
24 (56) 19 (44)
0.54
8 (53) 4 (27)
19 (44) 11 (26)
0.99
32 20 13 11
0.48 0.37 0.25 0.05
13 9 7 0
(87) (60) (47) (0)
(74) (47) (30) (26)
4 (27) 2 (13) 2 (13)
26 (60) 9 (21) 17 (39)
0.024
5 4 2 2 1 1 2 2 2 0
23 4 3 1 2 16 7 1 1 3
0.18 0.19 0.59 0.16 0.99 0.045 0.99 0.16 0.16 0.56
(33) (27) (13) (13) (7) (7) (13) (13) (13) (0)
(53) (9) (7) (2) (5) (37) (16) (2) (2) (7)
Data are number (%), unless otherwise indicated. NTM, nontuberculous mycobacteria.
Radiographic findings
Chest radiographs demonstrated either active or inactive tuberculosis in four (27%) patients (Table 2). Among them, two were found to have NTM pulmonary disease, but neither had a diagnosis of pulmonary tuberculosis. Radiological findings in patients with genital NTM infections included prostatic abscess (n = 2) and epididymal swelling (n = 2) (Table 2) but all of these patients had a normal chest radiograph. The most common finding in patients with urinary tract infections was hydronephrosis, followed by multiloculated renal cysts. Treatment and outcome
Twelve (80%) of the patients had been prescribed anti-NTM treatment, but only four of these regimens were adequate (Table 3). Other regimens included clarithromycin or ciprofloxacin monotherapy and clarithromycin plus ciprofloxacin. Three of the 12 patients had surgical intervention, including nephrectomy for suspected renal cancer in one with genitourinary MAC infection and surgical drainage of prostatic abscess in two with genitourinary M. abscessus infections.
ª2010 The Authors Journal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 1585–1590
Recovered
Recovered
Recovered Recovered Recovered Died of urosepsis Recovered Recovered Died of urosepsis Died of lung cancer Died of pneumonia Recovered Recovered Died of pneumonia Recovered
Clarithromycin, ethambutol, rifampin and amikacin
Clinical differences between genitourinary NTM infections and tuberculosis
NA, not available (four Mycobacterium species isolates were not available for 16S rRNA gene analysis.); NTM, nontuberculous mycobacteria.
Mycobacterium avium complex 43/M 15
AIDS
Mycobacterium avium complex
Clarithromycin, imipenem-cilastatin, amikacin Mycobacterium abscessus No 74/M 14
gordonae fortuitum
Mycobacterium abscessus
avium complex avium complex abscessus
avium complex
fortuitum avium complex
54/F 35/M 59/F 65/F 86/M 81/F 63/F 76/M 79/M 72/M 22/M 91/M 63/M 1 2 3 4 5 6 7 8 9 10 11 12 13
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The PSA levels returned to normal after the end of antiNTM treatment in two patients with prostatic abscess. Death occurred during treatment in three of 12 patients; the causes of death in these patients were bacterial pneumonia in two with genitourinary MAC infections and lung cancer in one. All other patients received complete anti-NTM treatment and had a good recovery. One patient who underwent epididymectomy alone for epididymitis also made a good recovery. Two patients died of refractory urosepsis before urinary NTM infections could be diagnosed: one of them had diabetes and liver cirrhosis and the other received chemotherapy for advanced gastric cancer.
No Epididymectomy No No No No No No No No Nephrectomy No Drainage of prostatic abscess Drainage of prostatic abscess No Ciprofloxacin No Ciprofloxacin No Ciprofloxacin and clarithromycin Ciprofloxacin No Ciprofloxacin Clarithromycin, ethambutol and rifampin Clarithromycin Ciprofloxacin and clarithromycin Ciprofloxacin and clarithromycin Clarithromycin, imipenem-cilastatin, amikacin Mycobacterium NA Mycobacterium Mycobacterium NA Mycobacterium Mycobacterium NA Mycobacterium NA Mycobacterium Mycobacterium Mycobacterium Mycobacterium gordonae Mycobacterium species Mycobacterium fortuitum Mycobacterium avium complex Mycobacterium species Mycobacterium gordonae Mycobacterium fortuitum Mycobacterium species Mycobacterium avium complex Mycobacterium species Mycobacterium avium complex Mycobacterium avium complex Mycobacterium abscessus Chronic renal disease, diabetes No Corticosteroid use Gastric cancer Chronic renal disease Chronic renal disease, diabetes Liver cirrhosis, diabetes Lung cancer, chronic renal disease No Chronic renal disease, diabetes No Rectal cancer, chronic renal disease Chronic renal disease
Age/ gender Case number
gordonae
Identification by sequencing of 16S rRNA Identification by conventional methods Underlying disease(s)
Anti-NTM therapy
Surgical management
Outcome
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from 1996–2008
TABLE 3. Summary of 15 patients with genitourinary infections caused by nontuberculous mycobacteria who were treated at the National Taiwan University Hospital
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Demographic characteristics and underlying diseases were not significantly different between patients with genitourinary NTM infections and those with genitourinary tuberculosis (Table 1). Patients with NTM infections were more likely to report constitutional symptoms, particularly fever, and to seek medical help within 1 month after the onset of symptoms than patients with tuberculosis. Leukocytosis was more frequent in patients with NTM infections (Table 2). AFS of urine was positive in 11 (26%) patients with tuberculosis, but in none of the patients with NTM infections. A comparison of the radiographic findings revealed that patients with tuberculosis were more likely to have ureteral strictures and chest radiographic evidence of active or inactive tuberculosis. Double-J ureteral stents were placed to relieve ureteral strictures in 15 (35%) patients with tuberculosis but none of the patients with NTM infection needed stenting.
Discussion The present series of 15 patients with genitourinary NTM infections over a 12-year period represents the largest single institutional experience of such infections reported to date. In accordance with the epidemiology of NTM infections in Taiwan, MAC and RGM were the most common NTM species involved in genitourinary infections [12]. Over the previous two decades, only 12 cases of genitourinary infection caused by NTM have been reported in the literature [7–9,13–20], and MAC, M. abscessus–chelonae complex and M. fortuitum were also the most commonly isolated NTM species in these cases [7,9,13,14,17,19,20]. Although the present study identified some features that might be useful for differentiating genitourinary NTM infections and tuberculosis, none of them was pathognomonic.
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Patients with NTM infections were more likely than tuberculosis patients to manifest signs and symptoms similar to conventional bacterial genitourinary infections, such as fever, leukocytosis and a short duration of symptoms. This may explain why only one patient with NTM infection had a ureteral stricture as a result of the limited time frame for contracture and scarring of the ureters to occur. Previous studies demonstrated that the presence of constitutional symptoms in patients with genitourinary tuberculosis is suggestive of active tuberculosis in other organs [21,22]; however this is not the case for NTM infections. Extragenitourinary disease was found in only two (20%) of the 10 patients presenting with fever. Chest imaging was useful for distinguishing NTM infection from tuberculosis. In the present study chest radiographs showed evidence of tuberculosis in 60% of patients with genitourinary tuberculosis, which is similar to the 50–75% reported in the literature [21,22]. By contrast, only 27% of patients with genitourinary NTM infections in this series had chest radiographic findings suggesting mycobacterial infection. Genitourinary tuberculosis is the result of haematogenous spread from the pulmonary site of primary infection; however, the pathogenesis of genitourinary NTM is poorly understood. The clinical manifestations of our patients suggest that there may be differences in pathogenesis between genital and urinary NTM infections. All of our patients with genital NTM infections had a normal chest radiograph and a history of previous instrumentation, supporting a previous hypothesis that NTM infections of the genital tract occur after surgical intervention with subsequent contamination [3,14]. On the other hand, none of the patients with urinary NTM infections had a history of urinary tract manipulation, whereas one-third had an abnormal chest radiograph. This indicates that the lungs are probably the portal of entry for these urinary tract infections. These patients likely had NTM pulmonary infections with subsequent dissemination [3]. Genitourinary NTM infections present a major management difficulty because of their resistance to commonly used antibiotics and antituberculous therapy. Experience in the treatment of NTM infections has mostly come from the management of pulmonary infections, which constitute threequarters of the reported NTM cases [3]. In this series, none of the patients who received either medical therapy, surgical intervention alone, or combined medical and surgical treatment, died of NTM infection. Although regimens against M. gordonae have not yet been defined [3], two patients with genitourinary M. gordonae infections responded well to ciprofloxacin monotherapy. Surgical debridement remains an important adjunct to the management of patients with RGM infections, especially in those with abscess, extensive disease
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or necrosis [23]. Two patients with M. abscessus prostatic abscess received treatment with surgical drainage combined with anti-NTM medications and recovered well. However, the anti-NTM treatment regimes were decided by treating physicians and were not standardized. More clinical experience is needed to determine the optimal therapy in this condition. Several limitations of the present study should be considered when interpreting its findings. First, the small number of cases limits the significance of some of the findings. Second, as a result of the retrospective design, the number of patients with genitourinary NTM infections during the study period may have been underestimated because mycobacterial cultures were not performed for all genitourinary specimens. Third, the data were collected from an urban, tertiary care centre, which might represent a high risk patient group with more comorbidities compared to other care settings and the results may not be generalizable to a community-based setting. In summary, although rare, genitourinary NTM infections are significant and potentially life-threatening and should be considered in the differential diagnosis of genitourinary infections, especially those unresponsive to conventional antibiotic treatment. Optimal treatment regimens remain unclear and each patient requires a judicious, individualized approach.
Transparency Declaration All authors have no conflict of interests.
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