L28 The Fluoroquinolones Flashcards
Why were the Fluoroquinolones (FQ) developed and what is good about them?
In response to growing resistance; broad spectrum, improved PK - excellent oral bioavailability, tissue penetration, long half-lives (but resistance has begun to develop)
What is the MOA of FQs?
Inhibition of DNA synthesis via inhibition of bacterial topoisomerases (DNA gyrase - gram-negative target, topoisomerase IV - gram-positive target)
FQs are ___-dependent and ___ (cidal/static).
Concentration; bactericidal
What is the major mechanism of resistance to FQs and three other minor mechanisms?
Major: altered target sites (mutations in genes that code for topoisomerases) leading to decreased binding affinity
Minor: active efflux, decreased porin expression, plasmid-mediated resistance
___-resistance occurs between FQs.
Cross
What are the important available FQs?
- Ciprofloxacin (both)
- Levofloxacin (both)
- Moxifloxacin (both)
- Gemifloxacin (oral)
Discuss the spectrum of activity of FQs broadly.
- Gram positive aerobes
- Gram negative aerobes
- Some anaerobes
- Atypical bacteria
What is the most important Gram positive bacteria FQs have activity against? Which of the FQs are best for this activity?
- Streptococcus pneumoniae (including PRSP)
Also: MSSA, strep viridans, Enterococcus
Levo and moxi
What is the most important Gram negative bacteria FQs have activity against? Which of the FQs are best for this activity?
- Pseudomonas aeruginosa (though significant resistance has emerged) - NOT MOXI, Cipro > Levo
Also: enterobacteriaceae, H. influenzae, M. catarrhalis, Neisseria spp.
Levo and cipro
Moxifloxacin (only) has some activity against which anaerobes?
Bacteroides species
Which atypical bacteria do (all) FQs have excellent activity against?
- Legionella pneumophila
- Chlamydophila and Chlamydia spp.
- Mycoplasma spp.
- Ureaplasma urealyticum
Discuss the absorption, distribution, and elimination of FQs.
- Good bioavailability after oral administration
- Distribution is extensive - lung, skin/soft tissue, bone, urinary tract and prostate (only cipro/levo), CSF (only moxi)
- Renal (levo, cipro), Hepatic (moxi)
What are the clinical uses for FQs?
- Upper respiratory tract infections (all)
- Community-acquired pneumonia (NOT cipro)
- Nosocomial pneumonia (cipro and levo)
- CF exacerbations (cipro)
- UTI, pyelonephritis, prostatitis (cipro, levo)
- Bone, intra-abdominal (w/metronidazole), STDs, TB (levo, moxi)
What are the most important adverse effects of FQs?
- Cardiac: prolongation of QTC interval -> Torsades
- Articular cartilage damage (contraindication in children, pregnant/breastfeeding women)
Also: GI (C. diff. colitis), CNS, hepatotoxicity, phototoxicity, tendonitis, hypersensitivity, rash
What are the important drug interactions of FQs?
- All oral FQs interact with divalent and trivalent cations, which impair absorption and lead to clinical failure
- Warfarin (all)
- Theophyllin and Cyclosporine (cipro)
What is metronidazole most active against?
Anaerobe and protozoa
What is the mechanism of metronidazole broadly?
Inhibition of DNA synthesis
How does metronidazole inhibit DNA synthesis?
Anaerobes and microaerophilic bacteria have ferredoxins; these are proteins that donate electrons to form a highly reactive anion that damages bacterial DNA and inhibits synthesis. Ferredoxins activate metronidazole, a pro-drug, into this anion.
Metronidazole is ___-dependent and ___ (cidal/static).
Concentration; bactericidal
What are the mechanisms of resistance of Metronidazole?
- Altered growth requirements (better growth in higher oxygen decreases activation of met)
- Altered ferredoxin levels (less activation of met)
Which anaerobic bacteria are most important acted upon by Metronidazole?
- Bacteroides spp.
- Clostridium spp.
Also: peptostreptococcus, fusobacterium, prevotella, H. pylori
Discuss the absorption, distribution, and elimination of Metronidazole.
- Oral/IV, rapid/complete absorption
- Well-absorbed, penetrates CSF
- Eliminated by the liver
What are the clinical uses of Metronidazole?
- Anaerobic infections (intra-abdominal, pelvic, SSTI, diabetic foot, decubitus ulcer, brain abscess)
- Pseudomembranous colitis due to C. diff.
- Trichomonas
Discuss the adverse effects of Metronidazole, including the most common and most serious.
Most common: GI (nausea, vomiting, stomatitis, metallic taste)
Most serious: CNS (peripheral neuropathy)
Also: mutagenic, avoid during pregnancy/breastfeeding
What are the important drug interactions with metronidazole?
- Warfarin (increase anti-coagulant effect)
2. Alcohol (disulfiram reaction)
