The high risk of transmission of M. tuberculosis to other persons mandates that
hospitalized persons with suspected or confirmed infectious TB be placed in
respiratory isolation until they are determined not to have TB, they are discharged
from the hospital, or they are confirmed to be noninfectious.
subjective and objective findings, he should be placed in respiratory isolation.
H.G.’s symptoms should improve within the first 4 weeks. He would be considered
to be noninfectious when he is receiving effective drug therapy, is improving
clinically, and has had negative results for three consecutive sputum AFB smears
34 Patients who have responded clinically may be
discharged to home despite positive smears if their household contacts have already
with positive smears must agree not to have contact with other susceptible persons.
Fluoroquinolones as Initial Therapy
Interest in fluoroquinolones for the treatment of TB dates back more than 30 years
with a report describing the use of ofloxacin in 19 patients with chronic, drugresistant TB disease.
68 Several fluoroquinolones possess in vitro activity against M.
tuberculosis, but moxifloxacin and gatifloxacin are four- to eightfold more potent than
69 Moxifloxacin was compared with ethambutol in the first 2 months of
treatment in adults with smear-positive pulmonary TB.
assigned to receive moxifloxacin 400 mg daily or ethambutol (based on body
weight), and all patients received isoniazid, rifampin, and pyrazinamide. Patients
receiving moxifloxacin were more likely to have negative sputum cultures at 4 weeks
and 6 weeks, but the 2-month conversion rates were equal in each group.
study, sputum culture conversion at 8 weeks was significantly greater in patients
treated with moxifloxacin when compared with ethambutol (80% vs. 63%).
conversion rates were also significantly higher in the moxifloxacin group at weeks 1,
2, 3, and 4, and the median time to consistently negative cultures was 35.0 days in the
moxifloxacin group and 48.5 days in the ethambutol group.
Moxifloxacin has been compared with isoniazid during the intensive phase of
72 Patients were randomly assigned to receive
moxifloxacin 400 mg or isoniazid 300 mg daily, and all patients received rifampin,
72 After 8 weeks, negative sputum cultures were
observed in 60.4% of the patients in the moxifloxacin group and 54.9% of patients in
the isoniazid group, but this difference was not statistically significant.
Despite the reported efficacy of fluoroquinolones in the treatment of TB, clinicians
must be cognizant of the potential development of resistance to this important drug
class. Fluoroquinolone resistance in M. tuberculosis has been described, occurring
more frequently in multidrug-resistant isolates.
73 Fluoroquinolones are the most
commonly prescribed antibiotic class in the United States, and outpatient use for
infections other than TB could be a potential risk factor for TB resistance in a patient
who becomes infected with M. tuberculosis. In a study evaluating risk factors for
fluoroquinolone-resistant M. tuberculosis, investigators identified newly diagnosed
patients with culture-confirmed TB in a Medicaid population.
evaluated, 116 (18%) patients had fluoroquinolone exposure within the 12 months
before diagnosis with TB, and 16 (2.5%) patients were infected with M. tuberculosis
strains that were fluoroquinolone resistant.
74 The study found that receipt of a
fluoroquinolone for more than 10 days, occurring more than 60 days before diagnosis
of TB, was associated with the highest risk for fluoroquinolone resistance.
Therefore, judicious use of fluoroquinolones, especially in patients at risk for TB
infection, is mandatory to maintain the utility of fluoroquinolones in the treatment of
Drug susceptibility testing is essential to ensure proper treatment of patients with
active disease and should be performed on the initial isolate of M. tuberculosis from
18 Susceptibility testing should also be performed if cultures remain
positive after 3 months of therapy or if negative cultures become positive after a
period of time. Traditionally, susceptibility testing is performed by growing the
organism on solid or in liquid media containing the drug. The agar proportion method
allows for quantitation of the proportion of organisms that are resistant to a given
drug, which is expressed as a percentage of the total organism population tested.
drug will not be useful for therapy if 1% or more of the total population are resistant
to the drug. Unfortunately, susceptibility results may not be available for several
weeks because of the slow growth of the organism and the need to isolate the
pathogen before susceptibility testing can be performed.
To expedite susceptibility reporting, molecular drug resistance tests have been
developed to detect mutations in the chromosomal sequence encoding for resistance
to a specific drug directly on clinical specimens without the need for growth on
55 For example, mutations in the rpoB gene block the activity of rifampin by
preventing the drug from binding to RNA polymerase. Approximately 95% of
rifampin-resistant M. tuberculosis carry this mutation, and treatment failures have
been associated with the presence of rpoB mutations.
resistance test amplifies the target genetic sequence using polymerase chain reaction,
and a second assay, such as DNA sequencing and hybridization assays, is used to
determine whether the sequence contains a mutation associated with drug resistance.
If a mutation is detected, the organism is considered to be drug resistant, but the
organism is presumed to be drug susceptible if a mutation is not detected. Molecular
tests can reliably detect the presence of known mutations within 1 to 2 days, which
may result in earlier initiation of effective therapy, shorter durations of infectivity,
and reduced spread of TB. However, these molecular drug resistance tests can only
detect a specific set of known mutations and cannot identify novel mutations
55 Therefore, traditional susceptibility testing continues to play
an important role in confirming results of molecular testing.
Kits for detecting mutations associated with rifampin resistance include GenoType
MTBDR(plus) and INNO-LiPA Rif.TB. Compared with culture-based drug
resistance tests, the sensitivity and specificity of the MTBDR(plus) line-probe assay
were 98% and 99%, respectively, for detecting rifampin resistance in isolates or
directly from clinical specimens.
78 The sensitivity of the INNO-LiPA Rif.TB assay
ranged from 80% to 100% and the specificity was 100% for detecting rifampin
resistance directly from clinical specimens.
78 Molecular beacons are hybridization
probes that use fluorescent-labeled, hairpin-shaped DNA probes with a fluorophore
adjacent to a molecule that prevents fluorescence.
35 Using a real-time polymerase
chain reaction assay, fluorescence occurs if the amplified PCR products have the
wild-type gene sequence, but fluorescence is not detected if mutations are present in
the target sequence. These tests have high sensitivity (96%–97%) and specificity
(99%–100%) for rifampin resistance in clinical specimens.
resistance tests for other antitubercular drugs are not fully developed compared with
tests for rifampin resistance. For detecting mutations associated with
isoniazid resistance, the specificity of the MTBDR(plus) assay was 100%, but the
sensitivity ranged from 57% to 100% (pooled sensitivity 85%).
resistance is a reliable surrogate for MDR-TB in the United States because isolated
rifampin resistance is uncommon.
The Xpert MTB/RIF assay is an automated molecular-based test that uses nested
real-time polymerase chain reaction, allowing for simultaneous detection of M.
tuberculosis and rifampin resistance. The test is approved for diagnostic testing of
raw sputum samples, and results are available within 2 hours.
98.2% in AFB culture or smear-positive specimens, but performance is correlated
with bacterial load because sensitivity is only 55% to 72.5% in smear-negative
81 Sensitivity is also lower in patients with HIV infection. Specificity
was 94% to 99.2% in patients with negative cultures.
also correctly identified 98.1% of patients with rifampin-susceptible bacilli and
97.6% of patients with rifampin-resistant bacilli.
CASE 68-1, QUESTION 9: Is H.G. a risk to the community and does anyone need to know?
Yes! Each case of active TB disease must be reported to the local, state, or both
82 This not only results in optimal therapy by
monitoring adherence to therapy, but it also ensures that contact and source-case
investigations will be performed. All individuals who have been in close contact to
H.G. should be evaluated for latent TB infection or active disease. Considering their
close contact to H.G. and his coworkers, his family members should be evaluated.
Reporting of cases also permits record-keeping and surveillance to determine
whether public health TB control efforts are achieving their goal of preventing the
drug regimen should be used for continued treatment of H.G.? How long should treatment be continued?
Successful treatment of uncomplicated TB can be achieved in 6 months (26 weeks)
if isoniazid, rifampin, pyrazinamide, and ethambutol are used for the first 2 months (8
weeks) and if patient adherence to the regimen and the organism susceptibility can be
33 Therefore, after 8 weeks of DOT with isoniazid, rifampin, pyrazinamide,
and ethambutol, H.G.’s regimen may be streamlined to isoniazid and rifampin daily
(5 days or 7 days/week) or 2 to 3 times/week under continued DOT for an additional
18 weeks (Table 68-2). Because H.G. is HIV negative and cavitary lesions were not
present on his chest radiograph, he may also be a candidate for once-weekly
administration of isoniazid and rifapentine, as long as his sputum AFB smear is
negative after completing the initial 8 weeks of therapy.
The effectiveness of a primarily twice-weekly treatment regimen has been
demonstrated in both pulmonary and extrapulmonary TB.
isoniazid 300 mg, rifampin 600 mg, pyrazinamide 1.5 to 2.5 g, and streptomycin 750
to 1,000 mg intramuscularly daily for 2 weeks, followed by the same drugs twice
weekly for an additional 6 weeks. The regimen was then reduced to isoniazid and
rifampin twice weekly for the remaining 16 weeks (4 months). At 3 months, 75% of
patients had negative sputum cultures, and all patients were culture negative at 20
83 Relapse occurred in two patients and only minor adverse effects were
reported. Another important feature is that this regimen is highly cost-effective.
Among the 6- and 9-month regimens, it is the second lowest in cost, primarily
because of the least number of patient–healthcare worker encounters (62 directly
If pyrazinamide cannot be included in the initial regimen, therapy should be
initiated with isoniazid, rifampin, and ethambutol for the first 8 weeks. Therapy
should be continued with isoniazid and rifampin for 31 weeks given either daily or
If drugs other than isoniazid and rifampin are used in the initial
phase, treatment must be continued for 18 to 24 months.
Twice-weekly administration of isoniazid (900 mg) and rifampin (600 mg) is
recommended for H.G. because this approach requires fewer doses and should result
once-weekly regimen of isoniazid and rifapentine 600 mg.
were associated with increased relapse risk in the isoniazid and rifapentine group:
sputum culture positive at 2 months; cavitation on chest radiograph; underweight;
bilateral pulmonary involvement; non-Hispanic Caucasian race.
explanation for these results is the high protein binding of rifapentine (98%). A study
evaluated the safety and tolerability of rifapentine 600, 900, and 1,200 mg once
weekly (with isoniazid 15 mg/kg) in 150 HIV-negative patients.
more adverse events was observed in the 1,200-mg treatment arm (p = 0.051), but the
900-mg dose was well tolerated.
86 However, relapse rates for the higher-dose
weekly rifapentine regimens with isoniazid are unknown. A subsequent study
demonstrated that low plasma concentrations of isoniazid were associated with
failure or relapse with once-weekly isoniazid and rifapentine.
relapsed with M. tuberculosis monoresistant to rifamycin had very low isoniazid
concentrations. Rapid acetylation status was a risk factor in those patients who failed
87 Rifamycin pharmacokinetics did not influence patient outcomes,
Treatment with isoniazid and rifampin should be continued for a minimum total
duration of 26 weeks. A full course of therapy can be more accurately determined by
the total number of doses ingested, not solely by the duration of therapy.
weeks is the minimum duration of treatment and accurately indicates the amount of
time the drugs are given only if there are no interruptions in drug administration.
Pyridoxine 10 to 25 mg/day should be continued throughout the treatment period. If
H.G. is symptomatic, or smear or culture is positive after 3 months of therapy, he
should be re-evaluated for possible nonadherence with his therapy, malabsorption of
the drugs, or infection with drug-resistant organisms. Evaluation should include a
second culture and a second susceptibility test, consideration of DOT (if not already
instituted), and consultation with experts in the treatment of TB.
CASE 68-1, QUESTION 11: H.G. is concerned about the long duration required for treatment of his
treatment regimens that may be administered for less than 26 weeks?
Treatment of active TB for 26 weeks is a challenge to ensure patients adhere to the
prescribed regimen for the total duration of therapy. Shorter-course treatment
regimens, if efficacious, could be helpful in improving adherence rates, decreasing
treatment costs, and reducing adverse events. Three published studies evaluated the
treatment of drug-susceptible TB for a total duration of 4 months using modified
regimens that included a fluoroquinolone (moxifloxacin or gatifloxacin).
control regimen was the same in each study and consisted of 8 weeks of isoniazid,
rifampin, pyrazinamide, and ethambutol followed
by isoniazid and rifampin for 18 weeks. In all three studies, unfavorable outcomes
and culture-confirmed relapse/recurrence were more common in patients receiving
the short-course regimens; therefore, noninferiority was not demonstrated for any of
88–90 Based on these studies, H.G. should receive 26 weeks of
therapy, and every effort should be made to ensure adherence to the treatment
CASE 68-1, QUESTION 12: What is directly observed therapy, and why is it important for H.G. to be
treated by directly observed therapy?
Directly observed therapy (DOT) is the practice of a healthcare provider or other
responsible person observing as the patient ingests and swallows the TB
medications. DOT is the preferred core management strategy for all patients with
33–35 The purpose of DOT is to ensure adherence to TB therapy. DOT not only
ensures completion of therapy, but it may also reduce the risk of developing drug
resistance. By improving these two factors, it also reduces the risk of transmission of
can be given at the patient’s home, school, or work.
66 Often, enablers or incentives,
such as food, clothing, or transportation, are used to improve adherence to DOT. A
comprehensive review of DOT-related articles found that the completion rate of TB
therapy exceeds 90% when DOT is used along with enablers.
culture-positive patients treated for active pulmonary TB with DOT had significantly
higher cure rates (97.8% vs. 88.6%; p < 0.002) and lower TB-related mortality (0%
vs. 5.5%; p = 0.002) compared with patients treated using self-administered
92 Although DOT is recommended for all patients, public health departments
may not be able to provide DOT for all patients because of the associated costs. The
initial cost of DOT is greater than self-administered therapy; however, when costs of
relapse and failure are included in a cost-effectiveness analysis, DOT is significantly
less expensive than self-administered therapy.
93 When drug resistance develops (in
those instances in which DOT is not used), the cost of salvage therapy increases to
It is, therefore, widely accepted that patients with TB
CASE 68-1, QUESTION 13: Why are multiple drugs recommended for treatment of active TB disease?
What is the role of each drug in the treatment of active TB?
The key to treating active TB disease is multiple-drug therapy for a period
sufficient to kill the organisms and to prevent development of resistant strains of M.
tuberculosis. Most cavitary lesions contain a concentration of 10
and the frequency of mutations that confer resistance to a single drug is approximately
for isoniazid and streptomycin, 10
Considering the inoculum of organisms involved, patients with active TB disease
likely harbor organisms with random mutations that confer drug resistance to a given
drug. If a single drug is given, it would reduce the number of drug-susceptible
organisms but allow the drug-resistant organisms to replicate. By using multiple-drug
therapy, the likelihood of encountering organisms with mutations to multiple drugs is
reduced. For example, the frequency of concurrent mutations to isoniazid and
simultaneous resistance to both drugs an unlikely event in an untreated patient.
Therefore, monotherapy should never be used in the treatment of active TB
Multiple-drug therapy also serves to sterilize the sputum and lesions as quickly as
possible. The drugs available for the treatment of TB vary in their ability to
33 Drugs effective against tubercle bacilli can be divided into
first-line and second-line agents (Table 68-3). The foundation of treatment should be
with first-line agents, such as isoniazid, rifampin, pyrazinamide, and ethambutol. Of
the various agents, isoniazid has the most bactericidal activity versus rapidly
multiplying M. tuberculosis during the initial phase of therapy (early bactericidal
activity), followed by ethambutol, rifampin, and streptomycin.
potent early bactericidal activity more rapidly decrease the infectiousness of the
patient and reduce the likelihood of developing resistance.
early bactericidal activity during the first 2 weeks of therapy and is less effective at
preventing emergence of drug resistance than isoniazid, rifampin, and
99 Therefore, pyrazinamide should not be combined with only one
other agent when treating active TB disease. Rifampin also has activity against
intracellular organisms that are usually dormant but undergo periods of active
growth. This ability to penetrate and destroy the persistent intracellular organisms
makes rifampin extremely valuable in short-course chemotherapy regimens.
Pyrazinamide is most effective against tubercle bacilli in the acidic environment
within the macrophage or areas of tissue necrosis. In addition, it is most effective in
sterilizing lesions when used in the first 2 months of treatment, but it does not offer
substantial sterilizing activity after 2 months. Pyrazinamide should be considered an
essential component of short-course regimens.
Ethambutol is bacteriostatic at low doses, but bactericidal at higher doses. It is
moderately effective against the fast-growing bacilli. It has little sterilizing activity
and is primarily used to prevent the emergence of drug-resistant organisms.
Streptomycin is bactericidal against rapidly multiplying extracellular organisms
and is effective when given daily for 2 months followed by twice- or thrice-weekly
administration thereafter. In the past, streptomycin was administered by intramuscular
injection, but these intramuscular injections were painful. Therefore, although it is
not labeled for intravenous use, streptomycin may be given in 50 to 100 mL of 5%
dextrose in water or normal saline and infused for 30 to 60 minutes.
can cause ototoxicity and nephrotoxicity, as with other aminoglycosides.
Other drugs used in the treatment of TB (bedaquiline, capreomycin, amikacin,
cycloserine, ethionamide, p-aminosalicylic acid) are usually reserved for cases
involving drug-resistant organisms, treatment failures, drug toxicity, or patient
intolerance to the other agents. Their use is discussed later in the chapter.
H.G. should be questioned about the occurrence of adverse reactions associated
with his therapy (Table 68-3). Specifically, he should be asked about anorexia,
nausea, vomiting, or abdominal pain, which may be an indication of possible
hepatitis secondary to isoniazid, rifampin, or pyrazinamide. He should be questioned
about numbness and tingling in his extremities; however, isoniazid-induced
peripheral neuropathy should not be a problem in H.G. because he is also taking
pyridoxine, which should prevent this adverse effect. H.G. also should be examined
questioned about, petechiae or bruises, because thrombocytopenia occurs
occasionally with intermittent rifampin therapy. This effect purportedly occurs more
frequently with intermittent rifampin therapy, but it is rare at the currently
recommended intermittent rifampin dose of 10 mg/kg/day (≈600 mg).
In a study comparing 6- versus 9-month antituberculosis therapies of mostly
isoniazid and rifampin, the incidence of side effects was similar between the two
groups. Adverse effects occurred in 7.7% of patients in the 6-month arm compared
with 6.4% in the 9-month arm, a difference that was not statistically significant.
Hepatic abnormalities occurred in 1.6% of patients in the 6-month regimen, a
nonsignificant difference from patients in the 9-month regimens (1.2%). Hematologic
events were rare at 0.2% and 0.0% in the 6- and 9-month groups, respectively. Other
reported effects, gastrointestinal (GI) problems, rash, and arthralgias were minor and
A pretreatment complete blood count, platelet count, blood urea nitrogen, hepatic
enzymes (serum aminotransferases), bilirubin, and serum uric acid should be
evaluated. Baseline visual examination should also be considered for patients
receiving ethambutol. These tests are performed to detect any abnormality that may
complicate or necessitate modification of the prescribed regimen. These tests should
be repeated if the patient experiences any evidence of drug toxicity or has
H.G. is 35 years of age and at increased risk for development of drug-induced
hepatotoxicity. Isoniazid can cause asymptomatic increases in serum transaminases
33 Pyrazinamide has also been associated with
hepatotoxicity, but the incidence is less common at doses of 25 mg/kg/day or less.
Transient asymptomatic hyperbilirubinemia and cholestatic hepatitis can occur in
33 Therefore, it is important that H.G. be educated about
possible symptoms of hepatotoxicity, primarily nausea, vomiting, abdominal pain,
anorexia, and jaundice. Monthly serum liver function tests (LFTs) are no longer
recommended because they are costly, and transient, asymptomatic elevations in
LFTs may occur, which could result in unnecessary discontinuation of optimal
therapy. The CDC recommends that medical personnel question patients about
Sputum cultures and smears for AFB should be ordered every 2 to 4 weeks
initially and then monthly after the sputum cultures become negative. With
appropriate therapy, sputum cultures should become negative in more than 85% of
patients after 2 months. Radiologic examination (chest radiographs) is not as
important as sputum examination, but it may be useful at the completion of therapy to
serve as a comparison for any future films.
Patients who are culture positive at 2 months need to be carefully re-examined.
Drug susceptibility testing should be performed to rule out acquired drug resistance,
and special attention should be given to drug adherence (i.e., DOT should be used). If
drug resistance is demonstrated, the regimen should be modified as needed. Sputum
cultures should also be obtained monthly until negativity is achieved.
As was the case for H.G., weight loss and nutritional depletion are common in
patients with active TB disease. In a large TB treatment study, 7.1% of patients
experienced relapse, with relapse greatest in patients who were underweight at
diagnosis or with a body mass index less than 18.5 kg/m2
underweight at diagnosis (defined as ≥10% below ideal body weight), weight gain of
5% or less between diagnosis and completion of 2 months of therapy was
independently associated with relapse.
In addition, the relapse rate was 50.5% in
underweight patients with a cavitary lesion on chest radiograph, positive sputum
cultures after 2 months of therapy, and a 5% or less weight gain in the first 2 months
103 Therefore, it may be prudent to monitor H.G.’s body weight during the
initial 2 months of therapy, and he may need to receive more intensive therapy or a
Routine follow-up usually is not required after the successful completion of
chemotherapy with isoniazid and rifampin. It may be prudent, however, to re-examine
the patient 6 months after completion of therapy or at the first sign of any symptoms
suggestive of active TB. This is especially important in patients who were slow to
respond to therapy or who have significant radiologic findings at completion of
therapy. These recommendations are only for those patients with organisms fully
susceptible to the medications being used.
Patients who are culture negative but have radiographic abnormalities consistent
with TB should have an induced sputum or bronchoscopy performed to establish a
microbiologic diagnosis and monitored radiographically. Patients with
extrapulmonary TB should be evaluated according to the site of involvement.
one more drug be added to his regimen?
No! Adding a single drug to a failing regimen is the most common and devastating
prescribing error in TB therapy. This practice is essentially monotherapy because the
assumption is that the organisms are resistant to the medications currently being used.
Resistance to the new drug will eventually develop, further reducing the patient’s
chance of cure. At least two, and preferably three, new drugs to which susceptibility
can be inferred should be added to lessen the probability of further acquired drug
resistance. Empiric retreatment regimens may include a fluoroquinolone,
bedaquiline, an injectable agent (e.g., streptomycin, amikacin, or capreomycin), and
an additional oral agent (e.g., p-aminosalicylic acid, cycloserine, or ethionamide).
New drug susceptibility testing should be performed and treatment adjusted
TREATMENT OF LATENT TUBERCULOSIS
Because J.G. is a household contact of a person with active TB disease and has a
positive tuberculin skin test, she is at great risk of developing active disease.
During the first year after infection from the index case, a household contact’s risk of
developing active disease is 2% to 4%, and contacts with a positive tuberculin skin
test are at the greatest risk.
66 As with active disease, the tuberculin skin test is usually
performed to detect the presence of latent TB infection. However, for contact
investigation, studies have demonstrated that IGRAs are a more accurate indicator of
the presence of latent TB infection than tuberculin skin testing.
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