Transcript Drugs for Tuberculosis and Mycobacterium avium complex disease

NUR 3703
Pharmacology
By Linda Self
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Dates back to ancient Egypt and Babylonia
“consumption”
Sanitoriums
Robert Koch in 1905
Development of BCG in 1924
Streptomycin 1943
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Gram positive mycobacterium
Divides slowly, only q15-20h
Can withstand weak disinfectants
Can survive in dry state for weeks
Must grow within a host organism
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Infectious disease caused by tubercle bacillus
80% affect lungs
Multiplies slowly
Can lie dormant
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Identified microscopically by staining
characteristics
Retains certain stains thus “acid-fast”
Can now obtain results of blood test within
24h—Quantiferon TB gold test (must follow
specific guidelines for obtaining test sample)
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Occurrence had waned
Now resurgence due to international travel,
persons with depressed immune systems
(medications and conditions), emergence of
AIDS
Incidence has been increasing since 1986
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Untreated, two of every three individuals with
active disease will die
With treatment, mortality less than 5%
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Transmission—inhalation
Contributors: number of bacteria, closeness
and duration of contact
Primary infection-30% exposed will become
infected. Dormant until optimal conditions.
Will test positive to PPD.
Latency-no symptoms but bacteria are there
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Active tuberculosis—reactivation of latent
infection although new infection can also
occur
Occurs more often in those with depressed
immunity
Among people with both latent TB and HIV
infection, latent TB will progress more
rapidly, is more severe and is often
extrapulmonary
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Multiple drug therapy
Clinical monitoring monthly
Lab testing—obtain baseline. In populations
with liver disease, will check liver function
studies monthly. May have to stop INH if
transaminase levels greater than 3 times
upper limit of normal if s/s, to 5 times
normal if no s/s
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One of biggest contributors to this
development is those who are not adherent
Should test certain groups which are at
higher risk for developing active tuberculosis
1. Immigration from areas of world w/high
incidence
2. Homeless
3. Injection drug user
4. Chronic renal failure
5. Diabetes mellitus
6. High dose steroids
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HIV infection or AIDS
Chest xray with fibrotic lesions
Cachexic
Silicosis
Older groups who reside in congregate
settings
Young children who test positive
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Weight loss
Anorexia
Malaise
Fever
Productive cough
Night sweats
Older adults s/s less prominent; in children,
resembles pneumonia
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Health centers
Medical clinics
Homeless shelters
Jails
Methadone clinics
Businesses
institutions
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PPD
Aplisol, Aplitest, Tine test
Sterile isotonic solution of tuberculin
Intradermally injected
Spurs immune response
Should be interpreted in 48-72h
Anergy is an issue
Induration of 5 mm or more deemed positive in
those with HIV, w/risk factors for HIV, those
with chest xrays consistent with previous TB,
in those who have had close contact with
someone with active TB
 Organ transplants
 Those on high dose steroids or on TNF
antagonists
Induration of 10mm or more—positive in those
at high risk such as immigrants, residents
and employees of prisons, children exposed
to adults in high risk groups
 Chronic renal failure
 Gastrectomy patients
 IV drug users
 Possibly cancer
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Induration of 15mm or more-essentially all
others
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False positives-may occur in those who have
had BCG (from Mycobacterium bovis)
False negatives in those with anergy
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Bacillus Calmette-Guerin
Vaccine developed from Mycobacterium
bovis—lost virulence in humans secondary to
engineering of the bacillus
Variable effectiveness, up to 15 years
May cloud reliability of PPD
Also useful in bladder cancer, leprosy
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Thorough history
Complete physical
Chest xray
Sputum studies
Baseline labs (liver enzymes, bili, CBC, lytes)
Isoniazid (INH)
 Prototype of antituberculars
 Bactericidal
 Inhibits cell wall synthesis
 Acetylators a consideration—slow, more
prone to toxicity; rapid, may need larger dose
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Penetrates body cells and mycobacteria
Inhibits growth of dormant organisms in
macrophages
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Hepatotoxicity
Peripheral neuropathies
Pyridoxine is usually given with INH to
minimize peripheral neuropathy
Rifamycin
 Bactericidal for intracellular and extracellular
organisms
 Inhibits synthesis of RNA so causes defective
proteins to be produced
 Synergistic with INH
 Produces clinical improvement faster than any
other drug regimen unless resistance is
present
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Diffuses well into tissues
Rapid oral absorption
Metabolized in liver, excreted in bile
Causes harmless red-orange discoloration of
body fluids
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GI upset
Skin rashes
Hepatitis
Drug interactions
Accelerates metabolism of some drugs
See p. 554
Another rifamycin
 Works like rifampin
 Main uses are in those with HIV infection, in
MAC and to substitute for rifampin in those
who need both antitubercular and certain
antiviral medications
 Advantages are its longer serum half-life and
reduced hepatic induction of metabolyzing
enzymes
Causes:
 Discoloration of body fluids
 GI upset
 Hepatitis
 Muscular aches
 Neutropenia
 Skin rash
 Uveitis
 Rare hepatotoxicity
Tuberculostatic drug that inhibits synthesis of
RNA and thus, protein synthesis
 Not recommended in young children (under
5)
 Well absorbed in GI tract
 Total daily dosage is given at one time
 Can affect renal function
 Can cause optic neuritis
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Used with INH and rifampin for first two
months of treating active TB and possibly as
single agent for four months in those with
LTBI
Pyrazinamide is contraindicated in pregnancy
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Bactericidal but mechanism is unclear
Good GI absorption
Rapid onset, peaks in two hours
Metabolized by liver, excreted by kidneys
Can cause:
 Hepatotoxicity
 Inhibits urate excretion
 Not to be used in liver compromise
 Monitor liver enzymes every 2 weeks during
course of Tx (usually 8 weeks)
Aminoglycoside
 Does not penetrate macrophages and
tuberculous lesions
 May be used in multi-drug therapy
MDR means the TB is resistant to at least two
of the first line medications (INH, RIF, PZA,
Ethambutol) so add:
 Amikacin
 Kanamycin
 fluoroquinolones
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Resistance present to INH, RIF, PZA,
ethambutol will use quinolones and at least
one of three injectable drugs (amikacin,
Kanamycin and capreomycin)
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Caution in those taking other hepatotoxic
drugs or who use alcohol
Recommended in those who are unlikely to
complete longer courses of Tx and who can
be monitored closely
Perform LFTs at baseline and at 2,4, 6 weeks.
Stop if levels are higher than five times the
upper limit, if s/s hepatitis are present or if
bilirubin is elevated
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Para-aminosalicyclic acid
Capreomycin
Cycloserine
ehtionamide
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Different regimens
Dosing most important element
Combination therapy
INH, Rifampin, and pyrazinamide daily for 2
months followed by INH and Rifampin for 4
additional months
If resistance in community, should add fourth
drug such as ethambutol or streptomycin
until susceptibility reports are available
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Rifampin, pyrazinamide, and ethambutol for
6 months
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INH daily or twice weekly for 9 months incl.
those with HIV infection or xray evidence of
prior TB
INH daily or twice weekly for 6 mos. Less
costly. Okay in HIV negative adults with
normal chest xrays. Not in HIV, <18 yo or
those with fibrotic lesions on chest films.
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RIF and PZA daily or twice weekly for 2
months. Indicated in those in contact with
INH resistant TB and for those unlikely to
complete a longer course of Tx.
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Pregnancy—INH daily or twice weekly for 6-9
months. Take B6. INH, rifampin, and
ethambutol relative safety. Pyrazinamide and
streptomycin are contraindicated.
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Children and adolescents. INH daily or twice
weekly for 9 months is optimum. Infants and
children under 5 are at high risk for
progression of disease.
INH more effective in children than adults
Risk for INH hepatitis in children is small
Felt not necessary for B6 supplementation
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Can’t use rifampin in people being treated
with PIs or NNRTIs. May substitute Rifabutin,
in one half the dose, unless patient is taking
delavirdine or saquinavir.
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When INH and rifampin cannot be given
because of resistance, drug therapy should
continue for 24 months after sputum smears
or cultures become negative
Cannot use fluoroquinolones in children
Older adults:
 Treatment may be based on both PPD and
other factors
 INH hepatotoxic in elderly
 Active disease-- INH, rifampin and
pyrazinamide are given cautiously
 Closely monitor liver function
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Tailor to the circumstances, allow patient
participation in selecting treatment
Directly Observed Therapy (DOT) should be
used consistently with intermittent regimens,
in those who are high risk for non-adherence
and in institutional settings
Ensure completion of therapy by determining
both total time and number of doses of
medication taken
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Clinical monitoring is indicated for all
patients.
Monitor for s/s of liver disease such as: dark
urine, jaundice, numbness or tingling of
hands or feet, jaundice, vomiting, loss of
appetite, abdominal tenderness, bruising or
bleeding.
Lab monitoring. Stop INH if LFTs 3x normal
with s/s or 5x normal if no s/s.
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Comprised of either mycobacterium avium or
mycobacterium intracellulare
Closely resemble each other
Found in water and soil
Transmitted by inhalation of droplets of
contaminated water
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Rarely affects immunocompetent people
Is opportunistic
S/S: productive cough, weight loss,
hemoptysis, fever to dissemination
Preventive drugs are macrolides and rifabutin
Need lifelong prophylaxis