ALATtc_TBincurable.pdf by Asociación Latinoamericana de Tórax ALAT

alat tb 4 Bolet铆n del Departamento de Tuberculosis de la Asociaci贸n Latinoamericana de T贸rax (ALAT)

Julio 2009

TERAPIA COMPASIVA PARA TB INCURABLE

Oswaldo Jave

DEFINICION DE TERAPIA COMPASIVA

http://www.tballiance.org/downloads/publications/Compassionate_Policy.12.6.06.pdf

Requerimiento de uso de emergencia o compasivo

http://www.tballiance.org/downloads/publications/Compassionate_Policy.12.6.06.pdf

Medicamentos propuestos en terapia compasiva de TB 1. 2. 3 3. 4. 5. 6. 7. 8. 9. 10. 11 11.

Linezolid Cefepime + EMB Imipenem 1gm c/12h EV (30mg/K/d (30 /K/d sii peso<50k) 50k) Meropenem Metronidazol Thioridazine Claritromicina Clofazimine Diclofenaco, Ibuprofeno, Aspirina Gallium Vit D + Zn 6

Synergistic antimycobacterial activity between ethambutol and the betabeta-lactam drug CEFEPIME.. CEFEPIME

The activity of cefepime alone and in combination with ethambutol was assessed, using the BACTEC radiometric system, on 33 mycobacterial strains, 14 Mycobacterium avium complex (MAC), 6 isolates of M. malmoense, and 13 multidrugmultidrug-resistant (MDR) isolates of M. tuberculosis.

All tested mycobacteria were resistant to 8 mg/l cefepime. However, at a concentration of 32 mg/l cefepime was active on 7/13 (54%) MDR isolates of M. tuberculosis and 2/6 (33%) M. malmoense strains. All MAC strains were also resistant to this concentration.

Synergistic antimycobacterial effects were seen for the combination of cefepime and ethambutol against all isolates of MAC and M. malmoense and on 4/13 (31%) MDR M. tuberculosis isolates.

Moreover this drug combination rendered 17/24 (71%) initially Moreover, resistant mycobacterial strains susceptible.

These promising results suggest that the antimycobacterial activity of

combinations of beta beta--lactam drugs and ethambutol should be studied further.

Render= verter = revertir Abate G, Hoffner SE. Diagn Microbiol Infect Dis. 1997 Jul;28(3):119-22

The vitro efficacy of betabeta-lactam and betabeta-lactamase inhibitors against multidrug resistant clinical strains off Mycobacterium M b t i tuberculosis. t b l i

In vitro activity of betabeta-lactam antibiotics and their beta beta--lactamase inhibitor combinations were evaluated l t d ffor th their i activity ti it against i t clinical li i l iisolates l t off M Mycobacterium b t i ttuberculosis b l i and dM M. tuberculosis H37Ra.

Agar dilution, the BACTEC 460 system and betabeta-lactamase activity tests were used. Results using the BACTEC 460 and enzyme activity tests showed the best

beta beta--lactamase inhibitor for M M. tuberculosis H37Ra to be clavulanic acid. Cefazolin Cefazolin--clavulanic acid gave the lowest minimal inhibitory concentration (MIC) values using dilution tests and M. tuberculosis H37Ra.

beta-Lactam antibiotics were combined with clavulanic acid and tested for betaf in vitro activity against 50 selected multidrugmultidrug-resistant (MDR) and 50

susceptible clinical isolates. SeventySeventy-four percent of the isolates were inhibited by cefazolincefazolinclavulanic acid combination.

These results suggested that an appropriate combination of beta beta--lactam and beta beta-g be useful in the treatment of tuberculosis due to multidrugmultidrug glactamase inhibitors might resistant strains.

Dinçer I, Ergin A, Kocagöz T. Int J Antimicrob Agents. 2004 Apr;23(4):408-11

Susceptibility of multidrugmultidrug-resistant strains of Mycobacterium tuberculosis to amoxycillin in combination with clavulanic acid and ethambutol ethambutol..

Thirty clinical isolates of Mycobacterium tuberculosis, 20 of which were multidrug multidrug-resistant (MDR), (MDR), were tested for susceptibility to different combinations of amoxycillin, clavulanic acid and subinhibitory concentrations of ethambutol.

beta-Lactamase production was assessed semiquantitatively with the nitrocefin method and betasusceptibility testing was performed with the BACTEC method. method

All isolates were betabeta-lactamase positive and were resistant to 16 mg/L amoxycillin. The MIC of amoxycillin in combination with clavulanic acid was > or =2 mg/L for 27/30 (90%) isolates. Addition of subinhibitory concentrations of ethambutol significantly reduced the MIC of amoxycillin for all tested isolates. TwentyTwenty-nine (97%) isolates had an MIC of amoxycillin of < or =0.5 mg/L when subinhibitory concentrations of ethambutol were added; this is well below the concentrations achievable in serum and tissue.

Abate G, Miörner H. J Antimicrob Chemother. 1998 Dec;42(6):735-40

Contribution of betabeta-lactamases to beta beta--lactam susceptibilities p of susceptible p and multidrugmultidrug gresistant Mycobacterium tuberculosis clinical isolates.

The beta beta--lactamases in 154 clinical Mycobacterium tuberculosis strains beta-lactam antibiotics, their combination with clavulanate were studied. Susceptibilities to beta(2 1) and (2:1), d ttwo flfluoroquinolones i l were d determined t i d iin 24 M M. ttuberculosis b l i strains t i susceptible tibl tto antimycobacterial drugs and in nine multiresistant strains.

All 154 M. tuberculosis isolates showed a single chromosomal betabeta-lactamase pattern (pI 4.9 and 5.1).

M. tuberculosis betabeta-lactamase hydrolyzes cefotaxime with a maximum rate of 22.5 +/+/- 2.19 IU/liter (strain 1382).

Neither amoxicillin, carbenicillin, cefotaxime, ceftriaxone, nor aztreonam was active alone. Except for aztreonam, beta beta--lactam combinations with clavulanate produced better antimycobacterial activity. activity.

Segura C, Salvadó M, Collado I, Chaves J, Coira A. Antimicrob Agents Chemother. 1998 Jun;42(6):1524-6

Imipenem for treatment of tuberculosis in mice and humans humans.

Chemotherapy of tuberculosis caused by multiplemultiple-drug drug--resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta beta--lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We i investigated ti t d th the efficacy ffi off iimipenem i iin a mouse model d l off ttuberculosis b l i and d iin h humans with ith MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenemimipenem-treated mice were compared to those of untreated or isoniazidisoniazid-treated mice.

Ten patients with MDR tuberculosis also were treated with imipenem in combination with other firstfirst- or second second--line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. t b tuberculosis l i organisms i iin llungs and d spleens l and d iimproved d survival i l off mice. i

Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. negative. Seven remained culture culture--negative off of therapy.

There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M tuberculosis. M. tuberculosis Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.

Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for treatment of tuberculosis in mice and humans. Antimicrob Agents Chemother. 2005 Jul;49(7):2816-21

DIARILQUINOLINAS

R-207910. 207910 Potente acción anti ATP sintasa de M. tuberculosis Fase I. tuberculosis. I

Umesh Lallo, Rishendran Naidoo, Anish Ambaram. Recenet advances in the medical and surgical treatment of multi-drug resistant tuberculosis. Curr Opin Pulm Med 2006;12:179-185.

NITROIMIDAZOPYRANS

PA PA--824

P Para T TBMDR. Tx TBMDR Tiene actividad contra bacilo no replicante resistente. Inhibe la síntesis de proteínas y lípidos lípidos. Baja toxicidad y genotoxicidad. Fase I 2005.

Umesh Lallo, Rishendran Naidoo, Anish Ambaram. Recenet advances in the medical and surgical treatment of multi-drug resistant tuberculosis. Curr Opin Pulm Med 2006;12:179-185.

DROGA

CLASE

FASE DE ENSAYO

ACTIVIDAD

MOXI

QNL Q

III

Bactericida

PAPA-824

Nitroimidazopyran

Bactericida

R-207910

Di il i l Diarilquinolona

B t i id Bactericida

LL LL--3858

Pyrrol

Indeterminado

OPC--67683 OPC

Nitro Nitro--dihidroimidazo dihidroimidazo-oxazole

Bactericida

Linezolid

Oxazolidinona

Indeterminado

SQ--109 SQ

1,2 diaminopharmaco diaminopharmaco-phore del ethambutol

Bactericida

Umesh Lallo, Rishendran Naidoo, Anish Ambaram. Recenet advances in the medical and surgical treatment of multi-drug resistant tuberculosis. Curr Opin Pulm Med 2006;12:179-185.

SYNERGISTIC ACTIVITIES OF CLARITHROMYCIN AND ANTITUBERCULOUS DRUGS AGAINST MULTIDRUGMULTIDRUGRESISTANT MYCOBACTERIUM TUBERCULOSIS

Stephen J. Cavalieri,* Jon R. Biehle, And W. Eugene Sanders, Jr.. Antimicrobial Agents And Chemotherapy, July 1995, p p. 1542–1545

Se determinó mediante método radiométrico BACTEC la susceptibilidad de 12 cepas de M. tuberculosis polirresistente a las drogas anti TB (Isoniacida, rifampicina, p ethambutol, y p pirazinamida), ) claritromicina, y sus metabolito, metabolito, 14--hidroxiclaritromycina. Todas las muestras fueron resistentes a por 14 menos dos drogas. Las MIC de Claritromicina y su metabolito 1414-hidroxiclaritromicina estuvieron en el rango indicando resistencia a >8.0 mg/ml para todas mas muestras. t La adición de claritromicina/14claritromicina/14-hidroxiclaritromicina a las mezclas de drogas anti TB resultó en una reducción en 4 a 32 veces en las MICs de isoniacida, rifampicina, y ethambutol y convirtieron en susceptibles a las cepas resistentes resistentes. Los resultados sugieren una interacción sinergística entre las drogas estándar anti TB y la claritromicina/14claritromicina/14-hidroxiclaritromicina. La habilidad de la claritromicina/14claritromicina/14- hidroxiclaritromicina para mejorar la actividad de isoniacida isoniacida, ethambutol ethambutol, y rifampicina in vitro sugiere que esta combinación puede ser eficaz en el tratamiento de TBMDR.

EFFICACY AND SAFETY OF LINEZOLID IN MULTIDRUG RESISTANT TUBERCULOSIS (MDR(MDR-TB). A REPORT OF TEN CASES

Bent von der Lippea, Per Sandvenb, Oddbjørn Brubakk. Journal of Infection (xxxx) xx, 1–5. Accepted 1 April 2005.

10 pacientes consecutivos con TBMDR demostrado por cultivo fueron tratados con linezolid in esquemas combinados por 66-40 semanas (media (media 17) 17) y seguidos hasta 11 11– –50 meses (media 24) después del final del tratamiento. Todas las cepas fueron sensibles a linezolid con un MIC=4 mg/l. Tratamiento fue dado bajo DOTS y se siguió mediante cultivos y otros exámenes bioquímicos. Resultados: 9 pacientes fueron curados, curados, falleciendo un paciente poco adherente al tratamiento y con SIDA avanzada. 7 de 10 pacientes experimentaron severos eventos adversos, lo que produjo suspensión del linezolid en todos ellos. 6 pacientes desarrollaron neuropatía periférica y 5 desarrollaron depresión de médula ósea, ósea, g a3p pacientes y en todos los 5 la función de la ocasionando transfusión de sangre médula ósea se normalizó después de la cesación del linezolid. La neuropatía periférica no revirtió totalmente en todos los pacientes. Conclusión: Linezolid parece ser altamente efectiva en tratamientos combinados de TBMDR. C lti Cultivos ll llegaron a ser negativos ti a los l 10– 10–37 dí días después d é d de lla iintroducción t d ió d de la droga.

ACTIVITY OF PHENOTIAZINES AGAINST ANTIBIOTICANTIBIOTIC-RESISTANT MICOBACTERIUM TUBERCULOSIS: A REVIEW SUPPORTING FURTER STUDIES THAT MAY ELUCIDATE THE POTENTIAL USE OF THIORIDAZINE AS ANTITUBERCULOSIS THERAPY.

Leonard Amaral, jette A Kristiansen, Miguel Viveiros, et al. Journal of Antimicrobial Chemotherapy 2001 Chemotherapy. 2001, 47 47, 505-511 505 511.

Este texto hace una revisión de la actividad in vitro e in vivo de las fenotiacinas. Estas drogas utilizadas para tratar psicosis (aunque actualmente no son de primera línea en esta enfermedad) inhiben el crecimiento de M. tuberculosis a mayores concentraciones que las recomendadas por seguridad. Sin embargo la clorpromazina se concentra en los macrófagos 10 10--100 veces p por encima de su concentración sérica y mostró actividad antimicobacteriana para estas micobacterias intracelulares. Las fenotiacinas tienen actividad contra M. tuberculosis sensible, resistente, polirresistente y MDR así como incrementa la actividad de drogas anti TB de primera línea. La thioridazina thioridazina,, un antipsicótico leve, tiene actividad anti TB similar a clorpromazina y es recomendada por los autores, como coadyuvante a las drogas anti TB. Esta aumenta la actividad de la RMP y SM. Su uso limitado a 22-3 meses evitaría los efectos secundarios al uso de este antipsicótico.

MEROPENEM-CLAVULANATO IN EFFECTIVE MEROPENEMAGAINST EXTENSIVE DRUG DRUG--RESISTANT MYCOBACTERIUM TUBERCULOSIS.

Jean-Emmanuel Hugonnet, lee W Tremblay, Helena I Boshoff et al. Sicence, Vol. 323 Feb 2009 323, 2009.

Los antibióticos betalactámicos son inefectivos contra M. tuberculosis siendo rápidamente hidrolizados por el producto del gene Blas. Los carbapenem son pobres sustratos para Blas. Cuando el meropenem fue combinado con clavulanato se observó b ó una potente t t actividad ti id d contra t M M. ttuberculosis. b l i (CIM<1ug/ml) y se observó negativización de los cultivos dentro de los 14 días. Tuvo T actividad ti id d tanto t t con las l micobacterias i b t i activas ti asíí como las persistentes y inhibió el crecimiento de 13 cepas TBXDR al mismo nivel que las cepas pansensibles pansensibles. 22

Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice. Â&#x192; Int J Antimicrob Agents. 2007 Oct;30(4):336Oct;30(4):336-40. Epub 2007 Jul 17 Dutta NK, Mazumdar K, Dastidar SG, Park JH.

alat tb 4 Boletín del Departamento de Tuberculosis de la Asociación Latinoamericana de Tórax (ALAT)

Julio 2009

El Departamento de TB de la ALAT no promueve ninguno de los medicamentos mencionados i d en esta t revisión i ió bibliográfica. bibli áfi

Departamento de Tuberculosis Director: Dr. Oswaldo Jave: osjave@amauta.rcp.net.pe Vice Director: Dr Miguel A. Salazar: msalazar@iner.gov.mx 24