The Expert Committee recommended the inclusion of meropenem and of
amoxicillin + clavulanic acid on the complementary list of the EML and EMLc
for the new indication of use in the treatment of MDR-TB. The Committee
recommended that imipenem could be considered as an alternative to meropenem
for use in adults, and that the EML should note this accordingly.
The Committee noted the limited clinical evidence base, and the
very low certainty in the estimates of effect associated with the carbapenems
in MDR‑TB treatment regimens. However, the Committee accepted the public
health need for effective treatments for MDR-TB and considered that the
updated WHO guideline recommendations would be supported by the inclusion
of these medicines on the EML.
The Committee expressed some concern in relation to increased use
of carbapenem antibiotics in the empiric treatment of MDR-TB and the
development of carbapenem resistance, and recommended that ongoing
monitoring for the development of resistance be undertaken.
The application requested listing on the complementary list for the new indication
of treatment of multidrug-resistant tuberculosis (MDR-TB) of:
– amoxicillin + clavulanic acid (EML and EMLc)
– imipenem + cilastatin; (EML only) and
– meropenem (EML and EMLc)
These medicines have not been previously considered for use in MDR-TB.
Amoxicillin + clavulanic acid and meropenem are currently included in the
EML and EMLc for use as first- and second-choice treatment of specified
infectious syndromes. Imipenem + cilastatin is noted as an acceptable alternative
to meropenem for most clinical situations. Amoxicillin + clavulanic acid is
classified as an AWaRe Access group antibiotic, while meropenem (and other
carbapenems) are categorized as AWaRe Watch group antibiotics.
Public health relevance
It is estimated that 558 000 new MDR-/RR-TB cases emerged in the world in
2017 and 230 000 patients died of this form of tuberculosis (1). Between 25 000
and 32 000 children are estimated to develop MDR-TB each year (2). Many of
these cases go undetected and are not placed on appropriate treatment, increasing
the risk of transmission of drug-resistant strains and death. In 2017, countries
reported that about 139 000 people started MDR-TB treatment worldwide. The
effectiveness of these efforts varies considerably, and data reported for treatment
outcomes in recent years show that only about half the MDR-/RR-TB patients
complete their treatment successfully. Among patients with XDR-TB the
likelihood of successful outcomes is even lower. Patients who are not cured –
often because their treatment fails or is interrupted – risk persistent disease or
death. Given these low levels of treatment success, all efforts must be made to
ensure that effective medications to treat drug-resistant TB become more widely
available to the patients who need them, particularly in low-resource settings
that carry the largest burden of MDR-/RR-TB (1).
The most recent data analysis conducted for the 2018 WHO MDR-TB
treatment guidelines revision attests to the effectiveness of the carbapenems
– imipenem + cilastatin and meropenem – in patients for whom other agents
cannot be used to compose an adequate regimen, such as those with strains
resistant to fluoroquinolones or who develop drug intolerance (3).
A typical longer MDR-TB regimen starts with a combination of at least four TB
medicines considered to be effective, primarily from Groups A and B (Table 1, page 104, TRS 1021).
The three proposed medications have a particular role in the composition of
longer treatment regimens for patients with MDR-/RR-TB, particularly those
who have additional resistance or intolerance to one or more of the agents
in Groups A and B. In such cases, the regimen is strengthened by Group C
agents. Both carbapenems in this application belong to Group C and must
be administered with clavulanic acid, which is only available in formulations
combined with amoxicillin. Amoxicillin + clavulanic acid is not considered
an additional effective TB agent, and should not be used without imipenem +
cilastatin or meropenem.
Mycobacterium tuberculosis (MTB) is resistant to most beta-lactam antibiotics
because it contains the gene blaC, which encodes an extended spectrum betalactamase
(4). BlaC beta-lactamase is only transiently inhibited by most betalactamase
inhibitors (i.e. sulbactam and tazobactam) except for clavulanic acid,
which irreversibly inhibits it (4, 5). The use of amoxicillin + clavulanic acid against
MTB has had mixed results. Of note, clavulanic acid is not available commercially
without amoxicillin. An early bactericidal activity (EBA) study from South Africa
showed no benefit of amoxicillin + clavulanic acid over the control (6). A study
from Pakistan examining the minimum inhibitory concentration (MIC) of drugresistant
clinical isolates of MTB found that 98% of the isolates were resistant to
amoxicillin + clavulanic acid (7). Another EBA study showed that over 7 days,
amoxicillin + clavulanic acid reduced the sputum colony-forming units (CFU) by
an average of 0.1 log10 cfu/mL per day (in comparison, isoniazid reduced CFU
by 0.27 log10 cfu/mL per day) (8). However, the mild efficacy of amoxicillin +
clavulanic acid may not be shared by all the beta-lactam antibiotics. Meropenem is
hydrolyzed five times slower than amoxicillin + clavulanic acid by blaC (4, 5) and
there have been several studies evaluating its activity (combined with clavulanic
acid) against MTB (9). In vitro studies have shown that the combination of
clavulanic acid improves the MIC of meropenem from 8 to 1 μg/mL (10), that
this combination sterilizes aerobic and anaerobic MTB cultures and was active
against drug susceptible and XDR-TB strains (5). Results have been mixed with
respect to the effect of meropenem + clavulanic acid on mouse mortality and
on MTB CFUs in the lung and spleen (10–13). The combination of imipenem +
cilastatin with clavulanic acid also has activity against MTB, although in some
studies meropenem + clavulanic acid seems to be superior (5).
Human data are sparse (case-control studies, case reports) (11, 14), but
meropenem with clavulanic acid as part of regimens (usually also containing
linezolid) for patients with MDR-TB and XDR-TB has shown improved culture
conversion and survival (15–17).
The updated WHO guidelines reported the relative and absolute
effects for treatment failure or relapse and death (versus treatment success) for
medicines used in longer regimens from the main IPD-MA dataset of 13 104
records from 53 studies in 40 countries (3, 18).
For imipenem + cilastatin or meropenem, the adjusted odds ratio for
treatment failure/relapse versus treatment success was 0.4 (95%CI 0.2 to 0.7)
(n=206). In absolute terms, 11 fewer (95%CI 19 to 3 fewer) treatment failures/
relapses per 100 patients treated (very low certainty evidence). For death versus
treatment success the adjusted OR was 0.2 (95%CI 0.1 to 0.5) (n=204). In
absolute terms, 18 fewer (95%CI 27 to 8 fewer) deaths per 100 patients treated
(very low certainty evidence).
Evidence for the safety of these medicines has been considered previously. The
common and uncommon adverse effects associated with these medicines are
Cost / cost effectiveness
Reported costs from the Global Drug Facility product catalogue (19) are:
Imipenem + cilastatin 500 mg + 500 mg powder for injection: US$ 31–36/10 vials
Meropenem 1 g powder for injection: US$ 3.70/vial
Amoxicillin + clavulanic acid 500 mg + 125 mg tablets: US$ 10.21–13.28/
Amoxicillin + clavulanic acid 125 mg/31.25 mg oral suspension: US$ 1.21/bottle
The 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment
(3) include the following recommendations regarding longer treatment regimens
■ In MDR-/RR-TB patients on longer regimens, all three Group A
agents and at least one Group B agent should be included to ensure
that treatment starts with at least four TB agents likely to be effective,
and that at least three agents are included for the rest of treatment
after bedaquiline is stopped. If only one or two Group A agents are
used, both Group B agents are to be included. If the regimen cannot
be composed with agents from Groups A and B alone, Group C
agents are added to complete it (conditional recommendation, very
low certainty in the estimates of effect).
■ Imipenem + cilastatin or meropenem may be included in the
treatment of MDR-/RR-TB patients on longer regimens (conditional
recommendation, very low certainty in the estimates of effect).
The proposed medicines are widely available globally and already included for
other indications on the EML and EMLc.
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9789241550529-eng.pdf, accessed 26 September 2019.
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