Tetracyclines ,Glyclines, Sulfonamides, Chloramphenicol and urinary tract agents Flashcards
MOA: tetracylines (tetracycline, doxycycline and minocycline) and glycylcyclines (tigecycline)
They reversibly bind the 30S ribosomal subunit to inhibit the binding of aminoacyl transfer-RNA to the
acceptor (A) site on the mRNA-ribosomal complex. This prevents addition of amino acid residues on
elongating peptide chain.
Bacteriostatic; Bactericidal against very susceptible organisms
MOR: tetracylines
- Acquisition of genes on mobile elements via efflux pumps, ribosomal protection proteins, and enzymes that deactivate drugs
Is there cross-resistance between tetracyclines?
Cross-resistance observed between tetracyclines, except
for minocycline
Which drug is not affected by the mechanisms of resistance?
• Tigecycline resistant to these mechanisms
Spectrum: tetracyclines
G+ aerobes (MSSA, PSSP is mostly susc.)
G- aerobes
Anaerobes
Rickettsia Chlamydia Mycoplasma Spirochetes Strep Legionella
Spectrum: tigecycline
G+ aerobes (incl. MRSA)
G- aerobes (incl, VRE)
Anaerobes
Not proteus or pseudomonas
Treating bacteremias with tigecycline?
No
Treating UTIs with tigecycline?
No
Absorption of tetracyclines and glycylcyclines overall
Absorbed best on an empty stomach
Absorption impaired by di- and trivalent cations
Bioavailiability of tetracycline
60-80%
Bioavailiability of doxycyline and minocycline
90-100%
Affect of food on absorption of tetracyclines and glycylcyclines
Absorbed best on an empty stomach
What slows down tetracycline and glycylcycline absorption
Divalent and trivalent cations
Distribution: tetracyclines and glycylcyclines
Widely distributed with good penetration into synovial fluid,
prostate, seminal fluid
Minimal CSF penetration
Elimination: tetracyclines
Tetracycline - excreted unchanged in the
urine
Is dosage adjusted in renal failure?
Yes
Half lives of tetracycline and demeclocycline
Tetracycline half-life = 6 to 12 hours; demeclocycline half-life = 16 hours
Elimination of doxycycline, minocycline and tigecycline
Doxycycline and minocycline (metab) and tigecycline (biliary)
Do doxycycline, minocycline and tigecycline require dose adjustment in renal failure?
No
Do doxycycline, minocycline and tigecycline require dose adjustment in renal failure?
Doxy and mino do not
Tigecycline DOES
Are tetracyclines and tigecyclines removed during hemodialysis?
Minimally
Half-lives of doxy, mine and tige and dosing (general)
Half-lives are long, but they are all dosed every 12 hours!
Indications: tetra, doxy, mino, tige
Atypical pneumonia
STDs
Rickettsial infections, incl. rocky mountain fever
Specific indications: doxy
- Community-acquired pneumonia – due to PSSP, Mycoplasma spp, and Chlamydophila spp.
- Chlamydial infections including psittacosis, lymphogranuloma venereum,
and nongonococcal urethritis
Specific indications: tige
Polymicrobial infections caused by susceptible bacteria (not caused
by Proteus or Pseudomonas) in the following conditions:
1. Complicated skin and skin structure infections
2. Complicated intra-abdominal infections
Can pregnant women take tetracyclines and tigecyclines?
No. They cause permanent tooth discolorations of primary dentition.
Children under 8 also shouldn’t take them.
Adverse effects: tetracycline, minocycline, doxycycline
GI photosensitivity hepatotoxic Discolor teeth (pregs + kids) Fanconi syndrome (if outdated)
MOA: trimethoprim-sulfamethoxazole (sulfonamides)
Bactrim
Sulfamethoxazole: competitively inhibits dihydropteroate synthetase, preventing the incorporation of PABA into folic acid
Trimethoprim: competitively inhibits the activity of dihydrofolate reductase to prevent the reduction of dihydrofolate to tetrahydrofolate
Synergistically inhibit folate synthesis, stopping the production of DNA.
Bactericidal
Resistance to Bactrim
Bacterial resistance is mediated by point mutations in dihydropteroate
synthase and/or altered production or sensitivity of bacterial dihydrofolate
reductase.
Resistance has been reported in E. coli, Klebsiella spp., Proteus mirabilis, H. flu, Salmonella spp, and Staph
Spectrum: Bactrim
G+ aerobes: S. aureus (incl. some MRSA, esp. CA-MRSA), S. pyogenes, and Nocardia
G- aerobes: most Enterobacteriaceae and
Stenotrophomonas maltophilia.
DOC - Pneumocystis carinii/ jiroveci
TMP-SMX is NOT active against pseudomonas or anaerobes
Indications: Bactrim
UTIs
Prostatitis
DOC- Pneumocystis carinii/jiroveci pneumonia
Skin and soft tissue infections due to CA-MRSA
Stenotrophomonas maltophilia infections
Adverse Effects: Bactrim
GI, rash, bone marrow
supprxn, renal
Drug Ixns: Bactrim
Warfarin
MOA: chloramphenicol
Inhibits protein
synthesis by reversibly binding to the larger 50S subunit
Binding to the ribosome prevents attachment of the amino acid-containing end of the aminoacyl-tRNA to its binding region preventing peptide bond formation.
This mechanism produces a static effect against most bacteria except
H flu, Strep. pneumo and Neisseria meningitidis.
Spectrum: chloramphenicol
G+ anaerobes: strep, NOT staph or enteroc
G- anaerobes: most, NOT pseudomonas
Anaerobes Spirochetes Rickettsiae Chlamydiae Mycoplasmas
Absorption: chloramphenicol
Encapsulated form - great bioavailability
IV administration produces active chloramphenicol levels in serum that are 70% of those obtained after oral administration, because the drug is not completely hydrolyzed.
The iv preparation is the soluble but inactive drug that is rapidly hydrolyzed within the body
to become biologically active.
Intramuscular injection produces levels similar to iv administration but
may have delayed absorption from the injection site.
Distribution: chloramphenicol
Due to high degree of lipid solubility, low protein bindingand small molecular size, chorampheicol diffuses well into tissues and body
fluids.
CSF levels are 30-50% of the serum concentration, even w/o meningitis
Elimination: chloramphenicol
i. 90% liver, where it is
conjugated with glucuronic acid forming monoglucoronide.
Due to wide variation in the metabolism and excretion in children, dosage requirements
vary by age with lower daily doses in newborns.
ii. Monoglucoronide is excreted in the bile into the small intestine,
hydrolyzed by bacterial enzymes to aglycone, reabsorbed and conjugated with glucuronic acid again. This enterohepatic circulation results in about 80-90% of the monoglucoronide being excreted by the kidney.
Toxicity: chloramphenicol
Narrow therapeutic window. Monitor newborns and premature infants, patients with
hepatic disease and patients taking interacting drugs. Peak serum levels should
be maintained between 15-25 g/mL and trough levels between 5-15 g/mL in
patients with meningitis, 10-20 g/mL in patients with other infections. Toxicity
occurs in those with levels 40 g/mL.
In renal insufficiency, adjust dose?
No
In hepatic insufficiency, adjust dose?
Yes - decrease dose
Indications: chloramphenicol
Not a first line treatment in the US
Developing countries:
Infant Meningitis w/
pcn allergy Rickettsia in kids and preg
Adverse effects: chloramphenicol
BM supprxn
Gray Baby
Drug ixns: chloramphenicol
A. Phenobarbital reduces serum concentrations of chloramphenicol by 30-40% with
increased concentrations of Phenobarbital by 50%.
B. Cyclosporine concentrations increased by chlorampnenicol increasing the risk for
renal dysfunction, cholestasis, paresthesias.
C. Decreased effectiveness of cyclophosphamide due to decreased metabolism to
active cyclophosphamide.
D. Rifampin/rifabutin decreases chloramphenicol levels
E. Reduces tacrolimus blood concentrations.
MOA: Nitrofurantoin
May require
enzymatic reduction within the bacterial cell wall. The reduced compounds are
capable of binding to ribosomal proteins.
Nitrofurantoin has also been shown to
inhibit synthesis of inducible enzymes by blocking translation and also to inhibit
bacterial respiration and pyruvate metabolism.
Spectrum: Nitrofurantoin
E. coli, Citrobacter sp, GBS, Staph
saprophyticus, Enterococcus (incl. many VRE strains)
Bioavailability: nitrofurantoin
40-50%.
Absorption occurs rapidly in the small intestine and is enhanced with food.
Distribution: nitrofurantoin
Urine concentrations are substantial
Low to undetectable serum concentrations after standard oral doses.
Does not go to prostate
Short half-life
Elimination: nitrofurantoin
Mostly kidneys, involving
filtration, secretion, and reabsorption.
Increase or decrease nitrofurantoin in kidney failure
Increase in renal failure, because we want more drug at the urethra
Counterindications: nitrofurantoin
Renal insufficiency
Elderly
MOA methenamine
Becomes formaldehyde at an acidic pH and denature proteins and DNA
Don’t use with proteus
MOR methenamine
Alkaline urine makes it harder for drug to kill things
Counterindications : methenamine
avoid with gout and liver insufficiency
Spectrum: methenamine
Not really…it makes it harder for things to live
Absorption: methenamine
82-88% recovery in urine
Enteric-coated formulations reduce degradation but also take longer to absorb
Distribution: methenamine
Broad distribution in tissue, incl. breastmilk
Indication: methenamine
Prophylaxis in people with frequent UTIs
Not effective in preventing UTIs in patients with chronic, indwelling urinary catheters
Adverse effects: methenamine
Gi, rash, prutitus, cystitis, neuropathy, anemia
