Tuberculosis - SOGAPAR

Tuberculosis TB pulmonar TB en paciente inmunodeprimido TB extrapulmonar Infección tuberculosa latente Enfermedad por micobacterias no TB

Unidade de TUBERCULOSE

Abel Rodríguez Canal

2017

tuberculosis • enfermedad infecto-contagiosa, granulomatosa

• transmisión aérea

• Mycobacterium tuberculosis complex

• M. tuberculosis

• M. bovis

• M. caprae

• M. africanum

• M. microtti

• M. pinnipedii

• inigualable capacidad de adaptación a medios adversos: en estado latente durante años

Gallardo Carrasco J. y col Tuberculosis, en Manual de Neumología Clínica, 2009

hacinamiento, pobreza, malnutrición, VIH…

10,4 millones de casos nuevos de TB en 2015 – seis países representaron el 60% de los nuevos casos: India,

Indonesia, China, Nigeria, Pakistán y Sudáfrica

– 11% coinfección TB / HIV

• 1,4 millones de muertes

• el nº de muertes disminuyó un 22% entre 2000 y 2015

• 480 000 TBMR y 100 000 TBRR

• 45% de la MR en India, China y Rusia

• la incidencia de TB ha disminuido en un promedio

de un 1,5% por año desde 2000

la carga mundial de TB sigue siendo enorme

hay nueve fármacos en las fases avanzadas de los ensayos

clínicos para el tratamiento de la tuberculosis: bedaquilina, delamanid,

linezolid, PBTZ169, pretomanid, Q203, rifampicina (dosis altas),

rifapentina y sutezolid

Cardona PJ

història natural de la tuberculosi ¡estado inmunitario del huésped!

J. Caminero Luna

la reactivación de la

TB se puede evitar

CHEST 2016; 149(2):516-525

… y la mayoría del riesgo se acumuló en los primeros 5 meses después de la infección … y el riesgo fue mayor en el grupo < 5 años

PPD: las proteínas utilizadas no son específicas de Mycobacterium tuberculosis

PT PPD

Mantoux Sokal

prueba de tuberculina

NO vacunados con BCG

+ si induración > 5 mm

vacunados con BCG

+ si induración > 5 mm …y *conviviente o contacto frecuente con

BK+

*Rx con lesiones sugestivas de TB antigua no tratada

*infectados VIH

*neumoconiosis

+ si induración > 15 mm

González-Martín J. y col. Documento de consenso sobre diagnóstico, tratamiento y prevención de la tuberculosis

Arch Bronconeumol. 2010; 46: 255-74

J. Caminero Luna

RIESGO reactivación de TB

• detecta la liberación de interferon gamma en respuesta a 3 Ags micobacterianos: • ESAT-6 (Early Secreted Antigenic Targert-6)

• CFP-10 (Culture Filtrate Protein-10)

• TB 7.7

• > especificidad con respecto al PPD: ausentes en M bovis BCG y la mayoría de MNT

(excepto M kansasii, M marinum y M szulgai)

IGRA interferon gamma release assays

QFT can be used in all circumstances in which the TST is used QFT usually can be used in place of (and not in addition to) the TST

WHO/HTM/TB/2015.01

estudio y tto masivos de ITBL NO son factibles: – las pruebas no son “perfectas” – riesgo de efectos secundarios graves o mortales – el costo es elevado

ITBL: estado de respuesta inmunitaria persistente a Ags de Mt adquiridos con anterioridad, que NO se acompaña de manifestaciones clínicas de TB activa

estudio y tratamiento de ITBL

• practicarse sistemáticamente en…

• una posibilidad a tener en cuenta en…

• no se recomienda sistemáticamente en…

WHO/HTM/TB/2015.01


• practicarse sistemáticamente en… • infectados por HIV

• niños y adultos en contacto con TB pulmonar

• previo a tratamiento con anti-TNF

• enfermos en diálisis

• previo a trasplantes de órganos o hemáticos

• enfermos de silicosis

WHO/HTM/TB/2015.01

(recomendación firme, datos científicos de poca a muy poca calidad)



• una posibilidad a tener en cuenta en… • presos

• personal sanitario

• inmigrantes

• personas sin hogar

• consumidores de drogas ilícitas

WHO/HTM/TB/2015.01

(recomendación condicional, datos científicos de poca a muy poca calidad)




• no se recomienda sistemáticamente en… • diabéticos

• abuso de alcohol

• fumadores

• personas de peso insuficiente

WHO/HTM/TB/2015.01

(recomendación condicional, datos científicos de muy poca calidad)




• no se recomienda sistemáticamente en…

para determinar si un individuo padece ITBL se deben utilizar las IGRA o la PT

las IGRA no deben sustituir a la PT

WHO/HTM/TB/2015.01

opciones recomendadas para tratar la ITBL • isoniazida 6 meses

• isoniazida 9 meses

• isoniazida + rifapentina 3 meses

• isoniazida + rifampicina 3-4 meses

• rifampicina 3-4 meses

WHO/HTM/TB/2015.01

(recomendación firme, datos científicos de calidad moderada a alta)

equivalentes

• isoniazid (INH) has been the mainstay of treatment of latent tuberculosis infection for almost 50 years

• the currently recommended preferred regimen is 9 months daily self-administered INH (9H)

• this has efficacy of more than 90% if completed properly

Respirology APR 2010 DOI: 10.1111/j.1440-1843.2010.01751.x

the most common treatment worldwide has been 6-9 months of isoniazid monotherapy, but adherence rates are low

shorter course rifamycin therapy is associated with higher rates of acceptance and completion, is as effective as INH, and has less hepatoxocity

Curr Opin Infect Dis 2016; 29: 205-211

Guía de Práctica Clínica del Grupo de Estudio de Infecciones por Micobacterias (GEIM) de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) y la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) sobre el uso de las pruebas de liberación de interferon gamma (IGRAs) para el diagnóstico de Infección Tuberculosa

Miguel Santín y col.

Arch Bronconeumol. 2016;52(9):477–481


1.- IGRAs en el estudio de contactos de pacientes con TB

• recomendación: iniciar el estudio de contactos en adultos inmunocompetentes con la PT, y confirmar los resultados + con un IGRA en los vacunados con BCG

(débil)

• evidencia: 5 estudios observacionales (baja)

• justificación:

– PT como prueba inicial por > accesibilidad

– si PT +, la confirmación con IGRA selecciona mejor los casos tributarios de tto

IGRA: VPN muy alto, cercano al 100%


2.- IGRAs para el cribado de los trabajadores sanitarios

• recomendación: realizar el cribado inicial y periódico con la PT, y confirmar los casos + con un IGRA en el momento de la lectura (débil)

– si PT + con IGRA negativo (y sin indicios clínicos de enfermedad activa ni inmunosupresión), se seguirá con cribado periódico con IGRA (débil)

• justificación:

– PT como prueba inicial por > accesibilidad

– si PT +, la confirmación con IGRA selecciona mejor los casos tributarios de tto


3.- IGRAs para el cribado de infección TB en personas HIV +

• recomendación: se sugiere realizar la PT y un IGRA (débil)

– con un nivel de CD4 < 200/ml se sugiere realizar solo un IGRA (débil)

• justificación:

– muy importante detectar todos los casos infectados, por el alto riesgo de progresión a TB activa

– por debajo de 200 CD4, la PT excepcionalmente podría añadir casos no detectados por los IGRAs


4.- IGRAs en los pacientes con enfermedades inflamatorias crónicas previo a recibir terapia biológica

• recomendación: para cribado en los pacientes con EIC se sugiere realizar la PT y un IGRA (débil)

• justificación:

– alto riesgo de progresión a TB activa, frecuentemente diseminada

– la combinación PT + IGRA aumenta la capacidad de detección de casos

– ¿estrategia simultánea o secuencial?


5.- IGRAs en pacientes tributarios de trasplante de órgano sólido y progenitores hematopoyéticos

• recomendación: para cribado de infección TB en estos pacientes se sugiere realizar la PT y un IGRA (débil)

• justificación:

– alto riesgo de progresión a TB activa, frecuentemente diseminada

– la combinación PT + IGRA aumenta la sensibilidad de detección de casos

– ¿estrategia simultánea o secuencial?

– cribado precoz (enfermedad que indica el trasplante menos evolucionada)


6.- IGRAs para el diagnóstico de TB activa

• recomendación: se recomienda no utilizar los IGRAs ni la PT como prueba única (fuerte)

– con sospecha fundada de enfermedad TB, con el objetivo de confirmar la infección TB, se sugiere realizar un IGRA como dato de apoyo al dx (débil)

• justificación:

– los inconvenientes de tomar decisiones terapéuticas basadas únicamente en esta pruebas superan los beneficios

– ¡ojo! sospecha clínica fundada en HIV +


PT IGRAs

estudio de contactos de pacientes con TB Sí si PT +, Sí

cribado de los trabajadores sanitarios Sí si PT +, Sí

cribado de infección TB en personas HIV + Sí CD4< 200, No

Sí

pacientes con enfermedades inflamatorias crónicas previo a recibir terapia biológica

Sí Sí

pacientes tributarios de trasplante de órgano sólido y progenitores hematopoyéticos

Sí Sí

diagnóstico de TB activa No No

¿secuencial?


Guía de Práctica Clínica del Grupo de Estudio de Infecciones por Micobacterias (GEIM) de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) y la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) sobre el uso de las pruebas de liberación de interferon gamma (IGRAs) para el diagnóstico de Infección Tuberculosa

Miguel Santín y col.

ausencia de evidencia de calidad que permita establecer recomendaciones fuertes

IGRAs: bajo VPP (aunque mejor que el de la PT) y muy alto VPN (cercano al 100%)


Documento de Consenso sobre el diagnóstico y tratamiento de la Infección Tuberculosa Latente en los pacientes candidatos a terapias biológicas

Mir Viladrich I, et al.

Arch Bronconeumol. 2016;52(1):36–45 Arch Bronconeumol. 2016;52(1):36–45


Documento de Consenso sobre el diagnóstico y tratamiento de la ITBL en los pacientes candidatos a terapias biológicas


debido a la vulnerabilidad de estos pacientes frente a la TB cuando se hallan en tratamiento anti-TNF, parece prudente realizar las 2 pruebas en paralelo (IGRA y PT) para maximizar la sensibilidad diagnóstica del cribado es importante mencionar que cuando se realizan las 2 pruebas de manera secuencial, se deben realizar las pruebas de IGRA en primer lugar, en prevención al «efecto booster» causado por la PT



1. todos los pacientes candidatos a tratamiento biológico deben ser estudiados para detectar una posible ITBL 2. el riesgo de estos pacientes de desarrollar la enfermedad está relacionado con el fármaco anti-TNF utilizado, siendo el infliximab (Remicade®) y el adalimumab (Humira®) los fármacos de > riesgo 3. los métodos diagnósticos de la ITBL se basan en: - búsqueda activa de antecedentes de TB y de haber tenido contacto con pacientes con TB activa -evidencia de posibles lesiones tuberculosas antiguas en la radiología de tórax; en caso de duda, se aconseja completar el estudio con una TAC torácica

- realización simultánea de pruebas de IGRA y de una PT: la positividad en cualquiera de estas pruebas se considera indicativa de ITBL



4. los resultados indeterminados en IGRA siempre deberán confirmarse con una segunda determinación, que suele ser negativa en la mayoría de los casos 5. la negatividad en la PT y las pruebas de IGRA no descarta la presencia de una ITBL 6. se aconseja realizar un tratamiento preventivo en todos los pacientes candidatos a terapias biológicas que presenten resultados positivos en alguna prueba diagnóstica de ITBL una vez se haya excluido la TB activa

7. la pauta de tratamiento aconsejada es INH durante 9 meses; solo en casos excepcionales puede estar indicado el tratamiento con INH + RIF durante 3 meses



• the preferred regimen for treating adults with TB caused by strains known or suspected to be drug-susceptible consists of an intensive phase of 2 months [isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB)] followed by a continuation phase of 4 months (INH and RIF)

• the use of four drugs during the intensive phase of treatment ensures its effectiveness in case of INH mono-resistance

• pyridoxine (vitamin B6) is given with INH to patients at risk of neuropathy (e.g. pregnant women, breastfeeding infants, individuals co-infected with HIV, the elderly, and patients with diabetes, alcoholism, malnutrition or chronic renal failure)

• the recommended frequency of treatment administration is once daily for both the intensive and continuation phases

clinical practice guidelines on treatment of drug-susceptible tuberculosis

• the preferred regimen for treating adults with TB caused by strains known or suspected to be drug-susceptible consists of an intensive phase of 2 months (isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB)) followed by a continuation phase of 4 months (INH and RIF)

• the use of four drugs during the intensive phase of treatment ensures its effectiveness in case of INH mono-resistance

• pyridoxine (vitamin B6) is given with INH to patients at risk of neuropathy (e.g. pregnant women, breastfeeding infants, individuals co-infected with HIV, the elderly, and patients with diabetes, alcoholism, malnutrition or chronic renal failure)

• the recommended frequency of treatment administration is once daily for both the intensive and continuation phases


2HRZE + 4 HR

• during treatment, a sputum specimen for direct smear and culture examination is recommended at monthly intervals until two consecutive specimens are negative on culture

• culture conversion needs to be assessed at the end of 2 months of treatment in new cases

• cavitation on the initial chest radiograph has also been shown to be a risk factor for relapse

• in patients with cavitation at baseline failing to convert culture after the intensive phase of treatment, rates of relapse have been shown to be higher than among patients with neither factor and the extension of the continuation phase with INH and RIF for an additional 3 months is an option left to the physician in discussion with the patient


• additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being underweight (>10%), being an active smoker, having diabetes, HIV infection or another immunosuppressing condition, or having extensive disease on chest radiography


2HRZE + 4 HR 7

• 4-month treatment regimen was shown to be adequate for sputum smear-negative, culture-negative pulmonary TB

• if all cultures on adequate samples are negative (culture-negative TB) and here is a clinical or radiographic response after 2 months of intensive phase therapy, the continuation phase with INH and RIF may be shortened to 2 months in HIV-negative adults

• at a minimum, patients suspected of having pulmonary TB should have two sputum specimens (using sputum induction with hypertonic saline if necessary) for alcohol acid-fast bacilli smears and cultures for mycobacteria or for rapid molecular testing for M. tuberculosis as part of the diagnostic evaluation


culture-negative pulmonary TB in adults

ATS/CDC/IDSA • CID 2016:63 (1 October)

IDSA GUIDELINE treatment of drug-susceptible TB 2016


2HRZE + 4HR

• if PZA cannot be included in the initial regimen, or the isolate is determined to be resistant to PZA (an unusual circumstance, except for M. bovis and M. bovis var BCG), experts recommend a regimen consisting of INH, RIF, and EMB for the initial 2 months followed by INH and RIF for 7 months

• fluoroquinolones (moxifloxacin and levofloxacin)

o in scenarios in which EMB or INH cannot be used, the role of moxifloxacin or levofloxacin has not been established through clinical trials. Experts on occasion use moxifloxacin or levofloxacin in place of EMB during intensive phase in adults in whom EMB cannot be used, or in place of INH throughout treatment in adults in whom INH cannot be used

IDSA GUIDELINE

Alternative Regimen Composition


2HRE + 7HR

2RMfxEZ + 7RMfxE 2RMfxEZ + 10RE

• fluoroquinolones (moxifloxacin and levofloxacin)

o there is no evidence that moxifloxacin or levofloxacin can be used in place of a rifamycin or PZA while maintaining a 6-month treatment duration

o importantly, all alternative regimens using fluoroquinolones in place of EMB or INH are 6 months or longer in duration

o there is definitive clinical trial evidence that 4-month daily regimens that substitute moxifloxacin or gatifloxacin for EMB, or moxifloxacin for INH, are significantly less effective than the preferred, standard daily 6-month treatment for drug-susceptible pulmonary tuberculosis

IDSA GUIDELINE

Alternative Regimen Composition


• obtain sputa for smear and culture at baseline, then monthly until 2 consecutive specimens are negative

• at least one baseline specimen should be tested using a rapid molecular test

• drug susceptibility for isoniazid, rifampin, ethambutol, and pyrazinamide should be obtained

• molecular resistance testing should be performed for patients with risk for drug resistance

• monitor weight monthly to assess response to treatment; adjust medication dose if needed

• patients on EMB: baseline visual acuity and color discrimination tests, followed by monthly inquiry about visual disturbance and monthly color discrimination tests

IDSA GUIDELINE

baseline and follow-up evaluations for patients treated with first-line TB medications


IDSA GUIDELINE

• in general, tuberculosis drugs are administered together

• bioavailability of all of the drugs (except for RPT) is greatest when taken on an empty stomach

• there is no significant difference between fixed-dose combinations (FDCs) and single-drug combinations for key outcomes, including sputum smear or culture conversion, failure, relapse, death, serious adverse events, or adverse events that lead to discontinuation of therapy

• the patient-specific advantages to using FDC drugs include ease of administration and the potential for reducing medication errors

• the key program and clinician-specific advantage of FDC formulations is the simplification of drug supply management (procurement, storage, and distribution) and simpler prescription writing


IDSA GUIDELINE

• gastrointestinal upset

• gastrointestinal intolerance not associated with hepatotoxicity: antacids, administration with food, with proton pump inhibitors, to splitting a dose or changing to a second-line drug

• rash

• if the rash is mainly itchy without mucous membrane involvement or systemic signs such as fever, treatment is symptomatic with antihistamines

• a petechial rash is more concerning and suggests thrombocytopenia from a rifamycin (RIF, RFB, RPT) hypersensitivity

• drugs are also stopped if the patient has a generalized erythematous rash

• when the rash has substantially improved, medications can be restarted individually at intervals of 2–3 days. RIF is restarted first (the most potent drug), followed by INH, then EMB or PZA


management of common adverse effects

IDSA GUIDELINE

• drug fever

• is essentially a diagnosis of exclusion

• generally feel well despite body temperatures ≥39°C

• stopping drugs usually resolves the fever within 24 hours

• once afebrile, the patient should restart drugs individually every 2–3 days

• hepatotoxicity

• drug-induced hepatitis is the most frequent serious adverse reaction to the first-line drugs

• INH, RIF, and PZA can cause drug-induced liver injury, which is suspected when the ALT level is ≥3 times the upper limit of normal in the presence of hepatitis symptoms, or ≥5 times the upper limit of normal in the absence of symptoms



<5 times, mild toxicity 5-10 times, moderate > 10 times, severe

IDSA GUIDELINE

• hepatotoxicity

• other causes of abnormal liver tests must be excluded before diagnosing drug-induced hepatitis

• if ALT levels are consistent with hepatotoxicity, all hepatotoxic drugs must be stopped and serum ALT and prothrombin time or INR levels followed until levels return to baseline

• once the ALT concentration returns to <2 times the upper limit of normal, antituberculosis medications are restarted individually

• RIF is much less likely to cause hepatotoxicity than INH or PZA, and it is restarted first ( INH PZA)

• if symptoms recur or ALT increases, the last drug added should be stopped



IDSA GUIDELINE

• optic neuritis

• EMB-related visual impairment during treatment of active tuberculosis has been estimated to occur in 22.5 per 1000 persons (2.25%) receiving EMB at standard doses

• the onset of optic neuritis is usually >1 month after treatment initiation but can occur within days

• baseline visual acuity (Snellen test) and color discrimination tests followed by monthly color discrimination tests are performed during EMB use

• to avoid permanent deficits, EMB is promptly discontinued if visual abnormalities are found

• if vision does not improve with cessation of EMB, experts recommend stopping INH as well, as it is also a rare cause of optic neuritis



IDSA GUIDELINE

relatively few interactions substantially change antituberculosis drug concentration

•absorption of the fluoroquinolones is markedly decreased by ingestion of medications containing divalent cations (calcium, iron, zinc) including antacids; supplements or vitamins containing calcium, iron, or zinc; sucralfate; and the chewable tablet formulation of didanosine

these drug interactions can be avoided by ingesting medications containing divalent cations at least 2 hours apart from fluoroquinolones

•in addition, moxifloxacin serum concentrations are decreased by 25%–30% in the presence of RIF due to the induction of phase II metabolic enzymes (sulfation and glucuronidation)

RPT and RFB also may decrease moxifloxacin serum concentrations, though the clinical significance of these drug–drug interactions in individual patients is uncertain


drug interactions

IDSA GUIDELINE

all of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 (CYP) system by inducing the activity of metabolic enzymes, rifamycins decrease the serum concentrations of many drugs, sometimes to subtherapeutic levels

• antiretroviral agents

• anti-infectives: macrólidos, doxycycline, azole antifungal agents…

• hormone therapy: oral contraceptives, tamoxifen, levothyroxine

• narcotics: methadone

• anticoagulants: warfarin

• immunosuppresive agents: cyclosporine, tacrolimus, corticosteroids

• anticonvulsivants: phenytoin, lamotrigine

• cardiovascular agents: verapamil, nifedipine, diltiazem, propranolol, enalapril, losartan, digoxin


drug interactions due to rifamycins

IDSA GUIDELINE

all of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 (CYP) system by inducing the activity of metabolic enzymes, rifamycins decrease the serum concentrations of many drugs, sometimes to subtherapeutic levels

• theophyline

• sulfonylurea hypoglycemics: repaglinide, glimepiride…

• hypolipidemics: simvastatin, fluvastatin

• psychotropic drugs: haloperidol, quetiapine, benzodiazepines…


drug interactions due to rifamycins

RIF is the most potent enzyme inducer and RFB the least

IDSA GUIDELINE

INH is a relatively potent inhibitor of several CYP isozymes and increases concentrations of some drugs to the point of toxicity such as the anticonvulsants phenytoin and carbamazepine

•of note, the inductive effect of RIF on CYP isozymes outweighs the inhibitory effect of INH, so that the overall effect of combined therapy with RIF and INH is a decrease in the concentrations of drugs such as phenytoin and diazepam


drug interactions due to INH

IDSA GUIDELINE

treatment of tuberculosis in patients with HIV infection has several important differences compared with treatment of patients who do not have HIV infection:

• the need for ART

• the potential for drug–drug interactions, especially between the rifamycins and antiretroviral agents

• paradoxical reactions that may be interpreted as clinical worsening

• the potential for developing resistance to rifamycins when using intermittent tuberculosis therapy

all individuals diagnosed with tuberculosis are tested for HIV infection


treatment in special situations HIV infection

2HRZE + 4HR 7RH

IDSA GUIDELINE

• the WHO recommends routine co-trimoxazole prophylaxis for all HIV-infected people with active tuberculosis disease regardless of the CD4 cell count; in high-income countries, co-trimoxazole prophylaxis is primarily used in tuberculosis patients coinfected with HIV with CD4 counts <200 cells/μL

• the overall reduction in mortality with ART initiated during treatment of tuberculosis was 24% and the overall risk of HIV disease progression was reduced by 34% with early or immediate ART

• initiation of ART during antituberculosis therapy was associated with an increased risk of IRIS

antiretroviral therapy should ideally be started within 2 weeks for those patients with a CD4 count <50 cells/μL and by 8–12 weeks for those with a CD4 count ≥50 cells/μL



IDSA GUIDELINE

• HIV protease inhibitors are metabolized by CYP3A4, and their concomitant administration with RIF leads to >80% reductions in serum concentrations of the protease inhibitors and loss of therapeutic benefit

•RIF also increases the metabolism of nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), and CCR-5 inhibitors

•the NNRTI efavirenz is the most widely used antiretroviral drug and is the preferred initial treatment for HIV. Coadministration of RIF-containing antituberculosis regimens with efavirenz results in satisfactory antiviral efficacy, despite reductions in trough efavirenz concentrations

•RFB is less potent an inducer of CYP isoenzymes and may be used in patients receiving ART



IDSA GUIDELINE

Immune Reconstitution Inflammatory Syndrome: IRIS

• high fevers

• worsening respiratory symptoms

• increase in size and inflammation of involved lymph nodes

• new lymphadenopathy

• expanding central nervous system (CNS) lesions

• worsening of pulmonary parenchymal infiltrations

• new or increasing pleural effusions

• and development of intra-abdominal or retroperitoneal abscesses

such findings are attributed to IRIS only after excluding other possible causes, especially tuberculosis treatment failure from drug-resistant tuberculosis or another opportunistic disease, such as non-Hodgkin lymphoma or infection



IDSA GUIDELINE

• the diagnosis of tuberculosis in children is challenging, especially in young children (<5 years) due to the paucibacillary nature of the disease

diagnosis is microbiologically confirmed in only 15%–50% of pediatric cases

•when drug resistance is suspected or no source-case isolate is available, attempts to isolate organisms are critical; approaches including obtaining

• 3 early morning gastric aspirations (optimally during hospitalization)

• sputum induction

• bronchoalveolar lavage

• or tissue biopsy must be considered

•in infants and children < 4 years of age, empiric treatment is started as soon as the diagnosis is suspected


treatment in special situations children

IDSA GUIDELINE

•children who are receiving EMB should be monitored monthly for visual acuity and red-green color discrimination if they are old enough to cooperate

• in young children whose visual acuity cannot be monitored requires consideration of risks and benefits

•pyridoxine, 25–50 mg/day, is given to infants, children, and adolescents undergoing INH treatment if they have nutritional deficiencies, symptomatic HIV infection, or are breastfeeding

•when feasible, daily dosing is preferred by experts

•hilar adenopathy and resultant atelectasis in children on occasion can require 1–2 years to resolve


treatment in special situations children

2HRZE + 4HR

IDSA GUIDELINE

•the exception is tuberculous meningitis where the optimal duration of therapy has not been established through randomized controlled trials, but most experts and society guidelines prescribe 12 months of treatment

•the preferred frequency of dosing for extrapulmonary tuberculosis is once daily for both the intensive and continuation phases

•response to treatment in extrapulmonary diseases is often judged on the basis of clinical and radiographic findings


treatment in special situations extrapulmonary tuberculosis

2HRZE + 4-7 HR

Diagnóstico y Tratamiento

Diagnóstico: preferentemente por cultivo y/o histología del material

obtenido por punción/biopsia • Técnicas microbiológicas poco sensibles por ser TB muy paucibacilares

• La baciloscopia acostumbra a ser negativa. El cultivo y las técnicas de amplificación

génica son más sensibles y deberían realizarse si están disponibles

• La Histología es la que frecuentemente da el apoyo diagnóstico

• Frecuentes diagnósticos clínico-radiológicos

Tratamiento • Farmacológico: igual que pulmonar (2HRZE/4HR), salvo TB del SNC en que se debe

prolongar hasta 12 meses

• Quirúrgico: Sólo si complicaciones

Tuberculosis extrapulmonar

Tuberculosis pleural

Manifestación más frecuente de TB extrapulmonar

Suele ser una complicación frecuente de la TB primaria

La clínica es inespecífica y poco expresiva

Habitualmente el derrame es unilateral y ocupa un tercio del hemitórax

El líquido pleural es amarillento, con predominio de linfocitos, el ADA

casi siempre por encima de 40 U/L

El diagnóstico suele establecerse por el hallazgo de granulomas

caseificantes en la biopsia pleural y en una tercera parte de los casos

por el hallazgo de bacilos tuberculosos en el líquido o el tejido pleural

IDSA GUIDELINE

• a 6-month regimen is adequate

•some clinicians consider using adjunctive corticosteroid therapy for tuberculous pleural effusions

•prednisone (or prednisolone) administration did not confer a beneficial effect on residual pleural thickening or prevention of other longterm pleural sequelae

•tuberculous empyema, a chronic, active infection of the pleural space containing a large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural space

• treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy


treatment in special situations extrapulmonary TB

pleural tuberculosis

2HRZE + 4HR

Tuberculosis Ganglionar

Manifestación más frecuente de TB extra pulmonar, después de la TB

Pleural

Localización más habitual: ganglios cervicales, aunque también puede

afectar los axilares, inguinales, mesentéricos, o mediastínicos

Masa unilateral no dolorosa a lo largo del borde superior del músculo

esternocleidomastoideo (más de un lugar afectado en el 35% de los

casos). Habitualmente no síntomas constitucionales

Prueba de la tuberculina (PT): + en mas del 75% de pacientes no VIH

Técnica diagnóstica de elección: PAAF y biopsia si PAAF no da el

diagnóstico

IDSA GUIDELINE

• a 6-month regimen is adequate

•affected lymph nodes may enlarge and new nodes can appear during or after therapy without any evidence of bacteriological relapse

•therapeutic lymph node excision is not indicated except in unusual circumstances

• large lymph nodes that are fluctuant and appear to be about to drain spontaneously, aspiration has been reported by some experts to be beneficial

•the majority of lymphatic cases of mycobacterial disease in US children are caused by nontuberculous mycobacteria



lymph node tuberculosis

2HRZE + 4HR

Tuberculosis osteoarticular

Localización

• Columna vertebral o enfermedad de Pott (50%), sobretodo afecta columna

lumbar y dorsal baja

• Artritis tuberculosa (cadera y rodilla, generalmente monoarticular)

• Osteomielitis extra espinal

Clínica

• TB vertebral: lumbalgia, contractura, rigidez de semanas o meses. Clínica

constitucional 40%

• Artritis: dolor, hinchazón y pérdida movilidad. Síntomas constitucionales 30%.

• Infección articular protésica: dolor, disfunción protésica

• Osteomielitis TB extra espinal: puede afectar cualquier estructura ósea

Diagnóstico

• Preferentemente por cultivo y/o histología del material obtenido por

punción/biopsia

IDSA GUIDELINE

•six- to 9-month regimens containing RIF is adequate

•in the setting of extensive orthopedic hardware, some experts extend the duration of treatment further to 12 months

•uncomplicated cases of spinal tuberculosis are managed with medical treatment

surgery can be considered in situations in which (1) there is poor response to chemotherapy with evidence of ongoing infection or

ongoing deterioration

(2) relief of cord compression is needed in patients with persistence or recurrence of neurologic deficits

(3) there is instability of the spine



bone, joint and spinal tuberculosis

2HRZE + 4-7 HR

Tuberculosis Pericárdica

Aparece entre la tercera y quinta décadas de vida (antes si VIH+)

Prestación clínica variable

• Pericarditis aguda

• Taponamiento cardíaco

• Pericarditis subaguda

• Síndrome constitucional

• Pericarditis constrictiva (aguda, subaguda, crónica)

Signos ecocardiográficos: filamentos de fibrina en líquido

pericárdico es altamente sugestivo, pero no patognomónico

Características de líquido pericárdico parecidas al pleural

IDSA GUIDELINE

•a 6-month regimen is adequate for patients with pericardial tuberculosis

•we suggest that adjunctive corticosteroids should not be used routinely in the treatment of patients with pericardial tuberculosis

•however, selective use of glucocorticoids in patients who are at the highest risk for inflammatory complications might be appropriate

• patients with large pericardial effusions, those with high levels of inflammatory cells or markers in pericardial fluid, or those with early signs of constriction



pericardial tuberculosis

2HRZE + 4HR

Ocurre en el 1% de los pacientes con TB activa

Las formas más frecuentes son:

• TB Meníngea (afectación difusa, más frecuente y grave)

• Tuberculoma intracraneal (lesiones ocupantes de espacio)

Factores de riesgo para meningitis TB

• Alcoholismo

• Diabetes mellitus

• Neoplasia

• Uso recientes de corticoides

• VIH

Afectación sistema nervioso central

Tuberculosis Meníngea

Clínica variable e inespecífica

Complicaciones neurológicas frecuentes • Parálisis nervios craneales, sobretodo III, IV, VI y VII

• Mono o hemiparesia en el 20%

• Paraparesia 1-5%

• Elevación presión intracraneal, hidrocefalia

• Hiponatremia >50%

LCR • 100-1000 leucocitos/mm3

• Predominio linfocitos, aunque en fases tempranas puede predominar los neutrófilos

• Puede ser acelular en ancianos y pacientes con VIH

• Proteínas 150-500 mg/dl

• Glucosa LCR/sangre < 0,5 en 95% de los casos, útil para diferenciar de meningitis vírica

• ADA y técnicas de amplificación del ADN (PCR)

IDSA GUIDELINE

•high short-term morbidity and mortality is reported regardless of HIV serostatus

•the optimal duration of chemotherapy is not defined

•based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy

•in children with tuberculous meningitis, ethionamide or an aminoglycoside in place of EMB

•selected complications of tuberculous meningitis warranting neurosurgical referral include hydrocephalus, tuberculous cerebral abscess, and clinical situations in which there is paraparesis



tuberculous meningitis

2HRZE + 7-10 HR

IDSA GUIDELINE

•high short-term morbidity and mortality is reported regardless of HIV serostatus

•a systematic review found a mortality benefit from the use of adjuvant corticosteroids

we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6–8 weeks for patients with tuberculous meningitis



tuberculous meningitis

2HRZE + 7-10 HR

Tuberculosis renal y vías urinarias

Más frecuente en varones jóvenes

Clínica

• Disuria y hematuria macroscópica (lo más frecuente)

• Cólico nefrítico

• Síntomas generales

• Manifestaciones extrarrenales:

• Estenosis ureteral

• Vejiga hipertónica

• Calcificaciones vasos deferentes, vesículas seminales y próstata

Diagnóstico

• Sedimento urinario alterado en el 90% de los casos

• Confirmación: demostración BK en orina (baciloscopia, con más falsos

negativos, o cultivo)

• Descartar amiloidosis secundaria en pacientes TB con proteinuria

Tuberculosis genital

Hombres: forma frecuente de TB extrapulmonar

• Pene

• Vaso deferente

• Vesículas seminales

Mujeres: enfermedad poco sintomática (infertilidad)

• > frecuencia, endometrio y trompas

• Ovario y cérvix

• Raro vulva y vagina

• Se ha descrito transmisión congénita de TB

IDSA GUIDELINE

•renal tuberculosis is treated primarily with medical rather than surgical therapy, and expert opinion is that a standard daily 6-month regimen is adequate

•if ureteral obstruction occurs, procedures to relieve the obstruction are indicated

•in cases of hydronephrosis and progressive renal insufficiency due to obstruction, renal drainage by stenting or nephrostomy is advised by experts

•nephrectomy is considered when there is a nonfunctioning or poorly functioning kidney, particularly if hypertension or continuous flank pain is present

•dose adjustment is required in patients with coexistent renal failure



genitourinary tuberculosis

2HRZE + 4HR

IDSA GUIDELINE

•renal tuberculosis is treated primarily with medical rather than surgical therapy, and expert opinion is that a standard daily 6-month regimen is adequate

•tuberculosis of the female or male genital tract responds well to standard chemotherapy, although surgery may be indicated for residual, large, tubo-ovarian abscesses

•a positive urine culture for M. tuberculosis is also sometimes seen in tuberculosis patients with advanced HIV infection, and may reflect disseminated disease



genitourinary tuberculosis

2HRZE + 4HR

Tuberculosis abdominal

La TB, a nivel abdominal, puede afectar

• Tracto gastrointestinal (TGI) (lo + frecuente)

• Peritoneo

• Ganglios

• Vísceras sólidas (hígado, bazo, páncreas, etc)

Las zonas de afectación más frecuente del TGI son íleon y región iliocecal, seguidos de colon y yeyuno

Las lesiones de TGI pueden ser ulcerativas, estenosantes o hipertróficas

La afectación peritoneal puede ser con ascitis o con adherencias

Predominio en adultos jóvenes

En niños la presentación es diferente (90% con afectación peritoneal y ganglionar)

Tuberculosis abdominal

La clínica depende del sitio afectado y del tipo de lesión

En caso de abdomen agudo puede ser necesaria la intervención quirúrgica

Lugar Tipo de lesión Clínica

Intestino delgado Ulcerada Diarrea, malabsorción

Estenosante Obstrucción

Intestino grueso Ulcerada Rectorragia

Hipertrófica Obstrucción

Peritoneo Ascitis Dolor, distensión

Adherencias Obstrucción

Ganglios Obstrucción

IDSA GUIDELINE

•a 6-month regimen is adequate for patients with peritoneal or intestinal tuberculosis

•the nonspecific presentation of abdominal tuberculosis means that a high index of suspicion is an important factor in early diagnosis and initiation of treatment

•data on adjunctive corticosteroid therapy in the treatment of tuberculous peritonitis are limited; thus, experts believe it should not be prescribed routinely



abdominal tuberculosis

2HRZE + 4HR

Tuberculosis cutánea

Enfermedad rara en España

Prestación clínica variable

• Tuberculosis primaria cutánea (chancro tuberculoso)

• Tuberculosis miliar cutánea

• Escrofulodermia

• Tuberculosis gomosa

• Tuberculosis ulcerosa de las mucosas

• Tuberculosis verrugosa

• Lupus tuberculoso

Diagnóstico: cultivo

Diagnóstico diferencial: enfermedades granulomatosas de la piel ( lepra, micobacterias atípicas, sarcoidosis, sífilis, reacciones por cuerpos extraños o estructuras queratinizadas, micosis profundas, linfomas)

Tuberculosis ocular

Forma poco común

Los casos se dividen en primarios y secundarios

Las formas de presentación más frecuente son:

• Uveítis anterior crónica

• Coroiditis

• Esclero-queratitis

A pesar de la existencia de herramientas moleculares altamente

sensibles, el diagnóstico de TB ocular sigue siendo presuntivo, basado en:

• Clínica

• Evaluación sistémica

• Respuesta terapéutica

IDSA GUIDELINE

•a standard daily 6-month regimen is adequate for tuberculosis at multiple sites and for miliary tuberculosis

•some experts believe concurrent corticosteroid therapy is indicated for treating severe respiratory failure or adrenal insufficiency caused by disseminated tuberculosis, though the role of adjunct corticosteroid treatment in patients with miliary tuberculosis remains unclear



disseminated tuberculosis

2HRZE + 4HR

IDSA GUIDELINE

•treatment for tuberculosis is initiated whenever the probability of maternal disease is moderate to high because of the risk of untreated tuberculosis to a pregnant woman and her fetus

•although antituberculosis drugs cross the placenta, they do not appear to have teratogenic effects in humans

•however, the inclusion of PZA in the treatment regimen for pregnant women is controversial in the United States

•PZA is recommended by the WHO for tuberculosis in pregnancy


treatment in special situations pregnancy and breastfeeding

2HRZE + 4HR 2HRE + 7HR

IDSA GUIDELINE

•expert opinion is that in pregnant women with tuberculosis and HIV, extrapulmonary or severe tuberculosis, it is more beneficial to include PZA in the treatment regimen than to not include PZA

•small case series of pregnant women treated with second-line drugs (from studies in drug-resistant tuberculosis) suggest that good outcomes are achievable and that termination of the pregnancy is not necessary

•breastfeeding is encouraged for women who are deemed noninfectious and are being treated with first-line agents


treatment in special situations pregnancy and breastfeeding

2HRZE + 4HR

IDSA GUIDELINE

•patients with renal insufficiency or end-stage renal disease (ESRD) are immunocompromised

•tuberculosis patients with chronic renal failure have worse clinical outcomes than those without renal failure

•decreasing the dose lowers peak serum drug concentrations and can compromise treatment efficacy

•based on expert opinion, the interval between drug doses in patients with a creatinine clearance of <30 mL/minute and those receiving hemodialysis should be increased instead

•RIF and INH are metabolized by the liver, and conventional dosing can be used in the setting of renal insufficiency


treatment in special situations renal disease

IDSA GUIDELINE treatment of drug-susceptible TB 2016


IDSA GUIDELINE

•with hemodialysis, PZA and, presumably, its metabolites are cleared to a significant degree, INH and EMB are cleared to some degree, and RIF is not cleared by hemodialysis

•postdialysis administration of all antituberculosis medications is preferred to facilitate DOT and to avoid premature clearance of drugs such as PZA

•monitoring serum drug concentrations, along with careful clinical and pharmacological assessment, in patients with ESRD, may be necessary

•peritoneal dialysis: there is currently a paucity of pharmacokinetic and dosing data

• patients may require close monitoring for toxicity, and measurements of the serum concentrations of antituberculosis drugs before and after peritoneal dialysis should be considered


treatment in special situations renal disease

IDSA GUIDELINE

•the likelihood of drug-induced hepatitis is increased with prior advanced liver disease, liver transplant, or hepatitis C infection

•abnormal baseline aminotransferases alone are an independent risk factor for DILI

•patients with a history of injection drug use, birth in Asia or Africa (or other hepatitis virus endemic regions), or HIV infection have hepatitis B and C virus screening at baseline

•hepatic tuberculosis may also cause elevated aminotransferases, which improve with effective tuberculosis treatment


treatment in special situations hepatic disease

IDSA GUIDELINE

•the crucial efficacy of INH and particularly RIF warrant their use and retention, if at all possible, even in the face of preexisting liver disease

•treatment without PZA: 2RHE + 7RH

•treatment without INH and PZA: for advanced liver disease patients, RIF and EMB with a fluoroquinolone, injectable, or cycloserine for 12–18 months, depending on the extent of the disease and response could be considered

•treatment without INH: a regimen of RIF, PZA, and EMB with or without a fluoroquinolone could be considered for a total duration of at least 6 months



IDSA GUIDELINE

•regimens with little or no potential hepatotoxicity: for patients with severe, unstable liver disease, EMB combined with a fluoroquinolone, cycloserine, and second-line injectable for 18–24 months can be considered

• some experts avoid aminoglycosides in patients with severe, unstable liver disease due to concerns about renal insufficiency or bleeding from the site of injected medication due to thrombocytopenia and/or coagulopathy



IDSA GUIDELINE

•clinical monitoring and patient education for manifestations of liver injury is warranted for all patients

•experts in the field recommend measuring serum aminotransferases and total bilirubin concentrations every 1–4 weeks for at least the first 2–3 months of treatment

•the INR may also be periodically followed for patients with severe hepatic impairment

•an increase in serum ALT is more specific for hepatocellular injury than an increase in AST, which can also signify abnormalities in muscle, heart, or kidney

•advanced preexisting disease: in addition to weekly or twice-weekly ALT monitoring, interrupting treatment for only a 3-fold elevation of ALT, even if asymptomatic



monitoring of treatment in hepatic disease

IDSA GUIDELINE

•in general, TB treatment for patients with diseases or conditions that alter immune responsiveness, including HIV infection, parasitic and helminthic infections, hematologic or reticuloendothelial malignancies, immunosuppressive therapy (eg, TNF-α inhibitors), chronic renal failure, diabetes mellitus, and malnutrition is based on the standard, daily 6-month regimen

•diabetes mellitus: some experts suggest extending the total duration of tuberculosis treatment to 9 months in poorly controlled DM

•silicotuberculosis: data demonstrate that cure rate is improved if the continuation phase is extended by at least 2 months


treatment in special situations other comorbid conditions

IDSA GUIDELINE

•solid organ transplant recipients: based on data suggesting increased mortality with shorter durations of treatment, some experts also suggest extending the total duration of tuberculosis treatment to at least 9 months

•rheumatologic disease: expert opinions that TNF-α inhibitor therapy is held if clinically feasible, when active tuberculosis is suspected or confirmed. There is no consensus on when TNF-α inhibitor therapy can be resumed


treatment in special situations other comorbid conditions

IDSA GUIDELINE

•in the United States, treatment failure is defined as continuously or recurrently positive cultures after 4 months (5 months in Europe and WHO guidelines) of treatment in a patient receiving appropriate chemotherapy

•recent mycobacterial isolates should be sent to a reference laboratory for susceptibility testing to both first-and second-line drugs

•a single new drug is never to be added to a failing regimen as it can lead to amplification of drug resistance, including acquired resistance to the newly added drug

• to lessen the likelihood of increasing resistance, it is generally prudent to add 2–3 new drugs to which susceptibility could logically be inferred

• when drug susceptibility results are available, the regimen is adjusted accordingly


treatment in special situations treatment failure

1. Shorter MDR-TB regimen for adults & children In patients with rifampicin-resistant or multidrug-resistant TB

who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen

(conditional recommendation, very low certainty in the evidence)

4-6 months: Gfx/Mfx + km + Pto + Cfz + Hh + Z + E 5 months: Gfx/Mfx + Cfz + Z + E

preferably, resistance to at least fluoroquinolones and the injectable agent used in the regimen is excluded before starting treatment by in vitro testing

2. Conventional MDR-TB regimens for adults & children

2a) In patients with rifampicin-resistant or multidrug-resistant TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core secondline TB medicines - one chosen from group A, one from group B, and at least two from group C (conditional recommendation, very low certainty in the evidence).

If the minimum of effective TB medicines cannot be composed as above, an agent from group D2 and other agents from D3 may be added to bring the total to five.

2. Conventional MDR-TB regimens for adults & children

2b) In patients with rifampicin-resistant or multidrug-resistant TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence).

It is recommended that any patient with rifampicin-resistant TB in whom isoniazid resistance is absent or unknown be treated with a recommended MDR-TB regimen.

15–20 mg/kg body weight/day

katG mutation: high-dose isoniazid may be less effective

GeneXpert MTB- RIF

GeneXpert System

• test genotípico: PCR en tiempo real

• Dx rápido de TB y detecta resistencia a RIF

• detecta la presencia de ADN de Mycobacterium tuberculosis en la muestra (esputo) e identifica los cambios en el ADN que pueden producir la resistencia a la RIF

• amplifica rpoB, el gen responsable del 95% de las resistencias a RIF

• en el terreno, más del 95% de los aislados resistentes a RIF lo son también a INH MDR-TB

Sistema Xpert MTB-RIF para el diagnóstico de las TB pulmonar y extrapulmonar en adultos y niños Recomendaciones OMS, 2013

• 27 estudios, 9558 participantes incluidos en la revisión

• en pacientes con baciloscopia negativa

• MTB-RIF aportó una sensibilidad global del 68% y una especificidad del 99%

• para detección de resistencia a RIF: sensibilidad global del 95% y especificidad del 98%

Genotype MTBDRplus

• para realizar diagnóstico rápido de TB y detectar resistencia a INH y RIF

• detecta presencia de ADN de Mycobacterium tuberculosis en la muestra e identifica cambios en el ADN que pueden producir resistencia a INH y RIF

• los ensayos de GenoType MDTBR demuestran una excelente precisión para la resistencia a rifampicina

• sensibilidad 98,1%, especificidad 98,7%

• la especificidad es excelente para la isoniazida, y las estimaciones de sensibilidad fueron más modestas y variables

• sensibilidad 84,3%, especificidad 99,5%

3. Surgical interventions in patients with MDR-TB

In patients with rifampicin-resistant or multidrug-resistant TB, elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen (conditional recommendation, very low certainty in the evidence).

Duration of conventional MDR-TB treatment regimens

(remains valid 2011 guidelines)

• An intensive phase of 8 months is suggested for most patients and the duration may be modified according to the patient´s response to therapy (conditional recommendation, very low quality evidence)

• A total treatment duration of 20 months is suggested for most patients (conditional recommendation, very low quality evidence)

The main changes in the 2016 recommendations are as follows:

• a shorter MDR-TB treatment regimen is recommended under specific conditions

• medicines used in the design of conventional MDR-TB treatment regimens are now regrouped differently based upon current evidence on their effectiveness and safety. Clofazimine and linezolid are now recommended as core second-line medicines in the MDR-TB regimen while paminosalicylic acid is an Add-on agent

• MDR-TB treatment is recommended for all patients with rifampicin-resistant tuberculosis, regardless if isoniazid resistance is confirmed or not

• clarithromycin and other macrolides are no longer included among the medicines to be used for the treatment of MDR-TB

fluoroquinolones

• high-dose levofloxacin, moxifloxacin, and gatifloxacin

• significantly improves treatment outcomes in adults with rifampicin-resistant or multidrug-resistant TB

• this group of drugs is considered to be the most important component of the core MDR-TB regimen and the benefits from their use outweighs potential risks: they should therefore always be included unless there is an absolute contra-indication for their use

• the order of preference for the inclusion of the later-generation fluoroquinolones in MDR-TB regimens is as follows: high-dose levofloxacin, moxifloxacin and gatifloxacin

high-dose levofloxacin, usually defined as 750 mg/day or more

Eur Respir J 2015; 45: 1119–1131 | DOI: 10.1183/09031936.00162314

bedaquiline and delamanid have been conditionally approved for the treatment of MDR-TB

bedaquiline

• BDQ: medicamento nuevo para TB en 40 años!

• cuenta con autorización de utilización

• prometedora como componente de nuevos esquemas de tto de TB normosensible (interacciona con rifampicina!)

• sirturo ®, tablet 100 mg, Janssen Pharmaceutica

the recommended dose in adults is 400 mg once daily for 2 weeks, followed by 200 mg three times weekly, for a total duration of 24 weeks

delamanid

• DLM: junto con BDQ, los dos únicos medicamentos nuevos para TB en 40 años!

• ausencia de interacciones medicamentosas con antiretrovirales

• prolongación de intervalo QT: también BDQ, clofazimina, quinolonas…

• deltyba®, tablet 50 mg, Otsuka Pharmaceuticals

the recommended dose in adults is 100 mg twice daily for 2 months followed by 200 mg once daily for 4 months

micobacterias no tuberculosas

MNT

déficit de leptina

Clin Chest Med 36 (2015)

MNT


• Clinical

1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or an HRCT scan that shows multifocal bronchiectasis with multiple small nodules

and

2. Appropriate exclusion of other diagnoses

• Microbiologic

1. Positive culture results from at least two separate expectorated sputum samples. If the results from the initial sputum samples are nondiagnostic, consider repeat sputum AFB smears and cultures

or 2. Positive culture results from at least one bronchial wash or lavage

or 3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM

MNT

Griffith DE et al. Am J Respir Crit Care Med 2007

criteria for diagnosing NMT lung disease

enfermedad pulmonar: la + frecuente

• enfermedad fibrocavitaria

• bronquiectasias / enfermedad nodular

• neumonitis por hipersensibilidad

infecciones cutáneas tras inoculación

linfadenitis cervical en niños

enfermedad diseminada en pacientes gravemente inmunodeprimidos

MNT

enfermedad por MNT


fármacos

• los macrólidos (claritromicina y azitromicina) son los pilares del tratamiento de la mayoría de infecciones por MNT de crecimiento lento

• M fortuitum y M abscessus son a menudo resistentes a macrólidos, por la presencia del gen erm

• etambutol: neuritis óptica (ojo en ancianos y disminución de función renal)

• isoniacida: M xenopi y M kansasii

• tigeciclina: MNT de crecimiento rápido

• cefoxitina, imipenem

el tratamiento de las infecciones por NTM es largo, difícil y a veces ineficaz

MNT


MNT de crecimiento rápido

the goal of curative therapy is 12 months of culture negativity

• M. abscessus

– amikacina + imipenem / cefoxitina + claritromicina (2-4 meses)

– 3 fármacos (macrólido + fluoroquinolona, linezolid, clofazimina, o amikacina inhalada)

• M. chelonae

– tobramicina + imipenem

• M. fortuitum

– ¿aspiración? trastorno de la deglución, reflujo

– fluoroquinilona, doxiclina, minociclina, sulfonamidas…

MNT


MNT National Jewish Health, Denver •estudio restrospectivo, 69 pacientes, seguimiento 34 meses •media de 4,6 antibióticos (media de 6 meses de antibióticos IV) •74%, macrólido + amikacina IV 24 fueron IQ: y 15 (65%) negativizaron los cultivos

¿cirugía? •insuficiencia del tratamiento médico •lesiones cavitarias •hemoptisis masiva


MNT

the presence of cavitary disease was associated with a higher mortality than disease associated with nodules and bronchiectasis

¿amikacina inhalada?


MNT

the most easily treatable of the NTM pulmonary pathogens

in patients with multiple comorbidities and coinfections and perhaps as a result have high all-cause mortality

disease occurs most commonly in patients with underlying lung disease, such as chronic obstructive lung disease


aparición de resistencia a macrólidos

• la aparición de resistencia a macrólido por MAC se asocia a fallo del tratamiento y > mortalidad

factores de riesgo para desarrollar resistencia a macrólido:

• monoterapia con macrólido

• combinación de macrólido y quinolona sin tercer fármaco acompañante

¡ojo! monoterapia con macrólido para disminuir exacerbaciones en pacientes con EPOC y BQ no FQ

MNT


cirugía

¿cirugía?

• criterios dx de ATS/IDSA

• enfermedad localizada (focal) susceptible de resección

• reserva pulmonar adecuada

indicaciones

• después del fracaso del tto médico

• ¿resistencia a macrólidos?

• alivio de síntomas

• ¿hemoptisis?

• limitar / ralentizar la progresión de la enfermedad

• enfermedad bilateral pero enfermedad cavitaria unilateral

MNT


Tuberculosis - SOGAPAR

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