Tetracyclines + Sulfa + Misc - SOA Flashcards
List the tetracyclines:
- tetracycline
- doxycycline
- minocycline
List the tetracycline analogs:
- tigecycline
- eravacycline
- omadacycline
What is the mechanism of action of the tetracyclines and tetracycline analogs?
- tetracycline, doxycycline, minocycline
- tigecycline, eravacycline, omadacycline
The tetracyclines inhibit protein synthesis by binding to 30S ribosomal subunits.
Blocks the binding of amino-acyl tRNA to the A site on the mRNA-ribosomal complex
What kind of activity do the tetracyclines and analogs display?
- bacteriostatic
- time-dependent
What are the mechanisms of resistance against tetracyclines?
tetracycline, doxycycline, minocycline
- tetracycline efflux pumps that decrease accumulation within the bacteria
- ribosomal protection proteins that prevent the drug from getting to the ribosome
- enzymatic inactivation of the tetracycline
The first two are most common and more important
Why do the tetracycline analogs retain activity against many tetracycline-resistant bacteria?
tigecycline, eravacyline, omadacycline
They are not affected by the two main tetracycline resistance mechanisms.
efflux and ribosomal protection
What is the general SOA of the tetracyclines?
tetracycline, doxycycline, minocycline
- some GP
- some GN
- some anaerobes
- some atypicals
Emergence of resistance and better abx have limited their usefulness.
What target organisms do the tetracyclines cover?
tetracycline, doxycycline, minocycline
- MSSA
- MRSA
- Legionella
One of the three classes that covers legionella
What is the general SOA of the tetracycline analogs?
tigecycline, eravacycline, omadacycline
- broad range of GP, GN
- aerobes and anaerobes
- some atypicals
What target organisms do the tetracycline analogs cover?
- MSSA
- MRSA
- BDA
Do not cover P. mirabilis nor p. aeruginosa
What impairs absorption of PO tetracyclines and analogs?
tertra, doxy, mino, omada
- Absorption of the oral tetracyclines and omadacycline is impaired by the concurrent ingestion of dairy, aluminum hydroxide gels, calcium, magnesium, iron, zinc, and bismuth subsalicylate due to the chelation with divalent or trivalent cations.
How are tetracyclines and analogs distributed?
- widely distributed
- gets into prostatic fluids
- do not get into CSF
How is tetracycline eliminated?
dose adjustment?
- excreted unchanged in the urine via glomerular filtration
- requires dosage adjustment in renal dysfunction
How are doxycycline and minocycline eliminated?
dose adjustment?
- excreted by nonrenal routes
- do not require dosage adjustment in renal dysfunction
How are the tetracycline analogs eliminated?
dose adjustment?
- The analogs are eliminated by biliary/fecal excretion and some unchanged drug gets excreted in the urine
- None of the analogs require dose adjustments in renal dysfunction nor patients receiving HD
- Tigecycline and eravacycline require dose adjustments in patients with severe hepatic impairment
What are the clinical uses for the tetracyclines?
mainly doxy
- outpatient community acquired pneumonia
- chlamydia
What are the adverse effects of the tetracyclines and analogs?
- GI
- dermatologic - photosensitivity
- teeth discoloration in developing teeth, decreased bone growth
Why are the tetracyclines and analogs contraindicated in pregnancy, lactating, and young children (<8 years)?
- They cause permanent discoloration of teeth
- They form a complex in bone-forming tissue leading to decreased bone growth
- What is the mechanism of action of sulfamethoxazole?
- What is the mechanism of action of trimethorpim?
- sulfamethoxazole competitively inhibits PABA by inhibiting dihydropteroate synthetase
- trimethoprim competitively inhibits the activity of bacterial dihydrofolate reductase
They both produce sequential blockade of microbial folic acid synthesis which then inhibits DNA production.
What kind of activity does TMP-SMX display?
- time-dependent
- bactericidal
What is the resistance mechanism to SMX-TMP?
- Mutation in dihydropteroate synthase or dihydrofolate reductase
What is the general SOA of TMP-SMX?
- some GP aerobes
- great activity for GN aerobes
- no anaerobes
- pneumocystis carinii/jirovecii
What target organisms does TMP-SMX cover?
- MSSA
- MRSA
TMP-SMX is NOT active against pseudomonas aeruginosa
What is TMP-SMX the drug of choice for?
pneumocystis carinii/jirovecii
What ratio of TMP-SMX is needed to achieve the optimal synergistic ratio of serum concentrations?
serum concentration ratio should be 1:20
A fixed oral or IV combination of 1:5 is needed.
Describe the pharmacokinetics of TMP-SMX:
absorption, distribution, elimination
- TMP-SMX is rapidly and well absorbed after oral administration
- It concentrates in most tissues including CSF, urine, and uninflamed prostatic tissue.
- SMX is 70% protein bound
- excreted in the urine
- Requires dose adjustment in patients with CrCl< 30 mL/min
What are the clinical uses for TMP-SMX?
- UTI
- bacterial prostatitis
- pneumocystis carinii pneumonia (prophylaxis and treatment)
What are the adverse effects from TMP-SMX?
- leukopenia, thrombocytopenia
- hypersensitivity, rash
- renal insufficiency
- crystalluria
What drug interactions can TMP-SMX cause?
TMP-SMX can potentiate the anticoagulant effects of warfarin.
Why can’t TMP-SMX be used in pregnant or lactating women?
It may cause kernicterus (jaundice) in the newborn due to bilirubin displacement from protein binding sites
List the polymyxins:
- polymyxin B
- colistin
What is the mechanism of action of the polymyxins?
polymyxin B, colisitin
They are cationic detergents that bind to the anionic phospholipids in the cell membrane which causes displacement of Ca and Mg. This displacement leads to changes in cell wall permeability and leakage of cellular contents –> which leads to cell death.
What kind of activity do the polymyxins display?
- concentration dependent
- bactericidal
What is the mechanism of resistance against the polymyxins?
Alteration in outer cell membrane
- decrease in calcium or magnesium
- decrease in lipopolysaccharide content
- decrease in membrane proteins
What is the general SOA of the polymyxins?
- ONLY active against GN aerobes
- NOTHING ELSE
What target organisms do the polymyxins cover?
Pseudomonas aeruginosa
Describe the absorption and elimination for the polymyxins:
- polymyxins are not absorbed from the GI tract
- small distribution
- polymyxin B and colistin are eliminated by nonrenal routes
- they do not require dosage adjustments in renal dysfunction
- CMS (colistin methanesulfate prodrug) is excreted in the urine and DOES require dose adjustment for CrCl< 80 mL/min
What are the clinical uses for the polymyxins?
- polymyxin B is good for GN systemic infections
- colistin is preferred for UTIs
What are the adverse effects of the polymyxins?
- nephrotoxicity - tubular necrosis
- neurotoxicity - paresthesia
What is the mechanism of action of clindamycin?
Clindamycin inhibits protein synthesis by binding to 50S ribosomal subunits
What is the mechanism of resistance against clindamycin?
Alteration in ribosomal binding site – coded by erm
What kind of activity does clindamycin display?
- time-dependent
- bacteriostatic
What is the general SOA of clindamycin?
- some GP
- NO GN
- anaerobes
- BDA
What target organisms does clindamycin cover?
- MSSA
- CA-MRSA
- BDA
What does clindamycin induce?
C. diff
Describe the pharmacokinetics of clindamycin?
- rapidly and well absorbed after oral administration
- penetrates most body tissues (including bone)
- does NOT penetrate CSF
- metabolized by the liver
- enterohepatic circulation prolongs presence in the stool
- half-life is prolonged in liver dysfunction
What are the clinical uses for clindamycin?
- diabetic foot infections
- anaerobic infections outside of CNS
- alternative agent for GP infections for patients allergic to penicillins
What are the adverse effects of clindamycin?
- GI
- C. diff colitis
- hepatotoxicity
What is the mechanism of action of metronidazole?
Metronidazole is a prodrug activated by ferredoxins whose activated metabolites damage bacterial DNA
What are the mechanisms of resistance to metronidazole?
- altered growth requirements
- reduced transcription of ferredoxin gene
If the organism grows in higher oxygen concentrations, metronidazole is less likely to be activated
What kind of activity does metronidazole display?
- concentration-dependent
- rapidly bactericidal
What is the general SOA of metronidazole?
Which target organisms does it cover?
- NO AEROBES
- ADA
- BDA
- C. diff
Describe the pharmacokinetics of metronidazole:
- rapidly and completely absorbed after oral administration
- well distributed
- penetrates into the CSF and brain tissue
- metabolized by liver to active metabolites
- excreted in the urine and feces
- dosage adjustments are no longer required
- removed during hemodialysis
What is metronidazole used for clinically?
Pseudomembranous colitis due to C. Diff
What are the adverse effects of metronidazole?
- GI
- metallic taste
- CNS - peripheral neuropathy
- may be teratogenic
Avoid during first trimester and breastfeeding
What are the drug interactions with metronidazole?
- increased activity of warfarin
- alcohol –> disulfram reaction
