12 Antifolates, Nitrofurantoin, Metronidazole Cupo Flashcards
What are Antifolates?
Sulfonamides. Dihydrofolate reductase inhibitors. Combination products
What are the different Sulfonamides used?
Sulfisoxazole. Sulfadiazine. Sulfamethoxazole. Sulfasalazine
What is the Dihydrofolate Reductase Inhibitor used?
Trimethoprim (Proloprim, Trimpex). Use as combination product
When is Trimethoprim used singularly?
In treatment of bacterial prostatitis (due to favorable penetration)
What is Trimethoprim/Sulfamethoxazole?
Bactrim (combination product). Available as fixed 1:5 ratio to provide therapeutic concentrations
What is Pediazole?
Erythromycin/Sulfamethoxazole combination
What is the MOA of sulfonamides?
Inhibits Dihydropteroate synthetase from making Dihydropteroic acid
What is the MOA of trimethoprim?
Inhibits Dihydrofolate reductase from making Tetrahydrofolic acid
How does the development of resistance occur?
Alteration to dihydropteroate synthetase –> lower affinity for the sulfonamide (E. coli). Increased production of an essential metabolite or drug (i.e. increased PABA with N. gonorrheae, S. aureus)
What is the absorption of Sulfonamides like?
Well absorbed from GI tract. Exception: Sulfasalazine; designed for local effects in bowel. Co-administration w/ food affects rate not extent
What is the distribution of sulfonamides like?
Pleural, peritoneal, synovial - about 50-80% of plasma. CNS - about 25-30% for sulfamethoxazole
Which sulfonamide is designed for local effects in bowel?
Sulfasalazine
What is the metabolism of Sulfonamides like?
In liver to inactive metabolites (N4 acetylation and glucuronidation)
What is the elimination of Sulfonamides like?
Via kidneys (GF; some tubular secretion). Renal excretion (SMX –> 10-30%, TMP 50-75%). Dose adjust for CrCl < 30ml/min by increasing interval (t1/2 ~ 10 hrs increases to ~10hrs)
What is the distribution of Trimethoprim like?
Well distributed in kidney, lung, sputum; also, bile, saliva. Prostatic tissue levels > 2-3x plasma levels. CSF ~40% of plasma levels
What is the metabolism of Trimethoprim like?
4 oxide/hydroxyl derivatives (not biologically active)
What is the elimination of Trimethoprim like?
About 60-80% excreted in urine via tubular secretion. Also biliary excretion
What is the DOC for Pneumocystis carinii?
TMP/SMX
What is the spectrum of activity like for TMP/SMX?
S. aureus, S. pneumoniae, S. pyogenes. L. monocytogenes. E. coli. H. influenzae. Klebsiella. P. mirabilis. S. maltophila. Nocardia asteroides. Shigella. Salmonella. Also, Pneumocystis carinii (DOC) and Toxoplasma gondii
What are the ADRs associated with TMP/SMX?
GI (N/V/D, anorexia). CNS (HA, confusion, dizziness, seizures). Dermatologic (generalized skin eruption). Hematologic (dose-related). Agranulocytosis. Hemolytic anemia. Aplastic anemia
What severe dermatologic reaction can occur in patients on TMP/SMX?
Erythema multiforme, SJS, TEN. Do not re-challenge if rash occurs in patient
What is TMP/SMX like for pregnancy?
Category C. AVOID in first and last trimester (may increase fetal blood levels of unconjugated bilirubin –> kernicterus)
What are some DDIs associated with TMP/SMX?
Sulfonylureas (hypoglycemia thru protein binding displacement of sulfonylurea). Phenytoin/Fosphenytoin (decreased phenytoin clearance). Methotrexate (increased MTX toxicity). Warfarin (increased bleeding)
What is some important patient information for TMP/SMX?
Photosensitivity - use sunscreen. Inform healthcare professional if HIV (+), G6PD, liver or kidney disease. Watch for fever, muscle pain, cough, difficulty breathing, skin turning yellow
What are some precautions for TMP/SMX use?
Fluid status. Monitor CBC to f/u blood dyscrasias
What is the clinical application for TMP/SMX?
Uncomplicated UTI. Skin & soft tissue infections caused by MRSA. Otitis media. P. carinii pneumonia (in both prophylaxis and treatment). T. gondii (prophylaxis; treatment w/ Pyrimethamine/sulfadiazine combo). S. maltophilia
What is doing like for Bactrim?
5mg/kg/d for UTI. 10mg/kg/d for systemic infection. 15mg/kg/d for P. carinii pneumonia
What is the MOA of Nitrofurantoin?
Interference w/ many bacterial enzyme systems. Requires enzymatic reduction w/in bacterial cell. Reduced derivatives –> bind proteins and inhibit the synthesis of inducible enzymes. Ultimately, damage bacterial DNA
What is the spectrum of activity for Nitrofurantoin?
Gram (+): S. saprophyticus, S. aureus, E. faecalis. Gram (-): E. coli (main use), Klebsiella, Enterobacter. NOT active against Proteus!
What is the absorption of Nitrofurantoin like?
F~80%, but enhanced w/ food. Rate of abs. differs w/r/t microcrystal vs. macrocrystal
What is the distribution of Nitrofurantoin like?
Does not obtain therapeutic tissue concentration except for urine. Protein binding = 90%
What is the metabolism of Nitrofurantoin like?
Metabolized to inactive compounds that may tint urine brown
What is the elimination of Nitrofurantoin like?
Predominantly renal via GF and tubular secretion. About 30-50% excreted unchagned
What are the ADRs associated with Nitrofurantoin?
GI (N/V/D, anorexia). Dermatologic. CNS (peripheral neuropathy - numbness, weakness, paresthesias: caused by long-term use, and patients with renal insufficiency. HA, Sedation. Hematologic. Hepatic. Respiratory
How does food affect Nitrofurantoin?
Delayed absorption
What is a DDI associated with Nitrofurantoin?
Probenecid: decreases Cl of nitrofurantoin and increases levels w/ possible increased ADRs
What pregnancy category is Nitrofurantoin?
Category B
What are the contraindications to Nitrofurantoin use?
Known hypersensitivity. CrCl < 60. Pregnancy (at term 38-42 weeks). Infants < 1 month
What are the precautions with Nitrofurantoin use?
G6PD. Lung disease. Peripheral neuropathy
What is some patient counseling for Nitrofurantoin?
May cause GI upset; take w/ food or milk. May cause brown discoloration of urine
When taking Nitrofurantoin, when should the patient contact a healthcare provider?
Fever, chills, cough, chest pain, difficulty breathing. Skin rash. Numbness or tingling of fingers or toes. Intolerable GI upset
How is Nitrofurantoin dosed?
Macrobid: 100mg for Q12h dosing. Macrodantin: 50, 100mg capsules for Q6h dosing
What is the therapeutic use of Nitrofurantoin?
Acute cystitis. Prophylaxis of cystitis
What is the MOA of Metronidazole?
Entry of drug into the bacterial cell. Reductive activation. Toxic effect of the reduced intermediate products. Produce inactive end products. Preferential reduction of the 5-nitro group. Reduction is a “pyruvate phosphoroclastic reaction”. Preferential for anaerobes as redox potential of METRO redox is only slightly above the electron transport redox (comp. to aerobes). Anaerobes are deprived of required reduction equivalents, hence loss of helical DNA structure, strand breakage and impairment to DNA
What is the absorption of Metronidazole like?
F = 100%. Rapid and complete oral absorption
What is the distribution of Metronidazole like?
Minimal protein binding (< 20%). Large Vd. Distributes to many tissue sites including amniotic fluid, biliary tract, bone, CSF, pleural fluid, saliva, breast milk
What is the metabolism of Metronidazole like?
5 major metabolites. Hydroxylation, acetylation and glucuronidation
What is the elimination of Metronidazole like?
60-80% in urine as “changed” drug. Up to 15% in feces. CrCl < 10: adjust dosing interval to Q12h to minimize accumulation of active metabolites
What is Metronidazoles spectrum of activity?
Bacteroides fragilis. Prevotella meninogenica. Peptococcus. Peptostreptococcus. Clostridium difficile (only mild to moderate case). H. pyolori. T. vaginalis, G. vaginalis, E. histolytica, G. lamblia
What are the ADRs associated with Metronidazole?
CNS (HA, dizziness, seizures, peripheral neuropathy). GI (N/V/D, abdominal pain/cramping), metallic taste. Genitourinary. Hematologic. Hypersensitivity
What are some DDIs associated with Metronidazole?
Barbs/Phenytoin. Warfarin (increase INR)
What is some patient counseling for Metronidazole?
May take w/ food to reduce stomach upset. Do not drink alcohol (includes cough/cold). May cause dizziness/caution driving. Metallic taste perversion possible. May color urine reddish-brown
When should the patient notify their healthcare professional when taking Metronidazole?
Skin rash, hives. Tingling pain, weakness in hands/feet
How is Metronidazole in pregnancy?
Category B. Avoid in first trimester. For 2nd, 3rd (if no other tx options available)
What are the therapeutic uses for Metronidazole?
Intra-abdominal infections (Gram (-) anaerobes). C. difficile infection. Parasitic GI infections (amebic dysentry, giardiasis)
How is Metronidazole dosed for Intra-abdominal infections?
500mg IV Q6-8h
How is Metronidazole dosed for C. difficile infection?
250mg po QID to 500mg po TID x 10-14 days
