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ID exam 4 > Tuberculosis > Flashcards

Tuberculosis Flashcards

1
Q

mycobacterium tuberculosis

A

Slow-growing aerobic bacterium - relatively resistant to most antibiotics
Can be dormant
Neither Gram-positive
nor Gram-negative
-Acid fast bacteria (AFB)
-After staining with a dye (Ziehl-Neelsen stain), cannot be decolorized by acid wash
Lipid rich cell wall contains mycolic acids and is impermeable to many drugs
Obligate aerobe
Facultative intracellular parasite

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2
Q

transmission

A

Only people with active* Tb infections transmit disease
Tb is spread by aerosol droplets* expelled during Speaking, Coughing, Spitting
Droplets can remain airborne for hours
An untreated person with active Tb can infect 20 people per year

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3
Q

pathology

A

Bacteria are phagocytosed by alveolar macrophages in the lung
Induce a localized proinflammatory response
Mononuclear cells from neighboring blood vessels are recruited to site of infection
Recruited cells form granuloma (tubercle)
-infected macrophages
-foamy macrophages and other mononuclear phagocytes
-lymphocytes with a fibrous cuff of collagen
Granuloma develops a fibrous sheath with fewer penetrating blood vessels in the later stages
Containment fails when immune status changes - old age, malnutrition, co-infection with HIV
Granuloma caseates (decays), ruptures and spills thousands of viable, infectious bacilli into the airways
Productive cough develops that facilitates aerosol spread of infectious bacilli

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4
Q

pathogenesis

A

Latent infections that overcome the immune system cause Tb disease
-10% lifetime risk of developing active infection
-Diabetics are 3 times more likely to develop active infection
-HIV positive - 10% per year
-50% death rate if untreated
•Mtb infects mainly the lungs (80-85% cases)
-Can spread to bones, brain, skin, and eyes (extrapulmonary)
Symptoms:
-productive, prolonged cough of >3 weeks, chest pain, & coughing up blood
-Fever, chills, night sweats, appetite loss, weight loss, and fatigue

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5
Q

treatment of active Tb infections

A

Most common: combination of rifampin, isoniazid (INH), pyrazinamide, and ethambutol (RIPE)
Why treat using a combination of drugs?
-Different drugs are needed to combat dividing and dormant forms
-Tb rapidly develops resistance to individual drugs - Mutants resistant to INH appear ~ 1 X 10^-6 ; If resistance to a second independently acting drug also arises at a frequency of ~ 1 X 10^-6, resistance to both will arise simultaneously at a frequency of ~1 X 10^-12

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6
Q

isoniazid

A

Isonicotinic acid hydrazide (INH)
Specific for M. tb
Bactericidal
Only active against growing M. tb
Prodrug – activated by M. tb KatG protein
metabolism: Acetylation by liver N-acetyltransferase (NAT2), Rate determined genetically, Slow metabolizers = 3 hours, Rapid metabolizers = under 1 hours, No therapeutic consequence if dosed daily, but can result in subtherapeutic levels if dosed weekly

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7
Q

isoniazid MOA

A 
Activation by KatG (catalase-peroxidase)
Forms adducts with NAD+ and NADP+
Inhibits enzymes that use NAD+ and NADP+
Activated isoniazid inhibits InhA
-Component of FAS II
-Catalyzes the NADH-dependent reduction of fatty acids bound to acyl carrier protein
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8
Q

isoniazed toxicity

A 
Hepatitis is major concern
-Occurs in 1% of patients
-Loss of appetite, nausea, jaundice, vomiting
-Can be fatal if treatment not halted
Risk increases with age
Isoniazid resembles pyridoxine (vitamin B6)
Isoniazid promotes pyridoxine depletion
Can cause peripheral neuropathy
-5 - 10 % of patients
-More frequent in slow acetylators
-Reversed by administering pyridoxine
mechanism: Acetylisoniazid can be converted to acetylhydrazine - CYP2E1 converts to hepatotoxic metabolites, NAT2 can acetylate acetylhydrazine to nontoxic diacetylhydrazine, rapid acetylators will rapidly remove acetylhydrazine, slower acetylators or induction of CYP2E1 will lead to more toxic metabolites, Rifampin induces CYP2E1 & potentiates isoniazid hepatotoxicity
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9
Q

pyrazinamide

A

Important part of anti-Tb therapy - sterilizing agent against residual intracellular bacteria (persister bacilli); Shortened treatment from 9-12 months to 6 months
Structurally similar to nicotinamide
Activity is pH dependent: Inactive at neutral pH; Activated by low pH - mechanism is complicated and not clear
Pyrazinamide is a prodrug - Requires conversion to pyrazinoic acid by pncA

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10
Q

pyrazinamide blocks trans-translation

A

Trans-translation:
-key component of protein quality control pathway
-ensures proteins are synthesized with high fidelity in spite of transcription errors, mRNA damage, and translational frame shifting
-performed by a ribonucleoprotein complex: tmRNA, a specialized RNA with properties of both a tRNA and an mRNA; the small protein SmpB
pyrazinoic acid binds to and inhibits ribosomal protein S1 (RpsA)

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11
Q

pyrazinamide resistance

A

Generated easily, but suppressed when used in combination
Primarily due to mutations in pncA
Genome sequencing of resistance strains
-RpsA
-panD - aspartate decarboxylase involved in coenzyme A biosynthesis
-ClpC1 - ATPase and molecular chaperone activities; works as an unfoldase with the caseinolytic protease complex

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12
Q

pyrazinamide toxicity

A 
Joint pain (arthralgia) is most common side effect (approximately 1%)
Hepatitis is most dangerous - Pyrazinamide is the most common cause of hepatitis in four-drug treatment; patients should undergo studies of hepatic function before treatment
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13
Q

ethambutol

A

Bacteriostatic inhibitor of M. tb
Mechanism of action: Inhibits mycobacterial arabinosyl transferases (Involved in the polymerization of arabinogalactan); Results in build up of arabinan; Inhibits formation of arabinogalactan and lipoarabinomannan (LAM)
Synergistic with Rifampin - Increases penetration into cell
Resistance is due to over-expression of or mutations in arabinosyl transferase
Not recommended for use alone due to resistance
Toxicity: Most important - optic neuritis - Can be irreversible if treatment not discontinued

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14
Q

rifampin

A

Semisynthetic derivative of rifamycin B - produced by Streptomyces mediterranei
Reduced length of therapy from 18 to 9 months
High sterilizing activity - rapidly renders patients non-infectious
Penetrates most tissues and phagocytic cells
Active against growing and stationary (non-dividing) cells with low metabolic activity
Can kill M. tb inaccessible to many other drugs
Bactericidal
Most effective when cell division is occurring
Optimize AUC/MIC (best bactericidal activity) or Cmax/MIC (better control of resistance and longer PAE)

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15
Q

rifampin MOA

A

Binds to RNA polymerase deep within the
DNA/RNA channel
-over 12 Å away from the active site
-Blocks the path of the elongating RNA

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16
Q

rifapentine

A

Derivative of rifampin - cyclopentyl ring
More lipophilic
Longer half-life (13.5 h vs. 2 - 5 h)

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17
Q

rifampin adverse reactions

A

Colors urine, tears and sweat orange - Can permanently stain contact lenses
Potent inducer of cytochrome P450s - CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4
Increase in CYP enzymes increases elimination of other drugs metabolized by these enzymes

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18
Q

streptomycin

A

Aminoglycoside - Only streptomycin, kanamycin & amikacin have activity against Mtb
Protein synthesis inhibitor
Penetrates poorly into cells
Active against extracellular forms
Employed when injectable drug needed - Severe tuberculosis (meningitis or disseminated)
Treatment of strains resistant to other drugs

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19
Q

toxicities associated with anti-Tb drugs

A

Ototoxicity: streptomycin
Hepatitis: isoniazid, pyrazinamide, rifampin
Eye damage: ethambutol - Loss of visual acuity & red-green color-blindness
Orange discoloration of the urine: rifampin
Patients should be monitored at least monthly for adverse effects

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20
Q

2nd line agents

A

Active anti-tubercular agents
-Less well tolerated
-Greater incidence of side effects
-Usually considered only if: Resistance to first line agent, Failure of clinical response to first line agents, Intolerance to first-line agents, Expert guidance available to deal with toxic side effects
Fluoroquinolones – DNA gyrase inhibitors
Ethionamide (Trecator SC®) - Chemically related to isoniazid
Para-aminosalicylic acid: Antimetabolite; Folate synthesis antagonist
Cycloserine (Seromycin®) - Analog of D-alanine; Cell wall synthesis inhibitor
Capreomycin (Capastat®) - Mechanism of action is unknown; Peptide protein synthesis inhibitor

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21
Q

primary multi-drug resistant Tb

A

By definition, no previous history of TB disease and resistance to at least INH and rifampin
History of treatment for TB – predictor for presence of MDR organisms
Factors associated with MDR-TB: Inadequate therapy (monotherapy; omission of 1 or more drugs; erratic/poor absorption; suboptimal dose; insufficient number of active drugs in regimen); Cavitary lesions
Transmission of MDR-TB from person to person (accounts for 10% of cases) – hospital residents, prisons, homeless shelters, HCWs, prison guards, etc. are at greatest risk

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22
Q

extensively drug-resistant Tb

A

Definition: resistance to isoniazid and rifampin among first line agents, plus resistance to any fluoroquinolone, and resistance to at least one of three injectable second line drugs (amikacin, kanamycin, capreomycin)
1 case of XDR-TB reported in United States in 2015 (2 cases in 2014; 5 cases in 2013; 2 cases in 2012; 5 cases in 2011); 15 cases of XDR-TB reported since 2009 (11 in foreign born persons)
Rapidly fatal in patients with HIV infection; more likely to disseminate (extrapulmonary); less likely to convert to negative sputum; longer time to convert to negative sputum.

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23
Q

prevention of treansmission

A

Adequate room ventilation (> 6 air exchanges/hr, negative air flow)
Ultraviolet light
Proper treatment of infected persons
Hood for cough-inducing procedures (inhaled pentamidine, etc.)
Disposable particulate respirators

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24
Q

pathogenesis

A

Prototype disease requiring cell-mediated** immune defense mechanisms for its control. Cell lines responsible for immunity to mycobacteria are macrophages and T-lymphocytes.

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25
Q

latent infection

A

Occurs when tubercle bacilli are present in body

No x-ray changes, no symptoms, negative bacteriologic studies, positive PPD

26
Q

active disease

A

Occurs when poor host defenses allow infection to progress or reactivate
X-ray changes, symptoms, positive bacteriologic studies

27
Q

primary infection

A

Droplets inhaled into lungs, reach bronchioles and alveoli
In non-immune (susceptible) host, tubercle bacilli initially multiply unopposed by normal host defense mechanisms - Ingested by alveolar macrophages, but continue to multiply intracellularly
After 14-21 days of replication, organisms spread through regional lymphatics to the hilar lymph nodes and bloodstream, then disseminate to organs with high blood flow and PaO2 (e.g., lung apex)
After 2-8 weeks, a specific T-lymphocyte-mediated immune response develops (delayed hypersensitivity) → prevents further replication - Positive tuberculin skin test or interferon-γ release assay
Activated T-lymphocytes → secrete interferon-γ → macrophages produce high concentrations of lytic enzymes (increase mycobactericidal capacity); cause local tissue necrosis and calcification of original infected site and regional lymph nodes
Activated T-cells & macrophages form granuloma → wall off M. tuberculosis organisms
When bacterial antigen load and intensity of immune response are both high, extensive tissue necrosis occurs → formation of caseous lesions (necrotic center, relatively unstable) → lesions liquefy in the center → cavity - Favors bacterial growth (5-6 logs > noncavitary lesions)
8. 3-5% of patients will experience “progressive primary” disease - Characterized by progressive pneumonia originating from original site of primary infection (usually lower lobes) → frequent dissemination

28
Q

progression of latent infection to active disease

A

3-4% of people will develop active tuberculosis during the first year after a positive PPD
If untreated, a total of 5-10% will develop active disease thereafter → reactivation
Reactivation of residual latent tuberculous foci (from earlier primary infection)
-Thought to be due to defects in T-cell and/or macrophage function
-Higher risk in elderly, malnutrition, diabetes mellitus, compromised host (chronic renal failure, neoplastic disorders), alcoholism, IV drug abuse, corticosteroid therapy or other immunosuppressive agents, HIV/AIDS
Annual risk of developing active disease in PPD-positive persons who acquire HIV infection is 7-10% per year*
AIDS patients who subsequently are infected with M. tuberculosis, the risk of tuberculosis is ≥ 50% within several months

29
Q

clinical presentation of early disease

A

asymptomatic

30
Q

clinical pres of late manifestations

A

insidious onset
Fever/chills, Night sweats, Anorexia, Weight loss (unexplained), Cough with increasing sputum production, Malaise, Hemoptysis and SOB – usually indicative of advanced disease

31
Q

laboratory data

A

WBC 10,000 to 15,000/mm3

Normochromic, normocytic anemia

32
Q

clinical presentation of extrapulmonary Tb

A

depends on the organ system involved
GU TB – sterile pyuria, hematuria, abnormal intravenous pyelogram, epididymitis, irregular menses, infertility
Tuberculous arthritis and osteomyelitis – most commonly occurs in elderly; usually affects lower spine and weight-bearing joints
Tuberculous meningitis – abnormal behavior, headaches, seizures

33
Q

clinical pres of Tb in HIB, elderly and children

A

Early HIV disease:
-Pulmonary tuberculosis clinically similar to immunocompetent patients
-Extrapulmonary disease – 33%
Late HIV disease:
-Diffuse pulmonary involvement (multiple lobes), infrequent cavitation
-Extrapulmonary disease > 70%
Skin testing – high false-negative rate in HIV patients
Any HIV patient with a cough or an abnormal chest x-ray should be isolated
Elderly – subtle or absent clinical findings; mimics other respiratory diseases
Children – similar appearance to bacterial pneumonia; involves middle and lower lobes of lungs; infrequent cavitation

34
Q

diagnosis - identification of latent infection - Tb skin testing

A

Purified protein derivative (PPD) – consists of proteins derived from a single strain of M. tuberculosis
Cutaneous hypersensitivity - Recruitment of T-lymphocytes sensitized during the primary infection; Results in erythema and induration (swelling) at the test site; maximal at 48 hrs
Mantoux method – most reliable technique
-Intradermal injection of 0.1 ml (5 TU) of PPD into dorsal surface of forearm
-At 48-72 hours, measure diameter of the zone of induration***
Criteria for a positive PPD skin test:
-Induration of ≥ 5 mm: Persons who have had recent close contact with persons who have active TB; Persons with HIV infection or risk factors for HIV but unknown status; Organ transplant patients and other immunosuppressed patients (receiving the equivalent of ≥ 15 mg/day of prednisone for 1 month or longer); Persons with fibrotic changes on chest x-ray consistent with prior TB
-Induration of ≥ 10 mm: Injecting drug users known to be HIV negative; Persons who have other medical conditions known to increase the risk for progressing from latent TB infection to active TB; Residents and employees of high-risk congregate settings (prisons, nursing homes, hospitals, homeless shelters, etc); Foreign-born persons, including children, recently arrived (within 5 years) from countries with high TB incidence or prevalence; High risk racial or ethnic minority populations; Infants, children, and adolescents exposed to adults in high-risk categories; Some medically underserved, low income populations, including migrant farm workers and homeless
-Induration ≥ 15 mm is classified as positive in persons who do not meet any of the above criteria
Limitations: poor sensitivity and specificity in patient groups most at risk for TB (e.g., HIV [false negative]; foreign-born [false-positive] due to BCG vaccine)
Health care workers – routine PPD; if exposed, PPD at 0 and 12 weeks

35
Q

diagnosis - identification of latent infection - interferon-gamma release assays (IGRAs)

A

Preferred in BCG-vaccinated patients instead of PPD
QuantiFERON-TB Gold In-tube test – ELISA tests that detect the release of interferon-γ from T cells in whole blood of sensitized patients; results within a few hours
T-SPOT TB test – enzyme-linked immunospot assay (ELISpot) that detects increases in the number of cells that secrete interferon-γ
Dependent of functioning T cells – poor sensitivity in HIV

36
Q

diagnosis - symptomatic disease

A

Chest radiograph - In reactivation, patchy infiltrates of the upper segments or apices of the lungs; in advanced cases, cavitation may be observed; Early primary tuberculosis in HIV – active disease radiologically indistinct from other bacterial pneumonias
Sputum examination/smear – demonstrate AFB from infected secretions or tissues - Sputum must contain 5,000-10,000 AFB/ml before smears reliably positive
Culture and speciation of organism – gold standard for laboratory confirmation
-Cultures require 10-100 organisms to become positive
-Conventional – 3 to 6 weeks
-Rapid (Bactec®) – 10 to 14 days (average 9 days)
Nucleic acid amplification – amplify specific target sequences of nucleic acids in M. tuberculosis that can be detected by nucleic acid probe in 24-48 hours*
Susceptibility testing
-Conventional – 4 to 8 weeks
-Molecular drug resistance tests – detect mutations in the chromosomal sequence encoding for resistance to a specific drug (e.g., mutations in rpoB gene for rifampin resistance); results in 24-48 hours

37
Q

susc testing

A

ALL ISOLATES OF M. TUBERCULOSIS SHOULD HAVE DRUG SUSCEPTIBILITY
TESTING PERFORMED

38
Q

isolation

A

Place all patients with suspected or confirmed pulmonary or laryngeal tuberculosis in respiratory isolation until noninfectious
-Noninfectious** when receiving effective therapy, improving clinically, and negative results for 3 consecutive sputum acid-fast smears collected on different days

39
Q

treatment - regimen 1

A 
Intensive Phase: Isoniazid (INH), rifampin, pyrazinamide, and ethambutol 7 days/week for 56 doses (8 weeks) OR 5 days/week for 40 doses (8 weeks) – preferred
Continuation Phase (2 Options):
-INH and rifampin 7 days/week for 126 doses (18 weeks) OR 5 days/week for 90 doses (18 weeks) – preferred
-INH and rifampin 3 times weekly for 54 doses (18 weeks)
Note: 5 day-a-week regimens are ALWAYS given by directly observed therapy***
40
Q

treatment - regimen 2

A

Intensive Phase: INH, rifampin, pyrazinamide, and ethambutol 3 times weekly for 24 doses (8 weeks)
Continuation Phase: INH and rifampin 3 times weekly for 54 doses (18 weeks)
Note: Use with caution in patients with HIV and/or cavitary disease. Missed doses can lead to treatment failure, relapse, and acquired drug resistance.***

41
Q

treatment - regimen 3

A

Intensive Phase: INH, rifampin, pyrazinamide, and ethambutol 7 days/week for 14 doses (2 weeks), then twice weekly for 12 doses (6 weeks)
Continuation Phase: INH and rifampin twice weekly for 36 doses (18 weeks)
Note: Do not use in HIV-infected patients and patients with smear-positive and/or cavitary disease.***

42
Q

other treatment considerations

A

Patients with cavitation on initial chest radiograph or positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase.
Administer pyridoxine (vitamin B6) 25-50 mg daily to patients receiving INH
Patients with HIV infection and TB should receive antiretroviral therapy (ART) with daily
TB medications.
-In patients with CD4 under 100 cells/µl, begin ART after ≥ 2 weeks of TB therapy
-In patients with CD4 of 100-200 cells/µl, delay ART until the end of the initial 8-week intensive phase.
-In patients with CD4 > 200 cell/µl, begin ART during the continuation phase.
If patient with HIV does not receive ART, continuation phase should be 7 months (31 weeks) for total of 9 months of therapy.
Rifamycin inducer potential: rifampin > rifapentine&raquo_space; rifabutin
Rifampin is not recommended in patients receiving HIV protease inhibitors, etravirine, rilpivirine, elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine, maraviroc – substitute rifabutin

43
Q

FQ as initial therapy

A

Moxifloxacin – most active fluoroquinolone versus M. tuberculosis
Moxifloxacin (INH, RIF, PZA) versus ethambutol (INH, RIF, PZA) – faster sterilization of sputum at 4 weeks and 6 weeks with moxifloxacin; no difference at 2 months
Moxifloxacin (RIF, PZA, ETH) versus isoniazid (RIF, PZA, ETH) – no difference in sterilization rates at 8 weeks
Short course (4 months total) regimens containing FQ less effective than standard 6 month regimen

44
Q

treatment of Tb in special populations

A

Treatment of extrapulmonary tuberculosis:
-Same regimen for pulmonary tuberculosis
-Extend duration of therapy to 9 months
-Extend duration of therapy to 9 to 12 months in patients with HIV
Treatment of tuberculous meningitis:
-Same 4-drug regimen for pulmonary tuberculosis
-Extend duration to 9 to 12 months
Treatment of infants and children:
-Same regimen as recommended for adults; may extend duration to 9 months
-Ethambutol is not recommended for children under 6 years of age
Treatment of tuberculosis during pregnancy
-Suggested to avoid streptomycin (congenital deafness) and pyrazinamide (insufficient safety data)
-INH, rifampin, and ethambutol for minimum of 9 months

45
Q

treatment considerations for MDR-Tb

A

Administer at least 3-4 drugs to which the organism is susceptible
If only bacteriostatic agents are available, 4 to 5 drug regimens may be used (aminoglycoside or capreomycin and a fluoroquinolone)
Begin therapy in hospital; document drug absorption
Duration of treatment in patients with HIV is 24 months after culture conversion
Bedaquiline (Sirturo®) – inhibits mycobacterial adenosine 5′-triphosphate synthase, thereby inhibiting energy production in M. tuberculosis; FDA-approved as part of combination therapy in adults for treatment of pulmonary MDR-TB when other alternatives are not available; boxed warning for increased risk of death compared with placebo, as well as prolongation of the QT interval

46
Q

monitoring therapy

A

Symptoms (cough, fever, malaise, anorexia) should markedly decrease in 2-4 weeks
Sputum collection every 1-2 days for AFB stain until a consistent downward trend in AFB number is seen (may take 10-14 days) → patient may be removed from isolation
On maintenance therapy, sputum for AFB stain every 2 weeks until negative and sputum cultures monthly until negative. Cultures usually become negative within 2 months.
If delayed response, suspect non-compliance or drug resistance
-Non-compliance more common – DOT
-Drug resistance – add at least 2 drugs to which the organism is likely to be susceptible
Drug interactions
Toxicity
Serum concentrations

47
Q

treatment of latent Tb infection

A

Child with documented recent exposure to index case of pulmonary TB – skin test and give INH for 3 months; continue for 9 months if skin test positive
Adult with positive PPD skin test and no other confounding factors – (1) INH 300 mg daily for 6-9 months (2) rifampin 600 mg daily for 4 months (3) INH 900 plus rifapentine 900 mg once weekly for 12 weeks
HIV-infected patient with positive PPD skin test or anergic with risk factors for TB – INH for 9 months
Positive skin test and documented exposure to INH-resistant TB – rifampin for 6 months
Positive skin test and documented exposure to INH- and rifampin-resistant TB – pyrazinamide/ofloxacin for 12 months; ethambutol/pyrazinamide or ethambutol/levofloxacin for 6 to 12 months

48
Q

isoniazid (INH) pharmacology

A

Well absorbed orally
Large Vd, including CSF
-Uninflamed meninges – 20% of serum
-Inflamed meninges - ≈ equal to serum
Metabolism – metabolized in liver by N-acetyltransferase - Genetically determined** (rapid vs. slow)
Bimodal distribution of half-lives
**Severe hepatic insufficiency – reduce dose by ½
***Renal failure – reduce dose to 150-200 mg/day in slow acetylators
drug interactions: P450 inhibitor

49
Q

Isoniazid adverse reactions

A

Hepatitis (elevated transaminases)
-Most likely to occur 8-12 weeks after starting therapy
-Correlation with age (> 35 years of age)
-More likely to occur in alcoholics or pre-existing liver disease
-Acetylhydrazine metabolite
Neurotoxicity – peripheral neuropathy in ≈ 17% of patients
-More likely with poor nutrition, pre-existing neuropathy, slow acetylator status, diabetes
Increase pyridoxine excretion – ALWAYS give pyridoxine with INH*****

50
Q

dosing INH

A

Adults: 5 mg/kg/day (max. 300 mg)
Children: 10 mg/kg/day (max. 300 mg)
Intermittent therapy: 15 mg/kg (max. 900 mg) once, twice, or thrice weekly (adults)

51
Q

rifampin pharmacology

A

Well absorbed orally
Disproportionate increase in serum concentrations with increasing dose
Widely distributed in body, including CSF
Primarily eliminated into GI tract
Half-life increases with dose:
-300 mg 2.5 hours
-600 mg 3 hours
-900 mg 5 hours
Adjust dose in hepatic failure
drug interactions: potent inducer of cytochrome P450 system

52
Q

rifampin adverse reactions

A

Hepatotoxicity
Hypersensitivity reactions – more likely with twice-weekly regimens
-Flushing, fever, pruritus with rash, eosinophilia, hemolysis, renal failure
-Flu-like syndrome
Discoloration of body fluids

53
Q

rifampin dosing

A

Adults: 600 mg daily
Children: 10-20 mg/kg/day (NMT 600 mg/d)
Intermittent regimen: 600 mg twice or thrice weekly

54
Q

rifabutin

A

Analog of rifampin with greater activity vs. M. avium complex; comparable to rifampin vs. M. tuberculosis
Less induction of cytochrome P450 than rifampin* – important in HIV patients on protease inhibitors
Dosing – 300 mg daily or 300 mg thrice weekly
If used concurrently with HIV protease inhibitors, 150 mg daily or 300 mg thrice weekly
If used concurrently with efavirenz, increase daily and thrice-weekly dose to 450-600 mg
If used concurrently with elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine, 150 mg daily or thrice weekly
Adverse effects – rash, hepatitis, fever, thrombocytopenia, orange-colored body fluids; arthralgias, uveitis, leukopenia* with increased concentrations

55
Q

pyrazinamide (pharmacolody, adverse reactions and dosing)

A

Pharmacology
-Well absorbed orally
-Large Vd; crosses inflamed meninges
-Long half-life – 12 to 24 hours
-Metabolized in the liver
Adverse reactions
-Hepatotoxicity* – dose-dependent
-Hyperuricemia – pyrazinoic acid competes with uric acid for renal elimination***
-Arthralgias
-Photosensitivity
-Rash
Dosing
-40-55 kg – 1 g daily; 2 g twice weekly; 1.5 g thrice weekly
-56-75 kg – 1.5 g daily; 3 g twice weekly; 2.5 g thrice weekly
-76-90 kg – 2 g daily; 4 g twice weekly; 3 g thrice weekly

56
Q

ehtambutol (pharmaclogy, adverse reactions and dosing

A

Pharmacology
-F = 75 to 80%
-Primarily renally eliminated unchanged (80%) – adjust for renal function* - Clcr 10-30 ml/min – reduce daily dose by 50%; Clcr under 10 ml/min – reduce daily dose by 65%
Adverse reactions
-Peripheral neuropathy
-Optic neuritis*** - Associated with high doses or prolonged administration; Reversible
-Rash, fever, arthralgias, GI irritation
Dosing
-40-55 kg – 800 mg daily; 2 g twice weekly; 1.2 g thrice weekly
-56-75 kg – 1.2 g daily; 2.8 g twice weekly; 2 g thrice weekly
-76-90 kg – 1.6 g daily; 4 g twice weekly; 2.4 g thrice weekly

57
Q

streptomycin

A

2nd line
Pharmacology - Peak concentrations ≈ 40 µg/ml one hour after a 15 mg/kg IM dose; > 90% excreted unchanged in the urine; Half-life 2-5 hours; prolonged in renal dysfunction
Adverse reactions:
-Ototoxicity** – vestibular (vertigo, ataxia)
-Nephrotoxicity – less common than other aminoglycosides
Dosing:
-1 gram daily for the first 2 to 8 weeks, followed by 1 gram twice weekly
-Adjust for renal dysfunction: Clcr 10-50 ml/min – every 24-72 hours; Clcr under 10 ml/min – every 72-96 hours

58
Q

P-aminosalicylate (PAS)

A

2nd line
Pharmacology: Readily absorbed from GI tract; distributes evenly to most tissues; Elimination half-life ≈ 1 hour; ≈ 50% of a dose is metabolized to the active, acetylated metabolite; Reduce dose in patients with severe renal dysfunction
Adverse effects:
-Gastrointestinal – take with meals***
-Hypersensitivity
-Thrombocytopenia
Drug interactions: Increases INH concentrations (competition for hepatic metabolism); Decreases rifampin concentrations (decreases GI absorption)
Dosing:
-Adults – 8 to 12 grams/day in 2 or 3 divided doses
-Children – 200 to 300 mg/kg/day in 4 divided doses (q6h)

59
Q

Ethionamide

A

2nd line
Cross resistance with INH
Pharmacology: Rapid absorption from GI tract; Half-life ≈ 3 hours; Elimination – hepatic metabolism
Adverse effects:
-Anorexia, N/V, metallic taste
-Increased salivation
-Hepatitis
-Others – arthralgias, impotence, photosensitivity, gynecomastia
Dosing
-Adults – 15-20 mg/kg/day (up to 1 gram)
-Divide dose into 2-4 doses and give after meals, if GI problems

60
Q

cycloserine

A

2nd line
Mechanism of action – inhibits the incorporation of D-alanine into the cell wall (static)
Rapidly absorbed from GI tract; widely distributed throughout most body fluids and tissues, including CSF
Adverse effects***: Depression, Personality changes, Psychosis, suicidal ideation, Seizures
Dosing – 10 to 15 mg/kg/d

ID exam 4 (9 decks)

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