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Vol. 51. Issue 10.
Pages e49-e52 (October 2015)
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Vol. 51. Issue 10.
Pages e49-e52 (October 2015)
Case report
DOI: 10.1016/j.arbr.2015.07.003
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First Series of Patients With XDR and Pre-XDR TB Treated With Regimens That Included Meropenen-clavulanate in Argentina
Primera serie de pacientes con TB-XDR y pre-XDR tratados con esquemas que incluyeron meropenem-clavulanato en Argentina
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Domingo Palmero
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djpalmero@intramed.net

Corresponding author.
, Pablo González Montaner, Mónica Cufré, Ana García, Marisa Vescovo, Susana Poggi
Instituto Prof. Dr. Raúl Vaccarezza, Hospital de Infecciosas Dr. F. J. Muñiz, Buenos Aires, Argentina
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Table 1. Drugs and Dosage Used in 10 Patients Receiving Treatment Regimens that Included Meropenem/Amoxicillin-clavulanate.
Table 2. Characteristics of the 10 Patients Receiving Treatment Regimens That Included Meropenem/Amoxicillin-clavulanate.
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Abstract

XDR (extensively drug-resistant) and pre-XDR tuberculosis (TB) seriously compromise prognosis and treatment possibilities, and inevitably require the use of group V drugs (World Health Organization). The progress of all patients with XDR and pre-XDR TB seen in a specialized unit during 2012 and 2013 and treated with regimens that included at least 6 months of meropenem-clavulanate (MPC), capreomycin, moxifloxacin, linezolid, clofazimine, high-dose isoniazid, PAS, and bedaquiline in 1 case, were retrospectively analyzed. Ten patients were treated, 9 with an extensive pattern of resistance to at least 6 drugs, and 1 because of adverse reactions and drug interactions leading to a similar situation. Eight of the 10 patients treated achieved bacteriological sputum conversion (2 consecutive negative monthly cultures) over a period of 2–7 months, while 2 died. No adverse reactions attributable to prolonged administration of MPC were observed.

Keywords:
Tuberculosis
XDR-TB
Carbapenems
Meropenem
Clavulanate
Resumen

La tuberculosis extensamente resistente (TB-XDR) y pre-XDR comprometen seriamente el pronóstico de la enfermedad, y su tratamiento requiere inevitablemente el uso de fármacos del grupo V (Organización Mundial de la Salud [OMS]). Se analizó retrospectivamente la evolución de todos los pacientes con TB pre-XDR y XDR asistidos en un servicio especializado durante 2012 y 2013, medicados con regímenes que incluyeron por lo menos 6 meses de meropenem-clavulanato (MPC), capreomicina, moxifloxacina, linezolid, clofazimina, isoniacida en alta dosis, PAS y en un caso bedaquilina. Fueron tratados 10 pacientes, 9 de ellos con un extenso patrón de resistencia a un mínimo de 6 fármacos y uno por reacciones adversas e interacciones medicamentosas que generaron una situación análoga. Ocho de los 10 pacientes tratados, hicieron la conversión bacteriológica del esputo (2 cultivos mensuales consecutivos negativos) en un lapso de 2 a 7 meses, en tanto que 2 fallecieron. No se observaron reacciones adversas atribuibles a la administración prolongada del MPC.

Palabras clave:
Tuberculosis
TB-XDR
Carbapenems
Meropenem
Clavulanato
Full Text
Introduction

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.

Methodology

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 1.

Drugs and Dosage Used in 10 Patients Receiving Treatment Regimens that Included Meropenem/Amoxicillin-clavulanate.

Drug  Dose and Administration  Most Common Adverse Effects 
Amikacin  15mg/kg/d, IM or IV, diluted  Oto- and nephrotoxicity, electrolyte disorders 
Amoxicillin-clavulanate  Amoxicillin 500mg-clavulanate 125mg, oral q8h. Used because clavulanate formulations were not available on the market.  Digestive, hepatic, hyper-sensitivity 
Bedaquiline  400mg/d for 2 weeks, then 200mg three times weekly for 22 weeks, oral  QTc prolongation, hepatitis, cannot be co-administered with Mfx. 
Capreomycin  15mg/kg/d, IM or IV  Oto- and nephrotoxicity, electrolyte disorders 
Clofazimine  100mg/d, oral  Skin pigmentation, abdominal colic 
Cycloserine  15mg/kg/d in 3 doses, oral  Convulsions, behavioral disorders, depression 
Etambutol  100mg/d, oral  Optic neuritis 
Ethionamide  15mg/kg/d in 3 doses, oral  Metallic taste, toxic hepatitis, hypothyroidism 
High dose isoniazid  10mg/kg/d, oral  Toxic hepatitis, polyneuritis 
Levofloxacin  700mg/d  Tendinitis, toxic hepatitis, neurotoxicity 
Linezolid  600mg/d, oral  Polyneuritis, mononeuritis, optic neuritis, bone marrow depression 
Meropenem  2g IV diluted q8h until sputum culture is negative, then 1g q8h, IV diluted  Inflammation of injection site, digestive, hypokalemia, convulsions, hepatotoxicity 
Moxifloxacin  400mg/d, oral  Tendinitis, toxic hepatitis, neurotoxicity 
PAS  15mg/kg/d in 3 doses, oral  Digestive, hypothyroidism, hepatotoxicity 
Pyrazinamide  25mg/kg/d, oral  Toxic hepatitis, hyperuricemia 

IM: intramuscular; IV: intravenous; Mfx: moxifloxacin; QTc: corrected QT interval; PAS: para-aminosalicylic acid.

Table 2 shows the drugs and doses given.

Table 2.

Characteristics of the 10 Patients Receiving Treatment Regimens That Included Meropenem/Amoxicillin-clavulanate.

Case  Age  Sex  Nationality  Previous Treatment  Category  Culture  Resistancesa  ARs to Anti-TB Drugs  Treatment  Evolution at 6 Monthsb  Comorbidities 
37  Uruguay  No  Pre-XDR (SLI)  C (−) at month 4  S, H, R, E, Z, Km, Cm, Amk  No  Amoxi-clav, MRP, Mfx, Cs, Eto, PAS, Lzd  Favorable  No 
35  Argentina  No  Pre-XDR (FQ)  C (−) at month 4  S, H, R, E, Z, Km, Cm, AMK  Polyneuritis  Amoxi-clav, MRP, AMK, Mfx, Eto, Lzd  Favorable  No 
26  Argentina  Yes  XDR  D (+)C (+)  S, H, R, E, Z, Km, Cm, Ofx, Lfx  No  Amoxi-clav, MRP, Mfx, Cs, Eto, PAS, Lzd  Treatment failure Died  CKFIDU 
58  Peru  Yes  XDR  C (−) at month 4  S, H, R, E, Z, Km, Cs, PAS, Ofx, Lzd, Clf  No  Amoxi-clav, MRP, Mfx, Hhd, Eto, Lzd, CFZ  Favorable  No 
57  Argentina  No (nurse)  Pre-XDR (SLI)  C (−) at month 6  S, H, R, E, Z, Km, AMK  Digestive  Amoxi-clav, MRP, Mfx, Cs, Eto, PAS, Lzd  Favorable  DBT 
31  Argentina  No  Pre-XDR (SLI)  C (−) at month 2  S, H, R, E, Z, Km, AMK  No  Amoxi-clav, MRP, Mfx, Cs, Eto, PAS, Lzd  Favorable  No 
48  Argentina  Yes  RA, R-tacrolimus interaction  C (−) at month 5  H, E, PAS, Cs  Hepatitis  Amoxi-clav, MRP, AMK, Mfx, Lzd  Favorable  CKFDBT Liver transplant 
24  Argentina  Yes  XDR  C (−) at month 6  S, H, R, E, Z, Km, Cs, PAS, Ofx  Digestive  Amoxi-clav, MRP, Mfx, Cm, PAS, Lzd  Favorable  No 
29  Peru  No  Pre-XDR (FQ)  C (−) at month 4  S, H, R, E, Z, Ofx  No  Amoxi-clav, MRP, AMK, Mfx, Cs, Eto, Lzd  Favorable  No 
10  30  Argentina  Yes  XDR  C (−) at month 4  S, H, R, E, Z, Km, Cm, Ofx, Mfx, Cs, Eto  DigestiveHematologic  Amoxi-clav, MRP, Cm, BDQ, PAS, Lfx  Diedc  AnorexianerviosaDiarrhea due to C. difficile 

AMK: amikacin; Amoxi-clav: amoxicillin-clavulanate; AR: adverse reactions; Bdq: bedaquiline; Cm: capreomycin; CKF: chronic kidney failure; Clf: clofazimine; Cs: cycloserine; DBT: diabetes; E: etambutol; Eto: ethionamide; FQ: fluoroquinolones; Hhd: high dose isoniazid (600mg/d); IDU: illegal drug user; Km: kanamycin; Lfx: levofloxacin; Lzd: linezolid; MRP: meropenem; Mfx: moxifloxacin; Ofx: ofloxacin; PAS: para-aminosalicylic acid; R: rifampicin; S: streptomycin; SLI: second line injectables; Z: pyrazinamide.

a

Ethionamide susceptibility testing frequently returned un-interpretable results. Resistance to group IV and V drugs was considered approximate due to poor consistency across results.

b

Favorable evolution: bacteriological conversion (2 consecutive negative monthly sputum cultures), the first occurring before the end of the 6-month treatment period.

c

Patient died in hospital due to respiratory failure, despite bacteriological conversion.

Results

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.

Discussion

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.

References
[1]
World Health Organization (WHO). Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2014.11
[2]
WHO. Global Tuberculosis Report 2014. WHO/HTM/TB/2014.08
[3]
J. González Martín, J.M. García García, L. Anibarro, R. Vidal, J. Esteban, R. Blanquer, et al.
Documento de consenso sobre diagnóstico, tratamiento y prevención de la tuberculosis.
Arch Bronconeumol, 46 (2010), pp. 255-274
[4]
M.C. Payen, S. de Wit, C. Martín, R. Sergysels, I. Muylle, Y. van Laethem, et al.
Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis.
Int J Tuberc Lung Dis, 16 (2012), pp. 558-560
[5]
S. De Lorenzo, J.W. Alffenaar, G. Sotgiu, R. Centis, L. D’Ambrosio, S. Tiberi, et al.
Efficacy and safety of meropenem/clavulanate added to linezolid containing regimens in the treatment of M/XDR-TB.
Eur Respir J, 41 (2013), pp. 1386-1392
[6]
X. Gonzalo, F. Drobniewski.
Is there a place for β-lactams in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis? Synergy between meropenem and amoxicillin/clavulanate.
J Antimicrob Chemother, 68 (2013), pp. 366-369

Please cite this article as: Palmero D, González Montaner P, Cufré M, García A, Vescovo M, Poggi S. Primera serie de pacientes con TB-XDR y pre-XDR tratados con esquemas que incluyeron meropenem-clavulanato en Argentina. Arch Bronconeumol. 2015;51:e49–e52.

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