Antifolate drugs are bacteriostatic but become bacteriocidal when?
Sulfonamethoxazole (SMX) + Trimethoprim (TMP)
combined = (Bactrim) = Synergism
What does Sulfonamethoxazole inhibit?
- Inhibits dihydropteroate synthase (DS)
- Mimics PABA (Para-aminobenzoic acid)
Folate Competitive inhibitor - Prevents Dihydrofolic Acid formation
What does Trimethoprim inhibit?
- Inhibits Dihydrofolate reductase (DHFR)
- Preventing Tetahydrfolic Acid formation
Bactrim uses synergistic effects which means?
- In combination
Additive effects = Greater effect
True or False
Trimethoprim (TMP) is a folate analog that binds to the bacterial DHFR 1000x more effectively than human DHFR ?
- True
What does Sulfamethoxazole mimic ?
- PABA (Para AminoBenzoic Acid)
- Absolute selective toxic
(Only in bacteria) - Humans depend on dietary folate
What does Trimethoprim mimic?
- Dihydrofolate reductase (DHFR)
- Relative selective toxic
Both in Humans and Bacteria
What does SMX + TMP treat?
- Topical MRSA
- AntiMycoplasma activity
Trimethoprim can block sodium channels in the kidney collecting tube leading to hyperkalemia and thus should be avoided in patients taking?
- Potassium-elevating agents
- ACE inhibitors
- Angiotensin receptor blockers
- Spironolactone
What are the three major side effects of bactrim?
- Hemolysis in G6PD deficiency
- Hypersensitivity to Sulfa (Do not prescribe to sulfa allergic pt’s)
- Stevens Johnson Syndrome Delayed IV reaction (Must Monitor)
Stevens Johnson Syndrome Delayed IV reaction is caused by what medications?
- Sulfa drugs
- Penicillins
- Mouth and Mucus membranes always affected
What does Ciprofloxain do ? MOA
- DNA gyrase inhibitor
- Blocks transcription
- Blocks DNA replication
DNA gyrase / Fluoroquinoloes are synthetic analogs of what?
- Nalidixic Acid
Ciprofloxain is NOT used first line, why?
- Because of all the adverse effects
- GI irritation
- Photosensitivity
- Risk of tendon rupture (x100)
- Aortic aneurysm
- Teratogen (Not in Prego)
T of F
Divalent/trivalent cations and acids impair Ciprofloxacin absorption?
- True
What does Ciprofloxacin treat?
- DOC for Anthrax
- Chlamydia
- Some antifungal activity
T of F
Ciprofloxacin has a post antibiotic effect?
- True
- Kills bacteria after treatment stops
Nitrofurantoin (Macrobid) treats what type of infection?
- Lower urinary tract infections
- Bladder and Urethra ONLY
- Urinary tract antiseptic
Nitrofurantoin (Macrobid) is safe in pregnancy?
T or F
- True
Nitrofurantoin (Macrobid) is contraindicated in pt’s with?
- Renal failure
- Drug can’t be cleared and builds up in body
What are the 5 questions to ask before prescribing an antibiotic?
1) Patient (Host)
2) Syndrome
3) Pathogen
4) Drugs
5) Cost
Two major mycobacterial infections in humans? that are difficult to treat?
- Tuberculosis
- Leprosy
What are the two strategies in fight mycobacterial infections?
- Multi drug therapy
- Long treatment course (6 to 12 months)
Two factors that my Mycobacteria hard to treat?
- Intrinsic Factors
- Environmental factors
What are the Mycobacteria environmental factors?
- Goes Dormant (Non-dividing)
- Cell Division (Long dividing time 1200mins)
- Physical barriers (Granuloma formation protects microb)
Intrinsic factors of Mycobacteria?
- Mycolic Acid (Sugar / Waxy fatty acid coating)
- Peptidoglycan (Unusual L - D linkage)
Insensitive to Vancomycin
Active TB disease treatment?
- Get RIPE
- Rifampin
- Isoniazid
- Pyrazinamide
- Ethambutol
For 2 months
Then
- Rifampin
- Isoniazid
For 6 months
Latent TB Disease treatment?
- Isoniazid (9 months)
T or F
Latent TB disease is always treated?
- False
Only Tx when
- High risk of active TB
- HIV
- Immuno Comp
- CXR with TB changes
- IV drug users
- High risk settings
(Correction facilities & Nursing homes)
What does multi drug therapy provide in mycobacteria diseases?
- Suppresses development of drug resistance
- Attacks fast and Attacks hard
MOA of Rifampin?
- Inhibitor of bacterial RNA polymerase from binding DNA
- Jams up active site
- Prevents elongation of RNA
T or F
Rifampin can penetrate the CNS but only when the Meninges are inflamed?
- True
T or F
Pt with liver disease can take Rifampin?
- False
- Extensive enterohepatic recirculation = hepatotoxicity
T or F
Bright orange bodily fluids is a good sign that Rifampin is working in a pt?
- True
- Orange Tears, Sweat, Urine
What does Extensive enterohepatic recirculation mean?
- Drug secreted inot duodenum via the bile after liver metabolism
- Reabsorbed downstream in the ilium
- Take back to the liver
- Taken back to the liver many times
- Prolonged lifetime of the drug in the body
Isoniazid (INH) MOA ?
- Vitamin B6 (pyridoxine) analog
- Prevents the synthesis of Mycolic acid
- By Inhibiting InhA reductase enzyme
Isoniazid inhibits what in the mycobacteria?
- Inhibits the growing fatty acid chain necessary for the completion of Mycolic acid Syn
What dose Isoniazid (INH) + NAD (Suicide Complex) prevent in Mycobactria?
- Prevents key reduction step necessary for Mycolic acid syn
- Inhibits INhA that prevents the saturation (Reduction) of Acyl chains
- No Acyl chains = No Mycolic acid syn
What are the two adverse side effects of INH (Isoniazid) ?
- INH Induced hepatitis
- INH Induced Neuropathy
What happens when a pt develops INH Induced hepatitis ?
- Stop taking Isoniazid ASAP
What happens when a pt develops INH Induced Neuropathy?
- Treat them with B6 Pyridoxine to reverse the symptoms
B6 Deficiency classically presents with?
- Seborrhoeic
Dermatitis - Craddle cap in Newborns
- Sore tongue
- Neurological effects
- Sideroblastic Anemia (Heme syn impaired)
What is Pyridoxine ?
- Dietary form of B6
- Serves as a cofactor for enzyme reactions
- AA metabolism
- Glucose metabolism
- Lipid metabolism
What medication is an analog of Vitamin B3 ?
- Pyrazinamide (PZA)
MOA of Pyrazinamide (PZA)?
- Enters mycobacteria via passive diffusion
- activated by pncA enzyme
- Accumulates in non-dividing cells and ultimately damages cell membranes to cause death
How does PZA enter the Mycobacteria?
- Via passive diffusion
What converts Pyrazinamide (PZA)
prodrug into its active metabolite Pyrazinoic Acid (POA) ?
- Mycobacteria Pyrazinamdase (pncA)
T or F
The Mycobacteria pumps POA out of the intracellular into the extracellular but then POA gets protonated and becomes uncharged and diffuses back into the cell.
- True
- Pumping only occurs in active TB
- Drug accumulates when the TB metabolism shuts down
- Driving Toxic acidification of the cytosol
What is the major resistance of Pyrazinamide (PZA) ?
- Mutations in the pncA Enzyme
T or F
PZA is highly effective against intracellular pathogens?
- True
- Sterilizing agent
- Diffuses through cell membranes @ Physiological ph
- Taken up by Macrophages
T or F
PZA only becomes POA - Protonated in the Low pH of the Lysosome but NOT neutral pH?
- True
- Prodrug into active Drug metabolite
Major side effect of Pyrazinamide (PZA) ?
- Hyperuricemia
- Gouty arthritis due to decreased renal excretion or urate
What medication blocks mycobacteria cell wall syn by Inhibiting Arabinosyltransferases?
- Ethambutol (Myambutol)
What does arabinosyltransferases do in the mycobactria?
- Catalyzes the attachment of Arabinose to Galactose to create Arabinogalactan
Why is Arabinogalactan important in mycobacteria?
- Needed for the hub attachment of Mycolic Acids
What layer does Ethambutol act on?
- Acts on the Arabinogalactan layer
- Acts on the layer upstream from the Isoniazid target, above the peptidoglycan layer
How is Ethambutol excreted?
- Renal 50%
- Liver 30%
- Feces 20%
Adverse effects of Ethambutol?
- Retrobulbar (optic) neuritis
- Damages optic nerve (Myelin Sheath)
- Causes red and green color blindness
Contraindication of Ethambutol ?
- Kids too young for an eye test
Only Aminoglycoside approved for treatment of TB?
- Streptomycin
MOA of Streptomycin?
- Multi modal activity all through ribosome 30S
1) Blocks ribosome initiation complex
2) Promotes translation errors
3) Blocks ribosomal translocation
When is Ethambutol used to treat TB?
- When Antimycobacterial agents are resistant
- Resistance mutations of Ribisomal subunits rpsl or rrs
- Or when injectable drug is needed
True of False
Ethambutol is very pain when given IM?
- True
What are the two major toxicity’s associated with Ethambutol?
- Ototoxicity Hearing lose
- Nephrotoxicity
Kidney damage
T or F
Ethambutol is contraindicated in pregnancy?
- True
- Risk of deafness in infant
What does Isoniazid (INH) treat?
- Mycobacterial infections
- Nosocomial CAP (Pneumonia)