In the United States, 49 cases of XDR-TB were identified between 1993
and 2006, and mortality was strongly associated with concomitant HIV infection.
Since 2009, 15 cases of XDR-TB have been reported in the United States, and 11
cases were among foreign-born individuals.
Risk factors for XDR-TB include previous treatment for TB, HIV infection,
homelessness, and alcohol use.
In a retrospective analysis of patients with
documented MDR-TB, emergence of XDR-TB was associated with baseline chronic
disease and nonadherence to MDR-TB therapy.
15 Treatment success is significantly
lower for XDR-TB, and XDR-TB is associated with increased all-cause and TBrelated mortality.
16 However, treatment outcomes are significantly improved when
later-generation fluoroquinolones are added to the treatment regimen for XDR-TB,
even if fluoroquinolone resistance was demonstrated on susceptibility testing.
The evolution of TB resistance continued in 2009 with the identification of strains
that were reported to be TDR, which was defined as resistance to all first-line and
7 Fifteen (10.3%) of 146 MDR-TB strains tested were found to be
TDR-TB in Iran, and cultures remained positive in these cases after 18 months of
treatment with second-line agents.
7 All of these TDR-TB cases were HIV negative.
This report illustrates the critical need to develop new and effective agents for the
treatment of TB caused by MDR, XDR, and TDR strains.
TB is caused by M. tuberculosis, an aerobic, non-spore-forming bacillus that resists
decolorization by acid alcohol after staining with basic fuchsin. For this reason, the
organism is often referred to as an acid-fast bacillus (AFB).
M. tuberculosis is different from other bacteria in that it replicates slowly—once
every 24 hours instead of every 20 to 40 minutes as with some other bacteria. The
organism thrives in environments in which the oxygen tension is relatively high, such
as the apices of the lung, the renal parenchyma, and the growing ends of bones.
M. tuberculosis is transmitted through the air by aerosolized droplet nuclei that are
produced when a person with pulmonary or laryngeal TB coughs, sneezes, speaks, or
sings. Droplet nuclei may also be produced by other methods, such as aerosol
treatments, sputum induction, bronchoscopy, endotracheal intubation, suctioning,
autopsy, and through manipulation of lesions or processing of secretions in the
18 These droplet nuclei, which contain one to three M.
tuberculosis organisms, are small enough (1–5 μm) to remain airborne for long
periods and reach the alveoli within the lungs when inhaled. Tubercle bacilli are not
transmitted on inanimate objects, and organisms deposited on skin or intact mucosa
Several factors influence the likelihood of transmission of M. tuberculosis,
including the number of organisms expelled into the air by the index patient, the
concentration of organisms in the air determined by the volume of the space and its
ventilation, the length of time an exposed person breathes the contaminated air,
location of the exposure (small room vs. outdoors), and the immune status of the
19 Family household contacts, especially children, and persons
working or living in an enclosed environment (e.g., hospitals, nursing homes,
prisons) with an infected person are at a significantly increased risk for becoming
infected. If the index case is smear positive, 50% of household contacts will have a
conversion of the tuberculin skin test from negative to positive; however, if the index
case is smear negative, only 5% will become infected.
cell-mediated immunity, such as HIV-infected persons or transplant patients, are
more likely to become infected with M. tuberculosis after exposure than persons with
19 Travelers to TB-endemic areas with international medical
exchange programs are also at risk of TB infection, regardless of involvement in
direct patient care activities or duration of stay.
Several techniques are effective in limiting airborne transmission of M.
tuberculosis by reducing the number of droplet nuclei in a given airspace. Adequate
room ventilation with fresh air is very important, especially in the healthcare setting,
in which six or more room air exchanges per hour are desirable.
construction or renovation of existing facilities should be designed so that airborne
infection isolation rooms achieve 12 or more room air exchanges per hour.
Ultraviolet irradiation of air in the upper part of the room can also reduce the number
of viable airborne tubercle bacilli. All healthcare workers and visitors who enter the
room of a patient with TB should wear at least N95 disposable respirators, and the
mask should be molded to fit tightly around the nose and mouth.
presumed or confirmed infectious TB should wear a protective mask when being
transferred to another area of the institution or after hospital discharge until they are
21 However, the most important means of reducing transmission of M.
tuberculosis is by treating the infected patient with effective antituberculosis therapy.
LATENT INFECTION VERSUS ACTIVE DISEASE
A clear distinction should be made between latent infection and active disease
(tuberculosis). Latent infection occurs when the tubercle bacilli are inhaled into the
body. After inhalation, the droplet nuclei containing M. tuberculosis settle into the
bronchioles and alveoli of the lungs. Development of infection in the lung is
dependent on the inoculum of organisms inhaled, the virulence of the organism, and
the innate immune response of the host.
In the nonimmune (susceptible) host, the
bacilli initially multiply unopposed by normal host defense mechanisms. The
organisms are then phagocytized by alveolar macrophages and resident dendritic
cells, but they may remain viable, multiplying within the cells for extended periods.
After 14 to 21 days of replication, the tubercle bacilli spread via the lymphatic
system to the hilar lymph nodes and through the bloodstream to many other organs of
Fortunately, certain organs and tissues in the body, such as the bone marrow, liver,
and spleen, are resistant to subsequent multiplication of these bacilli. Organs with
, such as the apices of the lungs, kidneys, bones, and brain,
are favorable for organism growth and may lead to extrapulmonary disease.
Organisms replicate for 2 to 12 weeks until they reach a concentration of 10
plateauing coincident with the development of a T-cell-mediated immune response in
+ T cells produce interferon-γ, which is an essential cytokine for
activation of macrophages and mycobacterial killing, as well as other cytokines.
this point, the patient has developed cell-mediated immunity, which can be detected
by a reaction to the tuberculin skin test or interferon-γ release assay (IGRA), and
bacterial replication is halted.
In persons with intact cell-mediated immunity, activated T cells and macrophages
may result in formation of a granuloma, a hallmark of TB, that is thought to represent
a physical and immunologic barrier to control the infection and limit dissemination of
the bacilli to the surrounding environment.
24 Cells found within the granuloma include
+ T cells, B cells, neutrophils, macrophages, multinucleated giant
24 The organisms tend to localize in the center of the granuloma,
which is frequently necrotic, and the tubercle bacilli may remain viable indefinitely
within the granuloma. In addition, maintenance of the integrity of the granuloma
allows for control of bacterial replication and depends on the immune status of the
24 Tumor necrosis factor (TNF) is a key cytokine that is critical for the
25 Most patients with latent TB infection are asymptomatic
with no radiographic evidence of the infection.
In some patients, there may be a
healed, calcified lesion on chest radiograph, but bacteriologic studies are negative. A
positive tuberculin skin test or IGRA is the only indication that the person has been
infected with M. tuberculosis. Individuals with latent TB infection are not infectious
and thus cannot transmit the organism to other individuals.
In the majority of patients, active TB disease results from reactivation of a
previously controlled latent infection, termed reactivation TB. It has been estimated
that approximately 10% of individuals who acquire TB infection and do not receive
therapy for the latent infection will develop active TB disease, and the risk of
developing active disease is greatest during the first 2 years after infection.
population-based tuberculin skin test survey conducted in Florida between 1997 and
2001, the rate of reactivation with latent TB infection but without HIV coinfection
was 0.040 to 0.058 cases per 100 person-years.
26 However, a recent study reported
that 1 in 4 cases of active TB in the United States may be caused by recent
27 The study included patients with culture-positive TB, and the M.
tuberculosis isolates were fully characterized by genotype. Clusters were defined as
cases with M. tuberculosis that were an exact match by genotype within specific
geospatial zones. Cases that were both genotypically and spatially clustered were
considered recent TB transmission, and cases that were not genotypically and
spatially clustered were considered reactivation TB. Of the 36,860 cases where
genotyping was performed, 8,499 cases (23.1%) met the criteria for recent TB
27 Groups at greatest risk for recent transmission were HIV-infected
individuals, members of a minority group or ethnic race, men, individuals born in the
United States, children 4 years of age or younger, substance abusers, and the
27 These patients may have limited access to health care, resulting in
delayed diagnosis and extended periods of infectivity.
Reactivation of TB in persons with latent TB infection is primarily a function of
the immune status of the host. The ability of the host to respond to M. tuberculosis
infection is reduced by certain diseases, such as diabetes mellitus, silicosis, chronic
renal failure, and diseases or drugs associated with immunosuppression (e.g., HIV
infection, anti-TNF-α agents, organ and hematologic transplantation, corticosteroids,
and other immunosuppressive agents). The likelihood of progression from latent
infection to active TB disease is greater in persons with these conditions.
22–24 HIVinfected persons, especially those with low CD4
+ T-cell counts, develop active TB
disease rapidly after becoming infected; up to 50% of these individuals may develop
active disease in the first 2 years after infection.
untreated latent TB infection who acquires HIV infection will progress to active TB
disease at an approximate rate of 5% to 10% per year.
progression from latent infection to active disease is 1.6 to 25 times higher in
patients treated with anti-TNF-α agents, depending on the clinical setting and the
31 Physical or emotional stress, gastrectomy, intestinal bypass surgery,
alcohol abuse, hematologic disease, reticuloendothelial disease, and intravenous
drug use are risk factors for development of active disease. The elderly, adolescents,
and children younger than 5 years of age are also at increased risk of developing
Drug treatment is the cornerstone for management of patients with TB. In a patient
with active TB, the overall treatment goals are to cure the individual patient and to
minimize transmission of M. tuberculosis. The primary goals of chemotherapy are
rapid bacterial killing, prevent emergence of drug resistance, and eliminate persistent
tubercle bacilli to prevent relapse.
33 To accomplish these goals, treatment must be
tailored to each patient’s clinical and social circumstances to ensure adherence to
and completion of treatment (patient-centered care). Effective TB treatment requires
a substantial period of drug therapy, and optimization of the initial treatment phase
prevents emergence of resistance and ensures success of TB therapy. Current
guidelines recommend four drugs for the initial 8-week treatment phase: isoniazid,
rifampin, pyrazinamide, and ethambutol.
33 The drug regimen and duration of the
continuation phase depends on patient response, susceptibility of the isolate, host
factors, extent of the disease (pulmonary vs. extrapulmonary), and drug tolerability.
The shortest duration of therapy is 6 months, but longer durations may be required
33 Because patients must be treated for months, directly
observed therapy (DOT) is the preferred core management strategy to ensure
In patients with latent TB infection, monotherapy with isoniazid for 6 to 9 months
remains the preferred regimen although other attractive options are available.
Clinical Presentation of Active Disease
QUESTION 1: H.G. is a 35-year-old Hispanic man who presents with a 4-week history of a productive
in the right upper lobe. Significant laboratory data include the following:
White blood cell count, 13,200/μL (72% polymorphonuclear leukocytes, 3% bands, 12% lymphocytes, 13%
Red blood cell count, 3.7 × 10
Serum electrolytes, renal function, and hepatic function are within normal limits.
What signs and symptoms consistent with active TB disease are present in H.G.?
H.G.’s history of cough (which gradually became productive), fever, night sweats,
fatigue, and weight loss are classic symptoms of active TB.
nonproductive early in the course of the illness, but with subsequent inflammation
and tissue necrosis, sputum is usually produced and is key to the diagnostic studies.
Sputum may contain blood (hemoptysis) in patients with advanced cavitary disease,
which is particularly worrisome because cavitary lesions harbor high concentrations
of organisms and the pulmonary location facilitates airborne transmission. Dyspnea
is unusual unless there is extensive disease.
18 Other symptoms of TB may include
pleuritic chest pain and general malaise.
In pulmonary TB, the chest radiograph usually reveals patchy or nodular infiltrates
in the apical or posterior segments of the upper lobes, but changes may be observed
The patchy infiltrates on H.G.’s chest radiograph are consistent with pulmonary
TB. Cavitary lesions may be seen; however, these were absent in this patient.
Moderate elevation of the white blood cell count with increased monocytes and
eosinophils and anemia are the most common hematologic manifestations of TB.
H.G. had an elevated white blood cell count with increased monocytes, and he was
Many patients with active pulmonary TB have no acute symptoms, and a lack of
symptoms may hinder diagnosis. In one study, approximately 50% of active TB cases
without classic symptoms were misdiagnosed.
36 More than one-third of the patients
with active TB had no sweats, chills, or malaise, and fewer than 50% were febrile.
Cough was evident in 80% of these patients, and only 25% had hemoptysis. Although
dullness over the apices of the lungs and posttussive rales are expected in TB, less
than one-third of these patients had any abnormal pulmonary signs. Similar findings
were reported in another study.
37 Absence of specific clinical symptoms underscores
the importance of skin testing, sputum smears for AFB, and chest radiographs in
suspected TB. Lastly, cases of active TB are often found after routine chest
radiographs for other illnesses.
Because many of the symptoms of TB also occur in persons with preexisting
pulmonary disease or pneumonia, they may be overlooked and not attributed to TB.
CASE 68-1, QUESTION 2: What risk factors for TB are present in H.G.?
The close contact with his coworkers, who have similar respiratory symptoms,
and their geographic origin from Mexico are risk factors for TB in H.G. In addition,
studies have implicated cigarette smoking as a risk factor for TB.
study conducted in Taiwan, smoking was associated with a twofold increase in the
risk of active TB. Furthermore, a significant dose–response relationship was
identified for number of cigarettes smoked per day, number of years of smoking, and
40 Smoking impairs mucociliary clearance, decreases
phagocytic pulmonary alveolar macrophage function, decreases intracellular
production of tumor necrosis factor-α, and causes iron overload in macrophages.
These defects in host defense mechanisms increase the risk of active disease after
Diagnosis of Active Tuberculosis
The tuberculin skin test (Mantoux method) has been used as a diagnostic tool for
infection with M. tuberculosis for decades, but a positive skin test is not necessary
for the diagnosis of active TB disease. The test is frequently referred to as the PPD
(purified protein derivative) test, which contains a protein prepared from a culture of
the tubercle bacilli. Skin testing is performed by injecting 0.1 mL of solution
containing 5 TU of PPD intracutaneously into the volar or dorsal surface of the
45 The injection is made using a one-quarter to one-half-inch, 27-gauge
needle and a tuberculin syringe. The solution should be injected just beneath the
surface of the skin, avoiding subcutaneous tissue.
46 A discrete, pale elevation of the
skin (a wheal) 6 to 10 mm in diameter is produced when the injection is performed
correctly. If the first injection was administered improperly, another test dose can be
given at once, selecting a site several centimeters away from the original injection
If the patient has been infected with M. tuberculosis, sensitized T cells are
recruited to the skin site where they release cytokines.
These cytokines induce an induration (raised area) through local vasodilatation,
edema, fibrin deposition, and recruitment of other inflammatory cells to the area.
Typically, the reaction to the tuberculin protein begins 5 to 6 hours after injection
with maximal induration observed at 48 to 72 hours. Therefore, the test should be
read between 48 and 72 hours after injection because tests read after 72 hours
underestimate the actual size of the induration.
23 For standardization, the diameter
of the induration should be measured transversely to the long axis of the forearm and
18 The diameter of the induration should be measured and not
the erythematous zone surrounding the induration.
An induration of at least 5 mm in diameter read 48 to 72 hours after injection is a
positive reaction in an individual with a recent history of close contact with a person
with active TB, a person with fibrotic changes on chest radiograph consistent with
previous TB, organ transplant patients and other immunosuppressed patients
(receiving the equivalent of ≥15 mg/day of prednisone for >1 month), or HIVinfected persons.
An induration of at least 10 mm in diameter is a positive reaction with clinical
conditions associated with increased risk for TB, such as diabetes mellitus, silicosis,
chronic renal failure, malnutrition, leukemia, lymphoma, gastrectomy, jejunoileal
bypass, and weight loss of greater than 10% of ideal body weight.
an induration of at least 10 mm is considered to be positive in recent immigrants (<5
years) from countries with a high prevalence of TB, injection drug users, residents
and employees of high-risk congregate settings (e.g., prisons, nursing homes,
homeless shelters), healthcare workers, mycobacteriology laboratory personnel, and
children younger than 4 years of age or infants, children, and adolescents exposed to
adults in high-risk catgories.
49 The skin test is also considered positive for
persons with an increase in induration diameter of at least 10 mm within a 2-year
49 For individuals with no risk factors for TB, an induration of at least 15
mm is required for a positive reaction.
It is very likely that H.G. has been in close contact with persons with active TB,
that is, his coworkers, even though they have not yet been diagnosed with active TB.
When all factors are considered, the PPD of 14 mm should be considered to be
CASE 68-1, QUESTION 4: Because H.G.’s PPD skin test is positive, does this confirm his diagnosis of
active TB? What other laboratory tests may be performed to aid in the diagnosis of TB in H.G.?
H.G.’s positive reaction to 5 TU of PPD alone does not imply active TB disease.
It only confirms that he has previously been infected with M. tuberculosis. To
confirm the diagnosis of active TB disease in H.G., M. tuberculosis must be detected
and isolated from sputum, gastric aspirate, spinal fluid, urine, or tissue biopsy,
depending on the site of infection.
18 As was performed in H.G., detection of AFB in
stained sputum smears examined microscopically should be the first test to confirm
the presence of mycobacteria in a clinical specimen. It is the easiest and fastest
procedure that can be performed and allows preliminary confirmation of the
diagnosis. Sputum samples for AFB stain and culture are best obtained early in the
morning on at least three separate days.
34 The cough reflex is usually suppressed at
night, and the first early morning expectoration represents secretions accumulated in
the chest overnight. The number of organisms in the morning sample is greater, and
the diagnostic yield is higher. Smears may be prepared directly from clinical
specimens or from concentrated preparations by placing the specimen on a glass
slide under a microscope with a Ziehl–Neelsen or fluorochrome stain (not a Gram
18 Sensitivity of sputum smear microscopy is low because 5,000 to 10,000
bacilli/mL of specimen must be present for AFB detection in stained smears.
Therefore, a negative AFB smear does not rule out active TB disease, and patients
with active TB and negative AFB smears may facilitate transmission of M.
tuberculosis. Additional limitations of the AFB smear are its inability to differentiate
among mycobacterial species and between viable and nonviable organisms. In many
areas of the United States, Mycobacterium avium complex organisms are commonly
isolated from the sputum of patients in whom a diagnosis of TB is highly probable,
such as the elderly and patients with HIV infection.
51 This finding has resulted in a
marked decrease in the specificity and positive predictive value of the sputum smear,
in some cases to as low as 50%.
The gold standard for laboratory confirmation of TB is culture.
may have a negative AFB smear, but a sufficient number of organisms may be present
to produce a positive culture. Only 10 to 100 organisms are needed for a positive
18 As a result of the limitations of the AFB smear, a positive culture for M.
tuberculosis is necessary to definitively diagnose TB in H.G. and all patients, even if
the AFB smear is positive. In addition, culture allows for genotyping and
susceptibility testing of the isolate.
51 Because M. tuberculosis grows slowly (i.e.,
once every 24 hours), it may take several weeks for the cultures to become positive.
Broth-based culture systems such as BACTEC, MGIT, MB/BacT, Septi-Check, and
ESP, when combined with DNA probes, can result in positive cultures in 2 weeks or
less for sputum smear-positive specimens and in 3 weeks or less for smear-negative
Nucleic acid amplification (NAA) tests are available to enhance and expedite
direct identification of M. tuberculosis in clinical specimens independent of
55 These tests amplify the specific target sequences of
nucleic acids in M. tuberculosis that can be detected by a nucleic acid probe within
24 to 48 hours. Two NAA tests are approved by the Food and Drug Administration
(FDA) for use in the United States. The enhanced amplified M. tuberculosis direct
patients with AFB-positive smears and 75% to 90% for patients with AFB-negative
smears. The Amplicor M. tuberculosis test is approved for detection of M.
tuberculosis in AFB smear-positive respiratory specimens. Sensitivity of the
Amplicor test is greater than 95% for patients with AFB-positive smears and 60% to
70% for patients with AFB-negative smears. Specificity of the NAA tests is greater
than 95% for both AFB smear-positive and smear-negative pulmonary specimens.
Compared with AFB smears, additional benefits of NAA testing include the ability
to rapidly confirm the presence of M. tuberculosis in a majority of patients with
NAA tests are cost-effective because they prioritize contact investigations, improve
decision making regarding respiratory isolation, and decrease unnecessary TB
57 Current guidelines recommend NAA testing on at least one respiratory
specimen from a patient with signs and symptoms of pulmonary TB for whom a
diagnosis has not been established and for whom the test result would alter case
management and infection control activities.
If the NAA result and the AFB smear
result are positive, the patient is presumed to have TB, and drug treatment should be
initiated while awaiting culture results.
If the NAA result is positive and the AFB
smear result is negative, clinical judgment should be exercised regarding initiating
drug therapy, and additional diagnostic testing may be needed. If the NAA result is
negative and the AFB smear result is positive, a test
for inhibitors should be performed and an additional specimen should be tested
with NAA. Sputum specimens (3%–7%) might contain inhibitors that prevent or
reduce amplification and cause false-negative NAA results.
the AFB smear result are negative, clinical judgment is recommended in the decision
to begin drug therapy because NAA tests lack the sensitivity in AFB smear-negative
specimens needed to exclude the diagnosis of TB.
A negative response to 5 TU of PPD in H.G. would not exclude active infection
with M. tuberculosis. The PPD skin test has a reported false-negative rate of 25%
during the initial evaluation of persons with active tuberculosis.
illness, or immunosuppression. False-negative results usually occur in persons who
have only recently been infected or are anergic. Anergy, the decreased ability to
respond to antigens, may be caused by severe debility, advanced age, immaturity in
newborns, high fever, sarcoidosis, corticosteroids, immunosuppressive drugs,
If anergy is suspected, control skin tests
(Candida, mumps, or Trichophyton) may be placed in the contralateral arm. If the
control test results are positive and the PPD test result is negative, infection with M.
tuberculosis is less likely. The Centers for Disease Control and Prevention (CDC)
changed its recommendations regarding anergy skin testing in HIV-infected patients
with a negative PPD. They cite problems with standardization and reproducibility, a
low risk for TB associated with a diagnosis of anergy, and the lack of apparent
benefit of therapy for latent TB infection in anergic HIV-infected patients. Therefore,
the use of anergy testing in conjunction with PPD is no longer routinely recommended
in this population or other patients who are immunocompromised.
BCG, or bacille Calmette–Guérin, is a live vaccine derived from an attenuated
strain of Mycobacterium bovis, and it is used in many foreign countries with a high
prevalence of TB to prevent the disease in persons who are tuberculin negative.
Many different BCG vaccines are available worldwide, and they differ with respect
to immunogenicity, efficacy, and reactogenicity. Additional factors, such as genetic
variability in the vaccinated subjects, the nature of the mycobacteria endemic in
different parts of the world, and the use of different doses and immunization
schedules, may contribute to the varied degrees of protection provided by the
vaccine. The protective effect derived from BCG vaccines in case–control studies
60 Two meta-analyses calculated estimates of the protective
efficacy of BCG vaccination for preventing TB. Results from the first meta-analysis
indicated a 75% to 86% protective effect against meningeal and miliary TB in
In the second meta-analysis, the overall protective effect of BCG vaccines
62 Vaccine efficacy was higher in studies in which persons
were vaccinated during childhood in contrast with those vaccinated at older ages.
Unfortunately, neither study could confirm vaccine efficacy for preventing pulmonary
Prior vaccination with BCG usually results in a false-positive tuberculin skin test
in patients who are not infected with M. tuberculosis, but skin test reactivity does not
correlate with protection against TB.
60 There is no reliable method of
distinguishing tuberculin reactions caused by BCG vaccination from those caused by
natural mycobacterial infections.
60 Therefore, it is prudent to consider “positive”
reactions to 5 TU of PPD in BCG-vaccinated persons as indicating infection with M.
tuberculosis, especially among persons from countries with a high prevalence of
18 Even though H.G. received the BCG vaccine when he was a child, the results
of the PPD skin test should still be considered positive, especially in light of his
In general, BCG vaccination is not recommended for routine prophylaxis in the
United States because the risk of exposure to TB is relatively low. BCG vaccination
should be considered only for very select persons who meet specific criteria and in
consultation with a TB expert. BCG vaccination should only be considered for
infants or children who are PPD negative and are continually exposed to a highly
infectious, untreated patient with active TB or a child who is continually exposed to
a person with infectious pulmonary TB caused by M. tuberculosis strains resistant to
60 BCG vaccination of healthcare workers should be
considered on an individualized basis in settings in which a high prevalence of
patients is infected with MDR-TB, transmission of MDR-TB strains to healthcare
workers and subsequent infection are likely, and comprehensive infection control
precautions have been unsuccessful.
60 BCG vaccination is contraindicated in
pregnancy and in persons who are immunocompromised (e.g., HIV infection) or
persons who are likely to become immunocompromised (e.g., organ
60 Adverse reactions to the BCG vaccine vary according to the type,
dose, and age of the vaccine. Osteitis, prolonged ulceration at the vaccination site,
lupoid reactions, regional suppurative lymphadenitis, disseminated BCG infection,
An interferon-γ release assay (IGRA) is preferred over the tuberculin skin test for
persons who have received the BCG vaccine.
63 Two IGRAs are currently approved
by the FDA as an aid for diagnosing both latent and active M. tuberculosis infection:
the QuantiFERON-TB Gold test and the T-SPOT.TB test. These IGRAs assess
response to synthetic peptides that represent specific proteins, early secretory
antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), that are present
in all M. tuberculosis strains.
In sensitized patients, ESAT-6 and CFP-10 are
recognized by T cells and stimulate release of interferon-γ. The QuantiFERON-TB
Gold test measures the interferon-γ concentrations released using an enzyme-linked
immunosorbent assay. The T-SPOT.TB test uses an enzyme-linked immunospot assay
(ELISpot) to detect increases in the number of cells that secrete interferon-γ.
However, ESAT-6 and CFP-10 are not present in BCG vaccine strains and most
within 24 hours compared to 2 to 3 days for tuberculin skin testing.
CASE 68-1, QUESTION 7: Should H.G. be tested for HIV infection?
The CDC recommends HIV screening for all patients with TB as well as those
persons suspected of having TB disease and contacts of patients with TB.
Therefore, H.G. should be tested for HIV. HIV infection is the most important risk
factor for progression of latent TB infection to active disease, and progression is
more rapid in HIV-infected persons. Unlike other AIDS-related opportunistic
infections, CD4 count is not a reliable predictor of increased risk of TB disease in
be the first manifestation of HIV infection because patients can have a relatively
high CD4 count when TB disease develops.
There are four basic regimens recommended for the treatment of adult patients
with active TB caused by organisms that are known or presumed to be drug
33 Because H.G. has not been treated previously for TB, he
should be started on isoniazid, rifampin, pyrazinamide, and ethambutol. However, he
has been in close contact with persons with symptoms resembling TB who are from
an area (Mexico) with a high prevalence of drug-resistant TB. Therefore, H.G. must
be closely monitored for resolution of symptoms, results of repeated sputum smears,
and culture and susceptibility results, regardless of the initial treatment regimen.
Previous guidelines recommended the addition of ethambutol only if the local
prevalence of isoniazid-resistant M. tuberculosis is at least 4%.
States, 9.3% of M. tuberculosis isolates recovered from patients with no previous
history of TB were resistant to isoniazid in 2014.
10 The prevalence of isoniazid
resistance was higher in foreign-born persons (10.2%) compared with US-born
In patients with a history of previous of TB, 18.9% of strains were
resistant to isoniazid in 2014, with 24.7% resistance in foreign-born persons versus
4.4% resistance in US-born persons.
10 Because of the relatively high likelihood of
TB caused by isoniazid-resistant organisms, four drugs are necessary in the initial 8-
The initial four-drug regimen may be administered daily throughout the 8-week
period (regimen 1), daily for the first 2 weeks and then twice weekly for 6 weeks
(regimen 2), or thrice weekly throughout (regimen 3).
33 Based on clinical experience,
administration of drugs for 5 days/week is considered to be equivalent to 7
days/week administration and either regimen 1 or 2 may be considered “daily.”
However, 5-day-a-week administration should always be given by DOT.
dosages for these recommended regimens are listed in Table 68-3. H.G. should be
started on isoniazid 300 mg daily, rifampin 600 mg daily, pyrazinamide 1,500 mg
daily, and ethambutol 1,200 mg daily. He should also receive pyridoxine 25 mg/day
to minimize the risk for development of isoniazid-induced peripheral neuropathy.
Treatment Regimens for Pulmonary Tuberculosis Caused by Drug-Susceptible
Initial Phase Continuation Phase Rating (Evidence)
conducted in other populations; III, expert opinion.
dNot recommended for HIV-infected patients with CD4+ cell counts <100 cells/μL.
completion of 2 months of therapy and who do not have cavitation on the initial chest radiograph.
EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.
Drugs Used in the Treatment of Tuberculosis in Adults and Children (continued)
Isoniazid Adults: 5 mg/kg (300
Rifampin Adults: 10 mg/kg (600
Rifabutin Adults: 5 mg/kg (300
Rifapentine Adults: Active disease,
Similar to rifampin Unknown Drug interactions
Pyrazinamide Adults: 40–55 kg: 1 g
Ethambutol Adults: 40–55 kg: 800
Cycloserine Adults: 10–15 mg/kg/day
Ethionamide Adults: 15–20 mg/kg/day
and thyroidstimulating hormone
Streptomycin Adults: 15 mg/kg/day (1
Amikacin Adults: 15 mg/kg/day (1
Capreomycin Adults: 15 mg/kg/day (1
Levofloxacin Adults: 500 to 1,000
Moxifloxacin Adults: 400 mg/day Nausea, diarrhea,
Bedaquiline Adults: 400 mg once
CNS, central nervous system; GI, gastrointestinal.
Fixed-dose combinations of drugs have been advocated to improve adherence to
the prescribed regimen, especially during the critical initial treatment phase. There
are two fixed-dose combination preparations available in the United States:
Rifamate, which contains isoniazid 150 mg and rifampin 300 mg/capsule, and
Rifater, which contains isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300
mg/tablet. These formulations are a means of minimizing inadvertent monotherapy,
especially when DOT is not possible, and they may decrease the risk of acquired
drug resistance while reducing the number of capsules or tablets that must be ingested
33 Safety and efficacy of a four-drug fixed-dose combination regimen was
compared with each drug administered separately in patients with pulmonary TB.
The combination tablet contained isoniazid 75 mg, rifampin 150 mg, pyrazinamide
400 mg, and ethambutol 275 mg, and two to five tablets were ingested per day based
on body weight. The number of patients who were culture negative at 18 and 24
months was similar between the treatment groups, in addition to the number of
treatment failures, relapses, and death. The four-drug fixed-dose combination was
noninferior to each drug administered
It should be noted that there was no difference in outcomes based on
HIV status, but less than 7% of the study subjects were HIV positive.
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