Extensively drug-resistant tuberculosis (XDR-TB) is caused by Mycobacterium tuberculosis strains with resistance to at least isoniazid (H), rifampicin (R), a fluoroquinolone, and a second-line injectable drug (SLI): kanamycin (Km), amikacin (Amk) or capreomycin (Cm). Pre-XDR-TB denotes resistance to H and R, as well as to at least one FQ or one SLI.1 The WHO has estimated the worldwide incidence of MDR-TB (multidrug-resistant TB: resistant to at least H and R) to be 480,000 cases in 2013, of which 9% were XDR-TB.2 In 2013, Argentina's National Reference Laboratory (ANLIS Malbrán) identified 6 cases of XDR-TB and 18 of pre-XDR.

The WHO divides anti-TB drugs into 5 groups: (1) first-line drugs; (2) FQ (ofloxacin, levofloxacin, moxifloxacin); (3) injectables (kanamycin, amikacin, capreomycin, streptomycin); (4) oral bacteriostatic second-line drugs (cycloserine/terizidone, ethionamide/prothionamide, PAS); and (5) anti-TB drugs with limited data on efficacy: clofazimine (Cfz), linezolid (Lzd), amoxicillin/clavulanate (amoxi-clav), carbapenems (imipenem-cilastatin and meropenem) high-dose H, bedaquiline (Bdq) and delamanid (the latter two have been approved for a 6-month course in pre-XDR/XDR-TB). Drugs in groups II to IV (except streptomycin) are considered second-line therapy, while group V drugs are also known as third-line drugs.1,3

Patients with pre-XDR and XDR-TB are usually treated with regimens that include group V drugs, as they are usually resistant to most of the remaining drugs. Treatment given to these patients, therefore, is likely to be less effective. In recent years, studies have shown that meropenem combined with clavulanate (MPC) can have an antimycobacterial and synergic effect.4–6 The aim of this study is to show the efficacy, measured in terms of bacteriologic conversion of sputum, of treatment regimens that include combination meropenem-clavulanate given in the initial stage of pre-XDR and XDR-TB therapy.

This is a retrospective study of all patients confined to the drug-resistant TB respiratory isolation unit from 1/1/2012 to 12/31/2013 with a bacteriological diagnosis of pre-XDR and XDR-TB, plus 1 case of adverse reaction/drug interaction. The patients were treated with regimens that included at least 5 group 2 to 5 drugs, including MPC, for at least 6 months. In our hospital, we receive patients from Argentina and also immigrants from neighboring countries who have come in search of work. Approximately half of all TB cases diagnosed in Buenos Aires involve recent immigrants from neighboring countries.

The hospital laboratory performed susceptibility testing for H, R, etambutol (E) and streptomycin (S) using quick fluorometric and solid media proportions methods. The ANLIS Malbrán performed susceptibility testing for ofloxacin (Ofx), cycloserine (Cs), ethionamide (Eto), PAS, kanamycin, amikacin and capreomycin using the solid media proportions method; for Cfz, Ldz and moxifloxacin [Mfx] using MIC determination in liquid medium; and for pyrazinamidase (Z) using the pyrazinamidase test.

Indication for MPC was determined empirically. Therapeutic regimens were designed on the basis of previous treatment received and the results of susceptibility testing, when available. Patients gave a sputum sample for culture each month. Favorable evolution was defined as bacteriologic conversion (negative results from two consecutive monthly cultures) when first negative result occurred before month 6 of treatment.

The results were published following approval by the Independent Ethics Committee of the Instituto Vaccarezza (authorization No. 30/15) (Table 1).

Table 2 shows the drugs and doses given.

A total of 10 patients (5 women) were enrolled in the study, with an average age of 37.5 years. Five had previously received multiple treatment, and 5 had received no treatment.

Radiologically, all showed bilateral involvement with cavitation. Nine cases were diagnosed as pre-XDR or XDR-TB, and 1 received a complicated therapy regimen due to serious adverse reactions and drug interactions (a liver transplant recipient who contracted TB).

Table 2 shows the characteristics and evolution of the 10 patients receiving therapy regimens including MPC. Briefly, 8 patients showed sputum conversion by the end of the follow-up period. These patients continued with a second, 18-month phase of treatment during which only MPC was discontinued. Two patients died during follow-up, 1 due to worsening of TB due to treatment failure, and the other due to respiratory failure secondary to pulmonary destruction, despite good bacterial response. At the date of publication, not all patients have completed their treatment. By way of preliminary data, of the 8 patients that continued to the end of the initial follow-up phase (receiving MPC), 1 died due to hepatic failure not associated with TB (liver transplant recipient), treatment failed in 1 case, with bacteriological reversion after conversion to negative. Of the remaining 6 patients, 3 completed the treatment after meeting WHO “cured” outcome criteria,1 and 3 continue receiving treatment, with bacteriological conversion at the time of publication.

Drug-resistance in TB is a major therapeutic challenge. Standard MDR-TB treatment guidelines have been drawn up, consisting of 2 core drugs, 1 FQ and 1 SLI, combined with 2 oral bacteriostatic agents and pyrazinamide.1,3 In the case of pre-XDR and XDR-TB, treatment consists of the best possible combination of drugs based on susceptibility testing, history of previous treatment regimens, and drug availability. Two important new drugs, bedaquiline and/or delamanid,1 are currently not available in Argentina in the context of disease management programs.

M. tuberculosis is resistant to beta-lactam antibiotics because it produces an extended-spectrum beta-lactamase (BlaC), which is irreversibly inhibited by clavulanate. Since meropenem is more resistant to BlaC than other beta-lactams, the combination of this drug with clavulanate could be highly bactericidal for both susceptible and resistant strains, including non-replicating strains.6

In this patient series we used regimens that included MPC in the initial 6-month phase in hospitalized patients. We observed no adverse reactions associated with MPC. However, the length of time needed to administer the drug is an inconvenience, and 2 patients required implantation of a port device. Eight of our 10 study patients responded well to this initial phase of treatment with Lzd-Mfx-MPC as core drugs.

In conclusion, MPC, however inconvenient due to the route of administration, combined with other group V drugs could be effective as a first-stage treatment strategy for pre-XDR and XDR TB.