Fluoroquinolones, Anti-folates, Nitrofurantoin, Metronidazole Flashcards
Are fluoroquinolones bactericidal or bacteriostatic?
Bactericidal
Fluoroquinolones inhibits _________
DNA replication
*Bind to DNA gyrase on gram -ve, topoisomerase IV on gram +ve
Does fluoroquinolone require dose adjustment?
Dose adj in renal impairment: Ciprofloxacin
Dose adj in hepatic impairment: Moxicloxacin
Can topoisomerase II in eukaryotic cells be inhibited by fluoroquinolones?
Yes at higher concentrations
*Topoisomerase II similar to DNA gyrase (introduce negative supercoiling)
What are the 2 antibiotics with high risk of causing CDAD?
Clindamycin and Fluoroquinolones
Name 2 drugs that distribute to the prostatic tissue and hence can be used for prostatitis
Fluoroquinolones
Trimethoprim (weak base, distribute to acidic prostatic and vaginal fluids)
Cotrimoxazole
Fluoroquinolones are generally avoided in ______ due to high incidence of resistance.
Ciprofloxacin is avoided in MRSA (and MSSA), due to high incidence of staphylococcal resistance
Levo and Moxi used with caution due to fast development of resistance
Fluoroquinolones are ineffective against _________
Anaerobes
*Does not cover Bacteroides (except Moxifloxacin)
Fluoroquinolones generally do not cover streptococcus and enterococcus, they cover more gram-negative strains and enteric coliforms including:
E coli
Klebsiella
Proteus
H influenzae
Pseudomonas
Salmonella, Shigella, Campylobacter
*Not too effective against ESBL producing strains
*Can cover gram-positive Bacillus
Levofloxacin and Moxifloxacin are known as respiratory quinolones and can be used against _____
They have better gram-positive coverage and can be used against:
Streptococcus pneumoniae
Added coverage against Atypicals, Mycobacterium TB (2nd line for TB)
What are the adverse effects associated with Fluoroquinolones?
*There are 10
- GI related
- Dysglycaemia risk
- Aortic dissections or ruptures of aortic aneurysm (take note to not use in pt with hist of blockages or aneurysm, also do not use in pt with high BP, elderly)
- Incr risk of CDAD (Clindamycin as well)
- Headache and dizziness (caution in pt with CNS disorders such as epilepsy)
- Phototoxicity
- Also in: Tetracycline, Cotrimoxazole, Pyrazinamide - Incr risk of tendinitis, tendon rupture
- Arthropathy
- Prolong QT interval
- Also in: Macrolides, Azoles, - Peripheral neuropathy
- Also in: Linezolid, Isoniazid, Nitrofurantoin, Metronidazole
Fluoroquinolones can have DDI, cause rise in serum levels of ____ and ______
Warfarin and cyclosporine
Cipro also incr serum levels of theophylline
What do anti-folate drugs interfere with?
Interfere with synthesis of amino acids, purine, pyrimidine which are precursors for DNA, RNA, and protein synthesis
*Because tetrahydrofolate cofactors are required in the synthesis of AAs, purine, pyrimidine
Sulfonamides inhibit _____ which _____(function)_____
Competitively inhibits dihydropteroate synthase, which is responsible for incorporating PABA into dihydropteroic acid
Trimethoprim inhibit _____ which _____(function)_____
Inhibit dihydrofolate reductase which reduces dihydrofolic acid to tetrahydrofolic acid
Explain how sulfonamides cause nephrotoxicity
Sulfonamides are acetylated and conjugated in the liver
Acetylated metabolite precipitate at neutral or acidic pH, form crystal, cause crystalluria => damage kidneys
How can nephrotoxicity be prevented when taking sulfonamides?
Hydration and alkalinization of urine can help to reduce conc. of drug + promote its ionization such that crystal don’t ppt
Sulfonamides and Trimethoprim are excreted ________, require dose adjustment in _________
Excreted renally, require dose adjustment in renal impairment
Explain why G6PD deficiency causes risk of hemolytic anemia
G6PD enzyme is the central factor of antioxidant defense system in RBCs, maintains high levels of reduced glutathione (GSH) and NADPH, to protect RBCs from oxidative damage caused by ROS
Explain how sulfa drugs cause kernicterus.
Sulfa drugs displace bilirubin from serum albumin, bilirubin can pass into fetal CNS and penetrate BBB, thereby causing brain damage
*Hence, sulfonamides should not be used in 3rd trimester, should not be used in infants <2months
(Also not used in these pt groups due to risk of G6PD deficiency)
Explain a possible DDI of sulfa drugs
Sulfa drugs can displace watfarin from serum albumin, cause potentiation of anticoagulant effect
What might cause Trimethoprim resistance?
- Altered dihydrofolate reductase enzyme with lower affinity for trimethoprim
- Efflux pump
Trimethoprim causes ______ deficiency
This results in _________
Folic acid (Vit B9) deficiency
*Vit B9 helps body make RBCs
This results in blood disorders such as megaloblastic anemia, leukopenia, granulocytopenia
Trimethoprim causes ______ deficiency
This results in _________
Folic acid (Vit B9) deficiency
*Vit B9 helps body make RBCs
This results in blood disorders such as megaloblastic anemia, leukopenia, granulocytopenia
*Not used in 1st trimester
How is folic acid deficiency managed?
Folinic acid administration
- Folinic acid is a 5-formyl derivative of tetrahydrofolic acid, readily converted to tetrahydrofolic acid
Cotrimoxazole (1:5, Trimethoprim : Sulfamethoxazole)
What are the two main indications?
- Simple UTI, UTI prophylaxis
- Pneumocystic pneumonia (fungal)
- Symptoms: fever, rash, hyperkalemia, hyponatremia, diarrhea
Cotrimoxazole has activity against:
+ve: MRSA, MSSA, Strep pneumoniae
-ve: E. coli, Klebsiella, Proteus, Haemophilus
*may have some activity against the ESBL producing strains
Others:
- Pneumocystis jiroveci (fungi)
Toxoplasma gondii (parasites)
Cotrimoxazole does not cover:
anaerobes, atypicals, pseudomonas
List some of Cotrimoxazole adverse effects
- Rashes
- Photosensitivity
- GI: nausea, vomiting
- Glossitis, stomatitis
- Hemolytic anemia (in G6PD deficiency)
- Blood disorders (due to folic acid deficiency)
What is the route of administration of nitrofurantoin?
ORAL only
Nitrofurantoin indications include:
Treatment of lower UTI, prophylaxis of lower UTI
What is nitrofurantoin MOA?
Gets reduced by to highly active intermediate that inhibits various enzymes + disrupts the synthesis of proteins, DNA, RNA, and metabolic processes
What are the 2 main organisms that Nitrofurantoin is active against?
- E coli
- Enterococci
*It is resistant against proteus, pseudomonas, klesiella, enterobacter
Explain the distribution and elimination of Nitrofurantoin
High urinary conc. as it concentrates in the bladder
Low systemic exposure as it is rapidly cleared renally (do not use in renal impairment as it can cause incr is systemic toxicity)
Nitrofurantoin adverse effects:
- Brown discolouration of urine
- GI: nausea, vomitting, diarrhea
- Adverse effects associated with nitroreductive metabolism (pdn of injurious oxidative free radicals)
- Hemolytic anemia in G6PD deficiency
- Cholestatic jaundice and hepatocellular damage (prolong incubation period to onset of liver injury)
- Pulmonary toxicity - Peripheral neuropathy (rare)
Metronidazole is an anti-protozoal agent (mixed amebicide), can be used for the treatment of amebiasis caused by ________
Entamoeba histolytica trophozoites
Explain the MOA of metronidazole
Metronidazole is a nitroimidazole that gets reduced as the nitro group serves as an electron acceptor, forms cytotoxic free radicals
=> result in protein and DNA damage
Metronidazole are only active against ______ bacteria because __________
Anerobic bacteria
Because reduction of metronidazole requires strong reducing conditions (and anaerobic organisms have more reducing potential)
Name the only two drugs that can treat CDAD
- Vancomycin (PO)
- Metronidazole (PO) - only available oral
Name the drugs that are effective against Bacteroides
- Penicillin + BLI
- Carbapenems
- Clindamycin
- Moxifloxacin
- Metronidazole (recommended)
What antibiotics are part of the triple therapy fo H. pylori?
- Clarithromycin (Macrolide)
- Amoxicillin / Metronidazole
- Omeprazole
How is Metronidazole eliminated?
Hepatic metabolism by CYP450, parent drug and metabolites excreted via urine
*require dose adj in hepatic impairment as drug can accumulate
What are Metronidazole adverse effects?
- GI effects
- Metallic taste
- Oral moniliasis (yeast infection in mouth)
- Central and peripheral nervous system effects (seizures, optic and peripheral neuropathy)
*Avoid alcohol
Can Metronidazole be used in pregnancy?
Cat B, but avoid in first trimester as it can cross placenta barrier and enter fetal circulation rapidly
Which drugs in this series can penetrate CSF?
Cotrimoxazole, Metronidazole
