Lecture 26 Fluoroquinolones, Metrondiazole Flashcards
What are examples of fluoroquinolones and what is the MOA?
Drugs: norfloxacin, ciprofloxacin, moxifloxacin, levofloxacin
MOA: inhibit bacterial DNA gyrase (topoisomerase II), DNA gyrase essential in uncoiling and recoiling DNA to facilitate replication, transcription, and repair of DNA
these drugs have 100x higher affinity for bacterial gyrase than human gyrase
also inhibit topoisomerase IV which normally allows segregation of duplicated DNA into daughter cells
What are ways bacteria gain resistance to fluoroquinolones?
decreased permeability (change in porin structure in Gram -)
decreased affinity of DNA gyrase (topoisomerase II) and/or topoisomerase IV
efflux pump (ex. S. aureus, NorA efflux pump)
Spectrum of activity of second gen fluoroquinolones ⇒ norfloxacin and ciprofloxacin, ofloxacin?
Gram +: S. aureus (limited, includes beta-lactamase, resistance often develops), Streptococci (limited)
Gram -: (HECPPEKS) H. influenzae, Enterobacter, Citrobacter, Proteus, P. aeruginosa (second drug), E. coli, Klebsiella, Serratia
N. meningitidis and gonorrhoeae, M. catarrhalis
Salmonella, Shigella, Campylobacter
Anthrax, Y. pestis
Second and Third Drug: M. tuberculosis, MAC, other mycobacteria
first drug only used in UTI and GI infections
Spectrum of activity of ciprofloxacin?
Gram +: limited staphylococci and streptococci and enterococci
B. anthracis
Gram -: (HECPPEKS): H. influenzae, Enterobacterales (including Y. pestis, Salmonella, many AmpC), Citrobacter, Proteus, P. aeruginosa, E. coli, Klebsiella, Serratia
M. catarrhalis, Legionella,, Others: Mycobacteria, C. pneumoniae, M. pneumoniae
What is the PK of second gen fluoroquinolones norfloxacin, ciprofloxacin, ofloxacin?
excellent oral bioavailability (first 35-70%, second 75-85%, third 90-95%)
second drug 500 mg PO = AUC 400 mg IV ⇒ good for switching IV to oral
distributes well, variable in CSF
second drug inhibits CYP1A2 (moderate) and 3A4 (weak)
long terminal t1/2 allows BID or QD dose
What are AEs of fluoroquinolones?
Skin: rash, urticaria, sunburn (photosensitivity),, GI: N/V/D,, CNS: Psychiatric - hallucinations,, Neurologic - seizures, avoid if hx of seizures, more common in >60 yrs with high dose and decreased renal fxn,,, Tendons: risk of tendonitis or rupture, most frequently achilles but can be other, may be preceded by pain, swelling, inflammation in area for up to 2 weeks before rupture, ⇒ risk fx - >60 yrs, corticosteroids, kidney or heart or lung transplant recipient, exercise, kidney failure, hx of tendon problems (RA)
Cartilage: damage, children <18 or babies
CV: increased QT, tachycardia, hypotension
Myasthenia Gravis: may exacerbate, rare but serious, AVOID in pt with this
Renal: interstitial nephritis, nephrosclerosis, tubular necrosis
Other: anaphylaxis, MSK, leukopenia, thrombocytopenia, anemia
What are common uses of ciprofloxacin?
available PO, IV, eye drop
useful in serious Gram - infections ⇒ particularly as PO/step-down/switch such as in pyelonephritis
useful alternative to aminoglycosides if renal damage concern in susceptible Gram - infections
Pseudomonas activity
What are common uses of levofloxacin and moxifloxacin?
improved Gram + coverage versus others in class
improved against S. aureus, S. pneumoniae, M. pneumoniae, C. pneumoniae
good against M. catarrhalis, H. influenzae, some Klebsiella, E. coli, Legionella
Spectrum of activity of levofloxacin?
Gram +: staphylococci, streptococci, limited enterococci
Gram -: (HECPPEKS) - H. influenzae, Enterobacterales (including Y. pestis, Salmonella, many AmpC), Citrobacter, Proteus, P. aeruginosa E. coli, Klebsiella, Serratia
M. catarrhalis, Legionella
Other: mycobacteria, C. pneumoniae, M. pneumoniae
Spectrum of activity of moxifloxacin?
Gram +: staphylococci, streptococci, limited enterococci
Gram -: (HECPPEKS) - H. influenzae, Enterobacterales (including Y. pestis, Salmonella, many AmpC), Citrobacter, Proteus, E. coli, Klebsiella, Serratia
M. catarrhalis, Legionella
Other: mycobacteria, C. pneumoniae, M. pneumoniae
What is the PK of moxifloxacin?
oral dose 96 +/- 4% absorbed
52% is metabolized to glucuronate and sulfate metabolites
45% excreted unchanged in urine (20%) and feces (25%)
t1/2 11.5-15.6 hours, no dose change required in renal failure
What is the PK of levofloxacin?
99% oral absorption, little affected by food
excellent for switch (step-down)
excreted primarily in urine and 4% in feces ⇒ reduce dose if CrCl <50
What are some drug intx of fluoroquinolones?
QT Interval: should be avoided or cautioned in pt with prolonged QT or receiving: class III antiarrhythmics (amiodarone, sotalol), Class 1A antiarrhythmics (quinidine, procainamide), or other agent that prolong QT
risk also may be increased with cardiomyopathy, bradycardia, hypokalemia, hypomagnesemia, hypocalcemia
Multivalent Cations and Bismuth: avoid or give drug 2 hours before or 6 hours after cation or bismuth
Steroids: may predispose pt to tendon rupture
NSAIDs: potential increased seizure risk (primarily in epileptics)
CYP1A2: may inhibit with cipro and may affect theophylline, tizanidine, olanzapine
Warfarin: may increase INR
What is delafloxacin (spectrum)?
new anti-MRSA fluoroquinolone
dosed BID, available IV or PO
Spectrum: S. aureus (MRSA), CoNS, S. pneumoniae, S. pyogenes, H. influenzae, M. catarrhalis, Enterobacterales, M. pneumoniae, C. pneumoniae, Legionella, B. fragilis
What is the MOA of metronidazole?
enters microbial cell ⇒ activated by reduction by bacterial nitroreductase ⇒ short-lived intermediates or free radicals interact with DNA and possibly other macromolecules = cell death
cytotoxic intermediates decompose (inactive)
What are ways that bacteria are resistant to metronidazole, and noted organisms gaining resistance?
decreased uptake in cell
decreased nitroreductase activity
resistance developing with H. pylori
Spectrum of activity of metronidazole?
Anaerobes: most,, B. fragilis, Bacteroides, C. perfringens, C. difficile, H. pylori (as part of multidrug Rx), Gardnerella vaginalis (bacterial vaginosis), C. acnes (LIMITED)
Parasites: Trichomonas vaginalis, Giardia lamblia (giardiasis, Beaver Fever)
Amoeba: Entamoeba histolytica
What bacteria are resistant to metronidazole?
aerobic bacteria as they lack nitroreductase and therefore do not activate metronidazole
What is the PK of metronidazole?
absorbed extremely well PO, PR and vaginally (ideal for PO switch)
peaks similar to IV (not affected by food)
large Vd,, distributes well to all tissues and fluids
extensively metabolized,, 8-20% excreted unchanged in urine
t1/2 6-8 hours
dosage adjustment only if CrCl < 10
suggested decreased dose by 50% in hepatic failure
What are AEs of metronidazole?
peripheral neuropathy with prolonged tx (reversible)
CNS toxicity - rare, high dose, prolonged
caution if previous seizures
d/c if any neurologic sx
Disulfiram effect with alcohol ⇒ ADVISE PATIENT NOT TO DRINK WHILE TAKING
dark red-brown urine (WARN PT)
with High Doses ⇒ metallic taste, nausea, epigastric distress, dizziness, vertigo, paresthesia
neutropenia - reversible and mild
What are some drug intx with metronidazole?
Alcohol: disulfiram effect
Disulfiram: confusion, psychosis
Warfarin: metabolism inhibited by metronidazole (CYP2C9) ⇒ avoid combo or monitor INR and decrease dose if needed
Lithium: increases lithium, avoid combo, if used together monitor lithium levels and adjust dose if needed
Busulfan, 5FU: increase busulfan levels and 5FU serum ⇒ avoid if possible
