Protein / Nucleic Acid Synthesis Inhibitors Flashcards
1
Q
Prokaryote ribosomes vs Eukaryote ribosomes
A
- Prokaryote ribosomes are 70s (30s and 50s subunits)
* Eukaryote ribosomes are 80s (40s and 60s subunits)
2
Q
General AB mechanisms:
70s initiation blocker
30s blockers
50s blockers
A
- 70s initiation blocker: oxazolidinones (linezolid)
- 30s blockers (elongation phase): aminoglycosides and tetracylins
- 50s blockers (elongation phase): macrolides, clindamycin
3
Q
Aminoglycosides 2 drugs and general uses Mechanism Spectrum 3 mechanisms of resistance Adverse rxns Uses
A
- Gentamicin – most active against Gram Positive Cocci
- Tobramycin – DOC for Pseudomonas and GNRs
- Mechanism – requires active transport into cells (requires O2). Binds irreversibly to 30s interfering w/ elongation at acceptor site. Bactericidal. Concentration-dependent killing (8x MIC is best, large once-daily dosing). Prolonged post-AB effects.
- Spectrum – Aerobic GNRs, especially Enterobacteriaceae (E coli, Klebsiella, Enterobacter, Serratia, Proteus). Also Pseudomonas. No anaerobes due to O2-dependent active transport. Not good for abscesses.
- Beta-lactam + aminoglycoside combo may be used for strep or enterococci.
- Resistance
- Inactivating enzymes – most common mechanism. Mediated by transposons / plasmids.
- Enhanced efflux – common in GNR’s, especially Pseudomonas
- Chromosomal mutation altering ribosomal binding site – rare
- Adverse effects – nephrotoxicity and ototoxicity
- Nephrotoxicity due to accumulation in renal cortex. Damage is reversible due to regeneration. Drugs enter via pinocytosis from urine side. Drug binds MEGALIN, which is a SATURABLE lipopeptide. This is why large single doses are best.
- Ototoxicity due to damage of hair cells. Hearing and balance. NOT reversible. Also reduced by single large dose.
- Uses
- Gentamicin is DOC for plague and tularemia
- Complicated UTI’s due to GNR’s
- Combine w/ beta-lactams for serious Pseudomonas / GNR infections and serious strep / enterococcal infections, such as endocarditis
- Surgical prophylaxis (oral bowel prep)
- 2nd line drugs for mycobacteria (always in combination)
4
Q
Tetracyclines Specific drug Mechanism Spectrum Not good for which 3? Resistance mechanisms Adverse effects Uses
A
- Doxycycline – semisynthetic.
- Mechanism – bind reversibly to 30s interfering w/ elongation at acceptor site. Bacteriostatic (exception: cidal for pneumococci). Time-dependent killing. Prolonged persistent effects
- Spectrum (broad) – Gram Pos (including MRSA, MSSA, and VRE), Gram Neg, mycoplasma, Chlamydia, rickettsia, spirochetes, malaria. Not good for strep, enterococci, or Pseudomonas.
- Resistance - Plasmids: Efflux pumps and ribosomal protection proteins
- Resistance to 1 tetracycline usually indicates resistance to all
- Adverse effects (relatively safe)
- Discoloration of teeth / bones. Avoid during pregnancy and kids less than 8 years old.
- GI – NVD
- Superinfection – Oral / vaginal candidiasis
- Photosensitivity to sunlight (risk of sun burn)
- Uses
- Alternative for CAP. Good for typical and atypical, especially mycoplasma and Chlamydia.
- SSTI’s – good for MRSA and MSSA. Not strep (so not classic cellulitis)
- STI’s – urethritis (Chlamydia), gonorrhea, syphilis, PID
- Borrelia infections (Lyme disease)
- Ehrlichia / Anaplsasma infections
- Rickettsia (Rocky Mountain Spotted Fever)
- Malaria tx and prophylaxis (Plasmodium falciparum)
- Anthrax tx and prophylaxis
5
Q
Macrolides 2 specific drugs Mechanism Why are high intracellular levels good? Spectrum (4) 4 methods of resistance Adverse rxns Uses (5)
A
- Erythromycin – natural, produced by Streptomyces.
- Azithromycin – semisynthetic. Most commonly used.
- Mechanism – Reversible binding to 23s (subunit of 50s). Interferes w/ tRNA attachment and peptide elongation. Bacteriostatic. Time-dependent killing.
- High intracellular levels. High concentrations in epithelial lining in lung is good for pneumonia.
- Spectrum – Gram Pos (mainly strep and pneumo, not staph), atypical pneumonia (Legionella, Mycoplasma, Chlamydia), and Helicobacter pylori.
- Resistance
- Target site alteration – methylation of 23s by enzymes encoded by erm genes (erythromycin ribosome methylation). Erm genes cause resistance in MLSb phenotype (macrolides, lincosamides, and strepogramin B). Most common in Europe.
- Efflux pumps – common in pneumo and strep. Encoded by mef (macrolide efflux) on transposons. Most common in North America.
- 50s mutation
- Drug inactivation – phosphotransferase and esterase enzymes
- Adverse effects
- GI intolerance – cramping, ND (less w/ azithromycin)
- Hepatitis in pregnant women
- Ototoxicity (reversible)
- Uses
- Respiratory infections – sinusitis, otitis media, pneumonia, bronchitis, pertussis, DOC for outpatient CAP including atypicals (in combo w/ beta lactam)
- Strep infections (pharyngitis and cellulitis) in pxs w/ penicillin allergy
- Atypical mycobacteria, such as mycobacterium avian complex (MAC)
- H pylori – used in combo w/ PPI
- Azithromycin good to reduce biofilms in CF pxs infected w/ Pseudomonas. Doesn’t actually kill Pseudomonas, but reduces biofilms.
- Azithromycin also good for Chlamydia and gonorrhea (2nd line)
6
Q
What does erm stand for?
What do erm genes do?
What does MLSb stand for?
Where does resistance occur?
A
erm genes (erythromycin ribosome methylation) Methylation of 23s --> resistance in MLSb phenotype (macrolides, lincosamides, and strepogramin B). Most common in Europe.
7
Q
What do mef genes do?
Where are they found?
A
mef (macrolide efflux) on transposons encode for efflux pumps in pneumo and strep.
Most common in North America.
8
Q
Clindamycin Family of antibiotics Mechanism Spectrum 3 mechanisms of resistance Adverse rxns Uses
A
- Lincosamine AB
- Mechanism – same as macrolides. Reversible binding to 23s. Interferes w/ tRNA attachment and peptide elongation. Bacteriostatic.
- Spectrum – Staph / Strep (cellulitis, abscess), Anaerobes including B fragilis (above the diaphragm), Toxoplasma, and Pneumocystic jirovecii
- Resistance (similar to macrolides). Resistance is inducible (must test for resistance in the presence of the drug)
- Target alteration (erm, MLSb)
- 50s mutation
- Drug inactivation via adenylation
- NOT efflux (no mef genes)
- Adverse effects – Rash, fever, diarrhea, Pseudomembranous colitis (C diff produces an enterotoxin and cytotoxin). Not used as much any more due to C diff.
- Uses
- Anaerobic infections above the diaphragm (ex: lung / oral abscess)
- Strep infections – used in combo w/ penicillin to decrease toxin production (used in toxic shock syndrome)
- Alternative for strep pharyngitis in pxs allergic to penicillin
- Staph infections – much better than macrolides. Good for MRSA.
- Alternative for toxoplasmosis and pneumocystis
- SSTI’s – strep and staph
9
Q
Linezolid Class Mechanism Distribution Spectrum Resistance mechanism Adverse Rxns (3) Uses (4)
A
- Oxazolidinone AB
- Mechanism – binds 50s to inhibit formation of 70s initiation complex. Bacteriorstatic, but does kill slowly. Binds upstream to most other AB’s.
- Lipid soluble – Excellent CSF penetration. Good oral bioavailability
- Spectrum – Gram Pos: staph including MRSA, strep, pneumo, enterococci including VRE
- Resistance – due to mutations near ribosome binding site.
- Adverse Rxns
- Thrombocytopenia / anemia (bone marrow suppression but rarely neutropenia)
- Peripheral neuropathy
- Monoamine oxidase inhibition – may cause serotonin syndrome in pxs taking SSRI’s
- Uses
- SSTI’s – strep and Staph including MRSA
- CNS infections including MRSA, MRSE, and VRE
- Pneumonia, especially MRSA VAP
- Select Nocardia and mycobacterial infections
10
Q
Nitrofurantoin Mechanism Spectrum Advers Rxns Use
A
- Mechanism – nitrofuran reductase → metabolites that inhibit protein synthesis. Only gets adequate concentrations in urine → good for UTI’s
- Spectrum – E coli, enterococci, group B strep
- Adverse rxns
- GI (common)
- Acute toxicity – reversible pulmonary hypersensitivity manifested by infiltrates, fever, cough, eosinophilia
- Chronic toxicity – interstitial lung disease (not reversible), peripheral neuropathy, hepatotoxicity
- Use – tx and prophylaxis of UTI’s. Doesn’t work if GFR is less than 50%. Does not work for upper kidney infections (pyelonephritis)
11
Q
Quinolones Mechanism 2 drugs w/ elimination route and spectrum Absorption problem Resistance mechanisms (4) Adverse Rxns (4) Uses (7)
A
- Mechanism – inhibits DNA gyrase (topoisomerase II) and topoisomerase IV. Bactericidal. Concentration-dependent killing.
- Ciprofloxacin – eliminated by urine. Used for UTI’s. Spectrum:
- Aerobic GNR’s. Only oral drug against Pseudomonas.
- Moxifloxacin – eliminated by liver (not good for UTI’s). Spectrum:
- Gram positive cocci (staph, strep, pneumo, NOT MRSA)
- Atypicals (mycoplasma, chlamydia, and legionella)
- Good for CAP (typical and atypicals)
- Mycobacteria
- Do not take w/ divalent cations such as TUMS. Ca chelates the drugs making them less effective.
- Resistance
- DNA gyrase / topoisomerase IV mutation
- Decreased permeability due to altered porins
- Efflux pumps – seen in staph, pneumo, Pseudomonas, and GNRs
- Plasmids (qnr gene)
- Adverse rxns
- GI – anorexia, nausea, vomiting, abdominal pain, C diff
- Cartilage damage due to low Mg – Achilles tendon rupture. Block box warning. Not approved in kids.
- CNS – dizziness, insominia, mood alteration, hallucinations (elderly)
- Phototoxicity (cipro)
- Peripheral neuropathy
- Uses
- Serious gram-negative infections including Pseudomonas (intraabdominal, respiratory, SSTI’s, burns, osteomyelitis)
- Enteric infections (Salmonella, Shigella, E. coli, Campylobacter)
- Respiratory infections – pneumonia (CAP and HAP; drug of choice for Legionella), acute exacerbations of chronic bronchitis, sinusitis
- Mycobacteria
- UTI’s, primarily pyelonephritis. Moxifloxacin NOT effective for lower UTI’s b/c it does not enter the urine.
- Prostatitis
- Anthrax tx and prophylaxis
12
Q
Rifampin Class Mechanism Spectrum Resistance Adverse Rxns Use
A
Rifamycin AB
•Mechanism – inhibits DNA-dependent RNA polymerase by binding to beta subunit. Bactericidal.
•Spectrum (broad) – mainly staph (MRSA / MSSA) and mycobacteria (TB)
•Resistance – mutation of beta subunit. MUST be used in combo w/ other drugs.
•Adverse Rxns
• GI (most common) – abdominal pain, cramping, NVD
• Hepatitis during 1st month
• Stimulate P450’s → clearance of other drugs, especially Coumadin, warfarin, and oral contraceptives (risk of pregnancy).
• Orange urine
• Flu-like illness (aches, pains, myalgias)
•Uses
• Mycobacterial infections (TB and MAC)
• Staph – used in combo w/ beta lactams or vancomycin for osteomyelitis, abscess, or endocarditis
• Biofilms, especially prosthetics
13
Q
Metronidazole Mechanism Distribution Spectrum Resistance Adverse Rxns Use
A
- Mechanism – Prodrug converted to active metabolite by reduction of nitro group in bacteria / protozoa, which binds / damages DNA
- Very lipid soluble – good for CNS / CSF
- Spectrum – Anaerobes (B fragilis and C diff), H pylori, and protozoans
- Resistance – organisms that lack nitro reductase
- Adverse Rxns – unpleasant taste, nausea / vomiting if take w/ alcohol (MUST EXPLAIN THIS), peripheral neuropathy
- Uses
- Anaerobes below the diaphragm including bacterial vaginosis
- C diff diarrhea or pseudomembranous colitis (mild / moderate)
- Protozoan infections
14
Q
Sulfamethoxazole Class Mechanism Spectrum Resistance Adverse Rxns Uses
A
- Sulfonamide AB
- Mechanism - Blocks dihydropteroate synthetase.
- Broad spectrum – Gram Pos and Neg. Good against nocardia, toxoplasma, and Pneumocystis jirovecii
- Resistance
- Mutation in dihydropteroate synthetase
- Microbial overproduction of PABA
- Decreased cell permeability
- Adverse effects – rash (erythema nodosum / multiforme) / hypersensitivity (vasculitis, anaphylaxis), crystals in urine
- Uses
- UTI’s
- Nocardia infections
- Toxoplasmosis
- Pneumocystitis pneumonia
- Burns
15
Q
Trimethoprim Class Mechanism Spectrum (4) Resistance Adverse Rxns Uses (7)
A
- Diaminopyridamine AB).
- Mechanism - Blocks dihydrofolate reductase.
- Spectrum – GNR’s (E coli, Klebsiella, NOT Pseudomonas), staph, pneumo, Pneumocystic jirovecii.
- Resistance
- Mutations in plasmid-mediated dihydrofolate reductases that reduce binding
- Microbial overproduction of dihydrofolate reductase
- Decreased permeability
- Adverse rxns (well tolerated overall)
- Uses (almost always paired w/ sulfamethoxazole
- UTI’s
- Respiratory – bronchitis, sinusitis, acute otitis media
- Pneumocystis pneumonia tx and prophylaxis
- Typhoid fever / enteric infections
- SSTI’s – staph / MRSA → boils / abscesses
- Nocardia
- Toxoplasma
