The Expert Committee did not recommend the addition of injectable
formulations of ethambutol, isoniazid, PAS and rifampicin to the EML and
EMLc for treatment of drug-susceptible TB in combination with other firstline
The Committee noted that WHO guidelines recommend use of oral,
preferably fixed-dose combination therapy for TB, but acknowledged that
parenteral administration of TB medicines may be useful in a small number
of critically unwell patients unable to tolerate oral therapy or patients with TB
meningitis. The Committee considered that the inclusion of these parenteral
TB formulations on the EML could result in inappropriate use of parenteral
therapy in patients otherwise able to take oral therapy.
The Committee also noted that the global market availability of these
products was limited, and the comparative cost unknown.
Four separate applications requested addition of injectable formulations of
ethambutol, isoniazid, p-aminosalicylic acid (PAS) and rifampicin to the EML
and EMLc for treatment of drug-susceptible tuberculosis in combination with
other first-line medicines.
Ethambutol, isoniazid, PAS and rifampicin are all currently included on the EML
and EMLc in oral dose forms.
Public health relevance
Worldwide, tuberculosis is one of the top 10 causes of death, and the leading cause
from a single infectious agent. In 2017, TB caused an estimated 1.3 million deaths
among HIV-negative people, and there were an additional 300 000 deaths from
the disease among HIV-positive people. There were an estimated 10.0 million
new cases of TB, equivalent to 133 cases per 100 000 population (1).
The IV formulations are proposed in the applications for use in cases of
severe forms of disease, such as central nervous system (CNS) TB or TB sepsis,
patients with gastrointestinal diseases and reduced oral absorption rates, and
other patient groups unwilling or unable to take oral dose forms.
There is evidence that there is a decrease in the functional absorptive
area of the intestine in TB patients, resulting in reduced serum concentrations
of orally administered antituberculosis drugs. Patients with malabsorption
syndromes can require higher doses to achieve minimum therapeutic levels
(2, 3). Malabsorption of anti-mycobacterial drugs has been reported HIVcoinfected
patients (4, 5).
A retrospective cohort study in Brazil found that among TB patients
admitted to intensive care units (ICU), over 90% have acute respiratory failure
(ARF) and require mechanical ventilation. The in-hospital mortality rate for
ICU-admitted patients was around 65% (6).
CNS TB has been reported to account for 5–10% of extrapulmonary
TB cases and approximately 1% of all TB cases (7). It is associated with high
morbidity and mortality (8).
No information was provided in the applications regarding the
proportion of total TB cases that would require IV treatment.
The clinical benefits and place in therapy of these medicines (per se) are well
established and have been evaluated previously by the Expert Committee.
Limited pharmacokinetic data were presented in the applications
indicating higher achievable concentrations with IV versus oral formulations,
which is to be expected from IV administration where 100% bioavailability
The adverse events (AE) associated with the medicines, rather than of the
proposed IV formulations, were described in the applications. The safety profiles
of these medicines are well established and have been evaluated previously by
the Expert Committee. It is reasonable to assume that the known safety profiles
would be applicable to the IV formulations.
An RCT investigating the efficacy and safety of IV chemotherapy during the
intensive treatment phase in patients newly diagnosed with pulmonary TB was
identified during the review process (9). 92 patients were randomized to receive
oral treatment with isoniazid, rifampicin, pyrazinamide and ethambutol or
IV isoniazid, IV rifampicin, IV ethambutol and oral pyrazinamide. Alleviation
of chest symptoms (cough, dyspnoea, chest pain) and intoxication symptoms
(weakness, loss of appetite, fatigue, night sweats, increased body temperature)
was more rapid in the IV therapy group. No serious adverse events associated
with IV therapy were observed.
Cost / cost effectiveness
Due to the limited availability of the proposed IV formulations on world markets,
no information on the comparative cost and cost-effectiveness of these products
are available. The applications suggest that the IV formulations will be more
expensive than the currently available oral formulations.
WHO guidelines recommend ethambutol, isoniazid, rifampicin and PAS in
treatment regimens for drug-susceptible TB and MDR-TB/RR-TB (10, 11).
The guidelines recommend the use of oral, preferably fixed-dose
combination therapy for TB treatment.
In the WHO Target regimen profiles for TB treatment, it is recommended
that IV formulations be reserved for cases of severe forms of disease such as CNS
TB or TB sepsis (12).
The proposed formulations have limited market approval and global availability:
IV ethambutol: Germany, Kazakhstan, Switzerland, Tajikistan, Ukraine and
IV isoniazid: Italy, Kazakhstan, Ukraine, United Kingdom, United States and
IV PAS: Belarus, Germany and Ukraine.
IV rifampicin: United States.
Comments on the applications were received from the WHO Global TB
Programme. The technical unit advised that it did not support inclusion of the
proposed IV formulations of tuberculosis (TB) medicines emphasizing the
– WHO recommends oral treatment regimens, ideally administered
in fixed-dose combinations (where such formulations exist) for
the treatment of drug-sensitive TB.
– WHO has recently updated treatment guidelines for MDR-TB
and RR-TB, recommending that injectable agents are no longer
among the priority medicines when designing longer MDR-TB
– In view of these WHO policy recommendations, in the large
majority of TB patients, IV administration for first- or second-line
medicines is not indicated.
– For the majority of indications listed in the applications for IV
formulations, patients can be treated with oral formulations, if
necessary, using alternative forms of oral administration.
– For adult patients with drug-sensitive TB, a four-drug regimen is
recommended; therefore, with only three of the four medicines
available as intravenous formulations, patients would still be
required to take pyrazinamide orally.
1. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Available from
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2. Kuzhko MM, Butov DO, Hulchuk NM, Avramchuk OV, Protsyk LM, Kuzhko ZF. Clinical case of using
intravenous forms of anti-tuberculosis drugs to improve the treatment efficiency of tuberculosis
in patients with malabsorption syndrome. J Pulm Respir Med. 2015;5(269).
3. Frame RN, Johnson MC, Eichenhorn MS, Bower GC, Popovich J, Jr. Active tuberculosis in the
medical intensive care unit: a 15-year retrospective analysis. Crit Care Med. 1987;15(11):1012–4.
4. Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, et al. Low
antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996;30(9):
5. Gordon SM, Horsburgh CR, Jr., Peloquin CA, Havlik JA, Jr., Metchock B, Heifets L, et al. Low serum
levels of oral antimycobacterial agents in patients with disseminated Mycobacterium avium
complex disease. J Infect Dis. 1993;168(6):1559–62.
6. Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with
tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54.
7. Cherian A, Thomas SV. Central nervous system tuberculosis. Afr Health Sci. 2011;11(1):116–27.
8. Efsen AM, Panteleev AM, Grint D, Podlekareva DN, Vassilenko A, Rakhmanova A, et al. TB
meningitis in HIV-positive patients in Europe and Argentina: clinical outcome and factors
associated with mortality. 2013;2013:373601.
9. Butov D, Feshchenko Y, Kuzhko M, Gumeniuk M, Butova T. Efficacy and safety of intravenous
chemotherapy during intensive treatment phase in patients with newly diagnosed pulmonary
tuberculosis. Adv Respir Med. 2018; 86(4):159-167.
10. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update.
Geneva: World Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/ha
ndle/10665/255052/9789241550000-eng.pdf, accessed 30 October 2019.
11. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health
Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/10665/311389/
9789241550529-eng.pdf, accessed 30 October 2019.
12. World Health Organization. Target regimen profiles for TB treatment: candidates: rifampicinsusceptible,
rifampici-resistant and pan-TB treatment regimens. 2016. Geneva, World
Health Organization. Available from https://apps.who.int/iris/bitstream/handle/10665/250044/
9789241511339-eng.pdf, accessed 30 October 2019.