RNTCP guidelines for tuberculosis management: Extended versionRxVichuZ
This presentation is an extension of the already made presentation before, that deals with RNTCP guidelines for some special aspects encountered during tuberculosis management, other than management of individual diagnoses alone.
Have a look!
Hello Guys,
This presentation consists of the updated guidelines under National tuberculosis elimination programme of India (MOHFW). The presentation includes case definitions and diagnostic algorithms for Pulmonary, Extrapulmonary and Drug resistant TB(MDR/ XDR TB) and the tratment protocols in pediatric cases.
Hope you find it useful.
RNTCP guidelines for tuberculosis management: Extended versionRxVichuZ
This presentation is an extension of the already made presentation before, that deals with RNTCP guidelines for some special aspects encountered during tuberculosis management, other than management of individual diagnoses alone.
Have a look!
Hello Guys,
This presentation consists of the updated guidelines under National tuberculosis elimination programme of India (MOHFW). The presentation includes case definitions and diagnostic algorithms for Pulmonary, Extrapulmonary and Drug resistant TB(MDR/ XDR TB) and the tratment protocols in pediatric cases.
Hope you find it useful.
DRUG RESISTANT TUBERCULOSIS,DIAGNOSIS AND TREATMENTDr.Lalit Kumar
VERY USEFUL PRESENTATION TO LEARN THE BASICS OF MDR/XDR-TB AS WELL AS THEIR MANAGEMENT.MOST OF THE CONTENT ARE BASED ON THE RNTCP GUIDELINES AND WHO 2013 UPDATE....
Newer diagnostic methods in tuberculosis detectionApollo Hospitals
One-third of the world's population has been infected with Mycobacterium tuberculosis, with new infections occurring in about 1% of the population each year. However 90–95% of infections remain asymptomatic. Thus early diagnosis of tuberculosis and drug resistance improves survival and helps to promote contact tracing, implementation of institutional cross-infection procedures, and other public-health actions. There have been many advances and modifications to the methodology for tuberculosis diagnosis some of which are very promising. But these advances have not kept pace with the explosion of tuberculosis or the outbreak of drug resistant tuberculosis. This review describes some of the newer advances in tuberculosis diagnostics and the challenges they face.
Febrile neutropenia - Infections in cancer patientsAli Musavi
This powerpoint provides a summary of infections in neutropenic patients and febrile neutropenia. It contains the definition, etiology, approach, treatments, and recommendations from ESMO and IDSA guidelines.
adult vaccination, types of vaccine, forms of vaccine, active immunity, passive immunity, schedule of vaccination, CDC, contraindications, cost of vaccines
The bacteria that cause tuberculosis (TB) can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the 2 most powerful anti-TB drugs.
The 2 reasons why multidrug resistance continues to emerge and spread are mismanagement of TB treatment and person-to-person transmission. Most people with TB are cured by a strictly followed, 6-month drug regimen that is provided to patients with support and supervision. Inappropriate or incorrect use of antimicrobial drugs, or use of ineffective formulations of drugs (such as use of single drugs, poor quality medicines or bad storage conditions), and premature treatment interruption can cause drug resistance, which can then be transmitted, especially in crowded settings such as prisons and hospitals.
In some countries, it is becoming increasingly difficult to treat MDR-TB. Treatment options are limited and expensive, recommended medicines are not always available, and patients experience many adverse effects from the drugs. In some cases even more severe drug-resistant TB may develop. Extensively drug-resistant TB, XDR-TB, is a form of multidrug-resistant TB with additional resistance to more anti-TB drugs that therefore responds to even fewer available medicines. It has been reported in 117 countries worldwide.
Drug resistance can be detected using special laboratory tests which test the bacteria for sensitivity to the drugs or detect resistance patterns. These tests can be molecular in type (such as Xpert MTB/RIF) or else culture-based. Molecular techniques can provide results within hours and have been successfully implemented even in low resource settings.
New WHO recommendations aim to speed up detection and improve treatment outcomes for MDR-TB through use of a novel rapid diagnostic test and a shorter, cheaper treatment regimen. At less than US$ 1000 per patient, the new treatment regimen can be completed in 9–12 months. Not only is it less expensive than current regimens, but it is also expected to improve outcomes and potentially decrease deaths due to better adherence to treatment and reduced loss to follow-up.
Solutions to control drug-resistant TB are to:
cure the TB patient the first time around
provide access to diagnosis
ensure adequate infection control in facilities where patients are treated
ensure the appropriate use of recommended second-line drugs.
In 2015, an estimated 480 000 people worldwide developed MDR-TB, and an additional 100 000 people with rifampicin-resistant TB were also newly eligible for MDR-TB treatment. India, China, and the Russian Federation accounted for 45% of the 580 000 cases. It is estimated that about 9.5% of these cases were XDR-TB.
DRUG RESISTANT TUBERCULOSIS,DIAGNOSIS AND TREATMENTDr.Lalit Kumar
VERY USEFUL PRESENTATION TO LEARN THE BASICS OF MDR/XDR-TB AS WELL AS THEIR MANAGEMENT.MOST OF THE CONTENT ARE BASED ON THE RNTCP GUIDELINES AND WHO 2013 UPDATE....
Newer diagnostic methods in tuberculosis detectionApollo Hospitals
One-third of the world's population has been infected with Mycobacterium tuberculosis, with new infections occurring in about 1% of the population each year. However 90–95% of infections remain asymptomatic. Thus early diagnosis of tuberculosis and drug resistance improves survival and helps to promote contact tracing, implementation of institutional cross-infection procedures, and other public-health actions. There have been many advances and modifications to the methodology for tuberculosis diagnosis some of which are very promising. But these advances have not kept pace with the explosion of tuberculosis or the outbreak of drug resistant tuberculosis. This review describes some of the newer advances in tuberculosis diagnostics and the challenges they face.
Febrile neutropenia - Infections in cancer patientsAli Musavi
This powerpoint provides a summary of infections in neutropenic patients and febrile neutropenia. It contains the definition, etiology, approach, treatments, and recommendations from ESMO and IDSA guidelines.
adult vaccination, types of vaccine, forms of vaccine, active immunity, passive immunity, schedule of vaccination, CDC, contraindications, cost of vaccines
The bacteria that cause tuberculosis (TB) can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the 2 most powerful anti-TB drugs.
The 2 reasons why multidrug resistance continues to emerge and spread are mismanagement of TB treatment and person-to-person transmission. Most people with TB are cured by a strictly followed, 6-month drug regimen that is provided to patients with support and supervision. Inappropriate or incorrect use of antimicrobial drugs, or use of ineffective formulations of drugs (such as use of single drugs, poor quality medicines or bad storage conditions), and premature treatment interruption can cause drug resistance, which can then be transmitted, especially in crowded settings such as prisons and hospitals.
In some countries, it is becoming increasingly difficult to treat MDR-TB. Treatment options are limited and expensive, recommended medicines are not always available, and patients experience many adverse effects from the drugs. In some cases even more severe drug-resistant TB may develop. Extensively drug-resistant TB, XDR-TB, is a form of multidrug-resistant TB with additional resistance to more anti-TB drugs that therefore responds to even fewer available medicines. It has been reported in 117 countries worldwide.
Drug resistance can be detected using special laboratory tests which test the bacteria for sensitivity to the drugs or detect resistance patterns. These tests can be molecular in type (such as Xpert MTB/RIF) or else culture-based. Molecular techniques can provide results within hours and have been successfully implemented even in low resource settings.
New WHO recommendations aim to speed up detection and improve treatment outcomes for MDR-TB through use of a novel rapid diagnostic test and a shorter, cheaper treatment regimen. At less than US$ 1000 per patient, the new treatment regimen can be completed in 9–12 months. Not only is it less expensive than current regimens, but it is also expected to improve outcomes and potentially decrease deaths due to better adherence to treatment and reduced loss to follow-up.
Solutions to control drug-resistant TB are to:
cure the TB patient the first time around
provide access to diagnosis
ensure adequate infection control in facilities where patients are treated
ensure the appropriate use of recommended second-line drugs.
In 2015, an estimated 480 000 people worldwide developed MDR-TB, and an additional 100 000 people with rifampicin-resistant TB were also newly eligible for MDR-TB treatment. India, China, and the Russian Federation accounted for 45% of the 580 000 cases. It is estimated that about 9.5% of these cases were XDR-TB.
Tuberculosis Treatment Symposia - The CRUDEM Foundation presented in Milot, Haiti at Hôpital Sacré Coeur.
CRUDEM’s Education Committee (a subcommittee of the Board of Directors) sponsors one-week medical symposia on specific medical topics, i.e. diabetes, infectious disease. The classes are held at Hôpital Sacré Coeur and doctors and nurses come from all over Haiti to attend.
While the world was focused on covid 19, WHO has made and issued consolidated guidelines making changes in how to prevent, diagnose and treat tuberculosis.
Similar to Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013 (20)
HIV and Cardiovascular Disease.How Worried Should We Be ? 2015Hivlife Info
In this downloadable slideset, David A. Wohl, MD, reviews the association between HIV and cardiovascular disease, including potential contributing factors and best practices in prevention.
Format: Microsoft PowerPoint (.ppt)
File size: 5.01 MB
Date posted: 6/26/2015
In this downloadable slideset, Joel E. Gallant, MD, MPH, reviews the evidence behind the latest antiretroviral guidelines and offers a glimpse at upcoming agents currently under investigation.
Format: Microsoft PowerPoint (.ppt)
File size: 3.00 MB
Date posted: 6/15/2015
Cardiovascular Disease in HIV-Infected Patients.Predict It and Prevent It.2015Hivlife Info
In this downloadable slideset, Priscilla Y. Hsue, MD, and David A. Wohl, MD, discuss data on using traditional and newer markers and modalities to predict and prevent cardiovascular disease in HIV-infected patients.
Format: Microsoft PowerPoint (.ppt)
File size: 3.21 MB
Date posted: 7/16/2015
“Тяжелые” категории пациентов с хроническим гепатитом C- возможности терапии....Hivlife Info
“Тяжелые” категории пациентов с хроническим гепатитом C- возможности терапии.
Бакулин И.Г,д.м.н.2015 Зав. научно-исследовательским отделом гепатологии Московского клинического научно-практического центра ДЗ г. Москва
Integrating Recent Data When Selecting First-line Antiretroviral Therapy.2015...Hivlife Info
Joseph J. Eron Jr., MD
W. David Hardy, MD
Paul E. Sax, MD
How do leading experts select first-line antiretroviral therapy for their HIV-infected patients?
Review these downloadable slides for key clinical trial data and the latest DHHS recommendations for first-line antiretroviral therapy.
HCV Alerts- Rapid Response to Practice-Changing Advances From EASL 2015Hivlife Info
In this downloadable slideset, Mark S. Sulkowski, MD, discusses key practice-changing data from the 2015 liver disease meeting in Vienna.
Format: Microsoft PowerPoint (.ppt)
File size: 751 KB
This downloadable slideset summarizes key studies selected by Andrew J. Muir, MD, David R. Nelson, MD, and Norah Terrault, MD, MPH, regarding the use of investigational agents for treating hepatitis C presented at the 2015 Annual Meeting of the European Association for the Study of the Liver.
Format: Microsoft PowerPoint (.ppt)
File size: 1.99 MB
Grinspoon S.Сердечно-сосудистые заболевания у пациентов с ВИЧ- парадигма и пр...Hivlife Info
Grinspoon S Cardiovascular disease in HIV patients: an emerging paradigm and call to action. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 134, 2015.
Сердечно-сосудистые заболевания у пациентов с ВИЧ- парадигма и призыв к действию.Статины. [CROI 2015]
Fall 2014 HIV Update.Clinical Impact of New Data From ICAAC 2014, IDWeek 2014...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD and Jürgen K. Rockstroh, MD, review key HIV studies presented at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2014 IDWeek, and 2014 HIV Drug Therapy Glasgow.
Format: Microsoft PowerPoint (.ppt)
File size: 1.70 MB
Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- E...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD, and Daniel Kuritzkes, MD, review key data on the evolving use of INSTIs in patients beginning HIV therapy.
Format: Microsoft PowerPoint (.ppt)
File size: 2.29 MB
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Antimicrobial stewardship to prevent antimicrobial resistanceGovindRankawat1
India is among the nations with the highest burden of bacterial infections.
India is one of the largest consumers of antibiotics worldwide.
India carries one of the largest burdens of drug‑resistant pathogens worldwide.
Highest burden of multidrug‑resistant tuberculosis,
Alarmingly high resistance among Gram‑negative and Gram‑positive bacteria even to newer antimicrobials such as carbapenems.
NDM‑1 ( New Delhi Metallo Beta lactamase 1, an enzyme which inactivates majority of Beta lactam antibiotics including carbapenems) was reported in 2008
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
2. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
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and data before treating patients or using any therapies described in these materials.
3. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Faculty and Disclosure Information
Richard E. Chaisson, MD
Professor of Medicine,
Epidemiology and International
Health
Johns Hopkins University
Director, Johns Hopkins Center
for AIDS Research and Center
for Tuberculosis Research
Baltimore, Maryland
Richard E. Chaisson, MD, has disclosed that his spouse has
ownership interest in Merck.
Maunank Shah, MD, has no significant financial relationships to
disclose.
Maunank Shah, MD
Assistant Professor
Department of Infectious Disease
Johns Hopkins University
Medical Director
Tuberculosis Program
Baltimore City Health Department
Baltimore, Maryland
5. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Tuberculosis Drug Resistance: Definitions
Acquired drug resistance
– Selection of resistant mutants by inadequate treatment
Primary drug resistance
– Disease caused by an organism that was resistant when
infection was acquired
Multidrug-resistant TB
– Resistance to at least isoniazid and rifampin (and other
rifamycins)
Extensively drug–resistant TB
– MDR-TB plus resistance to fluoroquinolones and an
injectable agent (amikacin, kanamycin, capreomycin)
6. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Drug-Resistant TB: MDR and XDR
Drug-resistant TB first arises from improper treatment
– Wrong selection of drugs by doctors or poor adherence to treatment by
patients results in selection of naturally occurring mutants with innate
resistance
Patients with acquired drug-resistant TB can spread infection to
others, causing primary resistance in their contacts
In many countries, transmission of drug-resistant TB is now more
common than acquired resistance[1]
The key prevention strategies for drug-resistant TB are:
– Avoid creating new cases by treating TB properly and thoroughly
– Prevent transmission of infection through early and proper diagnosis and
infection control
1. WHO. 2013. Surveillance of drug resistance in tuberculosis.
7. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
MDR-TB: Epidemiology
In 2012, an estimated 450,000 new cases of MDR-TB emerged
globally[1]
Among all new cases of TB, 3.6% are estimated to have MDR-
TB[1]
An estimated 20% of persons with previously treated TB have
MDR-TB[1,2]
More than one half of the new MDR-TB cases occur in China,
India, and the Russian Federation[1]
Mortality in MDR-TB patients usually exceeds 10%[3]
In 2012, MDR-TB caused an estimated 170,000 deaths[1]
1. WHO. 2013. Update on MDR-TB. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
3. Wells CD. Curr Infect Dis Rep. 2010;12:192-197.
9. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
MDR-TB Among Previously Treated TB
Cases, 1994-2013
WHO. 2013. Surveillance of drug resistance in tuberculosis.
11. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Diagnosis of MDR-TB
Gold-standard test: Culture of patient specimen (sputum) to assess inhibition of M
tuberculosis growth in the presence of antibiotics (phenotypic assay)
Solid-media assays: Result may not be available for 3-6 wks
Automated liquid culture systems: Faster and more sensitive than solid-media
cultures; results available in 1-2 wks
Rapid molecular tests can identify genotypic resistance in 1-2 days
– Xpert TB/RIF identifies M tuberculosis and rifampin resistance using cartridge-based real-time
PCR
– Line-probe assays (eg, Hain GenoType) identify genotypic resistance to both isoniazid and
rifampin
1-2 days 1-2 wks 3-6 wks 4-12 wks
Average Turnaround Time for Diagnostic Tests
12. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
WHO Recommendations: Diagnosis of
MDR-TB
Xpert MTB/RIF should be used as the initial diagnostic test in
individuals suspected of MDR-TB[1]
However, Xpert MTB/RIF does not eliminate need for
conventional microscopy, culture, and DST to monitor treatment
progress and to detect resistance to drugs other than rifampin[1]
1. WHO. Xpert MTB/RIF system policy statement 2011.
2. Aurum Institute. Managing TB in a new era of diagnostics. 2012.
Xpert
Result[2]
Xpert Positive,
Rifampin
Susceptible
Xpert Positive,
Rifampin Resistant
Xpert Positive,
Rifampin
Unsuccessful
Xpert Negative Xpert
Unsuccessful
Interpretation Drug-sensitive TB Presumed MDR-TB Presumed
drug-sensitive TB
TB unlikely but
further investigation
necessary
No diagnosis
Actions Treat for drug-
sensitive TB;
collect sputum for
microscopy and
culture with DST
Treat with regimen for
MDR-TB; collect
sputum for TB
culture/DST
Treat for drug-
sensitive TB;
collect sputum for
microscopy and
culture with DST
Collect sputum for TB
microscopy and
culture to exclude TB
Collect sputum
for TB
microscopy and
culture to
exclude TB
13. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Performance of Xpert MTB/RIF vs Other
Diagnostic Modalities
Boehme C, et al. Lancet. 2011;377:1495-1505.
Proportion of TB Cases and Resistance Results by Each Method in Culture-Positive Patients
Liquid culture
MTB/RIF test
Solid culture
Microscopy
TBCasesDetected(%)
100
90
80
70
60
50
40
30
20
10
0
1000 20 40 60 80
Days to Detection
100%
90%
89%
67%
Line-probe assay
MTB/RIF test
Phenotypic drug-susceptibility
testing
0 20 40 60 80 100 120 140
Days to Detection
100%
94%
RIFResistanceDetected(%)
100
90
80
70
60
50
40
30
20
10
0
14. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Time to DST Results Halved With MDR
Line Probe Assay in South Africa
Time Period Median Time, Days (IQR) P Value
Before LPA After LPA
1 Sputum collection to lab
receipt of sample
1 (0-1) 0 (0-1) < .001
2 Lab receipt to DST testing 27 (21-34) 19 (12-31) < .001
Smear positive 26 (21-43) 13 (9-16) < .001
Smear negative 29 (22-43) 29 (22-42) .497
3 DST testing 9 (2-14) 0 (0-1) < .001
Total Sputum collection to DST
results available
52 (41-77) 26 (11-52) .008
Sputum
collection
Lab receipt
of sputum
DST started DST results
reported
1 2 3
Hanrahan CF, et al. PLoS One. 2012;7:e49898.
15. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Time to MDR Treatment Before and After
Line-Probe Assay in South Africa
From initial patient sputum sample to date of appropriate MDR therapy
Mos to MDR Treatment
80 2 4 6
1.00
0.75
0.50
0.25
0
CumulativeProportionon
MDRTreatment
After LPA
Before LPA (study data)
Before LPA (undetected MDR modeled)
Hanrahan CF, et al. PLoS One. 2012;7:e49898.
16. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Resistance at Start of Second-line TB Therapy
Drug Resistance, n (%)
First-line drugs
Ethambutol 826 (64.6)
Streptomycin 881 (69.0)
4 first-line drugs* 625 (49.0)
Second-line drugs
Any second-line drug 559 (43.7)
At least 1 fluoroquinolone 165 (12.9)
Second-line Injectable drugs
Kanamycin 237 (18.5)
Amikacin 205 (16.0)
Capreomycin 152 (12.0)
At least 1 255 (20.0)
All 134 (10.5)
Other oral second-line drug
Ethionamide 249 (19.5)
Aminosalicylic acid 137 (10.7)
At least 1 346 (27.1)
XDR-TB 86 (6.7)
PETTS Study: Prevalence of Drug
Resistance in 1278 Pts With MDR-TB
1278 pts enrolled in several
countries at start of second-line
TB treatment, 2005-2008
DST done centrally at CDC
High levels of resistance to
second-line drugs detected
– 43.7% with resistance to
≥ 1 second-line drug
– 20% with resistance to ≥ 1
injectable second-line drug
– 12.9% with resistance to
≥ 1 fluoroquinolone
– 6.7% with XDR-TB
Dalton T, et al. Lancet. 2012;380:1406-1417.
*Isoniazid, rifampin, ethambutol, streptomycin.
18. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
MDR-TB General Principles
An individualized approach should be undertaken
– Guided by drug susceptibility testing when available
– Assessment of comorbidities that may affect therapy should
be undertaken before therapy
Never add a single drug to a failing regimen
Use at least 3-5 previously unused drugs to which an
isolate has in vitro susceptibility
Supervise treatment to ensure adherence
Continue treatment for at least 18-24 mos after culture
conversion
WHO. Guidelines for programmatic management of drug-resistant TB. 2011.
Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.
19. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Drugs for MDR-TB
Group 1: First-line oral drugs
Ethambutol
Pyrazinamide
High-dose isoniazid
Group 2: Fluoroquinolones
Levofloxacin
Moxifloxacin
Gatifloxacin
Ofloxacin
Group 3: Injectable drugs
Kanamycin
Amikacin
Capreomycin
Streptomycin
Group 4: Oral bacteriostatic second-line drugs
Ethionamide
Prothionamide
Cycloserine/terizidone
Para-aminosalicylic acid
Group 5: Drugs of unclear efficacy
Clofazimine
Clarithromycin
Amoxicillin-clavulanate
Linezolid
Thiacetazone
Meropenem-clavulanate
Thioridazine
*Other newer drugs
Adapted from: Chang KC, et al. Respirology. 2013;18:8-21.
*Newer drugs will be discussed later in the educational activity.
20. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Building a Treatment Regimen for MDR-TB
Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for
clinicians. Chang KC, et al. Respirology. 2013;18:8-21.
Step 1: Include any first-line
drugs to which the isolate is
susceptible
Injectables
Kanamycin
Amikacin
Capreomycin
Streptomycin
Step 2: Add a fluoroquinolone
Fluoroquinolone
Levofloxacin
Moxifloxacin
Gatifloxacin
First-line Drugs
Ethambutol
Pyrazinamide
Step 3: Include an
injectable agent
Oral Second-line Drugs
Ethionamide
Prothionamide
Cycloserine/terizidone
Para-aminosalicylic acid
Third-line Drugs
Clofazimine
Clarithromycin
Amoxicillin-clavulanate
Linezolid
Thiacetazone
Meropenem-clavulanate
Thioridazine
Other new drugs
Step 4: Include second-line
drugs until you have 4-6
drugs to which the isolate is
susceptible
Consider third-line drugs if
there are not 4-6 drugs to
which the isolate is
susceptible
21. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Treatment Regimens for MDR-TB
Resistance Pattern Regimen Comments
INH and RIF Strept PZA + EMB + FQN + injectable (for
≥ 6 mos) + second-line agent if
extensive disease
Treat 18-24 mos following
conversion
INH, RIF + (PZA or
EMB)
(PZA or EMB) + FQN + 2 second-
line agents + injectable agent (for
first 6 mos)
Treat 18-24 mos following
conversion;
consider additional agents,
high-dose INH
INH, RIF, PZA, EMB FQN + 3 second-line agents +
injectable drug for first 6-12 mos
Treat 18-24 mos following
conversion
INH, RIF, PZA, EMB,
FQN
Injectable + 3 second-line agents +
third-line agents
Treat 24 mos following conversion;
consider high-dose INH,
Surgery
INH, RIF, PZA, EMB,
injectables
FQN + all available second-line
agents; consider any third-line
agents if susceptible
Treat 24 mos following conversion;
consider surgery
Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for
clinicians.
22. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
“Bangladesh” Regimen: Experimental
Short-Course Treatment for MDR-TB
Controlled trial under way to confirm the efficacy of this regimen
van Deun A, et al. Am J Respir Crit Care Med. 2010;182:684-692.
*Resistance likely for many MDR patients.
Phase Drugs
4-mo intensive phase High-dose INH*
Prothionamide*
Kanamycin
Gatifloxacin
Ethambutol*
Pyrazinamide*
Clofazimine
5-mo continuation phase Gatifloxacin
Ethambutol*
Pyrazinamide*
Clofazimine
23. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Potency and Tolerability of Existing TB
Drugs
Dorman SE, et al. Nat Med. 2007;13:295-298.
Increasing potency,
reliability,
reproducibility of
susceptibility testing
Decreasing
tolerability
First-line
Drugs
Second-line
Drugs
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Fluoroquinolones
(moxifloxacin, gatifloxacin,
levofloxacin)
Injectable agents
Aminoglycosides (streptomycin,
amikacin, kanamycin)
Polypeptides (capreomycin)
Oral bacteriostatic agents
(ethionamide, protionamide, cycloserine/
terizidone, p-aminosalicylic acid, thiacetazone)
Agents with unclear efficacy (clofazimine,
amoxicillin-clavulanate, clarithromycin, linezolid)
24. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Adverse Effects of MDR-TB Drugs
Drug Toxicities and Adverse Effects
Ethambutol Visual acuity, color vision
Pyrazinamide Hepatotoxicity
Isoniazid Neurologic effects, hepatotoxicity
Injectables Vestibular, renal toxicity, hearing loss
Fluoroquinolones GI, CNS, cardiac toxicities, tendinopathy
Cycloserine/terizidone CNS toxicity, behavioral changes
Ethionamide GI toxicity, hypothyroidism
PAS GI toxicity, hypothyroidism, osteoarticular pain.
Clofazimine Changes in skin and ocular pigmentation, GI effects
Linezolid Thrombocytopenia, neutropenia, neuropathy, metallic taste
Aurum Institute. Managing TB in a new era of diagnostics. 2012.
26. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Bedaquiline
Oral diarylquinoline
Target: ATP synthase
– Activity specific to mycobacteria
Bactericidal activity
comparable to RIF-INH-PZA
in mice
Sterilizing activity comparable
to rifampin in mice
Synergy with PZA
No cross-resistance with other antimycobacterial drugs (INH, RIF,
EMB, PZA, streptomycin, amikacin, or moxifloxacin)
Andreas K, et al. Science. 2005;307:223-227. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
Br
N O
(S)
H
O(R) N
27. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
C208: Phase II Trial of Bedaquiline for
MDR-TB
Stage I study: 47 pts with newly
diagnosed pulmonary MDR-TB
randomized to bedaquiline or
placebo in combination with
5-drug second-line TB regimen
– BDQ dose: 400 mg QD for
2 wks, then 200 mg TIW for
6 wks
BL resistance: pyrazinamide,
65%; ethambutol, 59%;
kanamycin, 8%; ofloxacin, 8%;
ethionamide, 8%
BDQ reduced time to culture
conversion (HR: 11.8; 95% CI:
2.3-61.3; P = .003)
Incidence of AEs similar
between arms
– Nausea more frequent in
BDQ vs placebo: 26% vs 4%
(P = .04).Diacon AH, et al. N Engl J Med. 2009;360:2397.
0
0.2
0.4
0.6
0.8
1.0
0 7 42
Culture-PositivePatients(%)
14 21 28 35 49 56
Placebo (n = 24)
Bedaquiline (n = 23)
Days
52%
91%
28. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
C208: Phase II Trial of Bedaquiline for
MDR-TB
Stage II study: 15 sites in Brazil,
India, Latvia, Peru, Philippines,
Russia, South Africa, Thailand
Pts randomized to receive BDQ
(n = 67) vs placebo (n = 66) for
24 wks with 5-drug BR
– BDQ dose: 400 mg QD for
2 wks, then 200 mg TIW for
22 wks
After Wk 24, both groups
continued the 5-drug BR to
total of 96 wks
Culture conversion at Wk 24
significantly higher with
bedaquiline vs placebo
Cure rate also significantly
higher
WHO. The use of BDQ in treatment of MDR-TB—interim policy guidance. 2013.
Outcome BDQ Placebo P Value
Median time to
sputum conversion,
days (95% CI)
83
(56-97)
125
(98-168)
< .0001
Pts with culture
conversion, %
Wk 24
Wk 72
Wk 120
78.8
71.2
62.1
57.6
56.1
43.9
.008
.069
.035
Proportion cured, % 57.6 31.8 .003
29. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
FDA Bedaquiline Indication
Approved by FDA in 2012 as part of combination therapy
in adults with pulmonary MDR-TB
– Should be used only when an effective treatment regimen
cannot otherwise be provided[1]
Recommended dose: 400 mg PO QD for 2 wks, then
200 mg PO TIW, for a total duration of 24 wks
First drug with novel mechanism approved by FDA for TB
since 1971
Bedaquiline [package insert].
30. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
CDC Provisional Guidance on Bedaquiline
BDQ may be used as a component of TB therapy when an
effective treatment regimen cannot otherwise be provided
– Administer by DOT for 24 wks with food in adults with
laboratory-confirmed pulmonary MDR-TB
– Use on case-by-case basis in children, HIV-positive pts,
pregnant women, pts with extrapulmonary MDR-TB, and pts
with comorbid conditions on concomitant medications
– Use on case-by-case basis for durations > 24 wks
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
31. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
WHO Interim Guidance on Use of
Bedaquiline
BDQ may be added to a WHO-recommended regimen in
adult MDR-TB patients under following conditions:
– When an effective treatment regimen containing 4 second-
line drugs in addition to PZA, according to WHO
recommendations, cannot be designed
– When there is documented resistance to any fluoroquinolone
in addition to MDR
– Recommended for adults older than 18 yrs of age under
carefully monitored conditions
WHO. Bedaquiline for MDR-TB. 2013.
32. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Bedaquiline Safety Concerns
Black box warning: increase in all-cause mortality and
prolongation of QT interval—monitor EKGs[1]
– 30 deaths occurred in the clinical trial program in patients
receiving BDQ vs 6 on placebo[2]
BDQ should be used with caution with other drugs that
can cause QT interval prolongation and EKGs should be
monitored more often[1]
– Includes clofazimine and fluoroquinolones
BDQ should not be used with rifampin or rifapentine,
which are strong inducers of CYP3A4[1]
1. Bedaquiline [package insert]. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
33. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Bedaquiline Monitoring
All patients should be monitored wkly for adverse effects
EKGs should be monitored at baseline and at least 2, 12, and 24 wks after
starting treatment
Serum potassium, calcium, and magnesium should be measured at baseline
and whenever clinically indicated, especially if QT interval prolongation is
detected
All patients started should be included in a registry for ongoing monitoring
Additional notes:
– Bedaquiline should never be used as a single drug
– Bedaquiline has a long terminal half-life of 4-5 mos; should be discontinued before
other drugs in regimen
– Rifamycins and other CYP3A4 inducers reduce bedaquiline concentrations
– Bioavailability is significantly affected by food
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
34. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Delamanid (OPC-67683)
Nitro-dihydro-imidazooxazole
Derivative of metronidazole
Inhibits mycolic acid synthesis
Potent preclinical in vitro and in vivo activity against both
drug-susceptible and drug-resistant strains of TB
Skripconoka V, et al. Eur Respir J. 2013;41:1393-1400.
N
O
O
F
F
FO
OO
O
N+
N
N
35. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Delamanid: Phase II Trial vs Placebo
Multinational trial of pts with
pulmonary MDR-TB
Pts randomized to 2 mos of
– Delamanid 100 mg (n = 161)
– Delamanid 200 mg (n = 160)
– Placebo (n = 160)
– Each with WHO BR
Primary endpoint: sputum
culture conversion at 2 mos
Delamanid significantly
increased rate of sputum
conversion vs placebo after
2 mos of treatment
QT prolongation reported
significantly more frequently
with delamanid
All other AEs mild to moderate
and similar among groupsGler MT, et al. N Engl J Med. 2012;366:2151-2163.
Patients(%)
41.9
29.6
45.4
100
80
60
40
20
0
Delamanid
200 mg
Delamanid
100 mg
Placebo
57/136 37/12564/141
P = .04
P = .008
n/N =
Mycobacterial Growth Indicator Tube
Culture Conversion at Day 57
36. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
EMEA Delamanid Recommendation
In November 2013, the European Committee for Medicinal
Products for Human Use recommended granting a
conditional marketing authorization for delamanid for the
treatment of MDR-TB
Recommended indication:
– Use as part of an appropriate combination regimen for
pulmonary MDR-TB in adult patients when an effective
treatment regimen cannot otherwise be composed for
reasons of resistance or tolerability
EMEA. Marketing authorization for delamanid. November 2013.
37. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Linezolid
Oxazolidinone, approved to treat
drug-resistant, Gram-positive bacteria
Good activity against MDR-TB in vitro and in animal studies
Use in TB often limited due to long-term toxicities (bone marrow
suppression, neuropathy)
However, retrospective chart review (2003-2007) of 30 pts (29 with
pulmonary TB) who received linezolid 600 mg QD (plus vitamin B6) as
part of a regimen for MDR-TB concluded[1]:
– Culture conversion occurred in all pulmonary cases at median of 7 wks
– AEs occurred in only 9 patients, including peripheral and optic neuropathy,
anemia/thrombocytopenia, rash, and diarrhea
– Only 3 patients stopped linezolid treatment because of AEs
1. Schecter GF, et al. Clin Infect Dis. 2010;50:49-55.
F
O
N
N
O
O O
N
H
38. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Linezolid 600 mg QD
immediately*
Linezolid 600 mg QD
delayed by 2 mos*
Pts with sputum-
culture–positive XDR-
TB (no response to
any TB drugs in
previous 6 mos)
(N = 41)
Smear conversion or 4 mos
*All pts remained on background regimen of drugs they were taking before study entry.
Second randomization continued at least 18 mos after smear conversion or after 4 mos on first regimen.
Linezolid 600 mg QD
22 mos
Linezolid 300 mg QD
Lee M, et al. N Engl J Med 2012;367:1508-1518.
Phase II Trial of Linezolid in Patients With
XDR-TB
Phase II trial in South Korea
Primary endpoint: time to sputum-culture conversion on solid medium (data
censored 4 mos after study entry)
Linezolid 600 mg QD
Linezolid 300 mg QD
39. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Phase II Trial of Linezolid in Patients With
XDR-TB
Culture conversion at 4 mos:
– 79% (15/19) in immediate arm
vs 35% (7/20) in delayed arm
(P = .001)
87% (34/39) with negative
sputum culture within 6 mos
31 pts (82%) with clinically
significant AEs related to LZD
– 3 pts d/c therapy
Pts on LZD 300 mg on second
randomization had fewer AEs
13 pts completed therapy
without relapse
4 pts acquired LZD resistance
Lee M, et al. N Engl J Med. 2012;367:1508-1518.
1.0
0.8
0.6
0.4
0.2
0
0 30 60 90 120 150 180
Days Since Start of LZDCumulativeProbability
ofConversion
Conversion Probability
According to Time on Treatment
40. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Sutezolid (PNU-100480)
Oxazolidinone, related to linezolid
MOA: protein synthesis inhibition[1]
Like LZD, has a high barrier to
resistance
More potent than LZD in mice,
whole blood culture
Efficacy in mice similar to isoniazid and/or rifampin and may be
synergistic with other first-line drugs
May be safer than LZD
S
N
F
O
N O
OH
N
H
CH3
1. Alffenaar JW, et al. Antimicrob Agents Chemother. 2011;55:1287-1289.
41. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Early Bactericidal Activity of Sutezolid in
HIV+/- Pts With Drug-Susceptible TB
Significant log CFU reductions with
both sutezolid regimens during the
14-day treatment period
– 600 mg BID: -0.09 log/day
(90% CI: -0.06 to -0.11)
– 1200 mg QD: -0.07 log/day
(90% CI: -0.04 to -0.09)
– Trend toward superior response
with BID dosing
Both dosing schedules generally
safe and relatively well tolerated
– 7/50 sutezolid-treated pts
experienced ALT increases to
2-3 x ULN, which were
asymptomatic and resolved
spontaneously
Wallis RS, et al. AIDS 2012. Abstract THLBB02. Graphic used with permission.
0
-1
-2
-3
140 2 4 6 8 10 12
Day
ChangeinlogCFU 1200 QD
600 BID
HREZ
42. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
PA-824
PA-824: nitroimidazole-oxazine
– Active in vitro and in mouse
models
Cross-resistant with delamanid
High protein binding may render PA-824 less accessible in
cavities of pulmonary TB
May be useful in combination regimens; synergistic with
other drugs
F
F F
O
O
O
O
ON
N+
43. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Novel Drug Combinations With PA-824
Show Promise in Mouse Models
PA-824 with moxifloxacin and
pyrazinamide cures TB more
rapidly than the first-line regimen in
mice[1]
Bedaquiline + PA-824 + sutezolid
may provide a novel 3-drug
backbone for a universally active
short-course regimen[2]
Regimen
(Duration)
Mice Cured, % (n/N)
4 Mos 5 Mos 6 Mos
RIF-INH-PZA (2
mos) + RIF-INH (4
mos)
50
(10/20)
100
(20/20)
100
(20/20)
RIF-MXF-PZA (2
mos) + RIF-MXF (3
mos)
95
(19/20)
100
(20/20)
100
(20/20)
Pa-MXF-PZA (2
mos) + Pa-MXF (4
mos)
100
(20/20)
100
(20/20)
100
(20/20)
Regimen
Relapse, % (n/N) After Tx for
2 Mos 3 Mos 4 Mos
RIF + PZA +
INH
ND
100
(15/15)
64
(9/14)
BDQ + SUT +
CFZ + Pa
93
(14/15)
13
(2/15)
7
(1/15)
BDQ + SUT +
CFZ
87
(13/15)
27
(4/15)
7
(1/14)
BDQ + SUT +
Pa
100
(15/15)
43
(6/14)
0
(0/15)
BDQ + CFZ +
Pa
100
(15/15)
60
(9/15)
33
(5/15)
SUT + CFZ +
Pa
100
(15/15)
100
(15/15)
100
(15/15)
1. Nuermberger EL, et al. Antimicrob Agents
Chemother. 2008;52:1522-1524. 2. Williams K, et al.
Antimicrob Agents Chemother. 2012;56:3114-3120.
44. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
HIV-negative or
HIV-positive pts* with
newly diagnosed
pulmonary smear and
culture-positive drug-
sensitive TB
(N = 83)
Day 14
Early Bactericidal Activity of Novel
Combinations of TB Drugs
Phase II trial in TB-infected pts
Diacon AH, et al. Lancet. 2012;380:986-993.
Bedaquiline + Pyrazinamide
(n = 15)
Bedaquiline + PA-824
(n = 15)
PA-824 + Pyrazinamide
(n = 15)
Rifampin/Isoniazid/Ethambutol/Pyrazinamide
(n = 8)
Bedaquiline
(n = 15)
PA-824 + Pyrazinamide + Moxifloxacin
(n = 15)
*6 HIV-positive subjects.
45. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Early Bactericidal Activity of Novel TB
Regimens
0.5
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0 142 4 6 8 10 12
Day
LogCFUChangeFromBaseline
Bedaquiline
Bedaquiline + PZA
Bedaquiline + PA-824
RHEZ
PA-824 + PZA
PA-824 + PZA + moxifloxacin
Diacon AH, et al. Lancet. 2012;380:986-993.
Standard-of-
care regimen
Novel PA-824/
PZA/moxifloxacin
regimen
46. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Prevention of MDR-TB
Prevention of MDR-TB involves adequate, proper treatment of
initial disease to prevent selection of resistance
– Prompt diagnosis with adequate TB treatment under DOT
– Rapid identification of MDR-TB and use of appropriate second-line
regimens
– Avoid further evolution of resistance
– Airborne infection control
– Preventive treatment of TB/HIV coinfection with optimal use of
ART
Management strategies for established cases mainly rely on
specific alternative treatment regimens complemented with
surgery in carefully selected cases
47. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Preventive Therapy in Contacts of Pts
With MDR-TB in Micronesia
232 contacts of 5 pts with 2 different MDR-TB strains
105 with positive TST received preventive therapy
Strain A: resistant to isoniazid, rifampin, pyrazinamide,
ethambutol, and streptomycin
– Contacts offered fluoroquinolone alone or in combination
with ethionamide
Strain B: resistant to isoniazid, rifampin, and ethionamide
– Contacts offered fluoroquinolone with ethambutol
No cases of MDR-TB developed in those treated
– 28 untreated contacts developed MDR-TB
ECDC. Management of contacts of MDR TB and XDR TB patients. 2012.
48. clinicaloptions.com/hiv
Recent Advances in Multidrug-Resistant TB
Conclusions
Current approaches to MDR-TB therapy are long, with
much toxicity
Bedaquiline is the first drug with a novel mechanism of
action to be approved by FDA for MDR-TB since 1971
Delamanid recently approved by European Medicines
Agency
– Both agents indicated only when an effective regimen
cannot otherwise be provided
Multiple new drugs are in the pipeline
Successful eradication of MDR-TB will require new drug
regimens with novel drug combinations
49. Go Online for More CCO
Educational Content on Multidrug-
Resistant TB!
Interactive Virtual Presentation featuring streaming narration of these
slides by expert faculty Richard E. Chaisson, MD, and Maunank Shah,
MD
clinicaloptions.com/hiv