ATC codes: J01CR02
Multi-drug resistant tuberculous Mycobacterium ICD11 code: ML32.00
Amoxicillin + clavulanic acid
Complementary *For use only in combination with meropenem or imipenem + cilastatin (EML) * For use only in combination with meropenem (EMLc)
Oral > Liquid: 125 mg + 31.25 mg powder for oral liquid (EMLc) ; 250 mg + 62.5 mg powder for oral liquid (EMLc)
Oral > Solid: 500 mg (as trihydrate) + 125 mg (as potassium salt)
Oral > Solid: 500 mg (as trihydrate) + 125 mg (as potassium salt)
EML status history
Also recommended for children
The recommendation is for this specific medicine
Patents have expired in most jurisdictions
Read more about patents.
Expert Committee recommendation
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 well known.
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/ 100 tablets 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 for MDR-/RR-TB: ■ 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.
1. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf, accessed 30 October 2019. 2. Jenkins HE, Yuen CM. The burden of multidrug-resistant tuberculosis in children. Int J Tuberc Lung Dis. 2018;22(5):3–6. 3. 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 26 September 2019. 4. Hugonnet JE, Blanchard JS. Irreversible inhibition of the Mycobacterium tuberculosis betalactamase by clavulanate. Biochemistry. 2007;46(43):11998–2004. 5. Hugonnet JE, Tremblay LW, Boshoff HI, Barry CE, 3rd, Blanchard JS. Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science. 2009; 323(5918):1215–8. 6. Donald PR, Sirgel FA, Venter A, Parkin DP, Van de Wal BW, Barendse A et al. Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smearpositive pulmonary tuberculosis. Scand J Infect Dis. 2001;33(6):466–9. 7. Ahmed I, Jabeen K, Inayat R, Hasan R. Susceptibility testing of extensively drug-resistant and pre-extensively drug-resistant Mycobacterium tuberculosis against levofloxacin, linezolid, and amoxicillin-clavulanate. Antimicrob Agents Chemother. 2013;57(6):2522–5. 8. Chambers HF, Kocagoz T, Sipit T, Turner J, Hopewell PC. Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis. 1998;26(4):874–7. 9. Gonzalo X, Drobniewski F. Is there a place for beta-lactams in the treatment of multidrugresistant/ extensively drug-resistant tuberculosis? Synergy between meropenem and amoxicillin/ clavulanate. J Antimicrob Chemother. 2013;68(2):366–9. 10. Solapure S, Dinesh N, Shandil R, Ramachandran V, Sharma S, Bhattacharjee D et al. In vitro and in vivo efficacy of beta-lactams against replicating and slowly growing/nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(6):2506–10. 11. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for treatment of tuberculosis in mice and humans. Antimicrob Agents Chemother. 2005;49(7):2816–21. 12. Veziris N, Truffot C, Mainardi JL, Jarlier V. Activity of carbapenems combined with clavulanate against murine tuberculosis. Antimicrob Agents Chemother. 2011;55(6):2597–600. 13. England K, Boshoff HI, Arora K, Weiner D, Dayao E, Schimel D, et al. Meropenem-clavulanic acid shows activity against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother. 2012;56(6):3384–7. 14. Dooley KE, Obuku EA, Durakovic N, Belitsky V, Mitnick C, Nuermberger EL. World Health Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or untapped potential? J Infect Dis. 2013;207(9):1352–8. 15. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S et al. Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/ XDR-TB. Eur Respir J. 2013;41(6):1386–92. 16. Payen MC, De Wit S, Martin C, Sergysels R, Muylle I, Van Laethem Y et al. Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2012;16(4):558–60. 17. Dauby N, Muylle I, Mouchet F, Sergysels R, Payen MC. Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis. Pediatr Infect Dis J. 2011;30(9):812–3. 18. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Annexes 3–9. Geneva: World Health Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/ 10665/311390/WHO-CDS-TB-2019.3-eng.pdf, accessed 30 October 2019. 18. Stop TB Partnership | Global Drug Facility (GDF) – GDF Product Catalogue [website]. [cited 2017 Jul 7]. (http://www.stoptb.org/gdf/drugsupply/pc2.asp?CLevel=2&CParent=4, accessed 26 September 2019).