24 F. Olea-Popelka et al.
Other resistance patternsStrains of M. bovis have been shown to be resis-
tant to isoniazid. McLaughlin et al. (2012)
reported that 28.5% of M. bovis isolates evalu-
ated in their study in the US were resistant to
both pyrazinamide and isoniazid. Other reports
(LoBue et al., 2003; CDC, 2005) have also identi-
fied M. bovis with resistance to isoniazid, further
complicating the treatment of these patients.
Cases of M. bovis multidrug-resistant strains
(displaying resistance to both isoniazid and
rifampicin, the two most powerful first-line
drugs) have been reported in Scotland
( Armstrong and Christie, 1998), in Spain among
HIV-positive patients (Guerrero et al., 1997) and
in an immunocompetent patient (Palenque et al.,
1998), and in Mexico (Vazquez-Chacon et al.,
2015). Multidrug-resistant TB (regardless of the
causative agent) poses a serious public health
challenge, with only 50% of patients being suc-
cessfully treated globally in 2014 (WHO, 2015a).
Hence, it is important to quantify and evaluate
not only the impact of the inherent pyrazin-
amide-resistance of M. bovis but also the poten-
tial acquired resistance to other anti-TB drugs
on treatment outcomes. Understandably, the
success of treatment may be considerably worse
for TB patients with M. bovis strains resistant to
multiple anti-TB drugs.
2.4.2 Extra-pulmonary tuberculosisDespite the fact that TB disease caused by
M. bovis is clinically, radiographically and patho-
logically indistinguishable from TB caused by
M. tuberculosis (Cosivi et al., 1998; Grange,
2001; Wedlock et al., 2002; Michel et al., 2009),
there is nonetheless an association between
M. bovis infection and extra-pulmonary sites (de
Kantor et al., 2010; Dürr et al., 2013). In Europe
and the US, one-half to three-quarters of
zoonotic TB patients are affected by extra-
pulmonary disease, including lymph nodes, the
gastrointestinal tract and urogenital tract. In
regions where bovine TB is endemic, foodborne
infection (milk) is the principal cause of cervical
lymphadenopathy and abdominal and other
forms of non-pulmonary TB (Cosivi et al., 1998).
The predilection of M. bovis for extra-pulmonary
sites raises the risk of misdiagnosis or late
diagnosis (Sunnetcioglu et al., 2015), therefore
delaying the initiation of treatment. In India,
Shah et al. (2006) reported the results of a study
aiming to detect M. tuberculosis and M. bovis in
human cerebrospinal fluid (CSF) from TB
patients including patients with tuberculous
meningitis. The study evaluated 212 CSF sam-
ples including 100 from children. This study
showed that in 17% (36 out of 212) of CSF sam-
ples, M. bovis was detected (versus only 2.8%
containing M. tuberculosis). The authors con-
cluded that appropriate molecular diagnostic
techniques would allow the correct identifica-
tion of M. bovis and could aid and improve the
prevention of human TB. Although most TB
caused by M. tuberculosis in Europe and the US
affects the lungs, approximately one-quarter
presents as extra-pulmonary disease (Dürr et al.,
2013). Extra-pulmonary TB cannot therefore be
assumed to be caused by M. bovis. In Ethiopia,
where rates of extra-pulmonary TB are rela-
tively high, an association with M. bovis infec-
tion could not be demonstrated. This may be due
to an overall low prevalence of M. bovis infection
in livestock (Berg et al., 2015). Unfortunately, in
most parts of the world, the ability to diagnose
extra-pulmonary TB is limited.2.5 ConclusionIn light of the considerable number of people
estimated to contract zoonotic TB annually, and
the important epidemiologic and clinical differ-
ences of M. bovis compared to the more common
causal agent of human TB (M. tuberculosis), it is
important to recognize the implications for pre-
vention, diagnosis and treatment of human TB
caused by M. bovis. It is clear that there is a need
to strengthen the identification and prevention
of M. bovis as a causal agent of human TB, in
light of the aligned policy agendas of the End TB
Strategy of WHO, the UN Sustainable Develop-
ment Goals and the Stop TB Partnership’s Global
Plan to End TB.
Considering the public health implications
and challenges associated with zoonotic TB, it is
crucial to, first, obtain an accurate picture of the
burden both at national and global levels. For
this, comprehensive surveillance approaches
and laboratory methods must be implemented.