Antimycobacterials and Mycobacterial Infections Exam 4 Flashcards
What are the antimycobacterial agents?
- rifampin
- isoniazid
- ethambutol
- pyrazinamide
rifampin MOA
inhibits RNA synthesis
isoniazid MOA
inhibits the synthesis of mycolic acids which are essential components of the bacterial cell wall
ethambutol MOA
Inhibits arabinosyl transferase III which disrupts the transfer of arabinose into arabinogalactan biosynthesis subsequently disrupting the assembly of the mycobacterial cell wall
pyrazinamide MOA
in acid environment, pyrazinamide is converted to pyrazinoic acid (POA), POA disrupts mycobacterial cell membrane metabolism and transport functions
rifampin treatment for TB
- Rifampin: once daily
- Rifabutin: once daily
- Rifapentine: per week
rifampin ADE
- Generally well tolerated
- Most common significant adverse effects include rash, fever, nausea, vomiting, increased LFTs, immunologic reaction, flu like syndrome, GI
- Causes an orange-tan discoloration of skin, urine, feces, saliva, tears, and contact lenses
Drug-drug interactions of rifampin
- Potent inducer of CYPs 1A2, 2C9, 2C19, and 3A4
- p-glycoprotein (efflux pump)
- glucuronidation which decreases the Cmax and half-life of many medications ultimately reducing their therapeutic effects
Drug-drug interactions of rifabutin
- Less potent inducer of CYPs than rifampin, both in potency and number of CYPs involved
- Decreases the half-life of the following agents: Zidovudine, prednisone, digoxin, ketoconazole, propranolol, phenytoin, sulfonylureas, and warfarin
isoniazid treatment for TB
daily
isoniazid ADE
- Hepatic injury
- Peripheral neuritis
- Neurologic toxicities
- Mental abnormalities
isoniazid ADE
- Hepatic injury
- Peripheral neuritis
- Neurologic toxicities
- Mental abnormalities
- Other hematologic reactions, vasculitis, arthritic symptoms, dry mouth, epigastric distress, tinnitus, and urinary retention, lupus like syndrome, hypersensitivity
isoniazid ADE: Hepatic injury
increased ALT/AST (often normalize after continuous use)
isoniazid ADE: Neurologic toxicities
- convulsions in patients with seizure disorders, optic neuritis and atrophy, muscle twitching, dizziness, ataxia, paresthesias, stupor, and toxic encephalopathy
- *Pyridoxine (vitamin B6) can serve as a prophylactic agent for peripheral neuritis and other CNS effects listed above
isoniazid ADE: Mental abnormalities
- euphoria
- transient memory impairment
- loss of self-control
isoniazid ADE: Mental abnormalities
- euphoria
- transient memory impairment
- loss of self-control
Drug-drug interactions of isoniazid
Inhibitor of CYP2C19, CYP3A, weak inhibitor of CYP2D6, and induces CYP2E1
Which agents needs renal dose adjustments?
- Pyrazinamide
- Ethambutol
ethambutol treatment for TB
single daily dose
ethambutol ADE
- Generally well tolerated
- Retrobulbar neuritis
- Rash, peripheral neuritis, drug fever
- Other: pruritus, joint pain, GI upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations, skin reactions
ethambutol ADE: Retrobulbar neuritis
- loss of visual acuity, inability to distinguish red-green color
- Dose-related, rare at 15 mg/kg/d or less
- Recommend periodic screening at high doses
- Relative contraindication in children too young to assess visual acuity
pyrazinamide treatment for TB
daily dose
pyrazinamide ADE
- Hepatic injury
- Hyperuricemia
- Other: arthralgias, anorexia, nausea, vomiting, dysuria, malaise, GI, polyarthalgia, rash, and fever
pyrazinamide ADE: Hepatic injury
- increased ALT/AST
- jaundice
- hepatic necrosis
pyrazinamide ADE: Hyperuricemia
- may cause acute episodes of gout
- contraindicated in acute gout
pyrazinamide precaution
- Avoid in pregnancy due to lack of data
- contraindicated in acute gout
risk factors for infection of TB
- Location and place of birth
- Race, ethnicity, age, and gender
- Co-infected with HIV
risk factors for infection of TB: Location and place of birth
- California, Florida, New York, and Texas are states commonly reported
- 2 out of 3 cases are foreign born individuals majority originating from Mexico, Philippines, Vietnam, India, and China
risk factors for infection of TB: Race, ethnicity, age, and gender
- compared to non-Hispanic whites, the TB rate among non-Hispanic Asians was 29 times greater, and rates among non-Hispanic blacks and Hispanics were both 8 times greater
- For US born ethnic groups, non-Hispanic blacks had the highest reported cases in 2014
- Patients aged 45-64 have the highest reported cases
- Male predominance after the age of 24
risk factors for infection of TB: Co-infected with HIV
- TB and HIV act synergistically making each infection worse
- HIV does not increase the risk of getting TB but can increase the chances of progression to active disease
- Higher mortality rates in patients who have multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB
risk factors for (active) disease
- ~ 10% lifetime risk of developing active disease in those infected M. tuberculosis
- Greatest risk occurs during the first 2 years after infection
- Children less than 2 years and adults greater than 65
- Immuno-compromised patients -> HIV patients are 100 times more likely to develop active TB than non-infected persons
transmission of TB
- Person to person by coughing or other mechanisms (sneezing, speaking, singing, etc…) that cause the organism to be aerosolized
- The particles that are transmitted are called droplet nuclei which contains one to three organisms each
- ~ 30% of people who experience sustained exposure with an infectious TB patient will become infected
- Patient’s with latent tuberculosis that are not symptomatic do not transmit tuberculosis
What is the area of induration?
in TB skin test (PPD), the “bump,” NOT the area of redness
Reaction 5 mm of nduration means that you are positive for TB IF…
- HIV positive
- Recent contacts of TB case
- Fibrotic changes on chest radiograph consistent with prior TB
- Organ transplants and other immunosuppressed patients (receiving the equivalent of ≥ 15 mg/day of prednisone for ≥ 1 month)
Reaction >= 10 mm of nduration means that you are positive for TB IF…
- Recent immigrants (within 5 years) from high-prevalence countries)
- Injection-drug users
- Resident and employees of high risk congregate areas
Reaction >= 15 mm of nduration means that you are positive for TB IF…
Persons with no risk factors for TB
What are examples of high risk congregate areas?
- prisons and jails
- nursing homes and other long-term care facilities for elderly
- hospitals and other healthcare facilities
- residential facilities for patients with AIDS
- homeless shelters
How many patients will have a false negative test on the TB skin test?
20%
What is the purpose of treating latent infection?
decreases the lifetime risk of active TB from ~10% to ~1%
What is the preferred treatment of latent TB?
- isoniazid
- All patients should be monitored monthly for adverse drug reactions and possible progression to active TB
What are other agents that can be used for latent TB?
- Rifampin
- Isoniazid and rifapentine
What are the interval and duration of isoniazid that can be used for latent TB?
- Daily for 9 months: May be administered concurrently with antiretroviral therapy (ART) for HIV patients; fibrotic lesions; children
- Twice weekly for 9 months: Directly observed therapy (DOT) must be used
- Daily for 6 months: Not indicated for HIV patients, patients with fibrotic lesions, or children
- Twice weekly for 6 months: DOT must be used
What are the interval and duration of rifampin that can be used for latent TB?
- Daily for 4 months
- For persons who are contacts of patients with isoniazidresistant
What are the interval and duration of isoniazid + rifapentine that can be used for latent TB?
- Once weekly for 3 months
- Directly observed therapy (DOT) must be used
- Not recommended for children < 2
- HIV patients on ART
- isoniazid or rifampin resistant strains
- pregnant women or women expecting to become pregnant within the 12 week regimen
Standard treatment for active disease
- RIPE: rifampin, isoniazid, pyrazinamide, ethambutol for 2 months
- Followed by 4 months of isoniazid and rifampin (total of 6 months)
What are the different dosing options for RIPE for active TB?
- Daily for 8 weeks or 5d/wk for 8 weeks followed
- Daily for 2 weeks, then 2/wk for 6 weeks or 5d/wk for 2 weeks, then 2x/wk for 6 weeks
- 3x/week for 8 weeks
What are the different dosing options for RIE for active TB?
Daily for 8 weeks or 5d/wk for 8 weeks
If you dose RIPE at Daily for 8 weeks or 5d/wk for 8 weeks followed , how should you follow it?
- Isoniazid / rifampin: Daily for 18 weeks or 5d/wk for 18 weeks
- Isoniazid / rifampin: 2x/wk for 18 weeks
- Isoniazid / rifapentine: 1x/wk for 18 weeks
If you dose RIPE at Daily for 2 weeks, then 2/wk for 6 weeks or 5d/wk for 2 weeks, then 2x/wk for 6 weeks, how should you follow it?
- Isoniazid / rifampin: 2x for 18 weeks
- Isoniazid / rifapentine: 1x/wk for 18 weeks
If you dose RIPE at 3x/week for 8 weeks, how should you follow it?
Isoniazid / rifampin: 3x/wk for 18 weeks
If you dose RIE at Daily for 8 weeks or 5d/wk for 8 weeks, how should you follow it?
Isoniazid / rifampin: aily for 31 weeks or 5d/wk for 31 weeks or 2x/wk for 62 weeks
Treatment of TB is usually 6 months total. Under what conditions would you treat a pt for 9 months?
- Patients with cavitation on presentation and positive cultures after 2 months of therapy
- Patients who cannot take PZA (RIF/EMB/INH for 2 months and RIF/INH for 7 months)
When would you isolate a pt due to airborne precautions?
- They are coughing and/or have positive sputum cultures for acid fast bacilli (AFB)
- AND they are not receiving appropriate TB treatment, have just started TB treatment, or have poor clinical response to TB treatment
- Patients who have drug susceptible TB should remain under airborne precautions until they: produce 3 consecutive negative sputum smears and have received at least two weeks of standard TB treatment
What happens if you have MDR-TB?
- Resistance to isoniazid and rifampin
- There is no standard regimen and should be referred to specialists
- Avoid monotherapy and adding a single agent to a failing regimen
- May take several months for a patient to become culture negative
XDR-TB are resistant to which drugs?
- soniazid
- rifampin
- a fluoroquinolone
- one second-line injectable drug (amikacin, capreomycin, or kanamycin)
Special populations in TB
- Tuberculosis meningitis and extrapulmonary disease
- Children
- Pregnancy
- HIV
Special populations in TB: Tuberculosis meningitis and extrapulmonary disease
- CNS TB is usually treated longer (9-12 months)
- TB of the bone is usually treated for 9 months
- Isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the CSF readily
- Levofloxacin is the preferred quinolone
Special populations in TB: Children
- May be treated with regimens used for adults but some experts recommend a duration of 9 months
- Doses of isoniazid and rifampin are on a mg/kg basis and are higher than adult doses
Special populations in TB: Pregnancy
- Women should be counseled against conceiving because TB carries a risk to the fetus and mother
- Usual treatment for pregnant patients is isoniazid, rifampin, and ethambutol for 2 months and isoniazid and rifampin for 7 months
- Aminoglycosides are reserved for critical situations due to the potential of hearing loss to the baby
- Therapy with isoniazid for LTBI may be delayed until after pregnancy
Special populations in TB: HIV
- AIDS and other immuno-compromised patients can be treated with similar regimens for the immunocompetent
- Extended continuation phase to 7 months (9 months total) recommended for HIV patients who do not start ART during TB therapy
- Highly intermittent regimens (twice or once weekly) are not recommended
- Rifapentine not recommended
- Rifampin and rifabutin can interact with many antiretrovirals
How should you take Rifampin?
food decreases Cmax (best on empty stomach)
How should you take Rifapentine?
high fat meal ↑AUC (best with food)
If we can’t use RIPE, what are alternative agents that we can use?
- Aminoglycosides
- Fluoroquinolones
- Macrolides
- Clofazamine
- Ethionamide
- Para-Aminosalicylate Acid (PAS)
- Cycloserine
- Dapsone
