Otitis Media and Otomastoiditis Caused by. Mycobacterium massiliense (Mycobacterium abscessus. subspecies bolletii)

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1 JCM Accepts, published online ahead of print on 29 August 2012 J. Clin. Microbiol. doi: /jcm Copyright 2012, American Society for Microbiology. All Rights Reserved Otitis Media and Otomastoiditis Caused by Mycobacterium massiliense (Mycobacterium abscessus subspecies bolletii) Meng-Rui Lee 1,2, Hsih-Yeh Tsai 2,3, Aristine Cheng 2,3, Chia-Ying Liu 3, Yu-Tsung Huang 3, Chun-Hsing Liao 3, Sheng-Kai Liang 4, Li-Na Lee 2,5, Po-Ren Hsueh 2, 5, * 1 Department of Internal Medicine, Taoyuan General Hospital, Taoyuan County, Taiwan; 2 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 3 Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan; 4 Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu,Taiwan; 5 Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; * Corresponding author. Mailing address: Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, No.7, Chung-Shan South Road, 100 Taipei, Taiwan. Phone: x Fax: hsporen@ntu.edu.tw. Keywords: M. massiliense, Mycobacterium abscessus subspecies bolletii, otomastoiditis, otitis media, tigecycline, clarithromycin Running title: M. massiliense otologic infections 1

2 We described two patients with otologic infections caused by Mycobacterium massiliense (M. abscessus subspecies bolletti) which were identified using erm(41) PCR, 23S rrna, and rpob gene sequence analysis. They were middle-aged adults with underlying otologic diseases and were treated successfully with clarithromycin-based combination regimens for three and nine months, respectively. Downloaded from on November 15, 2018 by guest 2

3 Mycobacterium abscessus complex comprises three closely related Mycobacterium subspecies, namely M. massiliense, M. bolletii, and M. abscessus (sensu stricto) (1). Species-level identification of M. abscessus complex depends on sequencing analysis of several genes, including the erm(41) gene, the 23S rrna gene, and several housekeeping genes (e.g. rpob and hsp65), which is not available in many laboratories (1, 7, 9). A previous report also indicated that erm(41) PCR can be efficiently used to simply differentiate M. massiliense from M. abscessus and M. bolletii and inconsistency could be found between rpob and hsp65 sequence analysis (7). Recently, the taxonomic status of M. massiliense is under debate and currently M. abscessus subspecies bolletti is probably preferred (10). Infections due to M. massiliense (M. abscessus subspecies bolletti) include post-surgical infections, cutaneous infections, pulmonary infections, and central nervous system infections (3, 8, 11-12, 14). Otitis media and otomastoidits caused by nontuberculous mycobacteria (NTM) are common in children and species in the M. abscessus complex are the most frequently isolated pathogens in patients with those diseases (5, 17). In a recent study of 10 patients with otomastoiditis, van Ingen et al. reported that the causative pathogen in all patients was M. abscessus (sensu stricto) (17). During the period , eight patients with otitis media or otomastoidits, whose clinical specimens (biopsy and ear discharge) were positive for M. abscessus complex, were treated at the National Taiwan University Hospital. The biopsy or ear discharge specimens from the eight patients were processed and pretreated for mycobacterial cultures as previously described (13). The isolates of M. abscessus complex were identified to the subspecies level by screening for the presence of the erm(41) gene as well as sequencing of the 23S rrna and rpob (306 bp) genes (7). Minimum inhibitory concentrations (MICs) of 15 antimicrobial agents against the 3

4 four M. massiliense (M. abscessus subspecies bolletti) isolates were determined using the Sensititre RAPMYCOI panel test (TREK Diagnostic Systems, Magellan Biosciences, West Sussex, UK). MICs of all agents tested were read on the fifth day after incubation and those of clarithromycin were read after extended incubation (on day 14) (15). Among the eight isolates of M. abscessus complex, four were confirmed to be M. abscessus (sensu stricto) and the other four isolates were confirmed to be M. massiliense (M. abscessus subspecies bolletti) by erm(41) PCR (397 bp) and sequence analysis for 23S rrna (accession number F , similarity of 99%), and rpob genes (similarity of 100%) (7). The four patients with M. abscessus (sensu stricto) otitis media have been previously reported (6). The MIC values of the 15 agents against the four M. massiliense (M. abscessus subspecies bolletti) isolates are shown in Table 2. Amoxicillin-clavulanic acid, cephalosporins, imipenem, tetracyclines, linezolid, fluoroquinolones, and aminoglycosides were not active against all the four isolates. MICs of the four isolates to clarithromycin were μg/ml. MIC of one isolate (a colonizer from Patient 3) to clarithromycin was >16 μg/ml and that of other three isolates was 0.5 μg/ml (read on 14th day of incubation). Two of the four patients (Patients 3 and 4) with positive culture of M. massiliense (M. abscessus subspecies bolletti) from ear discharges were considered as contaminants or colonizations instead of infections due to the good response with topical treatment alone and negative acid-fast stain and one single positive culture from multiple specimens (two specimens from each of the two patients) (Table 1). Patient 1 was a 53-year-old male who suffered from Aspergillus niger chronic otitis media and received mastodectomy plus tympanoplasty one year ago. Otorrhea, 4

5 hearing impairment and vertigo developed three months after surgery. Three cultures from the right ear discharges all grew M. abscessus, which were then confirmed to be M. massiliense (M. abscessus subspecies bolletti). The patient received clarithromycin (500 mg twice daily) plus ciprofloxacin (750 mg twice daily) for nine months. Repeated culture from the right ear was negative at end of treatment and he remained uneventfully for 4 years without any sequelae. Patient 2 was a 58-year-old male patient with past history of perforation of tympanic membrane. He presented to the hospital with otorrhea, hearing impairment and Gradenigo syndrome (6, 15). He first received petrosectomy, mastoidectomy and tympanoplasty, followed by a combination therapy with clarithromycin (500 mg twice daily), ciprofloxacin (750 mg twice daily) and ethambutol (800 mg per day) for three months. Acid-fast bacilli were found in one ear discharge specimen that was also culture positive for M massiliense (M. abscessus subspecies bolletti). At the end of treatment, culture became negative for mycobacteria. The patient was complicated with abducens nerve palsy during the follow-up of three years after completion of treatment (6). The incidence of otitis media and otomastoiditis caused by NTM is increasing (17). M. abscessus complex, M. chelonae, M. fortuitum, and M. avium intracellulare complex have been reported to cause otologic infections (4). In our previous report, species in the M. abscessus complex were the most common causes of otitis media followed by M. chelonae (6). In the present study, infection due to M. massiliense (M. abscessus subspecies. bolletti) was found in one-third of the six patients with infection caused by M. abscessus complex (excluding Patients 3 and 4). This finding differs from that reported by van Ingen et al., who found that none of the otologic infections due to M. abscessus complex were caused by M. massiliense (M. abscessus 5

6 subspecies bolletti) (17). Common features of otomastoiditis caused by M. massiliense (M. abscessus subspecies bolletti) and M. abscessus (sensu stricto) included the presence of underlying otologic disease and the need of prolonged antibiotic combination therapy along with surgical intervention (17). Most of the M. massiliense isolates were susceptible to clarithromycin (2, 7). Kim et al reported that clarithromycin-resistant M. massiliense isolates invariably had a point mutation at the adenine, A(2058) or A(2059), in the peptidyltransferase region of the 23S rrna gene, which was quite different from M. abscessus and M. bolletii (7). Although one of the M. massiliense (M. abscessus subspecies bolletti) isolate in this report had high MIC value (>16 μg/ml) of clarithromycin, the described point mutations were not found in this isolate (7). Interestingly, otomastoiditis caused by M. abscessus (sensu stricto) has been reported predominately in children (17) while patients reported in this study and our previous study both disclosed the adult prevalence (6). Although tigecycline MICs were within μg/ml in our study, the clinical efficacy of this agent needs to be investigated. Systemic antibiotics may be warranted if otomastoiditis, osteomyelitis, or central nervous system invasion develops (12, 16). In conclusion, we discovered two patients with otologic infections due to M. massiliense (M. abscessus subspecies bolletti). M. massiliense (M. abscessus subspecies bolletti) should be considered when treating patients with otomastoiditis or otitis media and molecular techniques are warranted for species-level identification. 6

7 References 1. Adekambi, T., M. Reynaud-Gaubert, G. Greub, M. J. Gevaudan, B. La Scola, D. Raoult, and M. Drancourt Amoebal coculture of "Mycobacterium massiliense" sp. nov. from the sputum of a patient with hemoptoic pneumonia. J. Clin. Microbiol. 42: Bastian, S., N. Veziris, A. L. Roux, F. Brossier, J. L. Gaillard, V. Jarlier, and E. Cambau Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob. Agents. Chemother. 55: Duarte, R.S., M. C. Lorenco, L. S. Fonseca, S.C. Leao, E. L. Amorim, I. L. Rocha, F. S. Coelho, C. Viana-Niero, K. M. Gomes, M. G. da Silva, N. S. Lorena, M. B. Pitombo, R. M. Ferreira, M. H. Garcia, G. P. de Oliveira, O. Lupi, B. R. Vilaca, L. R. Serradas, A. Chebabo, E. A. Marques, L. M. Teixeira, M. Dalcolmo, S. G. Senna, and J. L. Sampaio Epidemic of postsurgical infections caused by Mycobacterium massiliense. J. Clin. Microbiol. 47: Flint, D., M. Mahadevan, R. Gunn, and S. Brown Nontuberculous mycobacterial otomastoiditis in children: four cases and a literature review. Int. J. Pediatr. Otorhinolaryngol. 51: Griffith, D. E., T. Aksamit, B. A. Brown-Elliott, A. Catanzaro, C. Daley, F. Gordin, S. M. Holland, R. Horsburgh, G. Huitt, M. F. Iademarco, M. Iseman, K. Olivier, S. Ruoss, C. F. von Rey, R. J. Wallace, Jr., and K. Winthrop An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am. J. Respir. Crit. Care. Med. 175:

8 Hsiao, C. H., C. M. Liu, and P. R. Hsueh Clinicopathological and microbiological characteristics of mycobacterial otitis media in a medical center, 2000 to J. Infect. 62: Kim, H. Y., B. J. Kim, Y. Kook, Y. J. Yun, J. H. Shin, and Y. H. Kook Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribosome methyltransferase gene (erm) and clarithromycin susceptibility patterns. Microbiol. Immunol. 54: Koh, W. J., K. Jeon, N. Y. Lee, B. J. Kim, Y. H. Kook, S. H. Lee, Y. K. Park, C. K. Kim, S. J. Shin, G. A. Huitt, C. L. Daley, and O. J. Kwon Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am. J. Respir. Crit. Care. Med. 183: Lai, C.C., and H. C. Wang Clinical significance of Mycobacterium abscessus isolates at a medical center in Northern Taiwan. J. Microbiol. Immuno. Infect. 44: Leao, S. C., E. Tortoli, J. P. Euzeby, and M. J. Garcia Proposal that Mycobacterium massiliense and Mycobacterium bolletii be united and reclassified as Mycobacterium abscessus subsp. bolletii comb. nov., designation of Mycobacterium abscessus subsp. abscessus subsp. nov. and emended description of Mycobacterium abscessus. Int. J. Syst. Evol. Microbiol. 61: Leao, S. C., C. Viana-Niero, C. K. Matsumoto, K. V. Lima, M. L. Lopes, M. Palaci, D. J. Hadad, S. Vinhas, R. S. Duarte, M. C. Lourenco, A. Kipnis, Z. C. das Neves, B. M. Gabardo, M. O. Ribeiro, L. Baethgen, D. B. de Assis, G. Madalosso, E. Chimara, and M. P. Dalcolmo Epidemic 8

9 of surgical-site infections by a single clone of rapidly growing mycobacteria in Brazil. Future. Microbiol. 5: Lee, M. R., A. Cheng, Y. C. Lee, C. Y. Yang, C. C. Lai, Y. T. Huang, C. C. Ho, H. C. Wang, C. J. Yu, and P. R. Hsueh CNS infections caused by Mycobacterium abscessus complex: clinical features and antimicrobial susceptibilities of isolates. J. Antimicrob. Chemother. 67: Liu, Y. C., S. J. Lee, Y. S. Chen, H. Z. Tu, B. C. Chen, and T. S. Huang Differential diagnosis of tuberculous and malignant pleurisy using pleural fluid adenosine deaminase and interferon gamma in Taiwan. J. Microbiol. Immuno. Infect. 44: Nakanaga, K., Y. Hoshino, Y. Era, K. Matsumoto, Y. Kanazawa, A. Tomita, M. Furuta, M. Washizu, M. Makino, and N. Ishii Multiple cases of cutaneous Mycobacterium massiliense infection in a "hot spa" in Japan. J. Clin. Microbiol. 49: Sherman, S. C., and A. Buchanan Gradenigo syndrome: a case report and review of a rare complication of otitis media. J. Emerg. Med. 27: Tarantino, V., R. D'Agostino, G. Taborelli, A. Melagrana, A. Porcu, and M. Stura Acute mastoiditis: a 10 year retrospective study. Int. J. Pediatr. Otorhinolaryngol. 66: van Ingen, J., F. Looijmans, P. Mirck, R. Dekhuijzen, M. Boeree, and D. van Soolingen Otomastoiditis caused by Mycobacterium abscessus, The Netherlands. Emerg. Infect. Dis. 16:

10 TABLE 1. Clinical manifestations of two patients with otologic infections (Patients 1 and 2) caused by M. massiliense (M. abscessus subspecies Patient no. Age/sex Initial presentation Underlying medical condition 1 53/M Otorrhea, hearing impairment, and vertigo 2 58/M Otorrhea, hearing impairment, and Gradenigo s syndrome 3 45/M Otorrhea, hearing impairment, and left facial palsy bolletti) and two patients (Patients 3 and 4) with colonization by the organism No No Predisposing factors Previously underwent tympanoplasty and/or mastoidectomy for chronic otitis media Tympanic membrane perforation 10 Topical antibiotics No No No No Topical framycetin sulphate, and gramicidine 4 51/F Otorrhea No Previously underwent tympanoplasty for chronic otitis media Topical ofloxacin for two weeks Systemic antibiotics (duration) Clarithromycin and ciprofloxacin (9 months) Ciprofloxacin, clarithromycin, and ethambutol (3 months) Surgical intervention No Petrosectomy, mastoidectomy, and tympanoplasty Sequelae No Abducens nerve palsy No No Left facial palsy No No Lost to follow-up

11 TABLE 2. Antimicrobial susceptibilities of four isolates of M. massiliense (M. abscessus subspecies bolletti) to 15 antimicrobial agents using the broth microdilution method Minimum inhibitory concentration (μg/ml) Patient no./ CLA AMC FOX CRO FEP IPM CIP MXF DOX MIN LZD TOB AMK TGC SXT isolate (5 th day/14 th day ) no. a 1 >64/32 64 >64 >32 32 >4 8 >16 > >8/ /0.5 2 >64/32 64 >64 >32 64 >4 >8 >16 >8 32 >16 > / /0.5 3 >64/ >64 >32 32 >4 >8 >16 >8 8 >16 > /4.75 >16/>16 4 >64/32 64 >64 >32 16 >4 >8 >16 >8 > >8/ /0.5 AMC, amoxicillin-clavulanate; FOX, cefoxitin; CRO, ceftriaxone; FEP, cefepime; IPM, imipenem; CIP, ciprofloxacin; MXF, moxifloxacin; DOX, doxycycline; MIN, minocycline; LZD, linezolid; TOB, tobramycin; AMK, amikacin; TGC, tigecycline; SXT, trimethoprim-sulfamethoxazole; CLA, clarithromycin. a Designation of isolates from indicated patients are shown in Table 1. 11

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