Download Table 3: Detailed Pediatric DR-TB Drug Information

Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines
SDC 4
Table 3: Detailed Pediatric DR-TB Drug Information
Drug Name
Pharmacology and
Killing Kinetics
Pediatric Dose*
Pharmacokinetic
Information
Common Adverse
Drug Reactions
Special
Considerations
- Inhibits mycolic acid
synthesis resulting in
disruption of the
bacterial cell wall
10-15 mg/kg once daily;
maximum dose: 300 mg/day
- Dose adjustment required in
renal failure
- Best absorbed on an empty
stomach; absorption
decreased by 50% with fatty
meal
-Hepatoxocity:
Baseline liver function
tests (LFT’s) and then
at least monthly during
therapy in those with
pre-existing liver
disease, or history of
prior hepatitis from the
same drug.
- Peripheral
neuropathy
- Hypersensitivity
- Gastrointestinal (GI)
intolerance
- Pyridoxine
(2mg/kg/day)
supplementation is not
routinely required unless
HIV infected,
nutritionally deficient, or
breastfeeding infants
whose mothers are
receiving INH.
- If paresthesias while
taking INH: increase
pyridoxine
- Orange staining of
body fluids
- Hepatotoxicity:
Baseline LFT’s and
repeat in
circumstances similar
to INH
- Hematologic
abnormalities
(thrombocytopenia,
hemolytic anemia):
Baseline CBC
- Anterior uveitis and
other eye toxicities:
Baseline visual testing
if possible.
- Rash and pruritus
- GI-intolerance
- RMP is by definition
not used in MDR/XDR
TB
- Dose related
retrobulbar neuritis and
exacerbated during renal
failure
- Use with caution in
children < 7 years old
since optic toxicity
cannot readily be
assessed
GROUP 1
Isoniazid (INH)
[1-6]
- Bactericidal against
actively dividing
bacilli
In patients with low level
resistance to INH the
recommended dose is 15-20
mg/kg/day
- Monitor for drug
interactions
- Bacteriostatic against
non-replicating bacilli
Rifampin (RMP),
Rifabutin (RFB)
[1-4, 6, 7]
- Inhibits bacterial
RNA synthesis by
binding to the beta
subunit of DNAdependent RNA
polymerase, blocking
RNA transcription
- Bactericidal and
sterilizing agent
Ethambutol (EMB)
[1-4, 6, 8]
- Suppresses
mycobacterial
multiplication by
interfering with RNA
synthesis
10-20 mg/kg/day once daily;
maximum dose: 600 mg/day
- Dose adjustment required in
renal failure
Rifabutin – 10 mg/kg/day once
daily doses have been used;
maximum dose: 300mg/day
(higher doses have been
recommended for children < 1
year of age, however no specific
pediatric dosing exists)
- Monitor for drug
interactions, especially with
anti-retroviral therapy
15-25 mg/kg/day once daily
(Higher doses up to 25mg/kg/day
have been safely used for MDR
TB); maximum dose: 2.5g/day
- Dose adjustment required in
renal failure
- Retrobulbar neuritis:
Baseline visual acuity
and color
discrimination testing
and then every month
(if possible)
30-40 mg/kg/day in single daily
dose; maximum dose: 2g/day
- Dose adjustment required in
renal failure
-Hepatotoxicity:
Baseline LFT’s and
repeat similar to INH
- Gout and arthralgias
– check uric acid level
if patient develops
arthralgias; reduce
dose, but do not give
allupurinol, as this
may cause severe
adverse effects.
- GI intolerance
- Rash
- Photosensitivity
- Bacteriostatic at low
concentrations
Pyrazinamide (PZA)
[1-4, 6, 8, 9]
- Converted to
pyrazinoic acid in
susceptible strains of
Mycobacterium which
lowers the pH of the
environment
- Bactericidal for semidormant M.
tuberculosis (active in
acidic environment)
- Dose adjustment of
anti-retroviral
medications may be
required in patients
infected with HIV
- Cross-resistance among
the rifamycin class of
drugs is typical.
GROUP 2
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SDC 4
Aminoglycosides
(Amikacin (AK),
Kanamycin (KM),
Streptomycin (SM))
[1, 4, 10, 11]
- Interferes with
protein synthesis in
bacterial cell by
binding to ribosomal
subunit
Amikacin and Kanamycin I.M.,
I.V. –
Infants and Children: 15–30
mg/kg/day once daily
- maximum dose: 1g/day
- Bactericidal against
actively dividing
extracellular bacilli
Streptomycin I.M., I.V.
Infants and Children: 20–40
mg/kg/day once daily; maximum
dose: 1g/day
- For obese patients dosing is
based on ideal body weight
(IBW) plus 40% of adipose
mass
- Dose adjustment required in
renal failure
- in children infuse I.V. dose
over 1-2hrs
- only 40–80% of the dose is
absorbed if given I.M. thus
not the preferred route
Levels:
- Target peak concentrations
for all three agents are 35 –
45 g/mL 90-120min post
infusion
- Trough concentrations are
generally < 5 g/mL in
patients with normal renal
function
Tuberactinomycins
(Capreomycin (CM),
Viomycin)
[1, 4, 10, 11]
- Capreomycin is a
cyclic polypeptide
antimicrobial. The
mechanism of action
of capreomycin is not
well understood.
- Nephrotoxicty:
Baseline serum
creatinine and blood
urea nitrogen and then
weekly; baseline
electrolytes including
magnesium and
calcium and then
every month
- Ototoxicity:
Baseline audiometric
testing and then every
month for prolonged
therapy
- Vestibular toxicity
- SM should be
used only in XDR-TB
with resistance to other
aminoglycosides and
polypeptides and
confirmed in vitro
susceptibility to SM
Capreomycin I.M., I.V.
15 mg/kg/day once daily;
maximum dose: 1g/day
- For obese patients dosing is
based on IBW plus 40% of
adipose mass
- Dose adjustment required in
renal failure
-Regarding “Levels”: same
approach as for
aminoglycosides above
- Similar to
Aminoglycosides
- LFT abnormalities
when used with other
TB medications
- Significant crossresistance with
viomycin, kanamycin
occurs
Moxifloxacin I.V., P.O. –
5mg/kg/dose IV every 24 hours
maximum dose: 400 mg/day
- Dose adjustment required in
renal failure except for MFX
- Rare: tendon rupture,
arthralgias
- Baseline ECG to
assess QTc interval
(for MFX only)
- Nausea and bloating
- Headache
- The long-term (more
than several weeks) use
of FQ’s in children and
adolescents has not been
approved because of
concerns about effects
on bone and cartilage
growth.
- Capreomycin Bactericidal against
non replicating
bacteria
- Viomycin Bactericidal against
actively dividing
extracellular bacilli
GROUP 3
Fluoroquinolones
(FQ)
(Moxifloxacin
(MFX), Levofloxacin
(LFX),
Ciprofloxacin
(CFX),
Ofloxacin (OFX))
[1-3, 12]
- Inhibits DNA-gyrase
and topoisomerase IV
in susceptible
organisms; inhibits
relaxation of
supercoiled DNA and
promotes breakage of
double-stranded DNA
- Bactericidal
Levofloxacin I.V., P.O. –
Children 6 months to 5 years: 10
mg/kg/dose every 12 hours
Children ≥5 years: 10
mg/kg/dose every 24 hours;
maximum dose: 750 mg/day
Ciprofloxacin I.V., P.O. –
Children: 20-40 mg/kg/day
divided every 12hours; P.O.
maximum dose: 2g/day and I.V.
maximum dose: 800 mg/day
Ofloxacin P.O. –
Children: 15-20
mg/kg/daydivided every 12
hours; maximum dose:
800mg/day
- FQ dosing is not TB
specific, i.e. data is
extrapolated from either
other indications or
clinical experience
- Moxifloxacin and
Levofloxcin have better
in vitro activity for MTB
than Ciprofloxacin.
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GROUP 4
Thioamides
(Ethionamide
(ETO),
Protionamide
(PTO))
[1, 3, 4]
Serine analogs
(Cycloserine (CS),
Terizidone (TZ))
[1, 4, 10]
- Inhibits peptide
synthesis in
susceptible organisms
Ethionamide 15-20mg/kg/day
divided every 12 hours;
maximum dose: 1g/day
- Bactericidal
- Inhibits bacterial cell
wall synthesis by
competing with amino
acid (D-alanine) for
incorporation into the
bacterial cell wall
- Bacteriostatic
Cycloserine
Children: 10-20 mg/kg/day in 2
divided doses or as single dose;
maximum dose: 1g/day
Terizidone is a double molecule
of cycolserine; given at the same
doses as cycloserine.
- Dose adjustment required in
renal failure
- Target peak serum levels
20-35g/mL; draw levels
2hrs post dose once a week
until at target is reached
- A second serum level 6-8
hours following dose may be
useful to calculate the
patient’s specific half-life
- Best absorbed on an empty
stomach
P-aminosalicylic
acid (PAS)
[1, 4]
- Is structurally related
to para-aminobenzoic
acid (PABA) and its
mechanism of action is
thought to be similar to
the sulfonamides, a
competitive
antagonism with
PABA; disrupts plate
biosynthesis in
sensitive organisms.
- GI intolerance and
anorexia, metallic
taste.
- Hepatotoxicity:
Baseline LFT’s, and
repeat similar to INH
- Endocrine effects:
Gynecomastia, hair
loss, acne, impotence,
menstrual irregularity,
and reversible
hypothyroidism (treat
with thyroid
replacement)
- Many individuals
require gradual
ramping up of the dose
and treatment in order
to monitor for drug
toxicity or intolerance
-Pyridoxine
supplementation
required
- CNS toxicity:
Inabilty to concentrate,
lethargy, seizures,
depression
psychosis, suicidal
ideations
- Peripheral
neuropathy
- Many individuals
require gradual
ramping up of the dose
and treatment in order
to monitor for drug
toxicity or intolerance
- Pyridoxine
supplementation
required (25mg of
pyridoxine per 250 mg
of cycloserine or
terizidone)
- Avoid in patients with
epilepsy or mental
illness
-Increased risk of
neurotoxicity if
concomitant use of INH,
ethionamide or
fluoroquinolones
- Avoid if a patient is
allergic to aspirin
- Increased risk of
hypothyroidism when
combined with
ethionamide
Tablets: 200-300 mg/kg/day in 24 divided doses.
Granules: 150mg/kg/day in 2
divided doses.
Maximum dose for both:
10gm/day.
- Delayed peak concentration
with the granule formulation
due to its enteric coating and
sustained release
- Reversible
Hypothyroidism:
Baseline TSH and then
every month
- Hepatotoxicity:
Baseline LFT’s and
then every month
- Coagulopathy:
Baseline CBC and
then every month
- GI intolerance
- Many individuals
require gradual
ramping up of the dose
and treatment in order
to monitor for drug
toxicity or intolerance
Safety and effectiveness in
pediatric patients have not been
established. Cases of pediatric
patients treated with clofazimine
1mg/kg/day have been reported
in the literature.
- Tissue half-life estimated to
be around 70 days.
- Discoloration of
skin, conjunctiva,
cornea, and body
fluids (skin changes
can be irreversible)
- GI intolerance
including bowel
obstruction and
- Bacteriostatic
- Risk of hypothyroidism
increases when
ethionamide and PAS
are taken together
- Cross-resistance to
INH may occur when
there is low level
resistance to Eto
GROUP 5 **
Clofazimine (CFZ)
[1]
- Inhibits
mycobacterial growth
and binds
preferentially to
mycobacterial DNA.
- Bacteriostatic
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SDC 4
bleeding
- Photosensitivity
- Pruritits
Amoxicllin/
Clavulinic Acid
(AMX/CLV)
[1, 2]
- Clavulanic acid binds
and inhibits betalactamases that
inactivate amoxicillin
resulting in amoxicillin
having an expanded
spectrum of activity;
amoxicillin interferes
with bacterial cell wall
synthesis by binding to
one or more of the
penicillin-binding
proteins and causing
cell wall death
Infants <3 months: 30 mg/kg/day
divided every 8-12 hours of the
amoxicillin component.
- Dose adjustment required in
renal failure
- Diarrhea, abdominal
discomfort, nausea,
and vomiting are most
common.
- Hypersensitivity
reactions
- Dose adjustment required in
renal failure
- Diarrhea, nausea, or
vomiting
- Seizure probability
imipenem >
meropenem in children
- Monitor for drug
interactions
(potential for drug
interactions azithromycin
<clarithromycin)
- Hepatotoxicty:
Baseline LFT’s and
then every month
- Baseline ECG to
assess QTc interval
- GI intolerance
Children: 80 mg/kg/day divided
every 12 hours of the amoxicillin
component.
To avoid large doses of
clavulanate and to
prevent GI intolerance,
amoxicillin/clavulanate
and additional
amoxicillin can be
prescribed to achieve the
same total daily dose of
amoxicillin
- Weakly bactericidal
Imipenem/
Cilastatin
[1, 2]
- Cilastatin prevents
renal metabolism of
impenem by
competitive inhibition
of dehydropeptidase;
imipenem interferes
with bacterial cell wall
synthesis by binding to
one or more of the
penicillin-binding
proteins and causing
cell wall death
I.V. –
Infants < 3 months: 100
mg/kg/day divided every 6 hours
Infants ≥3 months and Children:
60-100 mg/kg/day divided every
6 hours; maximum dose: 4 g/day
Meropenem preferred in children
when CNS infections suspected:
60-120mg/kg/day divided every
8 hours; maximum dose 2g/dose
- Bactericidal
Clarithromycin
(CLR),
Azithromycin
(AZM)
[1, 2]
- Inhibits bacterial
RNA-dependent
protein synthesis by
binding to the 50S
ribosomal subunit
- Bacteriostatic
Linezolid (LZD)
[1, 2, 13]
- Inhibits initiation of
protein synthesis by
binding to a site on the
bacterial 23S
ribosomal RNA of the
50S subunit preventing
the formation of a
functional 70S
initiation complex
which is an essential
component of the
bacterial translation
process
Clarithromycin P.O. –
Children: 15 mg/kg/day divided
every 12 hours; maximum dose:
1 g/day
Azithromycin I.V., P.O. –
Children: 5-10mg/kg/day once
daily; maximum dose:
500mg/day
P.O., I.V. –
10 mg/kg/dose every 8 hours
Maximum dose 600mg/dose
- Myelosuppression:
Baseline CBC and
then every month
- Peripheral
neuropathy
- Optic neuropathy:
Baseline visual
function in patients
requiring > 3months of
therapy or in patients
reporting new visual
symptoms.
- In vitro bactericidal
activity
*Refer to guidelines for duration of selected combination therapy.
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Al-Dabbagh et al., Pediatric Drug-Resistant TB Guidelines
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**The optimal dose specific to MDR TB is not known for these agents; thus dosing has
been adapted from other indications in other areas of pediatrics to provide guidance.
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