• 1.

    Selvarangan R, Wu WK, Nguyen TT, Carlson L, Wallis CK, Stiglich SK, Chen YC, Jost KC Jr, Prentice JL, Wallace RJ Jr, Barrett SL, Cookson BT, Coyle MB, 2004. Characterization of a novel group of mycobacteria and proposal of Mycobacterium sherrisii sp. nov. J Clin Microbiol 42: 5259.

    • Search Google Scholar
    • Export Citation
  • 2.

    van Ingen J, Tortoli E, Selvarangan R, Coyle MB, Crump JA, Morrissey AB, Dekhuijzen PN, Boeree MJ, van Soolingen D, 2011. Mycobacterium sherrisii sp. nov., a slow-growing non-chromogenic species. Int J Syst Evol Microbiol 61: 12931298.

    • Search Google Scholar
    • Export Citation
  • 3.

    Gamperli A, Bosshard PP, Sigrist T, Brandli O, Wildermuth S, Weber R, Mueller NJ, 2005. Pulmonary Mycobacterium sherrisii infection in a human immunodeficiency virus type 1-infected patient. J Clin Microbiol 43: 42834285.

    • Search Google Scholar
    • Export Citation
  • 4.

    Loulergue P, Lamontagne F, Vincent V, Rossier A, Pialoux G, 2007. Mycobacterium sherrisii: a new opportunistic agent in HIV infection? AIDS 21: 893894.

    • Search Google Scholar
    • Export Citation
  • 5.

    Tortoli E, Galli L, Andebirhan T, Baruzzo S, Chiappini E, de Martino M, Brown-Elliott BA, 2007. The first case of Mycobacterium sherrisii disseminated infection in a child with AIDS. AIDS 21: 14961498.

    • Search Google Scholar
    • Export Citation
  • 6.

    Tortoli E, Mariottin A, Mazzarelli G, 2007. Mycobacterium sherrisii isolation from a patient with pulmonary disease. Diagn Microbiol Infect Dis 57: 221223.

    • Search Google Scholar
    • Export Citation
  • 7.

    Barrera L, Palmero D, Paul R, Lopez B; Grupo de Investigacion de M. simiae, 2010. Disease due to Mycobacterium simiae and “Mycobacterium sherrisii” in Argentina. Medicina (B Aires) 70: 343346.

    • Search Google Scholar
    • Export Citation
  • 8.

    Ho J, Balm M, Huggan P, Chew N, Venkatachalam I, Archuleta S, 2012. Immune reconstitution inflammatory syndrome associated with disseminated Mycobacterium sherrisii infection. Int J STD AIDS 23: 369370.

    • Search Google Scholar
    • Export Citation
  • 9.

    Crump JA, van Ingen J, Morrissey AB, Boeree MJ, Mavura DR, Swai B, Thielman NM, Bartlett JA, Grossman H, Maro VP, van Soolingen D, 2009. Invasive disease caused by nontuberculous mycobacteria, Tanzania. Emerg Infect Dis 15: 5355.

    • Search Google Scholar
    • Export Citation
  • 10.

    Valero G, Moreno F, Graybill J, 1994. Activities of clarithromycin, ofloxacin, and clarithromycin plus ethambutol against Mycobacterium simiae in a murine model of disseminated infection. Antimicrob Agents Chemother 38: 26762677.

    • Search Google Scholar
    • Export Citation
  • 11.

    van Ingen J, Totten SE, Helstrom NK, Heifets LB, Boeree MJ, Daley CL, 2012. In vitro synergy between clofazimine and amikacin in nontuberculous mycobacterial disease. Antimicrob Agents Chemother 56: 53246327.

    • Search Google Scholar
    • Export Citation
  • 12.

    van Ingen J, Totten SE, Heifets LB, Boeree MJ, Daley CL, 2012. Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae complex disease. Int J Antimicrob Agents 39: 173176.

    • Search Google Scholar
    • Export Citation

 

 

 

Disseminated Infection by Mycobacterium sherrisii and Histoplasma capsulatum in an African HIV-Infected Patient

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  • Hospital de Sabadell and UDIAT Diagnostic Centre, Corporació Sanitària Parc Taulí, Sabadell; Department of Infectious Diseases and Microbiology Laboratory, Universitat Autònoma de Barcelona, Barcelona, Spain; Campus d´Excellència Internacional, Bellaterra, Spain; Microbiology Department-CDB, Hospital Clínic de Barcelona-Barcelona Centre for International Health Research (CRESIB), Barcelona, Spain; Pathology, Pharmacology and Microbiology Departments, University of Barcelona (UB), Barcelona, Spain

Mycobacterium sherrisii is a new species of opportunistic, slow-growing, non-tuberculous Mycobacterium closely related to Mycobacterium simiae that can currently be identified with the sequence of 16S rARN gene and the heat-shock protein 65. Few cases of patients infected by this Mycobacterium have been reported and all of them were associated with human immunodeficiency virus or other immunosuppressive conditions. Clinical management is complex, because there is not a clear correlation between the in vitro antibiotic susceptibility testing and the patient's clinical outcome.

Introduction

Mycobacterium sherrisii has been recently recognized as a new species mainly associated with pulmonary or disseminated disease in immunocompromised patients. A new case of disseminated infection by M. sherrisii in an African human immunodeficiency virus (HIV)-infected patient is described. The patient was simultaneously affected by a disseminated form of Histoplasma capsulatum infection. We discuss the clinical aspects of the M. sherrisii infection, the complexity of the diagnosis and clinical management, and review the literature.

Case Report

A 35-year-old man born in Ghana was admitted to our hospital in 2009 with severe asthenia, fever, and non-productive cough. On examination he was cachectic, had disseminated lymphadenopathy, and hepatosplenomegaly. The chest x-ray showed a faint interstitial pattern, and hilar and mediastinal enlarged lymph nodes with a pulmonary ground-glass pattern was observed in the thoracic computed tomographic scan. A fiberoptic bronchoscopy detected multiple ulcerated bronchial and tracheal lesions suggestive of fungal infection, which was confirmed by cultures of bronchial aspirate (BAS), bronchoalveolar lavage (BAL), blood culture, and bone marrow aspirate. All samples were positive for H. capsulatum. A diagnosis of HIV was simultaneously made, with a CD4 cell count of 26 cells/mm3 and an HIV viral load of 79,000 copies/mL. The patient was treated with lipidic amphotericin 3 mg/kg/day for 4 weeks followed by itraconazole 400 mg/day as a secondary prophylaxis. The patient also started antiretroviral (HAART) therapy with darunavir, ritonavir, tenofovir/emtricitabine (DRV/RTV/TDF/FTC), which resulted in clinical and immunological improvement. Mycobacterial cultures (VersaTREK system, Thermo Fisher, USA) of sputum, BAS, BAL, urine, and feces were negative. However, a non-tuberculous, non-chromogenic Mycobacterium was isolated in the blood culture; however, the species could not be determined by the Geno Type-CM/AS reverse line dot assay (Hain Lifescience, Germany). The strain was sent to a reference laboratory for identification and for antibiotic susceptibility testing (AST).

Two months later, the patient was admitted with acute respiratory failure. A miliary pattern was observed on the chest x-ray. The CD4 count was 96 cells/mm3 and the HIV viral load 458 copies/mL. The patient had adhered to the HAART and antifungal drug regimens. A new fiberoptic bronchoscopy showed complete healing of previous endobronchial lesions. The fungal cultures of BAL and BAS were negative; however, mycobacteria cultures were positive for a non-tuberculous Mycobacterium strain. Several samples of sputum and feces were also positive.

The strain isolated in the first blood culture was ultimately identified as M. sherrisii. The sequencing of the 16S ribosomal RNA gene showed the same sequence as the GenBank accession no. AY353699 (M. sherrisii) and 4 bp differences with M. simiae (GenBank accession no. AY604042). Moreover, the non-chromogenic colonies isolated were more consistent with M. sherrisii than with M. simiae. No biochemical or chromatographic analyses were performed because of their poor capacity to differentiate M. simiae from related strains.1,2 The AST was performed using the broth macrodilution system by the Mycobacteria Growth Indicator Tubes (Becton Dickinson, Sparks, MD) following the standardized methodology by the Clinical Laboratory Standards Institute. The following AST was obtained: rifampicin resistant (4 μg/mL), amikacin resistant (> 5 μg/mL), streptomycin resistant (> 6 μg/mL), clarithromycin resistant (> 8 μg/mL), linezolid resistant (> 2 μg/mL), ethambutol susceptible (< 8 μg/mL), and moxifloxacin susceptible (< 1 μg/mL).

Based on previous case reports, the patient initiated treatment with levofloxacin (500 mg/daily), ethambutol (800 mg/daily), and azithromycin (500 mg/daily), despite resistance to clarithromycin. Three months later viable mycobacteria were still isolated in the patient's feces but the pulmonary miliary pattern was visibly improved. The HAART therapy was modified to abacavir, lamivudine, and raltegravir (ABC/3TC/RAL) to prevent drug–drug interactions. Secondary antifungal prophylaxis with itraconazole and antimycobacterial therapy was continued. The patient was lost to follow-up because he went back to Ghana 10 months after the initial diagnosis of histoplasmosis and 8 months after starting antimycobacterial treatment, with a CD4 count of 254 cells/mm3 and a viral load under 20 copies/mL.

Twelve months later the patient returned to our hospital. He had maintained good adherence to HAART and his viral load was undetectable. Despite stopping the antifungal and antimycobacterial treatments, he did not present any symptoms of the previous disseminated infections.

Discussion

Mycobacterium sherrisii is a new species of opportunistic, slow-growing, non-tuberculous Mycobacterium closely related to M. simiae. It was first characterized by Selvarangan and others1 in 2004 however it was not recognized as a novel species until 2011.2 The first strains were isolated from HIV-infected patients born in Africa or who had resided there for a long time before moving to other countries.35 New cases appeared later in Italy,6 Argentina,7 and recently Singapore,8 not related to an African source.

There are only a few reported cases. All patients except one are men, and all are immunosuppressed by HIV or other diseases. Clinical and epidemiological data of all cases are summarized in Tables 1 and 2.

Table 1

Mycobacterium sherrisii infection in HIV-infected patients

Patient123*45*678910
Year Author2005 Gämperli and others32007 Loulergue and others42007 Tortoli and others52009 Crump and others92009 Crump and others92010 Barrera and others72010 Barrera and others72010 Barrera and others72012 Ho and others82013 Taján and others
Age (y)4753749364930293635
GenderMaleMaleMaleMaleMaleMaleMaleMaleFemaleMale
African descentYesYesYesYesYesNoNoNoNoYes
Lung diseaseYesYesNoNoNoNoNoNoNoYes
DisseminationNoYesYesYesYesNoNoYesYesYes
Positive samplesSputumSputumPeritoneal fluidBlood cultureBlood cultureSputumSputumSputumBlood cultureSputum
BALPeritoneal fluidLymph node    BALHepatic biopsyBAS
 Blood cultureBlood culture    Blood culture Feces
  Gastric aspirate      Blood culture
TreatmentClarithromycinClarithromycinClarithromycinAzithromycinAzithromycinUnknownClarithromycinClarithromycinClarithromycinAzithromycin
MoxifloxacinMoxifloxacinCiprofloxacinEthambutolEthambutol CiprofloxacinCiprofloxacinRifampicinLevofloxacin
RifabutinRifabutinEthambutol   EthambutolEthambutolEthambutolEthambutol
SulfamethoxazoleEthambutolAmikacin       
 Amikacin        
CD4/CD4%19/619/3,272133123089205826/3
HIV viral load595,000 (baseline)460 (on therapy)1,088,000 (baseline)UnknownUnknownUnknownUnknownUnknown963,500 (baseline)79,000 (baseline)
HAARTStart AZT/3TC/RTV/ LOPD4T/3TC/NVPStart D4T/3TC/RTV/LOPAZT/3TC/ABCD4T/3TC/NVP Non-adherenceUnknownUnknownUnknownTDF/FTC/EFVStart TDF/FTC/RTV/DRV
Immune reconstitutionProbablyProbablyProbablyNoNoUnknownUnknownUnknownYesYes
Time (weeks) to clinical symptomsFour Some     FourFour
OutcomeCuredImprovedCuredImprovedNegative blood culturesLost to follow-upDiedDiedCuredCured
Other conditions TBC TBC    Cerebral ToxoplasmosisDisseminated Histoplasmosis

Previously identified as M. simiae.

AZT = Zidovudine; 3TC = Lamivudine; d4T = Stavudine; NVP = Nevirapine; LOP = Lopinavir; ABC = Abacavir; EFV = Efavirenz; TDF = Tenofovir; FTC = Emtricitabine; RTV = Ritonavir; DRV = Darunavir.

Table 2

Mycobacterium sherrisii infection in non-HIV-infected patients

Patient1*/2*345
Year Author2007 Tortoli and others62007 Tortoli and others62010 Barrera and others72010 Barrera and others72010 Barrera and others7
Age (years)5853657265
GenderMaleMaleMaleMaleMale
African descentNoNoNoNoNo
Lung diseaseYesYesYesYesYes
DisseminationPleuralNoNoNoNo
Positive samplesPleural biopsySputumSputumSputumSputum
TreatmentIsoniazidNoClarithromycinClarithromycinClarithromycin
RifampicinUnclear clinical valueCiprofloxacynCiprofloxacynCiprofloxacyn
Ethambutol EthambutolEthambutol 
Pirazinamide    
OutcomeLost to follow-upUnknown“Cronification” Positive sputum persists“Cronification” Positive sputum persists“Cronification” Positive sputum persists
Cause of immunosuppressionReumatoid Arthritis TBC (before)TBC (before)Silicosis

Retrospective identification (samples from 1996 and 2006).

Previous identification Mycobacterium lentiflavum.

Two distinct clinical forms of this infection exist: the first, with an indolent course, affects older people with previous pulmonary tuberculosis or some non-HIV immunosuppressive condition. Here, M. sherrisii acts as a respiratory tract colonizer rather than a pathogen; and the second, associated with HIV-infection, where M. sherrisii disseminates and can cause the patient's death.

The main limitation for the laboratory diagnosis of M. sherrisii is that this strain is not included in the commercial reverse line dot assays available. In addition, biochemical tests are insufficient to identify these isolates, because they are similar to closely related mycobacteria. Indeed, the first report showed its similarity to M. simiae and Mycobacterium triplex1; currently, the sequence of 16S rARN gene and the heat-shock protein 65 are the reference identification methods.2 Until M. sherrisii was characterized, some of the strains were misdiagnosed as M. simiae or Mycobacterium lentiflavum5,6,9 and retrospectively identified as M. sherrisii by sequencing techniques. Consequently, any isolation of a non-tuberculous strain identified as M. simiae or other closely related species with commercially available methods should be confirmed by 16S rRNA sequencing.

Another important issue is the management of these patients. There seems to be a poor correlation between the in vitro AST and the clinical outcome3,6,9; the recommended empirical treatment includes macrolides and quinolones based on M. simiae cases.10 Ethambutol and rifampins could be added however the susceptibility patterns vary among isolates.

The AST performed in a M. sherrisii strains collection2 showed resistance to quinolones (ciprofloxacin, gatifloxacin, and moxifloxacin), linezolid, rifampicin, sulfamethoxazole, ethambutol, and streptomycin. Amikacin showed a variable susceptibility pattern among isolates. All strains, except one, were susceptible to clarithromycin and all were susceptible to rifabutin. The results are similar to the strain collection from Argentina7 and other cases3,4; our strain differs from these results because it is resistant to clarithromycin and susceptible to ethambutol and moxifloxacin.

Despite the AST results, most cases were treated with drugs that showed moderate susceptibility or resistance, with successful outcomes. We suggest two possible explanations: first, the initiation of HAART treatment in the HIV cases improves the immunological status of the patient; and second, the combination of antibiotics could act synergistically improving antimycobacterial drug activity. Indeed, two studies showed in vitro synergy in non-tuberculous mycobacteria, which included M. simiae and related species11,12; an alternative to the classic AST could be the synergy study of the drugs used.

In summary, the best empirical treatment should probably include rifabutin, clarithromycin, and ethambutol. Moxifloxacin or levofloxacin could be used as alternative drugs.

Recently, the first case of disseminated M. sherrisii associated with immune reconstitution inflammatory syndrome was reported8. In our patient, M. sherrisii dissemination occurred after the initiation of HAART treatment. Although the blood culture positive for M. sherrisii came from the first admission, clinical evidence of infection with respiratory failure and miliary pattern occurred after 8 weeks on HAART, when CD4 rose to 90 cells/mm3. Most likely, the patient immune reconstitution highlighted the clinical signs of mycobacterial dissemination. As seen in Table 1, the literature shows that in patients' 1, 2, 3, and 9 and in our patient, a variable period of time exists between starting HAART and clinical evidence of infection. We therefore agree with Ho and others8 that this new non-tuberculous Mycobacterium should be included in the list of opportunistic diseases to prevent when immune reconstitution inflammatory syndrome is suspected in HIV-infected patients, particularly when some relationship with Africa exists.

  • 1.

    Selvarangan R, Wu WK, Nguyen TT, Carlson L, Wallis CK, Stiglich SK, Chen YC, Jost KC Jr, Prentice JL, Wallace RJ Jr, Barrett SL, Cookson BT, Coyle MB, 2004. Characterization of a novel group of mycobacteria and proposal of Mycobacterium sherrisii sp. nov. J Clin Microbiol 42: 5259.

    • Search Google Scholar
    • Export Citation
  • 2.

    van Ingen J, Tortoli E, Selvarangan R, Coyle MB, Crump JA, Morrissey AB, Dekhuijzen PN, Boeree MJ, van Soolingen D, 2011. Mycobacterium sherrisii sp. nov., a slow-growing non-chromogenic species. Int J Syst Evol Microbiol 61: 12931298.

    • Search Google Scholar
    • Export Citation
  • 3.

    Gamperli A, Bosshard PP, Sigrist T, Brandli O, Wildermuth S, Weber R, Mueller NJ, 2005. Pulmonary Mycobacterium sherrisii infection in a human immunodeficiency virus type 1-infected patient. J Clin Microbiol 43: 42834285.

    • Search Google Scholar
    • Export Citation
  • 4.

    Loulergue P, Lamontagne F, Vincent V, Rossier A, Pialoux G, 2007. Mycobacterium sherrisii: a new opportunistic agent in HIV infection? AIDS 21: 893894.

    • Search Google Scholar
    • Export Citation
  • 5.

    Tortoli E, Galli L, Andebirhan T, Baruzzo S, Chiappini E, de Martino M, Brown-Elliott BA, 2007. The first case of Mycobacterium sherrisii disseminated infection in a child with AIDS. AIDS 21: 14961498.

    • Search Google Scholar
    • Export Citation
  • 6.

    Tortoli E, Mariottin A, Mazzarelli G, 2007. Mycobacterium sherrisii isolation from a patient with pulmonary disease. Diagn Microbiol Infect Dis 57: 221223.

    • Search Google Scholar
    • Export Citation
  • 7.

    Barrera L, Palmero D, Paul R, Lopez B; Grupo de Investigacion de M. simiae, 2010. Disease due to Mycobacterium simiae and “Mycobacterium sherrisii” in Argentina. Medicina (B Aires) 70: 343346.

    • Search Google Scholar
    • Export Citation
  • 8.

    Ho J, Balm M, Huggan P, Chew N, Venkatachalam I, Archuleta S, 2012. Immune reconstitution inflammatory syndrome associated with disseminated Mycobacterium sherrisii infection. Int J STD AIDS 23: 369370.

    • Search Google Scholar
    • Export Citation
  • 9.

    Crump JA, van Ingen J, Morrissey AB, Boeree MJ, Mavura DR, Swai B, Thielman NM, Bartlett JA, Grossman H, Maro VP, van Soolingen D, 2009. Invasive disease caused by nontuberculous mycobacteria, Tanzania. Emerg Infect Dis 15: 5355.

    • Search Google Scholar
    • Export Citation
  • 10.

    Valero G, Moreno F, Graybill J, 1994. Activities of clarithromycin, ofloxacin, and clarithromycin plus ethambutol against Mycobacterium simiae in a murine model of disseminated infection. Antimicrob Agents Chemother 38: 26762677.

    • Search Google Scholar
    • Export Citation
  • 11.

    van Ingen J, Totten SE, Helstrom NK, Heifets LB, Boeree MJ, Daley CL, 2012. In vitro synergy between clofazimine and amikacin in nontuberculous mycobacterial disease. Antimicrob Agents Chemother 56: 53246327.

    • Search Google Scholar
    • Export Citation
  • 12.

    van Ingen J, Totten SE, Heifets LB, Boeree MJ, Daley CL, 2012. Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae complex disease. Int J Antimicrob Agents 39: 173176.

    • Search Google Scholar
    • Export Citation

Author Notes

* Address correspondence to Juan Taján, Infectious Diseases Dept. CSPT. Parc Tauli, 1. 08208 Sabadell, Spain. E-mail: jtajan@tauli.cat

Authors' addresses: Juan Taján, Corporació Sanitària Parc Taulí, Infectious Diseases, Sabadell, Barcelona, Spain, E-mail: jtajan@tauli.cat. Mateu Espasa, Corporacio Sanitaria Parc Tauli – Microbiology, UDIAT-CD, Sabadell, Barcelona, Spain, E-mail: mespasa@tauli.cat. Montserrat Sala, Marta Navarro, Bernat Font, and Ferran Segura, Corporació Sanitària Parc Taulí - Infectious Diseases, Sabadell, Barcelona, Spain, E-mails: msala@tauli.cat, mnavarro@tauli.cat, bfont@tauli.cat, and fsegura@tauli.cat. Julián González-Martín, Hospital Clínic de Barcelona- Barcelona Centre for International Health Research (CRESIB) - Anatomia Patològica, Pathology, Pharmacology and Microbiology, Barcelona, Barcelona, Spain, E-mail: gonzalez@clinic.ub.es.

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