___ have nearly impermeable cell walls made up of mycolic acids
mycobacterium
> 60% of the cell wall of mycobacteria is lipid, which does what?
shields and thus prevents many drugs from accessing the cell membrane
describe how mycobacterial defenses make it exceptionally difficult for antimicrobials to do their jobs
- they have very thick, hydrophobic cell walls rich in mycolic acid
- efflux pumps
- some species can hid inside host cells
what are two key mycobacterium-related diseases?
mycobacterium tuberculosis (TB) and mycobacterium leprae (hansen’s disease or leprosy)
describe mycobacterium tubercosis (TB)
9 million new cases of TB and 2 million deaths annually
what bacteria has the following characteristics?
- hansen’s disease, leprosy
- 2 million new cases worldwide
- the bacteria grow better in areas with cooler body temperatures closer to skin surfaces (ex. extremities)
mycobacterium leprae
in 1882, TB killed ___ out of every ___ people living in the US and Europe
1/7
among infectious diseases, TB remains the ___ leading killer of adults in the world, with ___ million TB-related deaths annually
- 2nd
* 2 million
what is used to test for tuberculosis?
mantoux tuberculin skin test (TST)
with latent/asymptomatic primary TB infections, there will be no active disease, but a ___ TST
positive
what is the preventative treatment for latent/asymptomatic primary TB?
- initiate immediately
* prophylactic treatment of choice is isoniazid for 9 months
what type of infection is described by the following:usually in lungs, but can effect other organs; dyspnea, fever, productive cough and night sweats for >2 months; upper lobe consolidation on chest x-ray; acid fast bacilli on sputum test, positive TST
overt/active primary TB
the following is the treatment of choice for what type of tuberculosis?
- 2 months treatment with combination of ribampin + isoniazid + pyrazinamide + ethambutol (R+I+P+E)
- followed by 4 months with rifampin + isoniazid
- “2 with 4, then 4 with 2”
overt/active primary tuberculosis
describe the treatment of overt/active primary tuberculosis when it is an intracellular organism
- treat with RIPE for 12 months + azithromycin (macrolide) restrict use of pyrazinamide to only the 1st 2 months
- hepatotoxic
secondary, reactivated (resistant) TB is of greater risk in what patients?
HIV-positive, immunosuppressed, or other “high risk” patients
describe the secondary TB “rule of 5’s”
- otherwise healthy patients infected with mycobacterium tuberculosis have a 5% risk of reactivation in the first 2 years and then a 5% lifetime risk of reactivation
- high risk patients have a 5%+5% risk of reactivation per year
T or Fsecondary tuberculosis can only reactivate in the lungs
falseit can reactivate in a variety of different locations
the following is the treatment of choice for what type of tuberculosis? RIPES
- 2 months treatment with combination of rifampin, isoniazid, pyrazinamide, and ethambutol, PLUS STREPTOMYCIN
- followed by 4 months treatment with isoniazid and firampin (2 with 5, then 4 with 2)
secondary TB
what can be done in cases of secondary TB where drug resistance is a problem?
second line drugs can be added to overcome drug resistance
what are 7 tuberculosis drugs?
- streptomycin - aminoglycoside
- azithromycin - macrolide
- rifampin - nucleic acid synthesis inhibitor
- isoniazid
- pyrazinamide
- ethambutol
- bedaquiline
what is the clinical use of isoniazid (INH)?
- drug of choice for prophylaxis of mycobacterium tuberculosis
- also effective in combo against active TB
what is the mechanism of isoniazids?
decreases mycolic acid synthesis
___ is a prodrug that must be activated by the bacterial enzyme, KatG (TB catalase oxidase enzyme)
isoniazid
___ activation of isoniazid also produces free radicals, like NO (oxidative stress)
KatG
the following are adverse effects for which drug?hepatotoxicitycan cause a pyridoxine deficiency, so always administer along with vitamin B6 to maintain heme synthesis and prevent neurotoxicitytell patients to avoid alcohol 72 hours before and after administration (disulfuram-like reaction)
isoniazid (INH)
is pyrazinamide (PO) a prodrug?
yes
which drug has the following clinical use?treatment of active mycobacterium tuberculosis infection, especially tuberculous meningitis
pyrazinamide
is pyrazinamide bacteriostatic or bactericidal?
bacteriostatic
the following mechanism describes what drug?
- inhibits mycolic acid synthesis
- the net effect is that more pyrazinoic acid accumulates inside granulomas (more absorbed at high pH than at neutral pH)
pyrazinamide
pyrazinamide requires ___ pH to be activated, and is an essential part of the treatment of ___
- acidic pH, aka low pH
* tuberculous meningitis
what drug hasthe following adverse effects?
- hepatotoxicity if used >2 months
- increases uric acid (can cause gout or make it worse)
- rash
- contraindicated in pregnancy
pyrazinamide
what are the contraindications of pyrazinamide?
pregnancy
what is ethambutal used for?
treatment of active mycobacterium tuberculosis infections
the following mechanism describes what drug?
- obstructs the mycobacterial cell wall formation
- decreases carbohydrate polymerization by inhibiting arbinosal transferase
ethambutal
can ethambutal cross the BBB?
yes
what drug has the following adverse effects?
- ocular toxicity
- color blindness
- ocular neuritis→ blindness (in up to 6% of patients within the first 3 months of use
ethambutal
what are the drugs used for TB (RIPES)?
- rifampin
- isoniazid (INH)
- pyrazinamide
- ethambutol
- streptomycin (aminoglycoside)
of the RIPES drugs, which 3 are orally absorbed with excellent tissue penetration, but can cause hepatotoxicity?
- rifampin
- isoniazid (INH)
- pyrazinamide
isoniazid (INH) should always be given with ___ to prevent peripheral neuropathy
vitamin B6
___ should always be avoided during pregnancy and its administration should always be limited to 2 months max (hepatotoxic >2 months)
pyrazinamide
which of the RIPES drugs can be given IV or IM, it ototoxic, nephrotoxic, and should be avoided during pregnancy?
streptomycin (aminoglycoside)
in cases of mycobacterium avium (intracellular), ___ should be added in addition to the RIPES regimen
azithromycin
___ is generally safe, but may prolong QT interval and cause acute cholestatic hepatitis in certain patient populations at high doses
azithromycin
___ was approved in Dec 2012 for multi-drug resistant TB
bedaquiline
what is the mechanism of bedaquiline?
inhibits mycobacterial ATP synthase
the following adverse effects describe which drug?nausea, vomiting, arthralgias, headacheblack box warning for patients with arrhythmiasprolonged QT syndrome
bedaquiline
what are the two possible drugs of choice for the treatment of leprosy?
rifampin
- treatment for TB and leprosy dapsone
- prophylaxis
what is the mechanism of dapsone?
competes with PABA to inhibit bacterial dihydrofolate synthesis (antimetabolite)
which drug has the following clinical use?prophylaxis of leprosy and prophylaxis of pneumocystis jiroveci
dapsone
the following adverse effects apply to which drug?hepatotoxicity, hemolysis, cross-sensitivity if allergic to sulfonamides
dapsone
most (80%) traveller’s diarrhea infections are caused by ___, but other bacterial species include ___, ___, and ___
- e. coli
* campylobacter jejuni, shigella, and salmonella
what drug should be used to treat traveller’s diarrhea caused by e. coli
rifaximin
what drug should be used to treat traveller’s diarrhea caused by invasive campylobacter and shigella, or salmonella?
ciprofloxacin (fluoroquinolone)
pseudomembranous colitis is caused by an overgrowth of ___ and the drug of choice for treatment is ___
- c. difficile
* metronidazole
which type of hansen’s disease is described by the following:well-demarcated lesionsgood immune responseonly exhibits a few skin lesionsthe disease is mild, and is only mildly contageous
tuberculoid leprosy
which type of hansen’s disease is described by the following:poorly demarcated lesionspoor immune responseaffects the skin, nerves, and other organs
lepromatous leprosy
