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Reminiscences from Indian Pediatrics: A
Tale of 50 Years |
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Indian Pediatr 2020;57: 359-360 |
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Ethambutol: The Turtle of the Fifty Year
Race!
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Rakesh Lodha1 and Nidhi Bedi2*
1Department of Pediatrics, All India Institute of
Medical Sciences, Delhi; and 2Department of
Pediatrics, Hamdard Institute of Medical Sciences and Research,
Delhi.
Email:
[email protected]
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As we come closer to achieve the Sustainable development goal
of ending tuberculosis (TB) by 2030 [1], it is time to relook on
the journey of one of the earliest discovered and effective
anti-tubercular drug with a low potential for resistance –
Ethambutol. This bacteriostatic drug was discovered in 1961 at
the time when the then triple therapy (isoniazid, streptomycin,
para-amino salicylic acid) was starting to get overpowered by
resistant organisms, rising incidence of TB, and multiple
side-effects [2,3].
PAST
Almost
fifty years back, Patwardhan, et al. [2] concluded that
ethambutol-isoniazid (INH) combination was effective in
treatment of primary childhood TB [2]. This conclusion was based
their study on 60 children, 6 months to 5 years age, diagnosed
with primary tuberculosis. The study compared three regimens:
INH alone; streptomycin-INH combination; and ethambutol-INH
combination. INH was dosed at 15-20 mg/kg in two divided doses
whereas ethambutol was started at 25mg/kg, later reduced to 15
mg/kg as symptoms improved. Both the drugs were given for a
period of one year. Streptomycin was given at 40-50 mg/kg
intramuscular daily for 6 weeks followed by alternate day for
next 6 weeks. Children were then followed upto 2 years.
Significant clinical improvement was noted in all three groups,
maximum being in streptomycin-INH group. Radiological clearing
was earliest in the ethambutol-INH group. Recurrence was noted
more often in children receiving INH alone or those receiving
ethambutol-INH when the dose of ethambutol was decreased to 15
mg/kg. At that time INH alone was widely used and resistance
rates had started rising; rates were reported to be 16% in
primary cases and almost 49% in previously treated cases [2].
Streptomycin resistance was also high – varying from 14% in
primary cases to 46% in secondary cases.
On the other
hand, ethambutol was a less used, newer drug showing comparable
efficacy, ease of oral administration and low rates of
resistance. In the same year, another study in the journal by
Mankodi, et al. [3] concluded that ethambutol is an effective
bacterio-static drug to be used as an adjuvant to INH in
children who were poor responders or had failed triple drug
standard therapy. The study included 16 children diagnosed with
TB but unresponsive to streptomycin, INH or para-amino salicylic
acid (PAS). These children were treated with ethambutol-INH
combination for 8-18 months. Ethambutol was given as 25 mg/kg
daily for 3 months and then 15 mg/kg daily for rest of the
therapy duration along with INH at 20 mg/kg daily. Almost 80% of
the cases (13/16) showed good response. Most children showed
clinical improvement in first six months. Adverse effects, noted
to be disc edema and thyroid enlargement, were minimal and
reversible.
PRESENT
Fifty years
later, ethambutol continues to be one of the standard drugs in
TB management, now given in combination with INH, rifampicin and
pyrazinamide. With the latest guidelines, the drug is now part
of both intensive phase and continuation phase of treatment
[4,5] . The most significant side effects that need clinical
monitoring are optic neuritis and altered color vision.
Pre-treatment check and immediate cessation of drug at onset of
symptoms remains the key. Ethambutol has a clear dose-related
efficacy and toxicity as a result of which appropriate dosing
has always been a topic for research. In the last fifty years,
many more studies were conducted. In a major study from India
published in 1991, Seth, et al. [6] studied the visual evoked
responses (VER) of children between 3-13 years who were treated
with ethambutol at 20 mg/kg given for tuberculosis. They could
not find any greater risk of ethambutol induced optic damage as
compared to adults. In another review by Graham, et al.[7] in
1998, more than fifteen studies were analyzed for ethambutol
toxicity in children. They once again concluded that the risk
associated with ethambutol is minimal if given in appropriate
doses. Serum concentrations of ethambutol in children have been
reported to be lesser than adults when given at the same dose
[7,8]. Finally, World Health Organization in 2006 [9] reviewed
all the published literature on dosage, toxicity and
pharmacokinetics in which they found that ethambutol in
combination with INH shows better response when given at 25
mg/kg as compared to 15 mg/kg suggesting a dose-related efficacy
[10]. They also found that ocular toxicity was again
dose-related and occurred mostly above 50 mg/kg in adults. The
pharmacokinetics of the drug showed that the peak serum
ethambutol levels in children at the same dose were lesser than
adults making them less susceptible to side-effects. Considering
all the above facts, they standardized the daily dose of
ethambutol in children to 20 mg/kg (range 15-25 mg/kg). Another
Indian study published in 2016 [11] suggested that the two hour
serum levels of ethambutol were low in more than 50% of the
study population at a mean dose of 21.7 mg/kg further putting in
doubt if a still higher dose is actually needed.
The drug
is also valued for the protection it offers to other companion
drugs against development of drug resistance. In the first
national anti TB drug resistance survey in 2016 [12], primary
and secondary TB cases showed highest resistance to INH and
lowest to ethambutol (primary cases: INH-11.1%,
pyrazinamide-6.9%, streptomycin-6.9%, ethambutol-2.3%; secondary
cases: INH-25.1%, pyrazinamide-8.8%, streptomycin-13.3%,
ethambutol-7.0%). In the same survey, resistance to ethambutol
in MDR-TB was 46.98%. As per the RNTCP updated pediatric
guidelines for drug resistant TB, the drug continues to be used
in intensive and continuation phase of mono/poly - drug
resistant TB, shorter MDR-TB regime and MDR/RR TB without
additional resistance to fluroquinolones and/or second line
injectable drugs [5]. For the conventional long MDR TB regime,
it is now placed in category C; used as an add-on drug. With the
latest WHO 2019 update on drug resistant TB, the drug continues
to be part of complete therapy for INH resistant TB and as one
of the add on drugs for MDR TB[13].
CONCLUSION
As we move from Revised National Tuberculosis
Control Program (RNTCP) to National Tuberculosis
Elimi-nation Program (NTEP), ethambutol has come a long way. To
start as drug of choice in cases resistant to then TB drugs few
decades back, it still continues to be one of the drugs in
MDR-TB besides being an essential drug for complete regimen in
non-resistant cases.
REFERENCES
1. World Health Organisation. The End TB Strategy. Available at
https://www.who.int/tb/End_TB_brochure. pdf. Accessed on
February 20, 2020.
2. Patwardhan P, Bhatia M, Merchant
SM. Ethambutol in primary childhood tuberculosis. Indian
Pediatr. 1970;7: 194-201.
3. Mankodi NA et al. Ethambutol
in unresponsive childhood tuberculosis. Indian Pediatr.
1970;7:202–11.
4. Khurana AK, Dhingra B. What is new in
management of pediatric tuberculosis? Indian
Pediatr. 2019;56:213-20.
5. Revised National Tuberculosis
Control Program and Indian Academy of Pediatrics. RNTCP Updated
Pediatric TB guidelines. New Delhi: RNTCP and IAP;2019.
6. Seth V, Khosla PK, Semwal OP, D’Monty V.Visual evoked
responses in tuberculous children on ethambutol treatment.
Indian Pediatr.1991;28:713-7.
7. SM Grahama, HM Daleya, A
Banerjee, FM Salaniponi, AD Harries. Ethambutol in tuberculosis:
Time to reconsider? Arch Dis Child. 1998; 79:274-8.
8.
Zhu M, Burman WJ, Starke JR, Stambaugh JJ, Steiner P, Bulpitt
AE. Pharmacokinetics of ethambutol in children and adults with
tuberculosis. Int J Tuberc Lung Dis.2004; 8:1360-7.
9.
World Health Organisation. Ethambutol efficacy and toxicity:
literature review and recommendations for daily and intermittent
dosage in children. Geneva: WHO;2006.
10. Ferebee SH,
Doster BE, Murray FJ. Ethambutol: A substitute
for para-aminosalicylic acid in regimens for pulmonary
tuberculosis. Ann New York Acad Sci. 1966; 135:910-20.
11. Mukherjee A, Velpandian T, Singla M, Kanhiya K, Kabra
SK, Lodha R.Pharmacokinetics of isoniazid, rifampicin,
pyrazinamide and ethambutol in Indian children. BMC Infect Dis.
2015;15:126.
12. Ministry of Health and Family Welfare,
Government of India. Report of the first national
anti-tuberculosis drug resistance survey: India: MOHFW-GoI;
2014-16.
13. World Health Organisation. WHO consolidated
guidelines on drug-resistant tuberculosis treatment. Geneva:
WHO;2019.
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