International Standards for Tuberculosis Care

Home » Cyber Lectures » Community Medicine » International Standards for Tuberculosis Care

Download file pdf ISTC_report_FINAL

Developed by the Tuberculosis Coalition for Technical Assistance (TBCTA)

Funded by the United States Agency for International Development (USAID)

Endorsements:

For an updated list of endorsers, see the Francis J. Curry National Tuberculosis Center website at http://www.nationaltbcenter.edu/international/ or the Stop TB Partnership website at http://www.stoptb.org/.

Disclaimer:

Disclaimer: The information provided in this document is not official U.S. Government
information and does not represent the views or positions of the U.S. Agency for International
Development or the U.S. Government.

Suggested citation:

Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis
Care (ISTC). The Hague: Tuberculosis Coalition for Technical Assistance, 2006.

Summary

In addition to healthcare providers and government tuberculosis programs, both patients
and communities are part of the intended audience. Patients are increasingly aware of
and expect that their care will measure up to a high standard as described in the Patients’
Charter for Tuberculosis Care. Having generally agreed-upon standards will empower
patients to evaluate the quality of care they are being provided. Good care for individuals
with tuberculosis is also in the best interest of the community.
The Standards are intended to be complementary to local and national tuberculosis control
policies that are consistent with World Health Organization (WHO) recommendations.
They are not intended to replace local guidelines and were written to accommodate local
differences in practice. They focus on the contribution that good clinical care of individual
patients with or suspected of having tuberculosis makes to population-based tuberculosis
control. A balanced approach emphasizing both individual patient care and public
health principles of disease control is essential to reduce the suffering and economic
losses from tuberculosis.

The Standards should be viewed as a living document that will be revised as technology,
resources, and circumstances change. As written, the Standards are presented within a
context of what is generally considered to be feasible now or in the near future.
The Standards are also intended to serve as a companion to and support for the Patients’
Charter for Tuberculosis Care developed in tandem with the Standards. The Charter
specifies patients’ rights and responsibilities and will serve as a set of standards from
the point of view of the patient, defining what the patient should expect from the provider
and what the provider should expect from the patient.

Standards for Diagnosis

Standard 1. All persons with otherwise unexplained productive cough lasting two–three
weeks or more should be evaluated for tuberculosis.

Standard 2. All patients (adults, adolescents, and children who are capable of producing
sputum) suspected of having pulmonary tuberculosis should have at
least two, and preferably three, sputum specimens obtained for microscopic
examination. When possible, at least one early morning specimen
should be obtained.

Standard 3. For all patients (adults, adolescents, and children) suspected of having
extrapulmonary tuberculosis, appropriate specimens from the suspected
sites of involvement should be obtained for microscopy and, where
facilities and resources are available, for culture and histopathological
examination.

Standard 4. All persons with chest radiographic fi ndings suggestive of tuberculosis
should have sputum specimens submitted for microbiological examination.

Standard 5. The diagnosis of sputum smear-negative pulmonary tuberculosis should
be based on the following criteria: at least three negative sputum smears
(including at least one early morning specimen); chest radiography fi ndings
consistent with tuberculosis; and lack of response to a trial of broadspectrum
antimicrobial agents. (NOTE: Because the fl uoroquinolones are
active against M. tuberculosis complex and, thus, may cause transient
improvement in persons with tuberculosis, they should be avoided.) For
such patients, if facilities for culture are available, sputum cultures should
be obtained. In persons with known or suspected HIV infection, the diagnostic
evaluation should be expedited.

Standard 6. The diagnosis of intrathoracic (i.e., pulmonary, pleural, and mediastinal or
hilar lymph node) tuberculosis in symptomatic children with negative sputum
smears should be based on the fi nding of chest radiographic abnormalities
consistent with tuberculosis and either a history of exposure to an
infectious case or evidence of tuberculosis infection (positive tuberculin
skin test or interferon gamma release assay). For such patients, if facilities
for culture are available, sputum specimens should be obtained (by expectoration,
gastric washings, or induced sputum) for culture.

Standard 7. Any practitioner treating a patient for tuberculosis is assuming an important
public health responsibility. To fulfi ll this responsibility the practitioner must
not only prescribe an appropriate regimen but, also, be capable of assessing
the adherence of the patient to the regimen and addressing poor
adherence when it occurs. By so doing, the provider will be able to ensure
adherence to the regimen until treatment is completed.

Standard 8. All patients (including those with HIV infection) who have not been treated
previously should receive an internationally accepted fi rst-line treatment
regimen using drugs of known bioavailability. The initial phase should consist
of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol.
The preferred continuation phase consists of isoniazid and rifampicin given
for four months. Isoniazid and ethambutol given for six months is an alternative
continuation phase regimen that may be used when adherence
cannot be assessed, but it is associated with a higher rate of failure and
relapse, especially in patients with HIV infection.

The doses of antituberculosis drugs used should conform to international
recommendations. Fixed-dose combinations of two (isoniazid and rifampicin,
three (isoniazid, rifampicin, and pyrazinamide), and four (isoniazid,
rifampicin, pyrazinamide, and ethambutol) drugs are highly recommended,
especially when medication ingestion is not observed.

Standard 9. To foster and assess adherence, a patient-centered approach to administration
of drug treatment, based on the patient’s needs and mutual respect
between the patient and the provider, should be developed for all patients.
Supervision and support should be gender-sensitive and age-specifi c and
should draw on the full range of recommended interventions and available
support services, including patient counseling and education. A central
element of the patient-centered strategy is the use of measures to assess
and promote adherence to the treatment regimen and to address poor adherence
when it occurs. These measures should be tailored to the individual
patient’s circumstances and be mutually acceptable to the patient and
the provider. Such measures may include direct observation of medication
ingestion (directly observed therapy—DOT) by a treatment supporter who
is acceptable and accountable to the patient and to the health system.

Standard 10. All patients should be monitored for response to therapy, best judged in
patients with pulmonary tuberculosis by follow-up sputum microscopy (two
specimens) at least at the time of completion of the initial phase of treatment
(two months), at fi ve months, and at the end of treatment. Patients
who have positive smears during the fi fth month of treatment should be
considered as treatment failures and have therapy modifi ed appropriately.
(See Standards 14 and 15.) In patients with extrapulmonary tuberculosis
and in children, the response to treatment is best assessed clinically.

Follow-up radiographic examinations are usually unnecessary and may be
misleading.

Standard 11. A written record of all medications given, bacteriologic response, and
adverse reactions should be maintained for all patients.

Standard 12. In areas with a high prevalence of HIV infection in the general population
and where tuberculosis and HIV infection are likely to co-exist, HIV
counseling and testing is indicated for all tuberculosis patients as part of
their routine management. In areas with lower prevalence rates of HIV, HIV
counseling and testing is indicated for tuberculosis patients with symptoms
and/or signs of HIV-related conditions and in tuberculosis patients
having a history suggestive of high risk of HIV exposure.

Standard 13. All patients with tuberculosis and HIV infection should be evaluated to determine
if antiretroviral therapy is indicated during the course of treatment
for tuberculosis. Appropriate arrangements for access to antiretroviral
drugs should be made for patients who meet indications for treatment.
Given the complexity of co-administration of antituberculosis treatment
and antiretroviral therapy, consultation with a physician who is expert in
this area is recommended before initiation of concurrent treatment for tuberculosis
and HIV infection, regardless of which disease appeared fi rst.
However, initiation of treatment for tuberculosis should not be delayed.
Patients with tuberculosis and HIV infection should also receive cotrimoxazole
as prophylaxis for other infections.

Standard 14. An assessment of the likelihood of drug resistance, based on history of
prior treatment, exposure to a possible source case having drug-resistant
organisms, and the community prevalence of drug resistance, should be
obtained for all patients. Patients who fail treatment and chronic cases
should always be assessed for possible drug resistance. For patients in
whom drug resistance is considered to be likely, culture and drug susceptibility
testing for isoniazid, rifampicin, and ethambutol should be performed
promptly.

Standard 15. Patients with tuberculosis caused by drug-resistant (especially multipledrug
resistant [MDR]) organisms should be treated with specialized regimens
containing second-line antituberculosis drugs. At least four drugs
to which the organisms are known or presumed to be susceptible should
be used, and treatment should be given for at least 18 months. Patientcentered
measures are required to ensure adherence. Consultation with
a provider experienced in treatment of patients with MDR tuberculosis
should be obtained.

Standard 16. All providers of care for patients with tuberculosis should ensure that persons
(especially children under 5 years of age and persons with HIV infection)
who are in close contact with patients who have infectious tuberculosis
are evaluated and managed in line with international recommendations.
Children under 5 years of age and persons with HIV infection who have
been in contact with an infectious case should be evaluated for both latent
infection with M. tuberculosis and for active tuberculosis.

Standard 17. All providers must report both new and retreatment tuberculosis cases and
their treatment outcomes to local public health authorities, in conformance
with applicable legal requirements and policies.

Research Needs

As part of the process of developing the ISTC, several key areas that require additional
research were identifi ed. Systematic reviews and research studies (some of which are
underway currently) in these areas are critical to generate evidence to support rational
and evidence-based care and control of tuberculosis. Research in these operational and
clinical areas serves to complement ongoing efforts focused on developing new tools for
tuberculosis control.

Introduction

Purpose

The purpose of the International Standards
for Tuberculosis Care (ISTC) is to describe a
widely accepted level of care that all practitioners,
public and private, should seek to
achieve in managing patients who have,
or are suspected of having, tuberculosis.
The Standards are intended to facilitate
the effective engagement of all care
providers in delivering high-quality care
for patients of all ages, including those
with sputum smear-positive, sputum
smear-negative, and extrapulmonary
tuberculosis, tuberculosis caused by
drug-resistant Mycobacterium tuberculosis
complex (M. tuberculosis) organisms,
and tuberculosis combined
with HIV infection. A high standard of
care is essential to restore the health of
individuals with tuberculosis, to prevent
the disease in their families and others with
whom they come into contact, and to protect the health of communities.1 Substandard
care will result in poor patient outcomes, continued infectiousness with transmission of M.
tuberculosis to family and other community members, and generation and propagation of
drug resistance. For these reasons, substandard care is not acceptable.
The standards in this document differ from existing guidelines in that standards present
what should be done, whereas, guidelines describe how the action is to be accomplished.
Standards provide the foundation on which care can be based; guidelines
provide the framing for the whole structure of care. Guidelines and standards are, thus,
complementary to one another. A standard does not provide specifi c guidance on disease
management but, rather, presents a principle or set of principles that can be applied
in nearly all situations. In general, standards do not require adaptation to local circumstances.
Guidelines must be tailored to local conditions. In addition, a standard can be
used as an indicator of the overall adequacy of disease management against which individual
or collective practices can be measured, whereas guidelines are intended to assist
providers in making informed decisions about appropriate health interventions.2
The basic principles of care for persons with, or suspected of having, tuberculosis are
the same worldwide: a diagnosis should be established promptly and accurately; standardized
treatment regimens of proven effi cacy should be used with appropriate treatment
support and supervision; the response to treatment should be monitored; and the
essential public health responsibilities must be carried out. Prompt, accurate diagnosis
and effective treatment are not only essential for good patient care—they are the key elements
in the public health response to tuberculosis and are the cornerstone of tuberculosis control. Thus, all providers who undertake evaluation and treatment of patients with
tuberculosis must recognize that, not only are they delivering care to an individual, they
are assuming an important public health function that entails a high level of responsibility
to the community, as well as to the individual patient. Adherence to the standards in this
document will enable these responsibilities to be fulfilled.
h4. Audience

The Standards are addressed to all healthcare providers, private and public, who care for
persons with proven tuberculosis or with symptoms and signs suggestive of tuberculosis.
In general, providers in government tuberculosis programs that follow existing international
guidelines are in compliance with the Standards. However, in many instances (as
described under Rationale), clinicians (both private and public) who are not part of a tuberculosis
control program lack the guidance and systematic evaluation of outcomes provided
by government control programs, and, commonly, would not be in compliance with
the Standards. Thus, although government program providers are not exempt from adherence
to the Standards, non-program providers are the main target audience. It should
be emphasized, however, that national and local tuberculosis control programs may need
to develop policies and procedures that enable non-program providers to adhere to the
Standards. Such accommodations may be necessary, for example, to facilitate treatment
supervision and contact investigations.

In addition to healthcare providers and government tuberculosis programs, both patients
and communities are part of the intended audience. Patients are increasingly aware of
and expect that their care will measure up to a high standard as described in the Patients’
Charter for Tuberculosis Care. Having generally agreed-upon standards will empower
patients to evaluate the quality of care they are being provided. Good care for individuals
with tuberculosis is also in the best interest of the community. Community contributions to
tuberculosis care and control are increasingly important in raising public awareness of the
disease, providing treatment support, encouraging adherence, reducing the stigma associated
with having tuberculosis, and demanding that healthcare providers in the community
adhere to a high standard of tuberculosis care.3 The community should expect
that care for tuberculosis will be up to the accepted standard.

Scope

Three categories of activities are addressed by the Standards: diagnosis, treatment, and
public health responsibilities of all providers. Specifi c prevention approaches, laboratory
performance, and personnel standards are not addressed. The Standards are intended
to be complementary to local and national tuberculosis control policies that are consistent
with World Health Organization (WHO) recommendations. They are not intended to replace
local guidelines and were written to accommodate local differences in practice. They
focus on the contribution that good clinical care of individual patients with, or suspected
of having, tuberculosis makes to population-based tuberculosis control. A balanced approach
emphasizing both individual patient care and public health principles of disease
control is essential to reduce the suffering and economic losses from tuberculosis.

To meet the requirements of the Standards, approaches and strategies (guidelines), determined
by local circumstances and practices and developed in collaboration with local
and national public health authorities, will be necessary. There are many situations in
which the level of care can, and should, go beyond what is specifi ed in the Standards.
Local conditions, practices, and resources also will determine the degree to which this is
the case.

The Standards are also intended to serve as a companion to and support for the Patients’
Charter for Tuberculosis Care (http://www.worldcarecouncil.org) developed in tandem
with the ISTC. This Charter specifi es patients’ rights and responsibilities and will serve as
a set of standards from the point of view of the patient, defi ning what the patient should
expect from the provider and what the provider should expect from the patient.

There are several critical areas that the Standards do not address. Their exclusion should
not be regarded as an indication of their lack of importance but, rather, their being beyond
the scope of this document. The Standards do not address the extremely important concern
with overall access to care. Obviously, if there is no care available, the quality of care
is not relevant. Additionally, there are many factors that impede access even when care
is available: poverty, gender, stigma, and geography are prominent among the factors
that interfere with persons seeking or receiving care. Also, if the residents of a given area
perceive that the quality of care provided by the local facilities is substandard, they will not
seek care there. This perception of quality is a component of access that adherence to
the Standards will address.1

Also not addressed by the Standards is the necessity of having a sound, effective government
tuberculosis control program. The requirements of such programs are described in
a number of international recommendations from the WHO, the US Centers for Disease
Control and Prevention (CDC), and the International Union Against Tuberculosis and Lung
Disease (The Union). Having an effective control program at the national or local level with
linkages to non-program providers enables bidirectional communication of information including
case notifi cation, consultation, patient referral, provision of drugs or services such
as treatment supervision/support for private patients, and contact evaluation. In addition,
the program may be the only source of laboratory services to the private sector.
In providing care for patients with, or suspected of having, tuberculosis, clinicians and
persons responsible for healthcare facilities should take measures that reduce the potential
for transmission of M. tuberculosis to healthcare workers and to other patients by
following either local, national, or international guidelines for infection control. This is especially
true in areas or specifi c populations with a high prevalence of HIV infection. Detailed
recommendations are contained in the WHO Guidelines for Prevention of Tuberculosis in
Health Care Facilities in Resource-Limited Settings, and the updated CDC guidelines for
preventing the transmission of M. tuberculosis in healthcare settings.4,5
The Standards should be viewed as a living document that will be revised as technology,
resources, and circumstances change. As written, the Standards are presented within a
context of what is generally considered to be feasible now or in the near future. Within the
Standards, priorities may be set that will foster appropriate incremental changes. For example,
rather than expecting full implementation of all diagnostic elements at once, priorities
should be set based on local circumstances and capabilities. Pursuing this example, once
high-quality sputum smear microscopy is universally available, the fi rst priority activity to
be accomplished would be performing sputum cultures for persons suspected of having
tuberculosis but who have negative sputum smears, especially those in areas of high HIV
prevalence. The second priority would consist of obtaining cultures and drug susceptibility
testing for patients at high risk of having tuberculosis caused by drug-resistant organisms.
A third priority would be performing cultures for all persons suspected of having
tuberculosis. In some settings, as a fourth priority, drug susceptibility testing should be
performed for isolates of M. tuberculosis obtained from patients not responding to standardized
treatment regimens and, finally, for initial isolates from all patients.

Rationale

Although in the past decade there has been substantial progress in the development
and implementation of the strategies necessary for effective tuberculosis control, the disease
remains an enormous and growing global health problem.6–9 One-third of the world’s
population is infected with M. tuberculosis, mostly in developing countries, where 95% of
cases occur.8 In 2003, there were an estimated 8.8 million new cases of tuberculosis, of
which 3.9 million were sputum smear-positive and, thus, highly infectious.6,7 The number
of tuberculosis cases that occur in the world each year is still growing, although the rate of
increase is slowing. In the African region of the WHO, the tuberculosis case rate continues
to increase, both because of the epidemic of HIV infection in sub-Saharan countries and
the poor or absent primary care services in parts of the region.6,7 In Eastern Europe, after
a decade of increases, case rates have only recently reached a plateau, the increases
being attributed to the collapse of the public health infrastructure, increased poverty, and
other socio-economic factors complicated further by the high prevalence of drug-resistant
tuberculosis.6,7,9 In many other countries, because of incomplete application of effective
care and control measures, tuberculosis case rates are either stagnant or decreasing
more slowly than should be expected. This is especially true in high-risk groups such as
persons with HIV infection, the homeless, prisoners, and recent immigrants. The failure to
bring about a more rapid reduction in tuberculosis incidence, at least in part, relates to a
failure to fully engage non-tuberculosis control program providers in the provision of highquality
care, in coordination with local and national control programs.

It is widely recognized that many providers are involved in the diagnosis and treatment
of tuberculosis.10-13 Traditional healers, general and specialist physicians, nurses, clinical
officers, academic physicians, unlicensed practitioners, physicians in private practice,
practitioners of alternative medicine, and community organizations, among others, all play
roles in tuberculosis care and, therefore, in tuberculosis control. In addition, other public
providers, such as those working in prisons, army hospitals, or public hospitals and facilities,
regularly evaluate persons suspected of having tuberculosis and treat patients who
have the disease.

Little is known about the adequacy of care delivered by non-program providers, but evidence
from studies conducted in many different parts of the world show great variability
in the quality of tuberculosis care, and poor quality care continues to plague global tuberculosis
control efforts.11 A recent global situation assessment reported by WHO suggested
that delays in diagnosis were common.12 The delay was more often in receiving a
diagnosis rather than in seeking care, although both elements are important.14 This survey
and other studies also show that clinicians, in particular those who work in the private
healthcare sector, often deviate from standard, internationally recommended, tuberculosis
management practices.11,12 These deviations include: under-utilization of sputum
microscopy for diagnosis, generally associated with over-reliance on radiography; use of
non-recommended drug regimens, with incorrect combinations of drugs and mistakes in
both drug dosage and duration of treatment; and failure to supervise and assure adherence
to treatment.11,12,15–21 Anecdotal evidence also suggests over-reliance on poorly
validated or inappropriate diagnostic tests, such as serologic assays, often in preference
to conventional bacteriological evaluations.

Together these findings highlight flaws in healthcare practices that lead to substandard
tuberculosis care for populations that, sadly, are most vulnerable to the disease and are
least able to bear the consequences of such systemic failures. Any person anywhere in
the world who is unable to access quality health care should be considered vulnerable
to tuberculosis and its consequences.1 Likewise, any community with no or inadequate
access to appropriate diagnostic and treatment services for tuberculosis is a vulnerable
community.1 The development of the ISTC is an attempt to reduce vulnerability of individuals
and communities to tuberculosis by promoting high-quality care for persons with, or
suspected of having, tuberculosis.

Companion and Reference Documents

The Standards in this document are complementary to two other important companion
documents. The fi rst, Patients’ Charter for Tuberculosis Care (http://www.worldcarecouncil.
org), specifi es the rights and responsibilities of patients and has been developed in
tandem with this document. Second, the International Council of Nurses has developed
a set of standards, TB/MDR-TB Nursing Standards (www.icn.ch/tb/standards.htm), that
define in detail the critical roles and responsibilities of nurses in the care and control of
tuberculosis. As a single-source reference for many of the practices for tuberculosis care,
we refer the reader to Toman’s Tuberculosis: Case Detection, Treatment, and Monitoring
(second edition).22

There are many guidelines and recommendations on various aspects of tuberculosis care
and control. (For listing, see http://www.nationaltbcenter.edu/international/.) The Standards
draw from many of these documents to provide their evidence base. In particular,
we have relied on guidelines that are generally accepted because of the process by which
they were developed, and by their broad use. However, existing guidelines, although
implicitly based on standards, do not present standards that defi ne the acceptable level
of care in such a way as to enable assessment of the adequacy of care by patients themselves,
by communities, and by public health authorities.

In providing the evidence base for the Standards, generally we have cited summaries,
meta-analyses, and systematic reviews of evidence that have examined and synthesized
primary data, rather than referring to the primary data itself. Throughout the document
we have used the terminology recommended in the “Revised International Defi nitions in
Tuberculosis Control.”23

Standards for Diagnosis

Not all patients with respiratory symptoms receive an adequate evaluation for tuberculosis. These failures result in missed opportunities for earlier detection of tuberculosis and lead to increased disease severity for the patients and a greater likelihood of transmission of M. tuberculosis to family members and others in the community.

STANDARD 1.

All persons with otherwise unexplained productive cough lasting two–three
weeks or more should be evaluated for tuberculosis.

Rationale and Evidence Summary

The most common symptom of pulmonary tuberculosis is persistent, productive cough,
often accompanied by systemic symptoms, such as fever, night sweats, and weight loss.

In addition, findings such as lymphadenopathy, consistent with concurrent extrapulmonary
tuberculosis, may be noted, especially in patients with HIV infection.
Although most patients with pulmonary tuberculosis have cough, the symptom is not
specific to tuberculosis; it can occur in a wide range of respiratory conditions, including
acute respiratory tract infections, asthma, and chronic obstructive pulmonary disease.

Although the presence of cough for 2–3 weeks is nonspecific, traditionally, having cough
of this duration has served as the criterion for defi ning suspected tuberculosis and is used
in most national and international guidelines, particularly in areas of moderate – to high prevalence
of tuberculosis.22–25

In a recent survey conducted in primary healthcare services of nine low- and middleincome
countries, respiratory complaints, including cough, constituted on average 18.4%
of symptoms that prompted a visit to a health center for persons older than 5 years of
age. Of this group, 5% of patients overall were categorized as possibly having tuberculosis
because of the presence of an unexplained cough for more than 2–3 weeks.26 Other studies have shown that 4–10% of adults attending outpatient health facilities in developing
countries may have a persistent cough of more than 2–3 weeks in duration.27 This percentage
varies somewhat, depending on whether there is active questioning concerning
the presence of cough. Respiratory conditions, therefore, constitute a substantial proportion
of the burden of diseases in patients presenting to primary healthcare services.26,27
Data from India, Algeria, and Chile generally show that the percentage of patients with
positive sputum smears increases with increasing duration of cough from 1–2 weeks,
increasing to 3–4, and >4 weeks.28 However, in these studies even patients with shorter
duration of cough had an appreciable prevalence of tuberculosis. A more recent assessment
from India demonstrated that by using a threshold of > 2 weeks to prompt collection
of sputum specimens, the number of patients with suspected tuberculosis increased
by 61%, but more importantly, the number of tuberculosis cases identifi ed increased by
46%, compared with a threshold of >3 weeks.29 The results also suggested that actively
inquiring as to the presence of cough in all adult clinic attendees may increase the yield
of cases; 15% of patients who, without prompting, volunteered that they had cough,
had positive smears, but in addition, 7% of patients who did not volunteer that they had
cough, but on questioning admitted to having cough >2 weeks, had positive smears.29

Choosing a threshold of 2–3 weeks is an obvious compromise, and it should be recognized
that, while using this threshold reduces the clinic and laboratory workload, some
cases would be missed. In patients presenting with chronic cough, the proportion of
cases attributable to tuberculosis will depend on the prevalence of tuberculosis in the
community.27 In countries with a low prevalence of tuberculosis, it is likely that chronic
cough will be due to conditions other than tuberculosis. Conversely, in high-prevalence
countries, tuberculosis will be one of the leading diagnoses to consider, together with
other conditions, such as asthma, bronchitis, and bronchiectasis, that are common in
many areas.

Overall, by focusing on adults and children presenting with chronic cough, the chances
of identifying patients with pulmonary tuberculosis are maximized. Unfortunately, several
studies suggest that not all patients with respiratory symptoms receive an adequate evaluation
for tuberculosis.12,15,17–20,30 These failures result in missed opportunities for earlier
detection of tuberculosis and lead to increased disease severity for the patients and a
greater likelihood of transmission of M. tuberculosis to family members and others in the
community.

STANDARD 2.

All patients (adults, adolescents, and children who are capable of producing
sputum) suspected of having pulmonary tuberculosis should have at least two,
and preferably three, sputum specimens obtained for microscopic examination.
When possible, at least one early morning specimen should be obtained.

Rationale and Evidence Summary

To prove a diagnosis of tuberculosis, every effort must be made to identify the causative
agent of the disease. A microbiological diagnosis can only be confi rmed by culturing M.
tuberculosis complex (or, under appropriate circumstances, identifying specifi c nucleic
acid sequences in a clinical specimen) from any suspected site of disease. In practice, however, there are many resource-limited settings in which culture
is not feasible currently. Fortunately, microscopic examination
of stained sputum is feasible in nearly all settings, and the
diagnosis of tuberculosis can be strongly inferred by fi nding
acid-fast bacilli by microscopic examination. In nearly all clinical
circumstances in high-prevalence areas, fi nding acid-fast
bacilli in stained sputum is highly specifi c and, thus, is the
equivalent of a confi rmed diagnosis. In addition to being highly
specifi c for M. tuberculosis complex, identifi cation of acid-fast
bacilli by microscopic examination is particularly important for
three reasons: it is the most rapid method for determining if a
person has tuberculosis; it identifi es persons who are at greatest
risk of dying from the disease*; and it identifi es the most likely transmitters of infection.
Generally, it is the responsibility of government health systems (national tuberculosis programs
[NTPs] or others) to ensure that providers and patients have convenient access
to microscopy laboratories. Moreover, it is crucial that such laboratories undergo assessments
of quality and have programs for quality improvement. These quality assessments
are generally the responsibility of a government system (usually the NTP).

Failure to perform a proper diagnostic evaluation before initiating treatment potentially
exposes the patient to the risks of unnecessary or wrong treatment with no benefi t.
Moreover, such an approach may delay accurate diagnosis and proper treatment. This
Standard applies to adults, adolescents, and children. With proper instruction and supervision,
many children 5 years of age and older can generate a specimen. Adolescents,
although often classifi ed as children at least until the age of 15 years, can generally produce
sputum. Thus, age alone is not suffi cient justifi cation for failing to attempt to obtain
a sputum specimen from a child or adolescent.

The information summarized below describes the results of various approaches to sputum
collection, processing, and examination. The application of the information to actual
practices and policies should be guided by local considerations.
The optimum number of sputum specimens to establish a diagnosis has been examined
in a number of studies. In a recent review of data from a number of sources, it was stated
that, on average, the initial specimen was positive in about 83–87% of all patients ultimately
found to have acid-fast bacilli detected, in an additional 10–12% with the second
specimen, and in a further 3–5% on the third specimen.34 A rigorously conducted systematic
review of 41 studies on this topic found a very similar distribution of results: on
average, the second smear detected about 13% of smear-positive cases, and the third
smear detected 4% of all smear-positive cases.35 In studies that used culture as the reference
standard, the mean incremental yield in sensitivity of the second smear was 9% and
that of the third smear was 4%.35

A recent re-analysis of data from a study involving 42 laboratories in four high-burden
countries showed that the incremental yield from a third sequential smear ranged from
0.7–7.2%.36 Thus, it appears that in a diagnostic evaluation for tuberculosis, at least two
specimens should be obtained. In some settings, because of practicality and logistics, a
third specimen may be useful, but examination of more than three specimens adds minimally
to the number of positive specimens obtained.35 In addition, a third specimen is useful
as confi rmatory evidence if only one of the fi rst two smears has a positive result. Ideally,
the results of sputum microscopy should be returned to the clinician within no more than
one working day from submission of the specimen. The timing of specimen collection is
also important. The yield appears to be greatest from early morning (overnight) specimens.
35,37–39 Thus, although it is not practical to collect only early morning specimens, at
least one specimen should be obtained from an early morning collection.

A variety of methods have been used to improve the performance of sputum smear microscopy.
40–42 In general, the sensitivity of microscopy (as compared to culture) is higher
with concentration by centrifugation and/or sedimentation (usually after pretreatment with
chemicals such as bleach, NaOH, and NaLC) or both, as compared to direct (unconcentrated)
smear microscopy. A comprehensive, systematic review of 83 studies describing
the effects of various physical and/or chemical methods for concentrating and processing
sputum prior to microscopy found that concentration resulted in a higher sensitivity (15–
20% increase) and smear-positivity rate, when compared with direct smears.40 Although
there are demonstrable advantages to concentration of sputum, there are also disadvantages.
Centrifugation is more complex, requires electrical power, and may be associated
with increased infection risk to laboratory personnel. Consequently, it is not clear that the
advantages offset the disadvantages in low-resource settings.

Fluorescence microscopy, in which auramine-based staining causes the acid-fast bacilli
to fl uoresce against a dark background, is widely used in many parts of the world. A
systematic review, in which the performance of direct sputum smear microscopy using
fl uorescence staining was compared with Ziehl-Neelsen (ZN) staining using culture as the
gold standard, suggests that fl uorescence microscopy is the more sensitive method.41
The results of this review have been verifi ed in a more comprehensive, systematic review
of 43 studies. This review showed that fl uorescence microscopy is on average 10% more
sensitive than conventional light microscopy.42 The specifi city of fl uorescence microscopy
was comparable to Ziehl-Neelsen staining. The combination of increased sensitivity with
little or no loss of specifi city makes fl uorescence microscopy a more accurate test, although
the increased cost and complexity might make it less applicable in many areas.
For this reason, fl uorescence staining is probably best used in centers with specifi cally
trained and profi cient microscopists, in which a large number of specimens are processed
daily, and in which there is an appropriate quality control program.

STANDARD 3.

For all patients (adults, adolescents, and children) suspected of having extrapulmonary
tuberculosis, appropriate specimens from the suspected sites of involvement
should be obtained for microscopy and, where facilities and resources are
available, for culture and histopathological examination.

Rationale and Evidence Summary

Extrapulmonary tuberculosis (without associated lung involvement) accounts
for 15–20% of tuberculosis in populations with a low prevalence
of HIV infection. In populations with a high prevalence of HIV infection,
the proportion of cases with extrapulmonary tuberculosis is higher. Because
appropriate specimens may be diffi cult to obtain from some of
these sites, bacteriological confi rmation of extrapulmonary tuberculosis
is often more diffi cult than for pulmonary tuberculosis. In spite of the diffi
culties, however, the basic principle that bacteriological confi rmation
of the diagnosis should be sought still holds. Generally, there are fewer
M. tuberculosis organisms present in extrapulmonary sites, so identifi –
cation of acid-fast bacilli by microscopy in specimens from these sites
is less frequent and culture is more important. For example, microscopic
examination of pleural fl uid in tuberculous pleuritis detects acid-fast bacilli
in only about 5–10% of cases, and the diagnostic yield is similarly low in tuberculous
meningitis. Given the low yield of microscopy, both culture and histopathological examination
of tissue specimens, such as may be obtained by needle biopsy of lymph nodes,
are important diagnostic tests. In addition to the collection of specimens from the sites
of suspected tuberculosis, examination of sputum and a chest fi lm may also be useful,
especially in patients with HIV infection, in whom there is an appreciable frequency of
subclinical pulmonary tuberculosis.43

In patients who have an illness compatible with tuberculosis that is severe or progressing
rapidly, initiation of treatment should not be delayed pending the results of microbiological
examinations. Treatment should be started while awaiting results and then modifi ed, if
necessary, based on the microbiological findings.

STANDARD 4.

All persons with chest radiographic fi ndings suggestive of tuberculosis should
have sputum specimens submitted for microbiological examination.

Rationale and Evidence Summary

Chest radiography is a sensitive but nonspecifi c test to detect tuberculosis.
44 Radiographic examination (fi lm or fl uoroscopy) of the thorax or
other suspected sites of involvement may be useful to identify persons
for further evaluation. However, a diagnosis of tuberculosis cannot be
established by radiography alone. Reliance on the chest radiograph
as the only diagnostic test for tuberculosis will result in both over-diagnosis
of tuberculosis and missed diagnoses of tuberculosis and
other diseases. In a study from India in which 2,229 outpatients
were examined by photofl uorography, 227 were classifi ed as having
tuberculosis by radiographic criteria.45,46 Of the 227, 81 (36%)
had negative sputum cultures, whereas of the remaining 2,002 patients,
31 (1.5%) had positive cultures. Looking at these results in
terms of the sensitivity of chest radiography, 32 (20%) of 162 culturepositive
cases would have been missed by radiography. Given these
and other data, it is clear that the use of radiographic examinations
alone to diagnose tuberculosis is not an acceptable practice.

Chest radiography is useful to evaluate persons who have negative sputum smears to attempt
to find evidence for pulmonary tuberculosis and to identify other abnormalities that
may be responsible for the symptoms. With regard to tuberculosis, radiographic examination
is most useful when applied as part of a systematic approach in the evaluation of
persons whose symptoms and/or fi ndings suggest tuberculosis, but who have negative
sputum smears. (See Standard 5.)

STANDARD 5.

The diagnosis of sputum smear-negative pulmonary tuberculosis should be
based on the following criteria: at least three negative sputum smears (including
at least one early morning specimen); chest radiography fi ndings consistent
with tuberculosis; and lack of response to a trial of broad-spectrum antimicrobial
agents. (NOTE: Because the fl uoroquinolones are active against M. tuberculosis
complex and, thus, may cause transient improvement in persons with
tuberculosis, they should be avoided.) For such patients, if facilities for culture
are available, sputum cultures should be obtained. In persons with known or
suspected HIV infection, the diagnostic evaluation should be expedited.

Rationale and Evidence Summary

The designation of “sputum smear-negative tuberculosis” presents a diffi cult diagnostic
dilemma. As noted above, on average, sputum smear microscopy is only about 50–60%
sensitive when compared with culture. Nevertheless, given the nonspecifi c nature of the
symptoms of tuberculosis and the multiplicity of other diseases that could be the cause
of the patient’s illness, it is important that a rigorous approach be taken in diagnosing
tuberculosis in a patient in whom at least three adequate sputum smears are negative.
Because patients with HIV infection and tuberculosis frequently have negative sputum
smears, and because of the broad differential diagnosis (including Pneumocystis jiroveci
pneumonia and bacterial and fungal lower respiratory infections) in this group, such a systematic
approach is crucial. It is important, however, to balance the need for a systematic
approach, in order to avoid both over- and under-diagnosis of tuberculosis, with the need
for prompt treatment in a patient with an illness that is progressing rapidly. Over-diagnosis
of tuberculosis when the illness has another cause will delay proper diagnosis and treatment;
whereas, under-diagnosis will lead to more severe consequences of tuberculosis,
including disability and possibly death, as well as ongoing transmission of M. tuberculosis.
It should be noted that in making a diagnosis based on the above three criteria, a
the clinician who decides to treat with a full course of antituberculosis chemotherapy should
report this as a case of sputum smear-negative pulmonary tuberculosis to local public
health authorities (as described in Standard 17).

A number of algorithms have been developed as a means to systematize the diagnosis
of smear-negative tuberculosis, although none has been adequately validated under fi eld
conditions.47,48 In particular, there is little information or experience on which to base approaches
to the diagnosis of smear-negative tuberculosis in persons with HIV infection.
Figure 1 is modified from an algorithm developed by WHO and is included as an example
of a systematic approach.24 It should be recognized that, commonly, the steps in the algorithm
are not followed in a sequential fashion by a single provider. The algorithm should be
viewed as presenting an approach to diagnosis that incorporates the main components
of, and a framework for, the diagnostic evaluation.

There are several points of caution regarding the algorithm. First, completion of all of the
steps requires a substantial amount of time; thus, it should not be used for patients with
an illness that is worsening rapidly. This is especially true in patients with HIV infection
in whom tuberculosis may be rapidly progressive. Second, several studies have shown
that patients with tuberculosis may respond, at least transiently, to broad spectrum antimicrobial treatment.49–52 Obviously, such a response will lead one to delay a diagnosis
of tuberculosis. Fluoroquinolones in particular are bactericidal for M. tuberculosis
complex. Empiric fl uoroquinolone monotherapy for respiratory tract infections has been
associated with delays in initiation of appropriate antituberculosis therapy and acquired
resistance to the fl uoroquinolones.53 Third, the approach outlined in the algorithm may
be quite costly to the patient and deter her/him from continuing with the diagnostic
evaluation. Given all these concerns, application of such an algorithm in patients with at
least three negative sputum smear examinations must be done in a fl exible manner. Ideally,
the evaluation of smear-negative tuberculosis should be guided by locally validated
approaches, suited to local conditions.

FIGURE 1.
An illustrative approach to the diagnosis of sputum smear-negative
pulmonary tuberculosis²⁴

An illustrative approach to the diagnosis of sputum smear-negative pulmonary tuberculosis24

FIGURE 1.

Although sputum microscopy is the first bacteriologic diagnostic test of choice
where resources permit and adequate, quality-assured laboratory facilities
are available, culture should be included in the algorithm for evaluating patients
with negative sputum smears. Properly done, culture adds a signifi
cant layer of complexity and cost but also increases sensitivity, which
should result in earlier case detection.54,55 Although the results of culture
may not be available until after a decision to begin treatment has to be
made, treatment can be stopped subsequently if cultures from a reliable
laboratory are negative, the patient has not responded clinically,
and the clinician has sought other evidence in pursuing the differential
diagnosis.

The probability of finding acid-fast bacilli in sputum smears by microscopy
is directly related to the concentration of bacilli in the sputum. Sputum
microscopy is likely to be positive when there are at least 10,000
organisms per milliliter of sputum. At concentrations below 1,000 organisms
per milliliter of sputum, the chance of observing acid-fast bacilli in a smear is less than
10%.56,57 In contrast, a properly performed culture can detect far lower numbers of acidfast
bacilli (detection limit is about 100 organisms per ml).54 The culture, therefore, has
a higher sensitivity than microscopy and, at least in theory, can increase case detection,
although this potential has not been demonstrated in low-income, high-incidence areas.
Further, culture makes it possible to identify the mycobacterial species and to perform
drug susceptibility testing in patients in whom there is reason to suspect drug-resistant
tuberculosis.54 The disadvantages of culture are its cost, technical complexity, and the
time required to obtain a result, thereby imposing a diagnostic delay if there is less reliance
on sputum smear microscopy. In addition, ongoing quality assessment is essential for
culture results to be credible. Such quality assurance measures are not available widely in
most low-resource settings.

In many countries, although culture facilities are not uniformly available, there is the capacity
to perform culture in some areas. Providers should be aware of the local capacity
and use the resources appropriately, especially for the evaluation of persons suspected
of having tuberculosis who have negative sputum smears and for persons suspected of
having tuberculosis caused by drug-resistant organisms.
Traditional culture methods use solid media such as Lowenstein-Jensen and Ogawa.
Cultures on solid media are less technology-intensive, and the media can be made locally.

However, the time to identify growth is significantly longer than in liquid media. Liquid
media systems such as BACTEC® utilize the release of radioactive CO2 from C-14 labeled
palmitic acid in the media to identify growth. The MGIT® system, also using liquid medium,
has the advantage of having growth detected by the appearance of fl uorescence in
a silicone plug at the bottom of the tube, thereby avoiding radioactivity. Decisions to provide
culture facilities for diagnosing tuberculosis depend on fi nancial resources, trained
personnel, and the ready availability of reagents and equipment service.
Nucleic acid amplifi cation tests (NAATs), although widely distributed, do not offer major
advantages over culture at this time. Although a positive result can be obtained more
quickly than with any of the culture methods, the NAATs are not suffi ciently sensitive for a
negative result to exclude tuberculosis.58–63 In addition, NAATs are not suffi ciently sensitive
to be useful in identifying M. tuberculosis in specimens from extrapulmonary sites of disease.
59–61,63 Moreover, cultures must be available if drug susceptibility testing is to be performed.
Other approaches to establishing a diagnosis of tuberculosis, such as serological
tests, are not of proven value and should not be used in routine practice at this time.58

STANDARD 6.

The diagnosis of intrathoracic (i.e., pulmonary, pleural, and mediastinal or hilar
lymph node) tuberculosis in symptomatic children with negative sputum
smears should be based on the fi nding of chest radiographic abnormalities
consistent with tuberculosis and either a history of exposure to an infectious
case or evidence of tuberculosis infection (positive tuberculin skin
test or interferon gamma release assay). For such patients, if facilities
for culture are available, sputum specimens should be
obtained (by expectoration, gastric washings, or induced sputum)
for culture.

Rationale and Evidence Summary

Children with tuberculosis commonly have paucibacillary disease
without evident lung cavitation but with involvement of intrathoracic
lymph nodes. Consequently, compared with adults, sputum smears
from children are more likely to be negative. Therefore, cultures of
sputum or other specimens, radiographic examination of the chest,
and tests to detect tuberculous infection (generally, a tuberculin skin
test) are of relatively greater importance. Because many children less
than 5 years of age do not cough and produce sputum effectively,
culture of gastric washings obtained by naso-gastric tube lavage or induced
sputum has a higher yield than spontaneous sputum.64

Several recent reviews have examined the effectiveness of various diagnostic tools, scoring
systems and algorithms to diagnose tuberculosis in children.64–67 Many of these approaches
lack standardization and validation and, thus, are of limited applicability. Table
1 presents the approach recommended by the Integrated Management of Childhood
Illness (IMCI) program of WHO that is widely used in fi rst-level facilities in low- and middleincome
countries.68

TABLE 1: An approach to the diagnosis of tuberculosis in children68

The risk of tuberculosis is increased when there is an active case (infectious, smear-positive tuberculosis) in
the same house or when the child is malnourished, is HIV infected, or has had measles in the past few months.
Consider tuberculosis in any child with:

A history of:	On examination:
unexplained weight loss or failure to grow normally	fluid on one side of the chest (reduced air entry, stony dullness to percussion)
unexplained fever, especially when it continues for more than two weeks	enlarged non-tender lymph nodes or a lymph node abscess, especially in the neck
chronic cough	signs of meningitis, especially when these develop over several days and the spinal fl uid contains mostly lymphocytes and elevated protein
exposure to an adult with probable or definite pulmonary infectious tuberculosis	abdominal swelling, with or without palpable lumps
	progressive swelling or deformity in the bone or a joint, including the spine

Standards for Treatment

Treatment for tuberculosis is not only
a matter of individual health; it is
also a matter of public health. All
providers, public and private,
who undertake to treat a patient
with tuberculosis, must have
the knowledge to prescribe a
standard treatment regimen
and the means to assess
adherence to the regimen and
to address poor adherence in
order to ensure that treatment
is completed.

STANDARD 7.

Any practitioner treating a patient for tuberculosis is assuming an important
public health responsibility. To fulfi ll this responsibility, the practitioner must not
only prescribe an appropriate regimen but, also, be capable of assessing the
adherence of the patient to the regimen and addressing poor adherence when it
occurs. By so doing, the provider will be able to ensure adherence to the regimen
until treatment is completed.

Rationale and Evidence Summary

As described in the Introduction, the main interventions to prevent the spread of tuberculosis
in the community are the detection of patients with infectious tuberculosis and
providing them with effective treatment to ensure a rapid and lasting cure. Consequently,
treatment for tuberculosis is not only a matter of individual health (as is the case with, for
example, treatment of hypertension or diabetes mellitus); it is also a matter of public health.
Thus, all providers, public and private, who undertake to treat a patient with tuberculosis,
must have the knowledge to prescribe a standard treatment regimen and the means to
assess adherence to the regimen and address poor adherence to ensure that treatment
is completed.69 National tuberculosis programs commonly possess approaches and tools
to ensure adherence with treatment and, when properly organized, can offer these to
non-program providers. Failure of a provider to ensure adherence could be equated with,
for example, failure to ensure that a child receives the full set of immunizations. Communities
and patients deserve to be assured that providers treating tuberculosis are doing so
in accordance with this principle and are thereby meeting this standard.

STANDARD 8.

All patients (including those with HIV infection) who have not been treated
previously should receive an internationally accepted fi rst-line treatment regimen
using drugs of known bioavailability. The initial phase should consist of two
months of isoniazid, rifampicin, pyrazinamide and ethambutol.(Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, do not have
extensive pulmonary tuberculosis or severe forms of extrapulmonary disease, and who are known to be HIV negative.) The preferred
continuation phase consists of isoniazid and rifampicin given for four months.

Isoniazid and ethambutol given for six months is an alternative continuation
phase regimen that may be used when adherence cannot be assessed but is
associated with a higher rate of failure and relapse, especially in patients with
HIV infection.

The doses of antituberculosis drugs used should conform to international
recommendations. Fixed-dose combinations of two
(isoniazid and rifampicin), three (isoniazid, rifampicin, and pyrazinamide)
and four (isoniazid, rifampicin, pyrazinamide, and
ethambutol) drugs are highly recommended, especially when
medication ingestion is not observed.

Rationale and Evidence Summary

A large number of well-designed clinical trials have provided the evidence
base for this Standard and several sets of treatment recommendations
based on these studies have been written in the past
few years.24,25,69 These are referenced and data will not be reviewed
in this document. All these data indicate that a rifampicin-containing
regimen is the backbone of antituberculosis chemotherapy and is highly
effective in treating tuberculosis caused by drug-susceptible M. tuberculosis.
It is also clear from these studies that the minimum duration of treatment for smear
and/or culture-positive tuberculosis is six months. For the six-month treatment duration to
be maximally effective, the regimen must include pyrazinamide during the initial two-month
phase, and rifampicin must be included throughout the full six months. There are several
variations in the frequency of drug administration that have been shown to produce acceptable
results.24,25,69

Two systematic reviews of regimens of less than six months have found that shorter durations
of treatment have an unacceptably high rate of relapse.70,71 Thus, the current international
standard for smear or culture-positive tuberculosis is a regimen administered for a
minimum duration of six months.24,69

Although the six-month regimen is the preferred option, an alternative continuation phase
regimen, consisting of isoniazid and ethambutol given for six months, making the total
duration of treatment eight months, may also be used. It should be recognized, however,
that this regimen, presumably because of the shorter duration of rifampicin administration,
is associated with a higher rate of failure and relapse, especially in patients with HIV
infection.72–74 Nevertheless, the eight-month regimen may be used when adherence to
treatment throughout the continuation phase cannot be assessed.24 The rationale for this
approach is that if the patient is nonadherent, the emergence of resistance to rifampicin
will be minimized. A retrospective review of the outcomes of treatment of tuberculosis in
patients with HIV infection shows that tuberculosis relapse is minimized by the use of a
regimen containing rifampicin throughout a six-month course.72 Thus, the six-month regimen
containing rifampicin throughout the entire course is preferable in patients with HIV
infection to minimize the risk of relapse; however, the patient’s HIV stage, the need for and
availability of antiretroviral drugs, and the quality of treatment supervision/support must be
considered in choosing an appropriate continuation phase of therapy.

Intermittent administration of antituberculosis drugs enables supervision to be provided
more effi ciently and economically with no reduction in effi cacy. The evidence on effectiveness
of intermittent regimens was reviewed recently.75,76 These reviews, based on several
trials,77–82 suggest that antituberculosis treatment may be given intermittently three times a
week throughout the full course of therapy or twice weekly in the continuation phase without
apparent loss of effectiveness. However, WHO and The Union do not recommend the
use of twice-weekly intermittent regimens because of the potentially greater consequences
of missing one of the two doses.24,25,83 A simplifi ed version of the current WHO recommendations
for treating persons who have not been treated previously is shown in Table 2.²⁴

TABLE 2: Recommended treatment for persons not treated previously²⁴

RANKING	INITIAL PHASE	CONTINUATION PHASE
Preferred	INH, RIF, PZA, EMB^1,2 daily, 2 months, INH, RIF, PZA, EMB^1,2 3x/week, 2 months	INH, RIF daily, 4 months, INH, RIF 3x/week, 4 months
Optional	INH, RIF, PZA, EMB² daily, 2 months	INH, EMB daily, 6 months³
INH = isoniazid; RIF = rifampicin; PZA = pyrazinamide; EMB = ethambutol

Streptomycin may be substituted for ethambutol.
Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum
smears, do not have extensive pulmonary tuberculosis or severe forms of extra-pulmonary disease, and
who are known to be HIV negative.
Associated with higher rate of treatment failure and relapse; should generally not be used in patients with
HIV infection.

The evidence base for currently recommended antituberculosis drug dosages derives
from human clinical trials, animal models, and pharmacokinetic and toxicity studies. The
evidence on drug dosages and safety and the biological basis for dosage recommendations
have been extensively reviewed in publications by WHO,24 The Union,25 ATS, CDC,
the Infectious Diseases Society of America (IDSA),69 and others.83,84 The recommended
doses for daily and thrice-weekly administration are shown in Table 3.

TABLE 3: Doses of first-line antituberculosis drugs in adults and children

	Recommended dose in mg/kg body weight (range)
DRUG	DAILY	THREE TIMES WEEKLY
isoniazid	5 (4–6), maximum 300 daily	10
rifampicin	10 (8–12), maximum 600 daily	10 (8–12), maximum 600 daily
pyrazinamide	25 (20–30)	35 (30–40)
ethambutol	children 20 (15–25)`*` adults 15 (15–20)	30 (25–35)
streptomycin	15 (12–18)	15 (12–18)

* The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults (15mg/kg), because
the pharmacokinetics are different. (Peak serum ethambutol concentrations are lower in children than in adults
receiving the same mg/kg dose.)

Treatment of tuberculosis in special clinical situations, such as the presence of liver disease,
renal disease, pregnancy, and HIV infection, may require modifi cation of the standard
regimen or alterations in dosage or frequency of drug administration. For guidance
in these situations, see WHO and ATS/CDC/IDSA treatment guidelines.24,69
Although there is no evidence that fi xed-dose combinations (FDCs) are superior to individual
drugs, expert opinion suggests that they may minimize inadvertent monotherapy
and may decrease the frequency of acquired drug resistance and medication errors.24,69
FDCs also reduce the number of tablets to be consumed and may thereby increase patient
adherence to recommended treatment regimens.85,86

STANDARD 9.

To foster and assess adherence, a patient-centered approach to administration
of drug treatment, based on the patient’s needs and mutual respect between the
patient and the provider, should be developed for all patients. Supervision and
support should be gender-sensitive and age-specifi c and should draw on the
full range of recommended interventions and available support services,
including patient counseling and education. A central element of the patient-
centered strategy is the use of measures to assess and promote adherence
to the treatment regimen and to address poor adherence when
it occurs. These measures should be tailored to the individual patient’s
circumstances and be mutually acceptable to the patient and the provider.
Such measures may include direct observation of medication ingestion
(directly observed therapy—DOT) by a treatment supporter who
is acceptable and accountable to the patient and to the health system.

Rationale and Evidence Summary

The approach described is designed to encourage and facilitate a positive partnership
between providers and patients, working together to improve adherence. Adherence to
treatment is the critical factor in determining treatment success.87 The success of treatment
for tuberculosis, assuming an appropriate drug regimen is prescribed, depends
largely on patient adherence to the regimen. Achieving adherence is not an easy task,
either for the patient or the provider. Antituberculosis drug regimens, as described previously,
consist of multiple drugs given for a minimum of six months, often when the patient
feels well (except, perhaps, for adverse effects of the medications). Commonly, treatments
of this sort are inconsistent with the patient’s cultural milieu, belief system, and
living circumstances. Consequently, it is not surprising that, without appropriate treatment
support, a signifi cant proportion of patients with tuberculosis discontinue treatment
before completion of the planned duration or are erratic in drug taking. Yet, failure to
complete treatment for tuberculosis leads to prolonged infectivity, poor outcomes, and
drug resistance.88

Adherence is a multi-dimensional phenomenon determined by the interplay of fi ve sets of
factors (dimensions), as illustrated in Figure 2 and Table 4.⁸⁷

FIGURE 2: The five dimensions of adherence⁸⁷

Source: WHO, 2003⁸⁷

TABLE 4: Factors affecting adherence⁸⁷

TUBERCULOSIS	FACTORS AFFECTING ADHERENCE	INTERVENTIONS TO IMPROVE ADHERENCE
Social/economic factors	( – ) Lack of effective social support networks and unstable living circumstances; culture and lay beliefs about illness and treatment; stigma; ethnicity, gender, and age; high cost of medication; high cost of transport; criminal justice involvement; involvement in drug dealing	Assessment of social needs, social support, housing, food tokens, and legal measures; providing transport to treatment settings; peer assistance; mobilization of community-based organizations; optimizing the cooperation between services; education of the community and providers to reduce stigma; family and community support
Health system/healthcare team factors	services; inadequate relationship between healthcare provider and patient; healthcare providers who are untrained, overworked, inadequately supervised or unsupervised in their tasks; inability to predict potentially nonadherent patients ( + ) Good relationships between patient and physician; availability of expertise; links with patient support systems; fl exibility in the hours of operation	Uninterrupted, ready availability of information; training and management processes that aim to improve the way providers care for patients with tuberculosis; support for local patient organizations/ groups; management of disease and treatment in conjunction with the patients; multidisciplinary care; intensive staff supervision; training in adherence monitoring; use of DOT
Condition-related factors	( – ) Asymptomatic patients; drug use; altered mental states caused by substance abuse; depression and psychological stress ( + ) Knowledge about TB Education on use of medications; provision of information about tuberculosis and the need to attend for treatment	Education on use of medications; provision of information about tuberculosis and the need to attend for treatment
Therapy-related factors	( – ) Complex treatment regimen; adverse effects of treatment; toxicity	Education on use of medications and adverse effects of medications; adherence education; use of fi xeddose combination preparations; tailor treatment support to needs of patients at risk of nonadherence; agreements (written or verbal) to return for an appointment or course of treatment; continuous monitoring and reassessment
Patient-related factors	(-) Forgetfulness; drug abuse; depression; psychological stress; isolation due to stigma (+) Belief in the effi cacy of treatment; motivation	Therapeutic relationship; mutual goal-setting; memory aids and reminders; incentives and/or reinforcements; reminder letters, telephone reminders or home visits for patients who default
DOT = directly observed therapy; TB = tuberculosis; (+) = factors having a positive effect on adherence; (-) = factors having a negative effect on adherence Source: Modifi ed from WHO, 2003⁸⁷

Despite evidence to the contrary, there is a widespread tendency to focus on patientrelated
factors as the main cause of poor adherence.87 Sociological and behavioral research
during the past 40 years has shown that patients need to be supported, not blamed.87
Less attention is paid to provider and health system-related factors. Several studies have
evaluated various interventions to improve adherence to tuberculosis therapy. (These interventions
are listed in Table 4.) There are a number of reviews that examine the evidence
on the effectiveness of these interventions.69, 87, 89, 90–95

Among the interventions evaluated, DOT has generated the most debate and controversy.(There is an important distinction between directly observed treatment (DOT) and the DOTS strategy for tuberculosis control: DOT is
one of a range of measures used to promote and assess adherence to tuberculosis treatment, whereas the DOTS strategy consists five
components and forms the platform on which tuberculosis control programs are built.⁹⁶)

The third component of the global DOTS strategy, now widely recommended as
the most effective strategy for controlling tuberculosis worldwide, is the administration of a
standardized, rifampicin-based regimen using case management interventions that are appropriate
to the individual and the circumstances.23,24,69,97 These interventions may include
DOT as one of a range of measures to promote and assess adherence to treatment.
The main advantage of DOT is that treatment is carried out entirely under close, direct
supervision.92 This provides both an accurate assessment of the degree of adherence
and greater assurance that the medications have actually been ingested. When a second
individual directly observes a patient swallowing medications, there is greater certainty
that the patient is actually receiving the prescribed medications. This approach, therefore,
results in a high cure rate and a reduction in the risk of drug resistance. Also, because
there is a close contact between the patient and the treatment supporter, adverse drug
effects and other complications can be identifi ed quickly and managed appropriately.92

Moreover, such case management can also serve to identify and assist in addressing the
myriad other problems experienced by patients with tuberculosis, such as undernutrition,
poor housing, and loss of income, to name a few.

The exclusive use of health facility-based DOT may be associated with disadvantages
that must be taken into account in designing a patient-centered approach. For example,
these disadvantages may include loss of income, stigma, and physical hardship, all factors
that can have an important effect on adherence.87 Ideally, a fl exible mix of health
facility-based and community-based DOT should be available.

In a Cochrane systematic review that synthesized the evidence from six controlled trials
comparing DOT with self-administered therapy,89,90 the authors found that patients allocated
to DOT and those allocated to self-administered therapy had similar cure rates (Risk
Ratio [RR] 1.06, 95% Confi dence Interval [CI] 0.98, 1.14); and rates of cure plus treatment
completion (RR 1.06, 95% CI 1.00, 1.13). They concluded that direct observation of
medication ingestion did not improve outcomes.89,90

In contrast, other reviews have found DOT to be associated with high cure and treatment
completion rates.24,69,91,92,98 Also, programmatic studies on the effectiveness of the DOTS
strategy have shown high rates of treatment success in several countries.87 It is likely that
these inconsistencies across reviews are due to the fact that primary studies are often
unable to separate the effect of DOT alone from the overall DOTS strategy.87,94 In a retrospective
review of programmatic results, the highest rates of success were achieved with “enhanced DOT,” which consisted of “supervised swallowing” plus social supports, incentives,
and enablers as part of a larger program to encourage adherence to treatment.91
Such complex interventions are not easily evaluated within the conventional randomized
controlled trial framework.87

Interventions other than DOT have also shown promise.87, 95 For example, interventions that
used incentives, peer assistance, repeated motivation of patients, and staff training and
motivation all have been shown to improve adherence signifi cantly.95 In addition, adherence
may be enhanced by provision of more comprehensive primary care, as described
in the Integrated Management of Adolescent and Adult Illness (IMAAI),99-101 as well as by
provision of specialized services such as opiate substitution for injection drug users.
Systematic reviews and extensive programmatic experience demonstrate that there is
no single approach to case management that is effective for all patients, conditions, and
settings. Consequently, interventions that target adherence must be tailored or customized
to the particular situation and cultural context of a given patient.87 Such an approach
must be developed in concert with the patient to achieve optimum adherence. This
patient-centered, individualized approach to treatment support is now a core element
of all tuberculosis care and control efforts. It is important to note that treatment support
measures, and not the treatment regimen itself, must be individualized to suit the unique
needs of the patient.

In addition to one-on-one support for patients being treated for tuberculosis, community
support is also of importance in creating a therapeutic milieu and reducing stigma.3 Not
only should the community expect that optimum treatment for tuberculosis is provided,
but it also should expect and play a role in promoting conditions that facilitate and assist
in ensuring that the patient will adhere to the prescribed regimen.

STANDARD 10.

All patients should be monitored for response to therapy, best judged in patients
with pulmonary tuberculosis by follow-up sputum smear microscopy (two specimens)
at least at the time of completion of the initial phase of treatment (two
months), at fi ve months, and at the end of treatment. Patients who have positive
smears during the fi fth month of treatment should be considered as
treatment failures and have therapy modifi ed appropriately. (See Standards
14 and 15.) In patients with extrapulmonary tuberculosis and in children,
the response to treatment is best assessed clinically. Follow-up radiographic
examinations are usually unnecessary and may be misleading.

Rationale and Evidence Summary

Patient monitoring and treatment supervision are two separate functions. Patient
monitoring is necessary to evaluate the response of the disease to treatment and
to identify adverse drug reactions. For the latter function, contact between the
patient and a provider is necessary. To judge response of pulmonary tuberculosis
to treatment, the most expeditious method is sputum smear microscopy. Ideally, where
quality-assured laboratories are available, sputum cultures, as well as smears, should be
performed for monitoring.

Having a positive sputum smear at completion of fi ve months of treatment defi nes treatment
failure, indicating the need for determination of drug susceptibility and initiation of a
retreatment regimen.23 Radiographic assessments, although used commonly, have been
shown to be unreliable for evaluating response to treatment.102 Similarly, clinical assessment
can be unreliable and misleading in the monitoring of patients with pulmonary tuberculosis.
102 In patients with extrapulmonary tuberculosis and in children, clinical evaluations
may be the only available means of assessing the response to treatment.

STANDARD 11.

A written record of all medications given, bacteriologic response, and adverse
reactions should be maintained for all patients.

Rationale and Evidence Summary

There is a sound rationale and clear benefi ts of a record keeping system.103 It is common
for individual physicians to believe sincerely that a majority of the patients in whom they
initiate antituberculosis therapy are cured. However, when systematically evaluated, it is
often seen that only a minority of patients have successfully completed the full treatment
regimen.103 The recording and reporting system enables targeted, individualized follow-up
to identify patients who are failing therapy.103 It also helps in facilitating continuity of care,
particularly in settings (e.g., large hospitals) where the same practitioner might not be seeing
the patient during every visit. A good record of medications given, results of investigations
(such as smears, cultures, and chest radiographs), and progress notes (on clinical
improvement, adverse events, and adherence) will provide for more uniform monitoring
and ensure a high standard of care.

Records are important to provide continuity when patients move from one care provider
to another and to enable tracing of patients who miss appointments. In patients who default and then return for treatment and patients who relapse after treatment completion,
it is critical to review previous records in order to assess the likelihood of drug resistance.
Lastly, management of complicated cases (e.g., multidrug-resistant tuberculosis) is not
possible without an adequate record of previous treatment, adverse events, and drug
susceptibility results. It should be noted that, wherever patient records are concerned,
care must be taken to insure confi dentiality of the information.

STANDARD 12.

In areas with a high prevalence of HIV infection in the general population where
tuberculosis and HIV infection are likely to co-exist, HIV counseling and testing
is indicated for all tuberculosis patients as part of their routine management. In
areas with lower prevalence rates of HIV, HIV counseling and testing is indicated
for tuberculosis patients with symptoms and/or signs of HIV-related conditions
and in tuberculosis patients having a history suggestive of high risk of
HIV exposure.

Rationale and Evidence Summary

Infection with HIV both increases the likelihood of progression from
infection with M. tuberculosis to active tuberculosis and changes
the clinical manifestations of the disease.32,104,105 Further, in comparison
with non-HIV infected patients, patients with HIV infection
who have pulmonary tuberculosis have a lower likelihood of having
acid-fast bacilli detected by sputum smear microscopy.32,104,105
Moreover, data consistently show that the chest radiographic features
are atypical and the proportion of extrapulmonary tuberculosis
is greater in patients with advanced HIV infection compared with
those who do not have HIV infection. Consequently, knowledge of
a person’s HIV status would infl uence the approach to a diagnostic
evaluation for tuberculosis. For this reason, it is important, particularly
in areas in which there is a high prevalence of HIV infection, that the history and physical
examination include a search for indicators that suggest the presence of HIV infection.

Table 5 presents clinical features that are suggestive of HIV infection.105 A comprehensive
list of clinical criteria/algorithms for HIV/AIDS diagnosis and clinical staging is available
in the WHO document Scaling up Antiretroviral Therapy in Resource-Limited Settings:
Guidelines for a Public Health Approach (Geneva, 2002).106

Tuberculosis is highly associated with HIV infection worldwide.7,107 Although the prevalence
of HIV infection varies widely among and within countries, in persons with HIV infection
there is always an increased risk of tuberculosis. The differences in HIV prevalence
mean that a variable percentage of patients with tuberculosis will have HIV infection as
well. This ranges from less than 1% in low-HIV-prevalence countries to 50–70% in countries
with a high HIV prevalence, mostly sub-Saharan African countries.7 Even though
in low-HIV-prevalence countries few tuberculosis patients will be HIV-infected, the connection
is suffi ciently strong and the impact on the patient suffi ciently great that the test
should always be considered in managing individual patients, especially among groups in which the prevalence of HIV is higher, such as injecting drug users. In countries having a
high prevalence of HIV infection, the yield of positive results will be high, and, again, the
impact of a positive result on the patient will be great. Thus, the indication for HIV testing
is strong; co-infected patients may benefi t by access to antiretroviral therapy as HIV
treatment programs expand or through administration of co-trimoxazole for prevention of
opportunistic infections, even when antiretroviral drugs are not available locally.^105,107,108

TABLE 5: Clinical features suggestive of HIV infection in patients with tuberculosis¹⁰⁵

Past history

Sexually transmitted infections (STI)
Herpes zoster (shingles)
Recent or recurrent pneumonia
Severe bacterial infections
Recent treated tuberculosis

Symptoms

Weight loss (>10 kg or >20% of original weight)
Diarrhea (>1 month)
Retrosternal pain on swallowing (suggestive of esophageal candidiasis)
Burning sensation of feet (peripheral sensory neuropathy)

Signs

Scar of herpes zoster
Itchy popular skin rash
Kaposi sarcoma
Symmetrical generalized lymphadenopathy
Oral candidiasis
Angular cheilitis
Oral hairy leukoplakia
Necrotizing gingivitis
Giant aphthous ulceration
Persistent painful genital ulceration

Source: Modified from WHO, 2004¹⁰⁵

STANDARD 13.

All patients with tuberculosis and HIV infection should be evaluated to determine
if antiretroviral therapy is indicated during the course of treatment for tuberculosis.
Appropriate arrangements for access to antiretroviral drugs should be made
for patients who meet indications for treatment. Given the complexity of coadministration
of antituberculosis treatment and antiretroviral therapy, consultation
with a physician who is expert in this area is recommended before initiation
of concurrent treatment for tuberculosis and HIV infection, regardless of which
disease appeared fi rst. However, initiation of treatment for tuberculosis should
not be delayed. Patients with tuberculosis and HIV infection should also receive
co-trimoxazole as prophylaxis for other infections.

Rationale and Evidence Summary

The evidence on effectiveness of treatment for tuberculosis in patients with HIV co-infection
versus those who do not have HIV infection has been reviewed extensively.24,69,72,105,109–112
These reviews suggest that, in general, the outcome of treatment for tuberculosis is the
same in HIV-infected and non-HIV-infected patients with the notable exception that death
rates are greater among patients with HIV infection, presumably due in large part to complications
of HIV infection. With two exceptions, tuberculosis treatment regimens are the
same for HIV-infected and non-HIV-infected patients. The fi rst exception is that thioacetazone,
a drug used commonly in the past but no longer recommended, is contraindicated
in patients with HIV infection. Thioacetazone is associated with a high risk of severe skin
reactions in HIV-infected individuals and should not be used.24,105 Second, the results of
treatment are better if a rifampicin-containing regimen is used throughout the six-month
course of treatment.72 Thus, the six-month regimen containing rifampicin throughout the
entire course is preferable in patients with HIV infection to minimize the risk of relapse;
however, the patient’s HIV stage, the need for (and availability of) antiretroviral drugs, and
the quality of treatment supervision/support must be considered in choosing an appropriate
continuation phase of therapy.

All patients with tuberculosis and HIV infection either currently are, or will be, candidates
for antiretroviral therapy. Antiretroviral therapy results in remarkable reductions in morbidity
and mortality in HIV-infected persons and may improve the outcomes of treatment for
tuberculosis. Highly active antiretroviral therapy (HAART) is the internationally accepted
standard of care for persons with advanced HIV infection.

In patients with HIV-related tuberculosis, treating tuberculosis is the fi rst priority. In the
setting of advanced HIV infection, untreated tuberculosis can progress rapidly to death.
As noted above, however, antiretroviral treatment may be lifesaving for patients with advanced
HIV infection. Consequently, concurrent treatment may be necessary in patients
with advanced HIV disease (e.g., circulating CD4+ T lymphocyte count <200/μL). It should
be emphasized, however, that treatment for tuberculosis should not be interrupted in order
to initiate antiretroviral therapy, and, in patients with early stage HIV infection, it may
be safer to defer antiretroviral treatment until at least the completion of the initial phase of
tuberculosis treatment.105

There are a number of problems associated with concomitant therapy for tuberculosis
and HIV infection. These include overlapping toxicity profi les for the drugs used, drug-drug interactions (especially with rifamycins and protease inhibitors), potential problems
with adherence to multiple medications, and immune reconstitution reactions.69,105 Consequently,
consultation with an expert in HIV management is needed in deciding when
to start antiretroviral drugs, the agents to use, and the plan for monitoring for adverse
reactions and response to both therapies. (For a single-source reference on the management
of tuberculosis in patients with HIV infection see the WHO manual TB/HIV: A Clinical
Manual.105)

Patients with tuberculosis and HIV infection should also receive co-trimoxazole (trimethoprimsulfamethoxazole)
as prophylaxis for other infections. Several studies have demonstrated
the benefi ts of cotrimoxazole prophylaxis, and this intervention is currently recommended
by the WHO as part of the TB/HIV management package.105,107,113–118

STANDARD 14.

An assessment of the likelihood of drug resistance, based on history of prior
treatment, exposure to a possible source case having drug-resistant organisms,
and the community prevalence of drug resistance, should be obtained for all patients.
Patients who fail treatment and chronic cases should always be assessed
for possible drug resistance. For patients in whom drug resistance is considered
to be likely, culture and drug susceptibility testing for isoniazid, rifampicin, and
ethambutol should be performed promptly.

Rationale and Evidence Summary

Drug resistance is largely man-made and is a consequence of suboptimal regimens
and treatment interruptions. Clinical errors that commonly lead to the emergence
of drug resistance include: failure to provide effective treatment support and assurance
of adherence; failure to recognize and address patient non-adherence;
inadequate drug regimens; adding a single new drug to a failing regimen; and
failure to recognize existing drug resistance.119 In addition, co-morbid conditions
associated with reduced serum levels of antituberculosis drugs (e.g., malabsorption,
rapid transit diarrhea, HIV infection, or use of antifungal agents) may also lead
to the acquisition of drug resistance.119

Programmatic causes of drug resistance include drug shortages and stock-outs,
administration of poor-quality drugs and lack of appropriate supervision to prevent erratic
drug intake.119 Patients with drug-resistant tuberculosis can spread the disease to their
contacts. Transmission of drug-resistant strains of M. tuberculosis has been well described
in congregate settings and in susceptible populations, notably HIV-infected persons.120–123
However, multidrug-resistant (MDR) tuberculosis (tuberculosis caused by organisms that
are resistant to at least isoniazid and rifampicin) may spread in the population at large, as
was shown in China, the Baltic States, and countries of the former Soviet Union.
The strongest factor associated with drug resistance is previous antituberculosis treatment,
as shown by the WHO/IUATLD Global Project on Anti-TB Drug Resistance Surveillance,
started in 1994.124 In previously treated patients, the odds of any resistance are
at least fourfold higher and that of MDR at least tenfold higher than in new (untreated) patients.124 Patients with chronic tuberculosis (sputum-positive after retreatment) and
those who fail treatment (sputum-positive after fi ve months of treatment) are at highest
risk of having MDR tuberculosis, especially if rifampicin was used throughout the course
of treatment.124 Persons who are in close contact with confi rmed MDR tuberculosis patients,
especially children and HIV-infected individuals, also are at high risk of being infected
with MDR strains. In some closed settings, prisoners, persons staying in homeless
shelters and certain categories of immigrants and migrants are at increased risk of MDR
tuberculosis.119–124

Drug susceptibility testing (DST) to the fi rst-line antituberculosis drugs should be performed
in specialized reference laboratories that participate in an ongoing, rigorous quality
assurance program. DST for fi rst-line drugs is currently recommended for all patients
with a history of previous antituberculosis treatment: patients who have failed treatment,
especially those who have failed a standardized retreatment regimen, and chronic cases
are the highest priority.119 Patients who develop tuberculosis and are known to have been
in close contact with persons known to have MDR tuberculosis also should have DST
performed on an initial isolate. Although HIV infection has not been conclusively shown to
be an independent risk factor for drug resistance, MDR tuberculosis outbreaks in HIV settings
and high mortality rates in persons with MDR tuberculosis and HIV infection justify
routine DST in all HIV-infected tuberculosis patients, resources permitting.119
STANDARD 15. Patients with tuberculosis caused by drug-resistant (especially MDR) organisms
should be treated with specialized regimens containing second-line antituberculosis
drugs. At least four drugs to which the organisms are known or presumed
to be susceptible should be used, and treatment should be given for at least 18
months. Patient-centered measures are required to ensure adherence. Consultation
with a provider experienced in treatment of patients with MDR tuberculosis
should be obtained.

Rationale and Evidence Summary

Because randomized controlled treatment trials for MDR tuberculosis would be extremely
diffi cult to design, none have been conducted. Current recommendations are, therefore,
based on observational studies, general microbiological and therapeutic principles, extrapolation
from available evidence from pilot MDR tuberculosis treatment projects, and
expert opinion.125,126 Three strategic options for treatment of MDR tuberculosis are currently
recommended by WHO: standardized regimens, empiric regimens, and individualized
treatment regimens. The choice among these should be based on availability of second-
line drugs and DST for fi rst- and second-line drugs, local drug resistance patterns,
and the history of use of second-line drugs.119 Basic principles involved in the design of
any regimen include the use of at least four drugs with either certain or highly likely effectiveness,
drug administration at least six days a week, drug dosage determined by
patient weight, the use of an injectable agent (an aminoglycoside or capreomycin) for at least six months, treatment duration of 18–24 months, and DOT throughout the
treatment course.

Standardized treatment regimens are based on representative drug-resistance
surveillance data or on the history of drug usage in the country. Based
on these assessments, regimens can be designed that will have a high likelihood
of success. Advantages include less dependency on highly technical
laboratories, less reliance on highly specialized clinical expertise required to
interpret DST results, simplifi ed drug ordering, and easier operational implementation.

A standardized approach is useful in settings where second-line
drugs have not been used extensively and, consequently, where resistance
levels to these drugs are low or absent.

Empiric treatment regimens are commonly used in specifi c groups of patients
while the DST results are pending. Unfortunately, most of the available DST methods have
a turnaround time of several months. Empiric regimens are strongly recommended to
avoid clinical deterioration and to prevent transmission of MDR strains of M. tuberculosis
to contacts while awaiting the DST results.119 Once the results of DST are known, an empiric
regimen may be changed to an individualized regimen. Ongoing global efforts to address
the problem of MDR tuberculosis will likely result in broader access to laboratories
performing DST and a faster return of results.

Individualized treatment regimens (based on DST profi les and previous drug history of
individual patients, or on local patterns of drug utilization) have the advantage of avoiding
toxic and expensive drugs to which the MDR strain is resistant. However, an individualized
approach requires access to substantial human, fi nancial, and technical (laboratory)
capacity. DST for second-line drugs are notoriously diffi cult to perform, largely because
of drug instability and the fact that critical concentrations for defi ning drug resistance are
very close to the minimal inhibitory concentration (MIC) of individual drugs.127 Laboratory
profi ciency testing results are not yet available for second-line drugs; as a result, little can
be said about the reliability of DST for these drugs.124,127 Clinicians treating MDR tuberculosis
patients must be aware of these limitations and interpret DST results with this
in mind.

Current WHO recommendations for treatment of MDR tuberculosis can be found at
(http://www.who.int/tb/en/).119 MDR tuberculosis treatment is a complex health intervention,
and medical practitioners are strongly advised to consult colleagues experienced in
the management of these patients.

Standards for Public Health Responsibilities

The inability to conduct targeted contact investigations results in missed opportunities to prevent additional cases of tuberculosis, especially among children. Thus, more energetic efforts are necessary to overcome barriers to optimum tuberculosis control practices.

STANDARD 16.

All providers of care for patients with tuberculosis should ensure that persons
(especially children under 5 years of age and persons with HIV infection) who are
in close contact with patients who have infectious tuberculosis are evaluated
and managed in line with international recommendations. Children under 5 years
of age and persons with HIV infection who have been in contact with an infectious
case should be evaluated for both latent infection with M. tuberculosis and
for active tuberculosis.

Rationale and Evidence Summary

The risk of acquiring infection with M. tuberculosis is correlated with intensity and duration
of exposure to a person with infectious tuberculosis. Close contacts of patients with tuberculosis,
therefore, are at high risk for acquiring the infection. Contact investigation is considered
an important activity, both to fi nd persons with previously undetected tuberculosis
and persons who are candidates for treatment of latent tuberculosis infection (LTBI).128,129
The potential yield of contact investigation in high- and low-incidence settings has been
reviewed previously.128,129 In low-incidence settings (e.g., United States), it has been found
that, on average, 5–10 contacts are identifi ed for each incident tuberculosis case. Of
these, about 30% are found to have latent tuberculosis infection, and another 1–4% have active tuberculosis.128,130,131 Much higher rates of both latent infection and active
disease have been reported in high-prevalence countries, where about 50% of household
contacts have latent infection, and about 10–20% have active tuberculosis at the time of
initial investigation.129 A recent systematic review of more than 50 studies on household
contact investigations in high incidence settings showed that, on average, about 6%
(range 0.5–29%; N=40 studies) of the contacts were found to have active tuberculosis.132
The median number of household contacts that were evaluated to fi nd one case of active
tuberculosis was 19 (range 14–300).132 The median proportion of contacts found to
have latent infection was 49% (range: 7–90%; N= 34 studies).132 The median number of
contacts that were evaluated to fi nd one person with latent tuberculosis infection was 2
(range 1–14).132 Evidence from this review suggests that contact investigation in highincidence
settings is a high-yield strategy for case fi nding.

Among close contacts, there are certain subgroups that are particularly at high risk for acquiring
the infection with M. tuberculosis and progressing rapidly to active disease—children
and persons with HIV infection. Children (particularly those under the age of 5 years)
are a vulnerable group, not only because of the high likelihood of progressing from latent
infection to active disease, but because they are more likely to develop disseminated and
serious forms of tuberculosis such as meningitis. The Union, therefore, recommends that
children under the age of 5 years living in the same household as a sputum smear-positive
tuberculosis patient should be targeted for preventive therapy (after exclusion of tuberculosis
to prevent de facto monotherapy of tuberculosis).65,129 Similarly, contacts who have
HIV infection are at substantially greater risk for progressing to active tuberculosis.
Unfortunately, lack of adequate staff and resources in many areas makes contact investigation
diffi cult.65,129 This inability to conduct targeted contact investigations results in
missed opportunities to prevent additional cases of tuberculosis, especially among children.
Thus, more energetic efforts are necessary to overcome these barriers to optimum
tuberculosis control practices.

STANDARD 17.

All providers must report both new and retreatment tuberculosis cases and their
treatment outcomes to local public health authorities, in conformance with applicable
legal requirements and policies.

Rationale and Evidence Summary

Reporting tuberculosis cases to the local tuberculosis control program is an
essential public health function, and in many countries is legally mandated.
Ideally, the reporting system design, supported by a legal framework, should
be capable of receiving and integrating data from several sources, including
laboratories and healthcare institutions, as well as individual practitioners.
An effective reporting system enables a determination of the overall effectiveness
of tuberculosis control programs, of resource needs, and of the
true distribution and dynamics of the disease within the population as a
whole, not just the population served by the government tuberculosis control
program. In most countries, tuberculosis is a reportable disease. A system of
recording and reporting information on tuberculosis cases and their treatment
outcomes is one of the key elements of the DOTS strategy.103 Such a system is useful not
only to monitor progress and treatment outcomes of individual patients but also to evaluate
the overall performance of the tuberculosis control programs, at the local, national,
and global levels, and to indicate programmatic weaknesses.103

The recording and reporting system allows for targeted, individualized follow-up to help
patients who are not making adequate progress (i.e., failing therapy).103 The system also
allows for evaluation of the performance of the practitioner, the hospital or institution, local
health system, and the country as a whole. Finally, a system of recording and reporting
ensures accountability.

Although on the one hand reporting to public health authorities is essential; on the other
hand it is also essential that patient confi dentiality be maintained. Thus, reporting must follow
predefi ned channels using standard procedures that guarantee that only authorized
persons see the information. Such safeguards must be developed by local and national
tuberculosis control programs to ensure the confi dentiality of patient information.

Research Needs

As part of the process of developing the ISTC, several key areas that require additional research
were identifi ed (Table 6). Systematic reviews and research studies (some of which
are underway currently) in these areas are critical to generate evidence to support rational
and evidence-based care and control of tuberculosis. Research in these operational and
clinical areas serves to complement ongoing efforts focused on developing new tools for
tuberculosis control—new diagnostic tests,133 drugs,134 and vaccines.135

Key areas requiring additional research include:

Diagnosis and case fi nding
Treatment, monitoring, and support
Public health and operational research

RESEARCH AND REVIEW NEEDS 49

Research in operational and clinical areas serves to complement ongoing efforts focused on developing new tools for tuberculosis control—new diagnostic tests, drugs, and vaccines.

TABLE 6: Priority areas for research and evaluation

AREA OF RESEARCH and SPECIFIC RESEARCH QUESTIONS

Diagnosis and case finding

What is the sensitivity and specifi city of various thresholds for chronic cough (e.g., two
versus three weeks) as a screening test to determine who should be evaluated for
tuberculosis? How do local conditions such as the prevalence of tuberculosis, HIV infection,
asthma, and chronic obstructive pulmonary disease (COPD) infl uence the threshold?
What is the optimal diagnostic strategy/algorithm for establishing a diagnosis of tuberculosis
in patients suspected of having the disease but who have negative sputum smears? Should
the strategy be modifi ed in patients with HIV infection?
What is the optimal diagnostic algorithm for children with suspected tuberculosis?
What is the role of therapeutic antibiotic trials in the diagnosis of smear-negative
tuberculosis?
What is the value and role of sputum concentration in improving the accuracy and yield of
smear microscopy?
What is the impact of bleach treatment of sputum on the accuracy and yield of sputum
smear microscopy?
What is the role, feasibility, and applicability of fl uorescent microscopy in routine fi eld
conditions in areas of both high and low HIV prevalence?
Is there a role for more intensive case fi nding in high-HIV-endemic settings?
What is the contribution of routine use of culture in tuberculosis care and control in highprevalence
areas?
Is there a role for rapid culture methods in tuberculosis control programs?
What factors lead to delays in establishing a diagnosis of tuberculosis?
What is the impact of engaging former (or current) TB patients and/or patient organizations
in active case fi nding?
What is the role reporting by components of the healthcare system other than direct patient
care providers?

Treatment, monitoring, and support

What interventions are effective in improving patient (adults and children) adherence to
antituberculosis therapy?
What is the effi cacy of direct observation of treatment (DOT) versus other measures to
improve adherence to treatment?
What is the role of fi xed-dose combinations (FDCs) in improving adherence?
What is the optimal duration of antituberculosis therapy for patients who are HIV-positive?
What interventions help in reducing mortality among tuberculosis patients who have HIV
infection?
What is the effectiveness of standardized versus individualized treatment regimens in the
management of mono-resistant and MDR tuberculosis?
What is the relevance of second-line drug susceptibility test results in determining
individualized retreatment regimens?
What are the optimal drug doses and duration of treatment for children?
What is the impact of engaging former (or current) TB patients or patient organizations in
improving adherence

Public health and operational research

What is the effect of the DOTS strategy on tuberculosis transmission in populations with
high rates of MDR tuberculosis?
What is the impact of HIV infection on the effectiveness of DOTS programs?
What interventions or measures are helpful in improving tuberculosis management practices
in private practitioners?
What is the impact of treatment of latent tuberculosis infection on tuberculosis burden in
high-HIV-prevalence settings?
What is the impact of engaging former (or current) patients and/or patient organizations in
improving tuberculosis control programs in regions with insuffi cient human resources?
What are the optimum models for integration of tuberculosis and HIV care?

References:
1. Hopewell PC, Pai M. Tuberculosis, vulnerability, and access to quality care. JAMA 2005;293(22):2790–3.
2. World Health Organization. Guidelines for WHO Guidelines. Geneva: World Health Organization,
  2003: 1-24.
3. Hadley M, Maher D. Community involvement in tuberculosis control: lessons from other health care
  programmes. Int J Tuberc Lung Dis 2000;4(5):401–8.
4. World Health Organization. Guidelines for the prevention of tuberculosis in health care facilities in
  resource-limited settings. Geneva: World Health Organization, 1999.
5. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium
  tuberculosis in health-care settings, 2005. MMWR 2005;54(RR-17):1–141.
6. World Health Organization. Global tuberculosis control. Surveillance, planning, fi nancing. WHO Report
  2005. Geneva: World Health Organization, 2005: 1–247.
7. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions
  with the HIV epidemic. Arch Intern Med 2003;163(9):1009–21.
8. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis:
  estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and
  Monitoring Project. JAMA 1999;282(7):677–86.
9. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC. The evolution of tuberculosis control, and
  prospects for reaching the millennium development goals. JAMA 2005;293:2767–75.
10. Uplekar M. Involving private health care providers in delivery of TB care: global strategy. Tuberculosis
  2003;83(1-3):156–64.
11. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis
  control. Lancet 2001;358(9285):912–6.
12. World Health Organization. Involving private practitioners in tuberculosis control: issues, interventions,
  and emerging policy framework. Geneva: World Health Organization, 2001: 1–81.
13. World Health Organization. Public-private mix for DOTS. Practical tools to help implementation.
  Geneva: World Health Organization, 2003.
14. Cheng G, Tolhurst R, Li RZ, Meng QY, Tang S. Factors affecting delays in tuberculosis diagnosis
  in rural China: a case study in four counties in Shandong Province. Trans R Soc Trop Med Hyg
  2005;99(5):355–62.
15. Lonnroth K, Thuong LM, Linh PD, Diwan VK. Delay and discontinuity—a survey of TB patients’ search
  of a diagnosis in a diversifi ed health care system. Int J Tuberc Lung Dis 1999;3(11):992–1000.
16. Olle-Goig JE, Cullity JE, Vargas R. A survey of prescribing patterns for tuberculosis treatment
  amongst doctors in a Bolivian city. Int J Tuberc Lung Dis 1999;3(1):74–8.
17. Prasad R, Nautiyal RG, Mukherji PK, Jain A, Singh K, Ahuja RC. Diagnostic evaluation of pulmonary
  tuberculosis: what do doctors of modern medicine do in India? Int J Tuberc Lung Dis 2003;7(1):52–7.
18. Shah SK, Sadiq H, Khalil M, et al. Do private doctors follow national guidelines for managing pulmonary
  tuberculosis in Pakistan? East Mediterr Health J 2003;9(4):776–88.
19. Singla N, Sharma PP, Singla R, Jain RC. Survey of knowledge, attitudes and practices for tuberculosis
  among general practitioners in Delhi, India. Int J Tuberc Lung Dis 1998;2(5):384–9.
20. Suleiman BA, Houssein AI, Mehta F, Hinderaker SG. Do doctors in north-western Somalia follow the
  national guidelines for tuberculosis management? East Mediterr Health J 2003;9(4):789–95.
21. Uplekar MW, Shepard DS. Treatment of tuberculosis by private general practitioners in India. Tubercle
  1991;72(4):284–90.
22. World Health Organization. Toman’s tuberculosis: case detection, treatment, and monitoring (second
  edition). Geneva: World Health Organization, 2004: 1–332.
23. WHO/IUATLD/KNCV. Revised international defi nitions in tuberculosis control. Int J Tuberc Lung Dis
  2001;5(3):213–5.
24. World Health Organization. Treatment of tuberculosis. Guidelines for national programmes. Geneva:
  World Health Organization, 2003.
25. Enarson DA, Rieder HL, Arnadottir T, Trebucq A. Management of tuberculosis. A guide for low income
  countries. 5th edition. Paris: International Union Against Tuberculosis and Lung Disease, 2000.
26. World Health Organization. Respiratory care in primary care services: a survey in 9 countries. Geneva:
  World Health Organization, 2004.
27. Luelmo F. What is the role of sputum microscopy in patients attending health facilities? In: Frieden
  TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva:
  World Health Organization, 2004: 7–10.
28. Organizacion Panamericana de la Salud. Control de Tuberculosis en America Latina: Manual de Normas
  y Procedimientos para programas Integrados. Washington, D.C.: Organizacion Panamericana
  de la Salud, 1979.
29. Santha T, Garg R, Subramani R, et al. Comparison of cough of 2 and 3 weeks to improve detection
  of smear-positive tuberculosis cases among out-patients in India. Int J Tuberc Lung Dis
  2005;9(1):61–8.
30. Khan J, Malik A, Hussain H, et al. Tuberculosis diagnosis and treatment practices of private physicians
  in Karachi, Pakistan. East Mediterr Health J 2003;9(4):769–75.
31. Harries AD, Hargreaves NJ, Kemp J, et al. Deaths from tuberculosis in sub-Saharan African countries
  with a high prevalence of HIV-1. Lancet 2001;357(9267):1519–23.
32. Maher D, Harries A, Getahun H. Tuberculosis and HIV interaction in sub-Saharan Africa: impact on
  patients and programmes; implications for policies. Trop Med Int Health 2005;10(8):734–42.
33. Mukadi YD, Maher D, Harries A. Tuberculosis case fatality rates in high HIV prevalence populations
  in sub-Saharan Africa. AIDS 2001;15(2):143–52.
34. Harries A. What is the additional yield from repeated sputum examinations by microscopy and culture?
  In: Frieden TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition.
  Geneva: World Health Organization, 2004: 46–50.
35. Mase S, Ng V, Henry MC, et al. Yield of serial sputum smear examinations in the evaluation of
  pulmonary tuberculosis: a systematic review (unpublished report). Geneva: Special Programme for
  Research & Training in Tropical Diseases (TDR), World Health Organization, and Foundation for Innovative
  New Diagnostics (FIND). 2005.
36. Rieder HL, Chiang CY, Rusen ID. A method to determine the utility of the third diagnostic and the
  second follow-up sputum smear examinations to diagnose tuberculosis cases and failures. Int J
  Tuberc Lung Dis 2005;9(4):384–391.
37. Gopi PG, Subramani R, Selvakumar N, Santha T, Eusuff SI, Narayanan PR. Smear examination of
  two specimens for diagnosis of pulmonary tuberculosis in Tiruvallur District, south India. Int J Tuberc
  Lung Dis 2004;8(7):824–8.
38. Van Deun A, Salim AH, Cooreman E, et al. Optimal tuberculosis case detection by direct sputum
  smear microscopy: how much better is more? Int J Tuberc Lung Dis 2002;6(3):222–30.
39. Sarin R, Mukerjee S, Singla N, Sharma PP. Diagnosis of tuberculosis under RNTCP: examination of
  two or three sputum specimens. Indian J Tuberc 2001(48):13–16.
40. Steingart KR, Ng V, Henry MC, et al. Sputum processing methods to improve the sensitivity and
  yield of smear microscopy for tuberculosis: a systematic review (unpublished report). Geneva: Special
  Programme for Research & Training in Tropical Diseases (TDR), World Health Organization, and
  Foundation for Innovative New Diagnostics (FIND). 2005.
41. Henry MC. Conventional light microscopy versus fl uorescence microscopy for the diagnosis of pulmonary
  tuberculosis: a systematic review: University of California, Berkeley, Master’s Thesis, Spring
  2005.
42. Steingart KR, Ng V, Henry MC, et al. Fluorescence versus conventional sputum smear microscopy
  for tuberculosis: a systematic review (unpublished report). Geneva: Special Programme for Research
  & Training in Tropical Diseases (TDR), World Health Organization, and Foundation for Innovative New
  Diagnostics (FIND). 2005.
43. Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among HIV-infected
  ambulatory subjects in Tanzania. Clin Infect Dis 2005;40(10):1500–7.
  44. Koppaka R, Bock N. How reliable is chest radiography? In: Frieden TR, ed. Toman’s tuberculosis.
  Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health Organization, 2004:
  51-60.
44. Harries A. What are the relative merits of chest radiography and sputum examination (smear microscopy
  and culture) in case detection among new outpatients with prolonged chest symptoms?
  In: Frieden TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition.
  Geneva: World Health Organization, 2004: 61–65.
45. Nagpaul DR, Naganathan N, Prakash M. Diagnostic photofl uorography and sputum microscopy
  in tuberculosis case fi ndings. Proceedings of the 9th Eastern Region Tuberculosis Conference and
  29th National Conference on Tuberculosis and Chest Diseases 1974, Delhi.
46. Colebunders R, Bastian I. A review of the diagnosis and treatment of smear-negative pulmonary
  tuberculosis. Int J Tuberc Lung Dis 2000;4(2):97–107.
47. Siddiqi K, Lambert ML, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in lowincome
  countries: the current evidence. Lancet Infect Dis 2003;3(5):288–296.
48. Bah B, Massari V, Sow O, et al. Useful clues to the presence of smear-negative pulmonary tuberculosis
  in a West African city. Int J Tuberc Lung Dis 2002;6(7):592–8.
49. Oyewo TA, Talbot EA, Moeti TL. Non-response to antibiotics predicts tuberculosis in AFB-smearnegative
  TB suspects, Botswana, 1997-1999 (abstract). Int J Tuberc Lung Dis 2001(5(Suppl 1)):
  S126.
50. Somi GR, O’Brien RJ, Mfi nanga GS, Ipuge YA. Evaluation of the MycoDot test in patients with suspected
  tuberculosis in a fi eld setting in Tanzania. Int J Tuberc Lung Dis 1999;3(3):231–8.
51. Wilkinson D, De Cock KM, Sturm AW. Diagnosing tuberculosis in a resource-poor setting: the value
  of a trial of antibiotics. Trans R Soc Trop Med Hyg 1997;91(4):422–4.
52. Sterling TR. The WHO/IUATLD diagnostic algorithm for tuberculosis and empiric fl uoroquinolone use:
  potential pitfalls. Int J Tuberc Lung Dis 2004;8(12):1396–400.
53. van Deun A. What is the role of mycobacterial culture in diagnosis and case fi nding? In: Frieden TR,
  ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: World
  Health Organization, 2004: 35–43.
54. Kim TC, Blackman RS, Heatwole KM, Kim T, Rochester DF. Acid-fast bacilli in sputum smears of
  patients with pulmonary tuberculosis. Prevalence and signifi cance of negative smears pretreatment
  and positive smears post-treatment. Am Rev Respir Dis 1984;129(2):264–8.
55. Toman K. How many bacilli are present in a sputum specimen found positive by smear microscopy?
  In: Frieden TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition.
  Geneva: World Health Organization, 2004: 11-13.
56. Toman K. How reliable is smear microscopy? In: Frieden TR, ed. Toman’s tuberculosis. Case detection,
  treatment and monitoring, 2nd Edition. Geneva: World Health Organization, 2004: 14–22.
57. Menzies D. What is the current and potential role of diagnostic tests other than sputum microscopy
  and culture? In: Frieden TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring,
  2nd Edition. Geneva: World Health Organization, 2004: 87–91.
58. Pai M. The accuracy and reliability of nucleic acid amplifi cation tests in the diagnosis of tuberculosis.
  Natl Med J India 2004;17(5):233–6.
59. Pai M, Flores LL, Hubbard A, Riley LW, Colford JM, Jr. Nucleic acid amplifi cation tests in the diagnosis
  of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis 2004;4(1):6.
60. Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM, Jr. Diagnostic accuracy of nucleic acid
  amplifi cation tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect
  Dis 2003;3(10):633–43.
61. Flores LL, Pai M, Colford JM, Jr., Riley LW. In-house nucleic acid amplifi cation tests for the detection
  of Mycobacterium tuberculosis in sputum specimens: meta-analysis and meta-regression. BMC
  Microbiol 2005;5:55.
62. Nahid P, Pai M, Hopewell PC. Advances in the diagnosis and treatment of tuberculosis. Proc Am
  Thorac Soc In Press.
63. Shingadia D, Novelli V. Diagnosis and treatment of tuberculosis in children. Lancet Infect Dis
  2003;3(10):624–32.
64. Gie RP, Beyers N, Schaaf HS, Goussard P. The challenge of diagnosing tuberculosis in children: a
  perspective from a high incidence area. Paediatr Respir Rev 2004;5 Suppl A:S147–9.
65. Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. A critical review of diagnostic approaches
  used in the diagnosis of childhood tuberculosis. Int J Tuberc Lung Dis 2002;6(12):1038–45.
66. Nelson LJ, Wells CD. Tuberculosis in children: considerations for children from developing countries.
  Semin Pediatr Infect Dis 2004;15(3):150–4.
67. World Health Organization. Management of the child with a serious infection or severe malnutrition :
  guidelines for care at the fi rst-referral level in developing countries. Geneva: World Health Organization,
  2000.
68. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society
  of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167(4):603–62.
69. Gelband H. Regimens of less than six months for treating tuberculosis. Cochrane Database Syst Rev
  2000(2):CD001362.
70. Santha T. What is the optimum duration of treatment? In: Frieden TR, ed. Toman’s tuberculosis.
  Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health Organization, 2004:
  144–151.
71. Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. Effects of human immunodefi ciency virus infection
  on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect
  Dis 2003;37(1):101–12.
72. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of
  newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet
  2004;364(9441):1244–51.
73. Okwera A, Johnson JL, Luzze H, et al. Comparison of intermittent continuous phase ethambutol
  with two rifampicin containing regimens in human immunodefi ciency virus (HIV) infected adults with
  pulmonary tuberculosis in Kampala, Uganda. Int J Tuberc Lung Dis 2005 (in press).
74. Mitchison DA. Antimicrobial therapy for tuberculosis: justifi cation for currently recommended treatment
  regimens. Semin Respir Crit Care Med 2004;25(3):307–315.
75. Frieden TR. What is intermittent treatment and what is the scientifi c basis for intermittency? In: Frieden
  TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva:
  World Health Organization, 2004: 130–138.
76. Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary
  tuberculosis. Second report: the results up to 24 months. Hong Kong Chest Service/British
  Medical Research Council. Tubercle 1982;63(2):89–98.
77. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for
  smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid,
  rifampin, and pyrazinamide. Results at 30 months. Hong Kong Chest Service/British Medical
  Research Council. Am Rev Respir Dis 1991;143(4 Pt 1):700–6.
78. Tuberculosis Research Centre. Low rate of emergence of drug resistance in sputum positive patients
  treated with short course chemotherapy. Int J Tuberc Lung Dis 2001;5(1):40–5.
79. Bechan S, Connolly C, Short GM, Standing E, Wilkinson D. Directly observed therapy for tuberculosis
  given twice weekly in the workplace in urban South Africa. Trans R Soc Trop Med Hyg
  1997;91(6):704–7.
80. Caminero JA, Pavon JM, Rodriguez de Castro F, et al. Evaluation of a directly observed six months
  fully intermittent treatment regimen for tuberculosis in patients suspected of poor compliance. Thorax
  1996;51(11):1130–3.
81. Cao JP, Zhang LY, Zhu JQ, Chin DP. Two-year follow-up of directly-observed intermittent regimens
  for smear-positive pulmonary tuberculosis in China. Int J Tuberc Lung Dis 1998;2(5):360–4.
82. Rieder HL. What is the evidence for tuberculosis drug dosage recommendations? In: Frieden TR, ed.
  Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health
  Organization, 2004:141–143.
83. Rieder HL. What is the dosage of drugs in daily and intermittent regimens? In: Frieden TR, ed.
  Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health
  Organization, 2004:139–140.
84. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fi xed-dose combination
  tablets for treatment of tuberculosis. Bull World Health Organ 2001;79(1):61–8.
85. Panchagnula R, Agrawal S, Ashokraj Y, et al. Fixed dose combinations for tuberculosis: Lessons
  learned from clinical, formulation and regulatory perspective. Methods Find Exp Clin Pharmacol
  2004;26(9):703–21.
86. World Health Organization. Adherence to long-term therapies. Evidence for action. Geneva: World
  Health Organization, 2003.
87. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course
  chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998;2(1):10–5.
88. Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database Syst
  Rev 2003(1):CD003343.
89. Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet
  2000;355(9212):1345–50.
90. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis:
  Consensus Statement of the Public Health Tuberculosis Guidelines Panel. JAMA
  1998;279(12):943–8.
91. Sbarbaro J. What are the advantages of direct observation of treatment? In: Frieden TR, ed. Toman’s
  tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health Organization,
  2004: 183–184.
92. Sbarbaro J. How frequently do patients stop taking treatment prematurely? In: Frieden TR, ed.
  Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health
  Organization, 2004: 181–182.
93. Pope DS, Chaisson RE. TB treatment: as simple as DOT? Int J Tuberc Lung Dis 2003;7(7):611–5.
94. Gordon AL. Interventions other than direct observation of therapy to improve adherence of tuberculosis
  patients: a systematic review: University of California, Berkeley, Master’s Thesis, Spring 2005.
95. World Health Organization. An Expanded DOTS Framework for Effective Tuberculosis Control. Geneva:
  World Health Organization, 2002.
96. World Health Organization. The Global Plan to Stop Tuberculosis. Geneva: World Health Organization,
  2001.
97. Frieden TR. Can tuberculosis be controlled? Int J Epidemiol 2002;31(5):894–9.
98. World Health Organization. Integrated Management of Adolescent and Adult Illness (IMAI): Acute
  Care. Geneva: World Health Organization, 2004.
99. World Health Organization. Integrated Management of Adolescent and Adult Illness (IMAI): Chronic
  HIV care with ARV therapy. Geneva: World Health Organization, 2004.
100. World Health Organization. Integrated Management of Adolescent and Adult Illness (IMAI): General
  principles of good chronic care. Geneva: World Health Organization, 2004.
101. Santha T. How can the progress of treatment be monitored? In: Frieden TR, ed. Toman’s tuberculosis.
  Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health Organization,
  2004: 250–252.
102. Maher D, Raviglione MC. Why is a recording and reporting system needed, and what system is recommended?
  In: Frieden TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring,
  2nd Edition. Geneva: World Health Organization, 2004: 270–273.
103. Bock N, Reichman LB. Tuberculosis and HIV/AIDS: Epidemiological and Clinical Aspects (World
  Perspective). Semin Respir Crit Care Med 2004;25(3):337–44.
104. World Health Organization. TB/HIV: A clinical manual. Geneva: World Health Organization, 2004.
105. World Health Organization. Scaling up antiretroviral therapy in resource-limited settings. Guidelines
  for a public health approach. Geneva: World Health Organization, 2002.
106. Nunn P, Williams B, Floyd K, Dye C, Elzinga G, Raviglione M. Tuberculosis control in the era of HIV.
  Nat Rev Immunol 2005;5(10):819–26.
107. UNAIDS/WHO. UNAIDS/WHO Policy Statement on HIV Testing: UNAIDS, 2004: 1–3.
108. El-Sadr WM, Perlman DC, Denning E, Matts JP, Cohn DL. A review of effi cacy studies of 6-month
  short-course therapy for tuberculosis among patients infected with human immunodefi ciency virus:
  differences in study outcomes. Clin Infect Dis 2001;32(4):623–32.
109. Harries A. How does treatment of tuberculosis differ in persons infected with HIV? In: Frieden TR, ed.
  Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: World Health
  Organization, 2004: 169–172.
110. Hopewell PC, Chaisson RE. Tuberculosis and human immunodefi ciency virus infection. In: Reichman
  LB, Hershfi eld ES, eds. Tuberculosis: a comprehensive international approach, 2nd Edition. New
  York: Marcel Dekker, Inc., 2000: 525–552.
111. Dlodlo RA, Fujiwara PI, Enarson DA. Should tuberculosis treatment and control be addressed differently
  in HIV-infected and -uninfected individuals? Eur Respir J 2005;25(4):751–7.
112. Chimzizi R, Gausi F, Bwanali A, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole
  are associated with improved TB treatment outcomes under routine conditions in Thyolo District,
  Malawi. Int J Tuberc Lung Dis 2004;8(5):579–85.
113. Chimzizi RB, Harries AD, Manda E, Khonyongwa A, Salaniponi FM. Counselling, HIV testing and
  adjunctive cotrimoxazole for TB patients in Malawi: from research to routine implementation. Int J
  Tuberc Lung Dis 2004;8(8):938–44.
114. Grimwade K, Sturm AW, Nunn AJ, Mbatha D, Zungu D, Gilks CF. Effectiveness of cotrimoxazole
  prophylaxis on mortality in adults with tuberculosis in rural South Africa. AIDS 2005;19(2):163–8.
115. Mwaungulu FB, Floyd S, Crampin AC, et al. Cotrimoxazole prophylaxis reduces mortality in human
  immunodefi ciency virus-positive tuberculosis patients in Karonga District, Malawi. Bull World Health
  Organ 2004;82(5):354–63.
116. Zachariah R, Spielmann MP, Chinji C, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole
  reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS 2003;17(7):1053–61.
117. Zachariah R, Spielmann MP, Harries AD, Gomani P, Bakali E. Cotrimoxazole prophylaxis in HIV-infected
  individuals after completing anti-tuberculosis treatment in Thyolo, Malawi. Int J Tuberc Lung
  Dis 2002;6(12):1046–50.
118. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis.
  (WHO/htm/tb/2006.361) Geneva: World Health Organization, 2005.
119. Coninx R, Mathieu C, Debacker M, et al. First-line tuberculosis therapy and drug-resistant Mycobacterium
  tuberculosis in prisons. Lancet 1999;353(9157):969–73.
120. Edlin BR, Tokars JI, Grieco MH, et al. An outbreak of multidrug-resistant tuberculosis among hospitalized
  patients with the acquired immunodefi ciency syndrome. N Engl J Med 1992;326(23):1514–21.
121. Fischl MA, Uttamchandani RB, Daikos GL, et al. An outbreak of tuberculosis caused by multiple-drugresistant
  tubercle bacilli among patients with HIV infection. Ann Intern Med 1992;117(3):177–83.
122. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of multidrug-resistant tuberculosis. Pediatr Infect
  Dis J 2000;19(8):695–9.
123. World Health Organization. Anti-tuberculosis drug resistance in the world. Third Report. The WHO/
  IUATLD project on anti-tuberculosis drug resistance surveillance. Geneva: World Health Organization,
  2004.
124. Caminero JA. Management of multidrug-resistant tuberculosis and patients in retreatment. Eur
  Respir J 2005;25(5):928–36.
125. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant
  tuberculosis. Lancet 2004;363(9407):474–81.
126. Kim SJ. Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur Respir J
  2005;25(3):564–9.
127. Etkind SC, Veen J. Contact follow-up in high and low-prevalence countries. In: Reichman LB, Hershfi
  eld ES, eds. Tuberculosis: a comprehensive international approach, 2nd Edition. New York: Marcel
  Dekker, Inc., 2000: 377–399.
128. Rieder HL. Contacts of tuberculosis patients in high-incidence countries. Int J Tuberc Lung Dis
  2003;7(12 Suppl 3):S333–6.
129. Mohle-Boetani JC, Flood J. Contact investigations and the continued commitment to control tuberculosis.
  (Editorial). JAMA 2002;287:1040.
130. Reichler MR, Reves R, Bur S, et al. Evaluation of investigations conducted to detect and prevent
  transmission of tuberculosis. JAMA 2002;287(8):991–5.
131. Morrison JL, Pai M, Hopewell P. Yield of tuberculosis contact investigations within households in
  high incidence countries: a systematic review [Abstract 239]. Infectious Diseases Society of America
  (IDSA) 43rd Annual Meeting 2005, San Francisco, October 6–9, 2005.
132. Perkins MD. New diagnostic tools for tuberculosis. Int J Tuberc Lung Dis 2000;4(12 Suppl 2):S182-8.
133. O’Brien RJ, Spigelman M. New drugs for tuberculosis: current status and future prospects. Clin
  Chest Med 2005;26(2):327–40, vii.
134. Brennan MJ. The tuberculosis vaccine challenge. Tuberculosis 2005;85(1-2):7–12.
Contact information:

Philip C. Hopewell, MD
University of California, San Francisco
San Francisco General Hospital
San Francisco, CA 94110, USA
Email: [email protected]

This file available as a pdf download (1.89 mb)

The ISTC “Patients Charter for Tuberculosis Care, Patients Rights and Responsibilities” is also available for download. (989kb)

Share on Facebook

Save

Join The Community

Submit Post

Job Request

Click to apply

Tools

Pregnancy Calculator - Find out Estimated Conception, Estimated Due Date & Estimated fetal age.
Body Mass Index - Find out your Body Mass Index & know whether you are underweight, normal or overweight.

Also on Indmedica

Guestbook - Sign our Guestbook
E-Greetings - Send a greeting online
Humour - Enjoy some good jokes
User's News- News posted by our members
Book Reviews - Books reviewed by our members
Grievances/Complaints - Read/post any bitter experiences within the industry

International Standards for Tuberculosis Care