Lecture 25 TMP/SMX, Fosfomycin, nitrofurantoin Flashcards
What is the MOA of TMP/SMX?
first agent blocks production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting dihydrofolate reductase
second agent inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA)
all in all inhibits synthesis of purines for incorporation into DNA
How is resistance acquired for TMP/SMX?
overproduction of PABA, decreased affinity of enzyme dihydrofolate synthetase for sulfonamide, decreased affinity of dihydrofolate reductase for trimethoprim, decreased cell permeability
Spectrum of activity of TMP/SMX?
Gram +: S. aureus (MRSA), CoNS, S. pneumoniae, L. monocytogenes,, Gram -: (HECPEK) - H. influenzae, E. coli, Citrobacter freundii, P. mirabilis, Enterobacter, K. pneumoniae
M. catarrhalis, Legionella, acinetobacter baumannii, stenotrophomonas maltophilia
What are noted organisms that TMP/SMX isn’t active against?
S. pyogenes, enterococci, P. aeruginosa, M. pneumoniae, chlamydia, anaerobes, pneumocystis jiroveci, nocardia
What is the PK of TMP/SMX?
well absorbed PO, well distributed to many tissues, variable protein binding, extensively metabolized by liver (2C9 and 3A4)
both excreted in urine - dosage adjustment required in renal impairment
What are the AEs of TMP/SMX?
GI: N/V/D, jaundice, hepatic necrosis
Hematologic: anemia, agranulocytosis, thrombocytopenia, hemolytic anemia (G6PD deficiency)
teratogenic in pregnancy (1st and 3rd trimester)
photosensitivity
rashes: maculopapular around 1-3%, higher incidence in HIV pt
hyperkalemia
What are drug interactions involved with TMP/SMX?
it inhibits CYP2C9 - may substantially increase S-warfarin levels increasing INR, either use alternative antibacterial or monitor and adjust dose if no other choice
zidovudine increases risk of hematological effects
may increase phenytoin levels
possible hypoglycemia with SUs
What is the MOA of nitrofurantoin?
reduced by bacterial flavoproteins to reactive intermediates which alter bacterial ribosomal proteins or other macromolecules
remarkably stable to development of resistance
What is the PK of nitrofurantoin?
well absorbed, 2/3 rapidly metabolized in tissues and 1/3 unchanged in urine
low serum levels, only effective for UTIs
may be insufficient drug in urine if CrCl < 30-60
Spectrum of activity of nitrofurantoin?
Gram +: S. aureus, E. faecalis, E. faecium
Gram -: E. coli (89% of ESBL producers), K. pneumoniae
What is a noted organism resistant to nitrofurantoin?
P. mirabilis
What are AEs of nitrofurantoin?
GI: most common (take with food or milk), macrocrystals designed to decrease peak and nausea
Hepatotoxicity: rare
Hypersensitivity: rare, skin rash, anaphylaxis, drug fever, asthma, pneumonitis (reversible), chronic interstitial pulmonary fibrosis (may be irreversible)
Hematologic: hemolytic anemia (G6PD deficiency), can happen in pregnancies at term, leukopenia, granulocytopenia, eosinophilia
Neurologic: ascending polyneuropathy with prolonged tx or renal failure
Urine Discolouration: may be brown or rust-yellow
What are drug interactions with nitrofurantoin?
uricosuric agents - sulfinpyrazone, probenecid ⇒ decrease excretion, decrease effectiveness in UTIs, increase toxicity
What is the MOA of fosfomycin tromethamine?
phosphonic acid derivative
inhibits peptidoglycan cell wall synthesis at a very early stage
Spectrum of activity of fosfomycin?
Gram +: S. aureus, S. saprophyticus, enterococci
Gram -: (KESEC) Klebsiella, E. coli Serratia, Enterobacter, Citrobacter
How is resistance gained for fosfomycin?
develops frequently with multiple doses but not as frequently with single doses
chromosomal - decreased uptake into bacterial cell
plasmid mediated - catalytic conjugation with glutathione
What is the PK of fosfomycin?
34-65% bioavailability (OK with food), no protein binding (large Vd), excreted unchanged in urine
What are AEs of fosfomycin?
well tolerated,, GI: diarrhea (1.8%)
hypernatremia with IV
dizziness, H/A
Rarely: angioedema, asthma, aplastic anemia, cholestatic jaundice, hepatic necrosis, toxic megacolon
