The diagnosis of dr-TB should be based on the patients’ history
and on clinical suspicion. This diagnosis is always microbiological
and/or molecular (the clinical symptoms and radiological information
of dr-TB are indistinguishable from those of drug-sensitive TB).
Sensitivity testing to anti-TB drugs is recommended as early as
possible, as this could lead to an early introduction of an
appropriate treatment, resulting in higher cure rates, lower risk of
additional resistance, and less possibility of dr-TB
transmission.
Testes de laboratório
Laboratory tests
The majority of young children will not be able to produce
sputum samples, so sputum induction, gastric lavage, or
bronchoscopy may be needed to obtain a sample.
If a sample is available, testing for sensitivity to at least H
and R should be performed in all children with TB. If resistance
to R and/or H is shown, testing for susceptibility to
fluoroquinolones and second-line injectable drugs is
recommended.
There are two types of drug sensitivity tests
(Caminero et al., 2017)
:
-
Phenotypic testing (conventional test): determines whether
a strain is resistant to an anti-TB drug by evaluating growth
(or metabolic activity) in the presence of the drug. Results
take 2-3 weeks if liquid mediums are used, and up to 4-8 weeks
for solid mediums.
-
Genotypic testing (molecular test): detects mutations in
the genome associated with a specific resistance to a drug.
These tests provide results in a matter of hours, as they
detect mutations in the genes that encode resistance to
anti-TB drugs using gene amplification techniques. These
techniques include the following:
-
Xpert MTB/RIF (Cepheid): can detect R resistance in a
sputum sample within 2 hours. It may also be used as an
initial diagnostic test, as it is much more sensitive than
bacilloscopy.
-
GenotypeMDRplus (Hain) or Line Probe Assay: can
simultaneously detect mutations in the genes encoding
resistance to H (katG and inhA) and R (rpoB) in 6-24
hours.
-
GenotypeMDRsl (Hain) version 2: can detect resistance to
fluoroquinolones (mutations in the gyrA and gyrB genes) and
to second-line injectable drugs (mutations in the rrs genes
and eis promoter regions)
Treatment
The basic principles of TB treatment are the following:
-
Drugs should be associated and administered in single
dosages whenever possible to prevent resistance
-
Treatment should be extended long enough to ensure healing
and prevent relapse
Most cases of TB can be cured with a proper regimen and strict
monitoring of medication intake.
The treatment of children without bacteriological confirmation
or an antibiogram, who have clinical evidence of TB disease and a
history of contact with a case of dr-TB, should be guided by the
sensitivity test results and the history of exposure of the index
case to anti-TB drugs.
According to the WHO
(World Health Organization, 2019)
, treatment with rifampicin, ethambutol, pyrazinamide, and
levofloxacin for 6 months is recommended (6REZ-Lfx) for patients
with confirmed resistance to H who are sensitive to R. Adding
streptomycin or other injectable agents to the treatment regimen
is not recommended. Sensitivity to fluoroquinolones (FQs) should
be confirmed before starting treatment.
Dr. Caminero
(Caminero et al., 2017)
proposes alternative
treatment guidelines for cases with Hr-TB (mono or polyresistant),
with sensitivity to R:
-
9HRZE (isoniazid + rifampicin + pyrazinamide + ethambutol
for 9 months). If this scheme is chosen, high dosages of H
should be administered.
-
2FQ-REZ / 7FQ-RE (2 months with fluoroquinolone +
rifampicin + pyrazinamide + ethambutol and 7 months with
fluoroquinolone + rifampicin + ethambutol).
-
2RZE/10RE (2 months with rifampicin + pyrazinamide +
ethambutol and 10 months with rifampicin + ethambutol)
FQs (Lfx or moxifloxacin) should only be introduced into the
regimen if it is administered from the beginning with the rest of
the drugs. It should not be added if the result of H resistance is
received after 3-4 weeks of treatment because of the possible risk
of performing a covert monotherapy. In that case, the use of 9HRZE
is recommended.
Although FQs have been shown to retard cartilage development in
beagle puppies, similar effects have not been shown in humans. The
benefit of FQs in treating dr-TB in children has been shown to
outweigh any risks
(World Health Organization, 2014)
.
Close clinical monitoring is essential for all patients
receiving this regimen, particularly for liver function tests,
given the hepatotoxic potential of prolonged use of Z. All
patients should be tested monthly for transaminases, if possible.
In addition, to prevent and control the possible toxic effects of
E in children (e.g. retrobulbar neuritis), it is necessary to
administer the correct dosages recommended for children. Early
signs of E toxicity can be assessed in older children using
red-green colour discrimination tests.
In general, anti-TB drugs should be dosed according to body
weight
(Table 1. Recommended dosages of anti-TB drugs used in
children with Hr-TB and their main adverse effects).
Consequently,
monthly recording of weight is especially important in paediatric
cases, and dosages should be adjusted as children gain weight.
The expert opinion is that all drugs, including FQs, should be
dosed at the upper end of the recommended ranges whenever
possible, except E, which should be dosed at 15 mg/kg, rather than
25 mg/kg, as sometimes used in adults with dr-TB, as it is more
difficult to manage optic neuritis in children.
Adherence to treatment is one of the main challenges,
especially during the continuation phase. This is why it is
important to advise children and their families on the importance
of completing the full TB treatment cycle and to administer said
treatment under direct supervision.
In children, microbiological monitoring of their responses to
treatment is often difficult (for the same reasons that a
microbiological diagnosis is difficult to obtain). This makes the
diagnosis of treatment failure difficult. Persistent abnormalities
on chest X-rays do not necessarily mean a lack of improvement.
Weight loss or, more commonly, the inability to gain weight
adequately with an adequate food intake is often one of the first
(or only) signs of treatment failure. This is another fundamental
reason for careful weight control in children.
When additional resistance is suspected or confirmed, treatment
regimens should be designed individually, and referral to a
specialised dr-TB treatment unit is advised.
Recommended dosages of anti-TB drugs used in
children with Hr-TB and their main adverse effects
|
Drug
|
Dosage/kg/day
|
Maximum daily dosage
|
Toxicity
|
|
Rifampicin (R)
|
10-20 mg |
600 mg |
Gastrointestinal intolerance, arthralgia, flu-like
syndrome, 1% hepatitis, interstitial nephritis,
orange-coloured secretions |
|
Ethambutol (E)
|
15-25 mg |
2.5 g |
Optic neuritis, altered colour perception |
|
Pyrazinamide (Z)
|
30–40 mg |
2 g |
Hyperuricaemia, hepatitis, gastrointestinal intolerance,
arthralgia, photosensitivity |
|
Levofloxacin (Lfx)
|
15-20 mg |
1.5 g |
Gastrointestinal discomfort, paraesthesia, insomnia,
tendon rupture, QT prolongation |
|
Moxifloxacin (Mfx)1
|
10-15 mg |
400 mg |
Gastrointestinal discomfort, paraesthesia, insomnia,
tendon rupture, QT prolongation |
|
Isoniazid (H)2
|
15-20 mg |
300 mg |
Hepatotoxicity, peripheral neuropathy |
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