1. Therapeutics 2 course
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Tuberculosis

2. Risk Factors for Infection:
TB is caused by Mycobacterium tuberculosis, which can produce either a silent, latent infection or a progressive, active disease.
Risk Factors for Infection:
Location and Place of Birth: TB is most prevalent in large urban areas, places such as prisons, shelters, or nursing homes, abuse or illicit drug use
Race, Ethnicity, Age, and Gender: Hispanic Asians, blacks, primarily in the 25- to 44-year age group, male predominance increases with each decade of life after 15 years old
Coinfection with Human Immunodeficiency Virus
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3. Transmission Reactivation Disease
Children younger than 2 years of age and adults older than 65 years
Patients with underlying immune suppression
Transmission
M. tuberculosis is transmitted from person to person by coughing or other activities that cause the organism to be aerosolized.
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Reactivation Disease
within 2 years of infection, The apices of the lungs are the most common sites for reactivation (85% of cases)

4. Extrapulmonary Tuberculosis
Extrapulmonary TB without concurrent pulmonary disease is uncommon in normal hosts but more common in HIV-infected patients
Lymphatic and pleural diseases are the most common forms of extrapulmonary TB, followed by bone, joint, genitourinary, meningeal, and other forms.
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5. N.B

6. The Elderly
Positive skin tests, fevers, night sweats, sputum production, or hemoptysis may be absent, making TB hard to distinguish from other bacterial or viral infections or chronic lung diseases. mental status changes are twice as common in the elderly, and CNS disease must be considered when TB is entertained. Mortality is six times higher in the elderly, in part owing to delays in diagnosis.
Children
TB in children may present as atypical bacterial pneumonia, and often involves the lower and middle lobes. Extrapulmonary TB is more common in children.
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7. TREATMENT The desired outcomes during the treatment of TB are:
1. Rapid identification of a new TB case
2. Initiation of specific anti-TB treatment
3. Prompt resolution of the signs and symptoms of disease
4. Achievement of a noninfectious state in the patient, thus ending isolation
5. Adherence to the treatment regimen by the patient
6. Cure of the patient as quickly as possible (generally at least 6 months of treatment)
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8. Monotherapy can be used only for infected patients who do not have active TB (latent infection, as shown by a positive skin test).
Once active disease is present, a minimum of two drugs, and generally three or four drugs, must be used
The duration of treatment depends on the condition of the host, extent of disease, presence of drug resistance, and tolerance of medications. The shortest duration of treatment generally is 6 months, and 2 to 3 years of treatment may be necessary for cases of MDR-TB
N.B

9. Non-pharmacologic Therapy
Prevent the spread of TB
Find where TB has already spread using contact investigation
Replenish the weakened (consumptive) patient to a state of normal weight and well-being.
Fitted respirators, and closing doors to “negative- pressure” rooms.
Some may need nutritional support
Surgery may needed to remove damaged tissues in the lung and lesions
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These hospital isolation rooms draw air in from
surrounding areas rather than blowing air (and M. tuberculosis) into these surrounding areas. The air
from the isolation room may be treated with ultraviolet lights and then vented safely outside.
However, these isolation rooms work properly only if the door is closed.

10. Pharmacological therapy ……Drugs
Primary Antituberculosis Drugs:
Isoniazid, Rifampin, Pyrazinamide, and Ethambutol
Secondary line therapy:
Streptomycin, Cycloserine, Ethionamide, Clofazimine, Quinolones
New Drugs and Delivery Systems:
nitroimidazole derivatives, diarylquinoline, corticosteroids,
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11. Primary Antituberculosis Drugs:
Isoniazid is one of the two most important TB drugs
Isoniazid should be given on an empty stomach, and antacids should be avoided within 2 hours of dosing.
Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine (vitamin B6) 10 to 50 mg daily to reduce the incidence of CNS effects or peripheral neuropathies.
Without rifampin, treatment is generally 18 months or longer.
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12. Rifampin usually is given orally, but it also can be give as a 30-minute IV infusion. Oral doses are best given on an empty stomach
women who use oral contraceptives must use another form of contraception during therapy because increased clearance of the hormones may lead to unexpected pregnancies.
Patient records should be reviewed for potential drug interactions before dispensing rifampin. Rifampin may turn urine and other secretions orange-red and may permanently stain some types of contact lenses.
N.B

13. Adding pyrazinamide to the first 2 months of treatment with isoniazid and rifampin shortens the duration to 6 months for most patients.
Ethambutol It is used as a fourth drug for TB while awaiting susceptibility data.
Ethambutol should not be given with antacids, Patients may complain of a change in visual acuity, the inability to see the color green, or both.
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14. Second-Line Antituberculosis Drugs:
Streptomycin is one of three aminoglycoside antibiotics (along with amikacin and kanamycin) that are active against mycobacteria.
Streptomycin occasionally causes nephrotoxicity, causing ototoxicity … older or long duration … permanent deafness
Cycloserine is only used to treat MDR-TB
Cycloserine can produce dose-related CNS toxicity
addition of pyridoxine 50 mg daily may improve patient tolerance of cycloserine.
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Resistance to amikacin and kanamycin is frequently linked but independent of resistance to
streptomycin and independent of resistance to capreomycin. Therefore, susceptibility tests should
guide the selection of these injectable drugs.

15. Ethionamide is not used in the United States…GI toxicity, may cause goiter, gynecomastia, alopecia, impotence, menorrhagia, photodermatitis, and acne.
Levofloxacin, gatifloxacin (outside of the United States), and moxifloxacin are sometimes used to treat MDR-TB because of their excellent activity against M. tuberculosis
N.B

16. New Drugs and Delivery System:
The nitroimidazole derivatives are related to metronidazole and work through inhibiting mycolic acid synthesis.
diarylquinoline TMC207 (bedaquiline) works through targeting the ATP synthase pump, and does not demonstrate cross-resistance with existing TB drugs.
Liposomes have been investigated as delivery systems for various agents against mycobacteria, including isoniazid, rifampin, and the aminoglycosides.
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17. Adjunctive therapy with corticosteroids may be of benefit for some patients with tuberculous meningitis or pericarditis to relieve inflammation and pressure. They should be avoided in most other circumstances because they detract from the immune response to TB.
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18. Pharmacological treatment...Latent Infection
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19. Isoniazid is the preferred drug for treating LTBI
Isoniazid is the preferred drug for treating LTBI. Generally, isoniazid alone is given for 9 months.
Young children, the elderly, and HIV-positive patients are at greater risk of active disease once infected with M. tuberculosis.
Isoniazid adult doses are usually 300 mg daily (5 to 10 mg/kg of body weight)
Rifampin 600 mg daily for 4 months can be used when isoniazid resistance is suspected or when the patient cannot tolerate isoniazid
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20. There is a growing body of evidence that 4 months of rifampin may be a safer and more cost-effective alternative to 9 months of isoniazid.
The combination of pyrazinamide plus rifampin is no longer recommended because of higher than expected rates of hepatotoxicity.
It should be noted that hypersensitivity reactions were more common with the isoniazid/rifapentine regimen and close clinical follow up should be undertaken.
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There is a growing body of evidence that 4 months of
rifampin may be a safer and more cost-effective alternative to 9 months of isoniazid. Menzies and
colleagues showed that 4 months of rifampin was significantly cheaper per patient completing
treatment because of better completion and fewer adverse events.

21. Treatment algorithm for tuberculosis
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Note: Patients in whom tuberculosis is proved
or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and
ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of
treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast
smear is positive at completion of 2 months of treatment, the continuation phase of treatment should
consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months
of treatment. If cavitation was present on the initial chest radiograph and the culture at the time of
completion of 2 months of therapy is positive, the continuation phase should be lengthened to 7
months (total of 9 months of treatment). If the patient has HIV infection and the CD+ cell count is
<100/μL (<100 × 106/L), the continuation phase should consist of daily or three-times-weekly
isoniazid and rifampin. In HIV-uninfected patients having no cavitation on chest radiograph and
negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist
of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to
complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-
month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months). (CXR, chest radiograph; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF,
rifampin; RPT, rifapentine.) aEMB may be discontinued when results of drug susceptibility testing
indicate no drug resistance. bPZA may be discontinued after it has been taken for 2 months (56 doses).
cRPT should not be used in HIV-infected patients with tuberculosis or in patients with
extrapulmonary tuberculosis. dTherapy should be extended to 9 months if the 2-month culture is
positive. (From: American Thoracic Society, Centers for Disease Control and Prevention, Infectious
Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-
77.)

22. N.B

23. treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months.
A repeat smear and culture should be performed when 2 months of treatment has been completed.
In HIV-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to complete a total of 6 months
N.B

24. Drug susceptibility testing should be done on the initial isolate for all patients with active TB.
The standard TB treatment regimen is isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months, a total of 6 months of treatment.
If susceptibility to isoniazid, rifampin, and pyrazinamide is shown, ethambutol can be stopped at any time. Without pyrazinamide, a total of 9 months of isoniazid and rifampin treatment is required.
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25. Pharmacological treatment... Active Infection
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Primary Antituberculosis Drugs
inhibit mycolic acid synthesis and disruption of the cell wall in susceptible organisms. Most
with a MIC against M. tuberculosis of 0.01 to 0.25 mcg/mL (mg/L). It is bactericidal and is thought to
Isoniazid Isoniazid is one of the two most important TB drugs. It is highly specific for mycobacteria,
mutations in the katG or inhA genes.
Mycobacterium xenopi are susceptible. The most common mechanisms of resistance result from
nontuberculous mycobacteria such as M. avium are resistant to isoniazid, although M. kansasii and
should be given on an empty stomach whenever possible.53 N-Acetyltransferase 2 forms the principal
be given as a short IV infusion over 5 minutes if diluted in about 20 mL of normal saline.52 Isoniazid
Isoniazid is readily absorbed from the GI tract and from intramuscular injection sites. It also can
metabolite acetylisoniazid, which lacks antimycobacterial activity. The rate at which humans
2 hours. Approximately 50% of whites and blacks and 80% to 90% of Asians and Native Alaskans
reflects a relative lack of N-acetyltransferase 2. Fast acetylators have isoniazid half-lives of less than
acetylate isoniazid is determined genetically; slow acetylation is an autosomal recessive trait and
however, appears to be weak.54 Poor absorption and rapid clearance of isoniazid for patients
increased risk of neurotoxicity. The association of acetylator status and risk of hepatotoxicity,
are rapid acetylators. Slow acetylators have isoniazid half-lives of 3 to 4 hours and may be at an
isoniazid and usually occur within the first 8 to 12 weeks of therapy.37 Overt hepatotoxicity, however,
Transient elevations of the serum transaminases occur in 12% to 15% of patients receiving
receiving highly intermittent therapy are associated with poor clinical outcomes.55,56
neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, as seizures and
disease, excessive alcohol intake, pregnancy, and the postpartum state. Isoniazid also may result in
occurs in only 1% of cases. Risk factors for hepatotoxicity include patient age, preexisting liver
coma. Patients with pyridoxine deficiency, such as pregnant women, alcoholics, children, and the
monitored closely, and appropriate dose adjustments should be made when necessary.
carbamazepine, primidone, and warfarin.40 Patients who are being treated with these agents should be
malnourished, are at increased risk. Isoniazid may inhibit the metabolism of phenytoin,
Drug resistance to rifampin is an ominous prognostic factor because it is frequently associated with
treatment of TB (6 to 9 months).2,11,37 Without rifampin, treatment is generally 18 months or longer.
Rifampin The introduction of rifampin into routine use during the 1970s allowed for true short-course
bactericidal activity against M. tuberculosis and several other mycobacterial species, including M.
care to protect susceptibility to rifampin by carefully treating their patients. Rifampin shows
isoniazid resistance and leaves the patient with few good therapeutic options. Clinicians must take
rifampin resistance.37,57
target site on RNA polymerase, primarily through changes in the rpoB gene, leads to most forms of
bovis and M. kansasii.57 It also is active against a broad array of other bacteria. Alteration of the
Rifampin usually is given orally, but it also can be given as a 30-minute IV infusion.57 Oral doses
failures in some cases.40,42,56,59 Rifampin is metabolized to 25-desacetyl rifampin, which retains some
have difficulty absorbing rifampin after oral doses, and this has been associated with therapeutic
are best given on an empty stomach.58 Patients with AIDS, diabetes, and other GI problems appear to
concentration-dependent killing.40,42 Higher doses should be tested in humans within the context of
is given at 600 mg daily or intermittently, although this dose does not take full advantage of rifampin’s
of rifampin’s activity; most of rifampin and its metabolite are cleared in the bile. Rifampin generally
overt hepatotoxicity occurring in less than 1%.37,57 More frequent adverse effects of rifampin include
Elevations in hepatic enzymes have been attributed to rifampin in 10% to 15% of patients, with
clinical trials.
the form of a flu-like syndrome with development of fever, chills, headache, arthralgias, and, rarely,
frequently with intermittent rifampin doses 900 mg or more twice weekly. These reactions may take
rash, fever, and GI distress. Allergic reactions to rifampin have been reported and occur more
hypotension and shock.37 Alternatively, hemolytic anemia or acute renal failure may occur, requiring
the elimination of many other drugs, most notably the protease inhibitors used to treat HIV (Table 90–
Rifampin’s potent induction of hepatic enzymes, especially cytochrome P450 3A4, may enhance
permanent discontinuation.
Furthermore, women who use oral contraceptives must use another form of contraception during
6). HIV-positive patients may benefit from the use of rifabutin instead of rifampin.25,37,49,60
therapy because increased clearance of the hormones may lead to unexpected pregnancies. Patient
turn urine and other secretions orange-red and may permanently stain some types of contact lenses.
records should be reviewed for potential drug interactions before dispensing rifampin. Rifampin may
Other Rifamycins Rifabutin is used for disseminated M. avium infection in AIDS patients and is
receiving protease inhibitors.37,49,60,61 For HIV-positive patients, the ATS/CDC recommends
Because rifabutin is a less potent enzyme inducer than rifampin, it may be used for patients who are
quite active against M. tuberculosis. Most rifampin-resistant organisms are resistant to rifabutin.
regimens with three or more doses of the TB drugs per week (see Table 90–3). Rifapentine is a longacting
as rifampin, so similar drug interactions are likely.37,49,60,61
months) in carefully selected HIV-negative patients. It is approximately as potent an enzyme inducer
rifamycin that can be used once weekly in the continuation phase of treatment (after the first 2
bactericidal depending on the concentration and the susceptibility of the organism. It is usually well
shortens the duration to 6 months for most patients.2,37 Pyrazinamide may be bacteriostatic or
Pyrazinamide Adding pyrazinamide to the first 2 months of treatment with isoniazid and rifampin
experience true gout. Hepatotoxicity is the major limiting adverse effect and is dose-related when
distress, arthralgias, and elevations in the serum uric acid concentrations.37 Most patients do not
absorbed and displays a fairly long half-life.62,63 The most common toxicities of pyrazinamide are GI
pyrazinamide 300 mg is designed to prevent drug resistance by keeping the self-medicating patient
A fixed-combination product (Rifater, Aventis) of rifampin 120 mg, isoniazid 50 mg, and
pyrazinamide is given daily.
from using only one drug at a time. If the patient is receiving DOT, there is no particular advantage to
rifampin 300 mg) can be substituted.
discontinued after 2 months of treatment, the combination product Rifamate (isoniazid 150 mg and
this product. The typical dose of Rifater will be five to six tablets daily. When pyrazinamide is
data.37 If the organism is susceptible to isoniazid, rifampin, and pyrazinamide, ethambutol can be
was better tolerated by patients.2,37 It is used as a fourth drug for TB while awaiting susceptibility
Ethambutol Ethambutol replaced p-aminosalicylic acid as a first-line agent in the 1960s because it
Ethambutol should not be given with antacids.64 For patients with renal failure, the ethambutol
impairing cell metabolism, and is generally bacteriostatic.
stopped. Ethambutol is active against most mycobacteria, by inhibiting synthesis of metabolites and
should be monitored monthly while on the drug using Snellen wall charts for visual acuity and
Patients may complain of a change in visual acuity, the inability to see the color green, or both. They
dose should be reduced to three times per week.50,65 Retrobulbar neuritis is the major adverse effect.
Ishihara red-green color discrimination cards.31,37
kanamycin) that are active against mycobacteria. It is quite active against MAC and several other
Streptomycin Streptomycin is one of three aminoglycoside antibiotics (along with amikacin and
Second-Line Antituberculosis Drugs
water or normal saline) over 30 minutes, similar to the other aminoglycosides.66 Streptomycin, like
intramuscular dosing, streptomycin can be given safely as IV infusions (100 mL of 5% dextrose in
mycobacteria, enterococci, Brucella, Yersinia, and various other bacteria. Although labeled only for
Streptomycin occasionally causes nephrotoxicity, although it tends to be mild and reversible. It
patients with renal dysfunction.37,40
other aminoglycosides, is renally cleared by glomerular filtration and must be given less often to
experience hearing loss, whereas vestibular toxicity is highly unpredictable.
continued use.37 Older patients and those receiving long durations of treatment are most likely to
also is capable of causing ototoxicity (vestibular and cochlear), which may become permanent with
Resistance to amikacin and kanamycin is frequently linked but independent of resistance to
p-Aminosalicylic Acid In the United States, only the enteric-coated, sustained-release granule form
guide the selection of these injectable drugs.
streptomycin and independent of resistance to capreomycin. Therefore, susceptibility tests should
therapy. Occasionally, a few doses of an opioid will resolve the problem. It also is important to tell
acid. Diarrhea is usually self-limited, with symptoms improving after the first 1 to 2 weeks of
(Paser) is available.67–69 GI disturbances are the most common adverse effects from p-aminosalicylic
Various types of malabsorption, including steatorrhea, were reported with previous dosage forms
doses, pharmacokinetic data support twice-daily dosing.68
the patient that the empty granules will appear in the stool. Although FDA approved for three daily
concomitant ethionamide therapy.
acid is known to produce goiter, with or without myxedema, that seems to occur more frequently with
of p-aminosalicylic acid. Hypersensitivity and, rarely, severe hepatitis may occur. p-Aminosalicylic
Cycloserine Cycloserine is only used to treat MDR-TB. It is well absorbed orally and is best taken
including lethargy, confusion, or unusual behavior. Seizures, although reported, are exceedingly rare
requires dosage reduction in renal failure. Cycloserine can produce dose-related CNS toxicity,
on an empty stomach.70 It is cleared primarily through the kidneys by glomerular filtration and
750 mg daily, divided unevenly into two doses. This can be achieved by starting with 250 mg daily
between 20 and 35 mcg/mL (mg/L; 200 and 349 μmol/L).40,42 Most patients reach a maximum dose of
in U.S. patients.2,37 Therapy is improved by maintaining 2-hour postdose serum concentrations
concentrating. Serum concentrations can be checked 1 to 2 weeks into therapy. The addition of
maintained if the patient complains of only occasional mild CNS effects, such as difficulty
for 2 days, followed by 250 mg increments over 2-day intervals. This dose of cycloserine can be
isoniazid and, more distantly, thiacetazone, a drug not used in the United States. Prothionamide, the npropyl
Ethionamide Ethionamide shares structural features with two other antimycobacterial agents,
pyridoxine 50 mg daily may improve patient tolerance of cycloserine.
derivative of ethionamide, is used in Europe. Ethionamide is only active against organisms of
GI toxicity is the dose-limiting adverse effect. The drug should be introduced gradually in 250 mg
to achieve serum concentrations that would be bactericidal.37,40,42
the genus Mycobacterium, and it should be considered primarily bacteriostatic because it is difficult
to minimize GI intolerance. Food does not affect absorption significantly.71 Little ethionamide is
daily in divided oral doses. Ethionamide may be administered with a light snack or prior to bedtime
increments, as described earlier for cycloserine. Rarely will a patient tolerate more than 1,000 mg
alopecia, impotence, menorrhagia, photodermatitis, and acne. The management of diabetes also may
or without hypothyroidism (especially when given with p-aminosalicylic acid), gynecomastia,
recovered in the urine, so doses remain the same in renal failure. Ethionamide may cause goiter with
Clofazimine Clofazimine is a drug with good activity against Mycobacterium leprae and some
used when necessary.
be more difficult for patients receiving ethionamide. Because of these problems, ethionamide only is
activity against M. tuberculosis and M. avium. It is used in doses of 100 mg daily in advanced cases
adverse reactions. Although uncommon, severe GI pain may occur because of deposition of
elimination half-life that is weeks long. GI distress and skin discoloration are the most important
of MDR-TB or MAC, especially when therapeutic options are limited3.7,40 The drug has a terminal
its low cost. Skin reactions, including rash and Stevens-Johnson syndrome, may occur. Thiacetazone
Thiacetazone Thiacetazone is a weak agent used rarely in parts of the developing world because of
clofazimine crystals within the intestines; this may require surgical correction.
Quinolones Levofloxacin, gatifloxacin (outside of the United States), and moxifloxacin are
sulfamethoxazole, the incidence of skin reactions is much higher for AIDS patients.72
must be discontinued permanently as soon as a rash appears. Similar to trimethoprim–
agents.2,11,37,40,73–75 Moxifloxacin has been compared with isoniazid and ethambutol during the
studies have suggested a potential role for moxifloxacin as a possible replacement for certain firstline
sometimes used to treat MDR-TB because of their excellent activity against M. tuberculosis. Several
first 8 weeks of therapy for pulmonary TB. It did not demonstrate a significant increase in 8-week
IV dosage forms, so they can be used in critically ill patients. However, resistance of MTB to the
seen when compared with ethambutol. Quinolones are useful because most are available in oral and
culture negativity when compared with isoniazid. However, shorter time to culture conversion was
Macrolides/Azalides The macrolide clarithromycin and azalide azithromycin represent substantial
and can develop in a relatively short period of time.76
fluoroquinolones is a major concern. Resistance is attributed to mutations in the gyrA and gyrB genes
for the treatment of MTB. The nitroimidazole derivatives, OPC67683 (delamanid) and PA824, are
used frequently for TB New Drugs and Delivery Systems Several promising compounds are currently under development
advances in the treatment of MAC but demonstrate limited activity against M. tuberculosis and are not
demonstrate cross-resistance with existing TB drugs. All of these agents have potent in vitro and in
diarylquinoline TMC207 (bedaquiline) works through targeting the ATP synthase pump, and does not
chemically related to metronidazole and work through inhibiting mycolic acid synthesis. The
vivo activity with very low MICs against M. tuberculosis.77–79 Both TMC-207 and OPC67683 have
824 has moved from Phase 1 to Phase 2 trials. Linezolid has been used in some patients with MDRTB.
newly diagnosed MDR-TB and have shown rapid culture conversion and good tolerance.77,78,80 PA-
been evaluated in Phase 2b placebo-controlled, double-blind, randomized trials in patients with
giving linezolid 600 mg daily or 300 mg twice daily for the slow-growing M. tuberculosis rather than
anemia and thrombocytopenia. It may be possible to reduce the incidences of these toxicities by
81 Long-term use of linezolid requires careful monitoring of hematologic indices for potential
been investigated as delivery systems for various agents against mycobacteria, including isoniazid,
oxazolidinone class, PNU and AZD-5847, are currently in Phase 1 studies. Liposomes have
the usual 600 mg twice-daily dose used for gram-positive organisms. Two new compounds in the
licensed for use against TB.
in the treatment of mycobacterial infections could be enhanced greatly. Currently, no such product is
rifampin, and the aminoglycosides. By changing the pharmacokinetic profile of such agents, their use
Corticosteroids Adjunctive therapy with corticosteroids may be of benefit for some patients with
Bacille Calmette-Guérin Vaccine The BCG vaccine is an attenuated, hybridized strain of M. bovis.
avoided in most other circumstances because they detract from the immune response to TB.
tuberculous meningitis or pericarditis to relieve inflammation and pressure.2,37 They should be
Vaccination with BCG produces a subclinical infection resulting in sensitization of T lymphocytes
vaccine is compulsory in many developing countries and is officially recommended in many others.
It was developed in 1921 and is used as a prophylactic vaccine against TB. Administration of BCG
In the published clinical trials, several different BCG preparations were used, and the efficacy of
positive tuberculin skin test.
and cross-immunity to M. tuberculosis, as well as cutaneous hypersensitivity and, in many cases, a
The primary benefit of BCG vaccination appears to be the prevention of severe forms of TB in
80%.2,37 Trials within the United States and Puerto Rico have shown efficacy rates of 6% to 29%.
these vaccinations ranged from negative 56% (some patients did worse with the vaccine) to positive
children. Data from the BCG trials show that the incidence of tuberculous meningitis and miliary TB
Unfortunately, BCG does not appear to be very reliable in preventing disease by M. tuberculosis
children younger than 15 years of age than it was in unvaccinated controls.
is 52% to 100% lower and that the incidence of pulmonary TB is 2% to 80% lower in vaccinated
vulgaris. It is recommended that pregnant women and patients with impaired immune systems,
usually include severe or prolonged ulceration at the vaccination site, lymphadenitis, and lupus
in other segments of the population. Side effects occur in 1% to 10% of vaccinated persons and
are asymptomatic should receive BCG vaccine at birth or as soon as possible thereafter. Because
recommended, however, that in populations where the risk of TB is high, HIV-infected infants who
including those with HIV infection, avoid vaccination. The World Health Organization had
In the United States, BCG vaccination is recommended only for uninfected children who are at
infection should not be vaccinated.2,37
BCG infection has occurred in AIDS patients given the vaccine, individuals with symptomatic HIV
failed or are not feasible.2,37 Its use is very limited.
unavoidable risk of exposure to TB and for whom other methods of prevention and control have

26. Special groups of patients
Children: TB in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months.
Pregnancy:
Women with TB should be cautioned against becoming pregnant
the usual treatment is isoniazid, rifampin, and ethambutol for 9 months
B vitamins are particularly important during pregnancy and should be provided to women being treated for TB. Rifampin is associated rarely with birth defects, including limb reduction and CNS lesions
N.B

27. cycloserine generally cannot be recommended during pregnancy
Streptomycin use during pregnancy may lead to hearing loss in the newborn, including complete deafness.
Ethionamide may cause premature delivery and congenital deformities when used during pregnancy.
cycloserine generally cannot be recommended during pregnancy
Ciprofloxacin, levofloxacin, moxifloxacin, and the other quinolones are associated with permanent damage to cartilage in the weight-bearing joints of immature animals
N.B

28. Quinolones should be avoided in nursing mothers, if possible.
Pregnant women with LTBI are not at the same level of risk compared with those with active disease. Therapy with isoniazid for LTBI may be delayed until after pregnancy or, if recent skin-test conversion has occurred, started during the second trimester of pregnancy.
Although most anti- TB drugs are excreted in breast milk, the amount of drug received by the infant through nursing is insufficient to cause toxicity.
Quinolones should be avoided in nursing mothers, if possible.
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29. Renal Failure:
For nearly all patients, isoniazid and rifampin do not require dose modification in renal failure. They are eliminated primarily by the liver.
Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly.
Ciprofloxacin and moxifloxacin are approximately 50% cleared by the kidneys but may not require a change in dose from once daily, as used for TB.
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30. Bacille Calmette-Guérin Vaccine
The BCG vaccine is an attenuated, hybridized strain of M. bovis.
Vaccination with BCG produces a subclinical infection resulting in sensitization of T lymphocytes and cross- immunity to M. tuberculosis, as well as cutaneous hypersensitivity and, in many cases, a positive tuberculin skin test.
In the United States, BCG vaccination is recommended only for uninfected children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible
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31. WHO Policy Recommendations 2016
In patients with rifampicin-resistant or multidrug- resistant TB who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen.
In patients with rifampicin-resistant or multidrug- resistant TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines - one chosen from group A, one from group B, and at least two from group C
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32. N.B

33. Case example
H.G. is a 35-year-old Hispanic man who presents with a 4-week history of a productive cough. The cough was initially nonproductive but became productive of yellow sputum after 2 weeks. The patient has been self-medicating with over-the- counter antitussives without relief, but he experienced hemoptysis this morning. He also complains of subjective fevers, chills, night sweats, dyspnea on exertion, fatigue, and an unintentional 15-pound weight loss during the last 2 months. He immigrated to the United States from Mexico when he was 12 years old, but he has not traveled outside the United States for more than a decade.
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34. He currently works as a laborer on new home construction projects, and several of his coworkers, who moved to the United States from Mexico within the past year, have similar respiratory symptoms. He is currently married with 3 children. The patient has a 20-pack-year smoking history and drinks alcohol on the weekends but denies illicit drug use.
On physical examination, H.G. is a thin-appearing man in mild respiratory distress. His heart rate is 94 beats/minute, his respiratory rate is 24 breaths/minute, and his temperature is 38.9◦C. Bronchial breath sounds are noted in the right upper lobe on chest auscultation, and the chest radiograph shows extensive patchy infiltrates in the right upper lobe.
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35. Significant laboratory data include the following: White blood cell count, 13,200/μL (72% polymorphonuclear leukocytes, 3% bands, 12% lymphocytes, 13% monocytes) Red blood cell count, 3.7 × 106/μL, Hemoglobin, 11.2 g/dL, Hematocrit, 34%, Platelets, 269 × 103/μL, Serum electrolytes, renal function, and hepatic functionare within normal limits.
He is 69 inches tall, and his weight is 68 kg. The remainder of his physical examination is unremarkable.
What signs and symptoms consistent with active TB disease are present in H.G.?
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H.G.’s history of cough (which gradually became productive),
fever, night sweats, fatigue,andweight loss are consistent with the
classic symptoms of active TB.19 Cough may be nonproductive
early in the course of the illness, but with subsequent inflammation
and tissue necrosis, sputum is usually produced and is key to
most of the diagnostic studies. The 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.19 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 in any segment.
The patchy infiltrates on H.G.’s chest radiograph is consistent
with pulmonary TB. Cavitary lesions may be seen; however,
thesewere absent in this patient. Moderate elevation of thewhite
blood cell count, with an increase in monocytes and eosinophils,
and anemia are the most common hematologic manifestations
of TB.19 H.G. had an elevated white blood cell count with an
increase in monocytes, and he was also anemic.
Many patients with active pulmonaryTBhave no acute symptoms,
and a lack of symptoms may hinder diagnosis. During a
1-year span, approximately 50% of the cases of active TB without
classic symptoms are misdiagnosed.33 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-thirdof these patients had any abnormalpulmonary
signs. Similar findings have been reported in other trials.34 The
lack 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 pre-existing pulmonary
disease or pneumonia, they may be overlooked and not
attributed to TB.

36. What risk factors for TB are present in H.G.?
H.G.’s HIV test is negative. How should treatment be initiated in H.G., pending the results of sputum culture and susceptibility testing? Can he transmit M. tuberculosis to others during treatment?
Four weeks later, H.G.’s initial sputum cultures were reported to be positive for M. tuberculosis. Drug susceptibility testing to isoniazid and rifampin revealed susceptibility to both agents. What drug regimen should be used for continued treatment of H.G.? How long should treatment be continued?
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Mexico, are risk factors for TB. In addition, studies have now
respiratory symptoms, and their geographical origin from
The close contact of H.G. with his coworkers who have similar
a twofold increase in the risk of active TB. Furthermore, a significant
cohort study conducted in Taiwan, smokingwas associated with
implicated cigarette smoking as a risk factor for TB.35–37 In a
number of pack-years smoked.37 Smoking impairs mucociliary
of cigarettes smoked per day, number of years of smoking, and
dose–response relationship was identified for number
factor-α, and causes iron overload in macrophages.38–41 These
function, decreases intracellular production of tumor necrosis
clearance, decreasesphagocyticpulmonaryalveolarmacrophage
There are four basic regimens recommended for the treatment
disease after exposure to M. tuberculosis.
defects in host defense mechanisms increase the risk of active
Because H.G. has not been treated previously for TB, he should
known or presumed to be drug susceptible (Table 65-2).30
of adult patients with TB caused by organisms that are
symptoms resembling TB who are from an area (Mexico) with
However, he has been in close contact with persons with
be started on isoniazid, rifampin, pyrazinamide, and ethambutol.
sputum smears, and culture and susceptibility results, regardless
closely monitored for resolution of symptoms, results of repeated
a high prevalence of drug-resistant TB. Therefore, H.G. must be
of isoniazid-resistant M. tuberculosis is at least 4%.31,61 In
the addition of ethambutol only if the local prevalence
of the initial treatment regimen. Previous guidelines recommended
isoniazid.14 The prevalence of isoniazid resistance was higher in
patients with no previous history of TB in 2009 were resistant to
the United States, 8.6% of M. tuberculosis isolates recovered from
of strains were resistant to isoniazid in 2009, with 20.5% resistance
(6.0%).14 In patients with a history of previous of TB, 15.2%
foreign-born persons (10.1%) compared with US-born persons
by isoniazid-resistant organisms, four drugs are necessary in the
persons.14 Because of the relatively high likelihood of TB caused
in foreign-born persons versus 4.5% resistance in US-born
throughout the 8-week period (regimen 1), daily for the first
The initial four-drug regimen may be administered daily
initial 8-week treatment phase.30
administration of drugs for 5 days/week is considered to
weekly throughout (regimen 3).30 On the basis of clinical experience,
2weeks and then twiceweekly for 6weeks (regimen 2), or thrice
these recommended regimens are listed in Table Therefore,
should always be given by DOT.30 Drug dosages for
be equivalent to 7 days/week administration and either regimen 1 or 2 may be considered “daily.” However, 5-day-a-week administration
1,200 mg daily. He should also receive pyridoxine 25 mg/day to
600 mg daily, pyrazinamide 1,500 mg daily, and ethambutol
H.G. should be started on isoniazid 300 mg daily, rifampin
results of susceptibility testing demonstrate that the isolate is
neuropathy. Ethambutol can be discontinued when the
minimize the risk for development of isoniazid-induced peripheral
is no longer recommended as being interchangeable with ethambutol
resistance has increased globally; therefore, streptomycin
susceptible to isoniazid and rifampin. The incidence of streptomycin
unlikely.30
or the patient is from an area in which streptomycin resistance is
unless the organism is known to be susceptible to the drug
and ethambutol are used for the first 2 months
in 6 months (26 weeks) if isoniazid, rifampin, pyrazinamide,
Successful treatment of uncomplicated TB can now be completed
DOT with isoniazid, rifampin, pyrazinamide, and ethambutol,
susceptibility can be assured.30 Therefore, after 8 weeks of
(8weeks) and if patient adherence to the regimen and the organism
week under continued DOT for an additional 18 weeks (Table
daily (5 days or 7 days per week) or two to three times per
H.G.’s regimen may be streamlined to isoniazid and rifampin
once-weekly administration of isoniazid and rifapentine, as long
present on his chest radiograph, he may also be a candidate for
65-2). Because H.G. is HIV-negative and cavitary lesionswere not
The effectiveness of a primarily twice-weekly treatment regimen
8 weeks of therapy.30
as his sputum AFB smear is negative after completing the initial
rifampin 600 mg, pyrazinamide 1.5 to 2.5 g, and streptomycin
TB.80 The regimen consisted of isoniazid 300 mg,
has been demonstrated in both pulmonary and extrapulmonary
isoniazid and rifampin twice weekly for the remaining 16 weeks
for an additional 6 weeks. The regimen was then reduced to
750 to 1,000 mg intramuscularly daily for 2 weeks, followed by the same drugs twice weekly at higher doses (except rifampin)
sputum cultures, and all patients were culture negative at
after beginning therapy, 75% of all patients studied had negative
(4 months). All doses were administered by DOT. Three months
regimen is that it is highly cost-effective. Among the 6- and
adverse effects were reported. Another important feature of this
20 weeks.80 A 1.6% relapse rate (two patients) and only minor
encounters (62 directly observed doses).
because of the least number of patient–health care worker
9-month regimens, it is the second lowest in cost, primarily
for the first 8 weeks. Therapy should be continued with
therapy should be initiated with isoniazid, rifampin, and ethambutol
If pyrazinamide cannot be included in the initial regimen,
in the initial phase, treatment must be continued for 18 to
weekly.30 If drugs other than isoniazid and rifampin are used
isoniazid and rifampin for 31 weeks given either daily or twice
24 months.6

37. Pharmacotherapy, Principles & Practice,4th ed, 2016
References
Pharmacotherapy, Principles & Practice,4th ed, 2016
WHO treatment guidelines for drug-resistant tuberculosis update
Pharmacotherapy, physiological approach, 2014, Chapter 90
Applied therapeutics, 2013, Chapters 65
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