antibacterials II

DNA disruptors

sulfonamides

fluoroquinolones

sulfonamide abx

sulfanilamide

sulfisoxazole

sulfadizaine

sulfamethoxazole/trimethoprim (bactrim)

sulfacetamide

what do bacterial cells need to synthesize to be used for DNA synthesis

folate

mechanism of folic acid synthesis in bacteria

PABA > dihydropteroate synthase > dihydrofolate reductase > purines > DNA

sulfonamides are _____ ______ of PABA

structural analogs

sulfonamides MOA

competitively inhibit dihydropteroate synthase

notable resistance mechanisms of sulfonamides

- utilization of alternative pathways

- increase production of PABA

sulfonamides clinical uses

limited because of resistance

sulfonamides spectrum of activity

MRSA

sulfonamides adverse effects

N/V/D

crystalluria

sulfa allergies usually cause

dermatologic hypersensitivity reactions

relationship between antimicrobial sulfonamide and non-antimicrobial sulfonamide

not cross-reactive

fluoroquinolone abx

ciprofloxacin

levo-

moxi-

gemi-

dela-

nor-

do eukaryotic cells contain topoisomerase IV or DNA gyrase

topoisomerase IV

fluoroquinolone MOA

inhibit DNA gyrase and topoisomerase IV (disrupts DNA replication > cell death)

notable fluoroquinolone resistance mechanisms

- mutations in quinolone binding region of DNA gyrase or topoisomerase IV

- develop proteins to protect DNA gyrase

fluoroquinolone clinical uses

URI

UTI (except moxifloxacin)

fluoroquinolone spectrum of activity

psuedomonas

atypicals (levo, moxi, gemi only)

what 3 fluoroquinolones have the best coverage of atypical bacterial infections

levofloxacin

moxifloxacin

gemifloxacin

fluoroquinolone adverse effects

-N/V/D

- impaired absorption with dairy or antacids

- QT prolongation and Torsades

fluoroquinolone black box warnings

tendinitis/tendon rupture

peripheral neuropathy

CNS effects (agitation and impaired memory/attention)

aminoglycoside abx

gentamicin

tobramycin

amikacin

streptomycin

neomycin

aminoglycoside MOA

block 30S subunit

premature termination

misreading

notable aminoglycoside resistance mechanisms

- lack of oxidative metabolism for transport (anaerobes)

- aminoglycoside-modifying enzymes

aminoglycoside clinical uses

- used in combo with other drugs to tx drug resistant organisms

- life threatening infections

aminoglycoside spectrum of activity

pseudomonas

aminoglycoside adverse effects

acute neuromuscular blockade and apnea

aminoglycoside toxicity

ears and kidneys

how are aminoglycosides dosed?

based on peak concentrations (Cmax)

high dose, extended-interval (once daily)

common mycobacterial infections

Tb, leprosy, avium complex

unique characteristics of mycobacterium

- grow slower

- (can be) dormant

- cell wall impermeable to many abx (d/t mycolic acid)

- intracellular

- exceptional drug resistance

antimycobacterial drugs

RIPE

rifamycins

isoniazid

pyrazinamide

ethambutol

rifamycin abx

rifampin

rifapentine

rifabutin

rifamycins MOA

bind to RNA polymerase making a drug-enzyme complex that inhibits RNA synthesis

notable rifamycins mechanisms of resistance

alterations to RNA polymerase

rifamycins side adverse effects

rash, N/V, fever

turns all bodily fluids orange

rifamycins special considerations

- strong inducer of most CYP enzymes (increases metabolism)

- take on empty stomach

rifamycins toxicity

hepatoxicity, most commonly cholestasis

isoniazid MOA

activated by KatG > inhibits synthesis of mycolic acid

isoniazid resistance mechanisms

KatG mutations

isoniazid adverse effects

fever, skin rash, increased LFTs

isoniazid special considerations

- take on empty stomach

- metabolized in liver by NAT2

reduced NAT2 enzyme function =

increased toxicity risk

increased NAT2 enzyme function =

reduced cure rates and infection relapse

isoniazid toxicity

peripheral neuropathy and overdose

overdose (clinical triad)

coma

seizures refractory to tx

anion gap metabolic acidosis

pyrazinamide MOA

activated by mycobacterial pyrazinamidase

notable pyrazinamide resistance mechanisms

mutations in pyrazinamidase

pyrazinamide adverse effects

N/V, fever, photosensitivity

pyrazinamide special considerations

- dose reductions for renal dysfunction

- re-dose after dialysis

pyrazinamide toxicity

hyperuricemia (gout flares)

hepatoxicity

ethambutol MOA

inhibits mycobacterial arabinosyl transferase 3

notable ethambutol resistance mechanisms

mutations to arabinosyl transferase 3

ethambutol side effects

RARE

rash, fever, pruritis

ethambutol special considerations

dose reduce in renal dysfunction

ethambutol toxicity

optic neuritis (red/green color blind)

tuberculosis first line drugs

RIPE + moxifloxacin

4 month TB regimen

4 drugs / 8 weeks then 3 drugs / 9 weeks

6 month TB regimen

4 drugs / 8 weeks then 2 drugs / 18 weeks

drug resistant TB

will use a combo of 4-5 drugs for 18-20 months

leprosy first line drugs

rifampin

clofazimine

dapsone

mycobacterium avian complex (MAC) first line drugs

rifamycins

ethambutol

clarithromycin/azithromycin

when are MAC first line drugs used

in patients who are immunocompromised, specifically those with HIV/AIDS