Pharmacology - Quinolones, Folic Acid Antagonists, Urinary Antiseptics, Metronidazole

Question 1

List the fluoroquinolones.

Answer 1

Ciprofloxacin, Levofloxacin, Moxifloxacin

Question 2

What is the mechanism of action of the fluoroquinolones?

Answer 2

Targets DNA gyrase in Gram-negatives and topoisomerase IV in Gram-positives to inhibit DNA replication - inhibition of DNA replication results in bacterial lysis

Question 3

How far should fluoroquinolones be spaced from consumption of dairy products or substances that contain divalent cations?

Answer 3

2h before or 6h after

Question 4

How can fluoroquinolones be administered?

Answer 4

PO/IV/Opthalmic

Question 5

What is the spectrum of action of ciprofloxacin?

Answer 5

Most active against Gram-negatives and enteric coliform (incl penicillin, cephalosporin and aminoglycoside resistant strains)

Highly effective against P.aeruginosa (only oral agent available)

Traveller’s diarrhoea caused by E.coli, food poisoning caused by all Enterobacteriaceae and Campylobacter jejuni

Typhoid fever caused by Salmonella typhi
Prostatitis

Anthrax caused by Bacillus anthracis

Uncomplicated UTI, but not recommended as first-line (mainly for penicillin allergy)

Avoid in MSSA/MRSA - is thus not considered a respiratory quinolone

Question 6

What is the spectrum of action of levofloxacin?

Answer 6

Better Gram-positive coverage than ciprofloxacin - Streps and S.pneumoniae
(use for MSSA/MRSA coverage w caution)

Active against Gram-negatives - H.influenzae, E.coli, Klebsiella spp, Proteus mirabilis, Pseudomonas aeruginosa

Better coverage against Atypicals than ciprofloxacin

Useful against respiratory infections
NOT FIRST LINE FOR TB

Question 7

What is the spectrum of action of moxifloxacin?

Answer 7

Better Gram-positive coverage than ciprofloxacin, esp S.pneumoniae, Finegoldia magna
(use for MSSA/MRSA coverage w caution)

Only used for H.influenzae amongst the gram negatives (no breakpoints from CLSI)

Better coverage against Atypicals than ciprofloxacin

Useful against respiratory infections
NOT FIRST LINE FOR TB

Question 8

Are the fluoroquinolones used for CSF?

Answer 8

No

Question 9

How are the fluoroquinolones excreted?

Answer 9

Renal - cipro, levo
Hepatic - moxi
All need adjustment in respective organ failures

Question 10

Can fluoroquinolones be used in G6PD deficiency?

Answer 10

No

Question 11

What are the adverse reactions associated with the fluoroquinolones?

Answer 11

1. GI Sx - N/V/D
2. Dysglycaemia risk, esp in DM
3. Aortic dissections (rare)
4. Inc C.diff colitis risk, esp w ciprofloxacin
5. Headache and dizziness - treat CNS disorder pts carefully
6. Phototoxicity
7. Tendonitis risk
8. QTc prolongation
9. Peripheral neuropathy (can be reversible or irreversible)

Question 12

What drugs interact w the fluoroquinolones?

Answer 12

The fluoroquinolones interact w warfarin and cyclosporine

Question 13

What groups of patients are fluoroquinolones contraindicated in?

Answer 13

Children <18yo
Pregnancy

Question 14

What is the mechanism of action of sulfamethoxazole?

Answer 14

Competitive inhibitors of dihydropteroate synthase, which stops dihydropteroic acid synthesis (immediate precursor of folic acid) - only active against microorganisms that solely synthesise their own folic acid

Question 15

What is the mechanism of action of trimethoprim?

Answer 15

Inhibits reduction of dihyrofolic acid by dihydrofolate reductase to its active form, dec purine, pyrimidine & aa synthesis

Question 16

What is the spectrum of action of co-trimoxazole?

Answer 16

MSSA, MRSA, E.coli, Klebsiella spp, Proteus mirabilis

Use w caution for S.pneumoniae, H. influenzae, ESBL producing E.coli, Enterobacter

Question 17

Sulfonamides are only effective in bacteria that synthesize their own __________?

Answer 17

folic acid

Question 18

How should co-trimoxazole be taken by oral route?

Answer 18

Take with a full cup of water

Question 19

What are the adverse reactions associated with co-trimoxazole?

Answer 19

1. Hypersensitivity: can range from mild rash to SJS
2. GI Sx: N/V, CDAD also possible
3. Can cause haemolytic anemia in G6PD deficient patients
4. Can impair haematopoiesis due to folate antagonism - admin folinic acid tgt to prevent
5. Hyperkalaemia

Question 20

How is co-trimoxazole excreted?

Answer 20

Sulfamethoxazole - metabolised hepatically (acetylation and conjugation), excreted renally

Trimethoprim - 60-80% renally as unchanged drug

Question 21

What groups of patients is co-trimoxazole contraindicated for?

Answer 21

1. G6PD deficient
2. Folate deficient
3. Pregnant women (G6PD deficiency concern + sulfamethoxazole causing kernicterus)
4. Infants <2months (G6PD deficiency concern)

Question 22

What can be given to patients on trimethoxazole/co-trimoxazole for folic acid deficiency?

Answer 22

Simultaneous admin of folinic acid

Question 23

What is the mechanism of action of nitrofurantoin?

Answer 23

Nitrofurantoin sensitve bacteria reduce the drug to a highly active intermediate that inhibits various enzymes and disrupt the synthesis of proteins, DNA, RNA and metabolic processes

Question 24

How is nitrofurantoin administered?

Answer 24

PO

Question 25

What is the spectrum of action of nitrofurantoin?

Answer 25

Active against many strains of E.coli & Enterococci Most species of Proteus and Pseudomonas, as well as many species of Enterobacter and Klebsiella are resistant

Question 26

How is nitrofurantoin excreted?

Answer 26

~40% excreted unchanged into urine (is targeted at the urinary tract)

Question 27

What are the adverse effects associated with nitrofurantoin?

Answer 27

1. GI Sx: N/V/D 2. Hypersensitivity: chills, fever 3. Leukopenia, hemolytic anemia from G6PD deficiency 4. Cholestatic jaundice and hepatocellular damage - rare, but nitroreductive metabolism produces oxidative free radicals that can damage hepatocytes 5. Elderly esp susceptible to pulmonary & hepatic toxicities, peripheral neuropathies (risk increases w impaired renal function and long-continued Tx)

Question 28

What is a side effect of nitrofurantoin to counsel on?

Answer 28

urine will turn brown

Question 29

What groups of patients is nitrofurantoin contraindicated in?

Answer 29

1. G6PD deficient 2. Patients with impaired renal function (CrCl<40ml/min) 2. Pregnant women (at term > 37 weeks) 3. Infants <1 mth of age

Question 30

What is G6PD, and why is it important in red blood cells?

Answer 30

The glucose-6-phosphate dehydrogenase (G6PD) enzyme is the central factor of the antioxidant defense system in red blood cells, which helps maintain high levels of reduced glutathione (GSH) and nicotine adenine dinucleotide phosphate (NADPH), to protect the RBC from oxidative damage caused by reactive oxygen species.

Question 31

What is nitrofurantoin indicated for?

Answer 31

uncomplicated lower UTI

Question 32

What is the mechanism of action of metronidazole?

Answer 32

Metronidazole possesses a nitro group that serves as an electron acceptor from the electron transport proteins in amoebas. This results in formation of cytotoxic free radicals that result in protein and DNA damage, & death of E. histolytica trophozoites

Question 33

How is metronidazole administered?

Answer 33

PO

Question 34

What is the spectrum of action of metronidazole?

Answer 34

Mainly anaerobes - eg C.diff, Bacteroides fragilis, Finegoldia magna Amoebic infections as well - Entamoeba histolytica, Trichomonas vaginalis (vaginitis), Giardia lamblia etc

Question 35

Can metronidazole be used for CSF?

Answer 35

Yes - can reach therapeutic levels

Question 36

How is metronidazole excreted?

Answer 36

Hepatic metabolism, affected by CYP450 inducers/inhibitors, will accumulate in severe hepatic disease Parent drug and metabolites excreted in urine

Question 37

What are the adverse reactions associated w metronidazole?

Answer 37

1. GI Sx: N/V, epigastric distress, abdominal cramps 2. Commonly has unpleasant metallic taste 3. Oral moniliasis (yeast infection of mouth) 4. Central and Peripheral Nervous System Effects: Convulsive seizures, optic and peripheral neuropathy - rare but must discontinue if it happens

Question 38

What DDIs does metronidazole have?

Answer 38

potentiates the effect of warfarin

Question 39

How is the distribution of metronidazole like?

Answer 39

Distributes well throughout body tissues and fluids, therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk and CSF