L7 Pharm: Fluoroquinolones & Metronidazole Flashcards
1
Q
Fluoroquinolones
- Mechanism of action?
- What is the primary target of gram negative bacteria?
- What is the primary target of gram positive bacteria?
- Is their bactericidal activity concentration dependent or time dependent?
A
- Inhibit DNA synthesis by inhibiting bacterial topoisomerases necessary for DNA synthesis
- Gram Negative- DNA Gyrase- Topoisomerase II (removes excess positive supercoiling in the DNA helix)
- Gram positive- Topoisomerase IV (essential for separation of interlinked daughter DNA molecules)
- FQs display rapid, concentration-dependent bactericidal activity
2
Q
What are 5 ways bacteria can confer resistance to FQs?
A
- Alter target sites
- Mutate topoisomerase genes to decrease binding affinity)
- Most important and most common form of resistance - Express active efflux
- Pumps FQs out of the cell - Altered cell wall permeability
- Decreased porin expression
- Plasmid mediated resistance - Plasmid mediated resistance
- Cross-Resistance
- Occurs between FQs- if you have resistance to one, you’ll likely have resistance to the whole class
3
Q
What are the four major FQs and how can they be administered?
A
- Ciprofloxacin- PO, IV (older FQ)
- Levofloxacin- PO, IV (newer)
- Moxifloxacin- PO, IV (newer)
- Gemifloxacin- PO (newer)
4
Q
FQs Spectrum of Activity
- What are the best FQs to use against gram positive aerobes?
- What are the two main gram positive aerobes FQs can be used against?
- What gram positive aerobes do they have limited activity against?
A
- Levo & Moxi
* *Cipro only has activity against gram negatives** - MSSA & Streptococcus Pneumoniae (including Penicillin Resistant Strep. Pneumoniae)
- Limited activity against Viridians strep & enterococcus spp.
5
Q
- What FQs are best against gram negative aerobes?
- What species of bacteria do they have activity against?
- Which one should you not use for pseudomonas aeurginosa?
A
- Cipro=Levo > Moxi
* *Cipro & Levo have excellent gram negative activity** - Enterobacteriaceae Species
- Citrobacter, E.Coli, Klebsiella spp., Enterobacter spp., Proteus spp., Salmonella, Shigella, Serratia marcescens
- H. influenzae, M. Catarrhalis, Neisseria spp. - Pseudomonas Aeruginosa- use Cipro or Levo
- Significant resistance has emerged
- Do not use Moxi!
6
Q
What FQ should be used against:
- Anaerobes?
- Atypical bacteria (Legionella, Chlamydia, Mycoplasma, etc)?
- Mycobacterium tuberculosis?
- Bacillus anthracis?
A
- Anaerobes: Moxi
- Has activity against Bacteroides spp. (30% resistance with B. Fragilis) - Atypicals- ALL FQs
- M. Tuberculosis: Levo & Moxi
- B. Anthracis: Cipro & Levo
7
Q
What FQs should be used in the following clinical scenarios:
- Upper Resp. Tract Infections (sinusitis/bronchitis)
- Community acquired pneumonia?
- Nosocomial infection?
- Cystic Fibrosis flair up?
- UTIs, pyelonephritis and prostatitis?
- Bone infections, intraabdominal (with metronidazole) infections, STDs, and TB?
A
- Sinusitis/bronchitis: ALL (levo, moxi, gemi, cipro)
- CA-pneumonia: Levo, moxi, gemi
* *NOT Cipro due to poor gram positive coverage** - Nosocomial infection/pneumonia: Cipro & Levo (anti-pseudomonals)
- CF flair up: Cipro
- UTI, pyelonephritis, prostatitis: Cipro & Levo
- Levo & Moxi
8
Q
At least 7 FQs have been removed from the market due to adverse effects…
- Which are the most common?
- What cardiac side effects to FQs cause?
- What type of cartilage damage can FQs cause?
- What are 3 rare side effects?
- FQs are contraindicated in what patients?
A
- GI & CNS side effects are most common
- GI: N/V, Diarrhea, dyspepsia, C. Diff colitis
- CNS: headache, agitation, insomnia, dizziness, confusion, hallucinations/seizures (rare- seen in elderly patients) - Prolonged QTc interval- serious cardiac SE
- Caution in pts with hypokalemia, preexisting QT prolongation, concomitant antiarrhythmics - Tendonitis & Tendon rupture (increased risk if you’re >60 yrs old, on corticosteroids, transplant patients)
- Other cartilage damage: arthropathy, joint swelling - Rare side effects:
- Hypersensitivity
- Phototoxicity
- Hepatotoxicity (LFT elevation/liver failure) - Contraindicated in pregnant women & children
9
Q
PK of FQs
1. Good bioavailability after what type of administration?
2. What tissues do the FQs distribute to? Which distribute to Urinary tract? Which can penetrate CSF?
3. How are Levo, Cipro, and Gemi eliminated?
How is Moxifloxacilin eliminated?
A
- Good F after oral administration
- extensive distribution to lungs, skin/soft tissue, bone;
- Urinary tract: Cipro & Levo
- CSF: Moxi has good penetration - Renally Eliminated: Levo (90%), Cipro (60%), Gemi (36%)
-Dosage adjustments needed in the case of renal insufficiency
Hepatic elimination: Moxi (80%)
SAMPLE Q:
49 yo female was admitted with a UTI. Urine culture is positive for E.Coli >100,000 colonies sensitive to fluoroquinolones. Which of the following is NOT appropriate treatment.
A. Ciprofloxacin
B. Levofloxacin
C. Moxifloxacin*- doesn’t distribute to urinary tract; hepatic elimination
10
Q
- How do divalent & trivalent cations affect FQ treatment?
- What FQs have interaction with Warfarin?
- What FQs have interactions with Theophylline & Cyclosporine?
A
- All FQs interact with di/trivalent cations (Zinc, Calcium, Aluminum, Magnesium)
- Impair absorption of orally-administered FQs- may lead to clinical failure
- Remedy by administering doses 2-4 hours apart, with FQs being administered first
- Clinical examples of di/trivalent cations: antacids, sucralfate, didanosine, enteral feedings, calcium rich foods (OJ) - All have idiosyncratic interactions with Warfarin
- Cipro has interactions with Theophylline & Cyclosporine
- Inhibitions of metabolism- increases levels & toxicity
11
Q
Pseudomonas Aeruginosa
What is the best FQ to give?
A
Cipro>levo NOT moxi or gemi
12
Q
Metronidazole
- Extremely useful against what?
- Mechanism of Action?
- Concentration or time dependent killing?
A
- Anaerobes and protozoa
- Inhibits DNA Synthesis
- Concentration-dependent killing like FQs
Extra Info- killling mechanism:
- Selective toxicity against anaerobic and microaerophilic bacteria due to the presence of ferredoxins within these bacteria
- Ferredoxins are proteins that donate electrons to form highly reactive nitro anion that damages bacterial DNA, inhibit DNA synthesis, and cause cell death
- Metronidazole is catalytically recycled
- Not active in oxygen environment since it competes with metronidazole for electrons
13
Q
What are the 2 relatively uncommon ways bacteria can confer resistance to Metronidazole?
A
- Alter growth requirements
- grow in higher local oxygen concentrations (decreases metronidazole activation) - Alter ferredoxin levels
- reduce ferredoxin levels- less activation of metronidazole
14
Q
What are two major species of bacteria that Metronidazole has activity against?
A
- Bacteriodes spp.
- Clostiridium spp. (including C-Diff!)
Also has activity against:
- Peptostreptococcus (found in the mouth)
- Heliocobacter pylori (need two other drugs to help it cure H. Pylori)
- Anaerobic Protozoa
15
Q
PK of Metronidazole
- How is the drug absorbed? What effect does food have on absorption?
- Does Metronidazole penetrate the CSF?
- How is it primarily metabolized/eliminated?
- What is the half life?
A
- Rapid and complete absorption (>90% bioavail.)
- Food has minimal effect on absorption - Good distribution, DOES penetrate CSF
- Primarily metabolized by liver, metabolites excreted in urine
- 6-15% eliminated in feces - Half life= 6-8 hours
Extra Info:
Metronidazole is removed during hemodialysis
