Miscellaneous Flashcards
What is the mechanism of action of tetracyclines/tetracycline analogs?
inhibit bacterial protein synthesis by reversibly binding to the 30S ribosome, blocking binding of amino-acyl tRNA to the acceptor (A) site on the mRNA-ribosomal complex. This prevents the addition of amino acid residues to the elongating peptide chain and inhibits protein synthesis. Bacteriostatic.
What are the tetracyclines?
tetracycline, doxycycline, minocycline
What are the tetracycline analogs?
tigecycline, eravacycline, omadacycline
What are the sulfonamides?
trimethoprim-sulfamethoxazole
What is the mechanism of action of trimethoprim-sulfamethoxazole?
The sulfonamides were the 1st effective antimicrobial agents to be used systemically in the treatment and prevention of bacterial infections. Produce sequential blockade of microbial folic acid synthesis.
1. Sulfamethoxazole: competitively inhibits the incorporation of p-aminobenzoic acid (PABA) into folic acid by inhibiting dihydropteroate synthetase, which inhibits the formation of dihydrofolic acid.
2. Trimethoprim competitively inhibits the activity of bacterial dihydrofolate reductase to prevent the reduction of dihydrofolate to tetrahydrofolate.
3. Together they produce sequential inhibition of the synthesis of folate, which is necessary for microbial production of DNA, producing a synergistic bactericidal effect against gram-positive and gram-negative aerobic bacteria.
What are the polymyxins?
colistin (polymyxin E), polymyxin B
What is the mechanism of action of polymyxins?
cationic detergents that bind to the anionic lipopolysaccharide molecules of the outer cell membrane of gram-negative bacteria causing displacement of calcium and magnesium, which normally stabilize the cell membrane changes in cell wall permeability, leakage of cellular contents, and subsequent cell death. Concentration dependent bactericidal activity.
What are the lincosamides?
clindamycin
What is the mechanism of action of clindamycin?
Inhibits protein synthesis by exclusively binding (reversibly) to the 50S ribosomal subunit. Primarily bacteriostatic but can display time-dependent bactericidal activity.
What are the nitroimidazoles?
metronidazole
What is the mechanism of action of metronidazole?
One of the most useful agents in the treatment of anaerobic and polymicrobial infections. Prodrug that is activated by a reductive process. Selective toxicity towards anaerobic and microaerophilic bacteria is due to presence of electron transport components such as ferredoxins within these bacteria. Ferredoxins are small Fe-S proteins that donate electrons to metronidazole to form a highly reactive nitro radical anion. These damage bacterial DNA (inhibit nucleic acid synthesis) cell death. Metronidazole is rapidly bactericidal in a concentration dependent manner.
1. Does not treat aerobes because increased levels of oxygen inhibit metronidazole-induced cytotoxicity since oxygen competes with metronidazole for generated electrons.
What are the mechanisms of resistance of tetracyclines/tetracycline analogs?
- Decreased accumulation of tetracycline within the bacteria due to either altered permeability or the presence of tetracycline-specific efflux pumps (overexpression if mutation in repressor gene).
- Decreased access of the tetracycline to the ribosome due to the presence of ribosomal protection proteins.
- Enzymatic inactivation of the tetracycline.
- Cross-resistance except in minocycline.
- Tigecycline, eravacycline, and omadacycline retain activity against many tetracycline resistant bacteria because they are NOT affected by efflux pumps or ribosomal protection.
What are the mechanisms of resistance of trimethoprim-sulfamethoxazole?
- Bacterial resistance mediated by point mutations in dihydropteroate synthase and/or altered production or sensitivity of bacterial dihydrofolate reductase.
What are the mechanisms of resistance of polymyxins?
- Alteration of outer cell membrane: decreased lipopolysaccharide content, reduction in calcium and magnesium content, decreased outer membrane proteins.
- Cross-resistance between polymyxin B and colistin.
What are the mechanisms of resistance of clindamycin?
Alteration of the ribosomal binding site – ribosomal methylation by erm-coded enzymes. Cross resistance with macrolides and streptogramins.
What are the mechanisms of resistance of metronidazole?
- Altered growth requirements: organism grows in higher local oxygen concentrations causing decreased activation of metronidazole.
- Altered levels of ferredoxin: reduced transcription of ferredoxin gene.
Spectrum of activity of tetracyclines
- Gram-positive aerobes: minocycline and doxycycline most active – streptococcus pneumoniae (PSSP), enterococcus spp, staphylococcus aureus (MSSA).
- Gram-negative aerobes: many Enterobacteriaceae are relatively resistant.
- Anaerobes: actinomyces, Propionibacterium spp.
- Miscellaneous organisms: atypical bacteria such as legionella pneumophila, Chlamydophila pneumoniae, and psittaci.
Spectrum of activity of tetracycline analogs
- Gram-positive aerobes: enterococcus faecalis (VSE and VRE), staphylococcus aureus (MSSA and MRSA)
- Gram-negative aerobes: eravacycline has come activity against ESBL, AmpC, and KPC producing bacteria
- Tetracycline analogs are NOT active against proteus mirabilis or pseudomonas aeruginosa!
- Anaerobes: Bacteroides spp.
- Miscellaneous organisms: atypical bacteria (eravacycline and omadacycline).
Spectrum of activity of TMP-SMX
- Gram-positive aerobes: S. aureus (MRSA, CA-MRSA)
- Gram-negative aerobes: Stenotrophomonas maltophilia; NOT active against P. aeruginosa
- Anaerobes: INACTIVE
- Other organisms: pneumocystis carinii/jirovecii (DRUG of CHOICE)
Spectrum of activity of polymyxins
- Gram-positive aerobes: INACTIVE
- Gram-negative aerobes: Acinetobacter spp, pseudomonas aeruginosa (including MDR strains).
- NOT active against Burkholderia spp, Proteus spp, Providencia spp, Serratia spp, and Brucella spp
- Anaerobes: INACTIVE
Spectrum of activity of clindamycin
- Gram-positive aerobes: streptococcus pneumoniae (PSSP) and staphylococcus aureus (MSSA and CA-MRSA).
- Anaerobes: most useful for above the diaphragm – clostridium spp (NOT C. diff), Bacteroides spp
- Atypical bacteria: pneumocystis carinii/jirovecii, toxoplasmosis gondii, plasmodium falciparum and vivax (malaria).
Spectrum of activity of metronidazole
- Antianaerobic agent most reliably active against Bacteroides fragilis.
- Gram-negative aerobes: bacteroides fragilis, Bacteroides distasonic, ovatus, thetaiotamicron, bivius (B fragilis group DOT organisms).
- Gram-positive anaerobes: clostridium spp (including C diff.)
- INACTIVE against all common aerobic bacteria.
PK parameters of tetracyclines
- Doxycycline, minocycline have best oral bioavailability, then tetracycline, demeclocycline, and then omadacycline. Absorption of the oral tetracyclines and omadacycline is impaired by the concurrent ingestion of dairy products, aluminum hydroxide gels, calcium, magnesium, iron, zinc, and bismuth subsalicylate due to chelation with divalent or trivalent cations.
- Only small amounts diffuse into CSF, not useful for meningitis.
- Demeclocycline and tetracycline required dosage adjustment in renal insufficiency. Doxycycline and minocycline mainly metabolized, no need for dosage adjustment. Tetracycline analogs mainly eliminated by biliary/fecal excretion of unchanged drug and its metabolites. None require dosage adjustments in renal insufficiency. Tigecycline and eravacycline need dosage adjustments in severe hepatic impairment.
- Tetracyclines and tetracycline analogs not removed during hemodialysis.
PK parameters of TMP-SMX
- Optimal synergistic ratio of TMP to SMX is 1:20 and is achieved by using a fixed oral or IV combo of 1:5 (TMP: SMX). Well absorbed after oral administration. Concentrates in CSF in presence of inflamed meninges. Also concentrates in urine, uninflamed prostatic tissue.
- Doses should be adjusted in patients with CrCl < 30 ml/min.
PK parameters of polymyxins
- Colistin displays extensive interpatient variability and a narrow therapeutic window – TDM may be needed.
- Not absorbed from GI tract. Poor penetration into CSF.
- Polymyxin B and colistin are primarily eliminated by nonrenal routes and do NOT require dosage adjustment in renal dysfunction. ~50% of CMS is excreted unchanged in urine by glomerular filtration (CMS is a prodrug). CMS requires dosage adjustment in presence of renal insufficiency when the creatinine clearance is <80 ml/min.
PK parameters of clindamycin
- Oral bioavailability approaches 90%. Penetrates bone, does NOT penetrate CSF. Primarily metabolized by the liver to metabolites with varying antimicrobial activity. Enterohepatic circulation of clindamycin and its metabolites can lead to prolonged antimicrobial presence in the stool why it’s a big inducer of C. diff. NOT removed by hemodialysis.
PK parameters of metronidazole
- One of the few drugs you can use ORALLY to treat a CNS infection.
- Almost completely absorbed after oral administration. DOES penetrate the CSF and brain tissue.
- Metabolized by liver, 6-15% excreted in feces.
- Removed during hemodialysis.
Clinical uses of tetracyclines
- Primarily for outpatient CAP (doxycycline) or infections due to unusual organisms.
- Mild-moderate outpatient community-acquired pneumonia (doxycycline). Chlamydial infections and nongonococcal urethritis (doxycycline).
Clinical uses of tetracycline analogs
NOT for proteus spp or pseudomonas spp. Complicated skin/skin structure infections, intraabdominal infections.
Clinical uses for TMP-SMX
- DRUG of CHOICE for acute, chronic or recurrent infections of the urinary tract.
- Acute or chronic bacterial prostatitis.
- Pneumocystis carinii/jirovecii pneumonia (DRUG OF CHOICE)
- Stenotrophomonas maltophilia infections.
Clinical uses of polymyxins
- Infections caused by gram-negative bacteria (including P. aeruginosa and A. baumannii) that are resistant to other available antibiotics.
- Polymyxin B preferred for systemic infections; colistin preferred for UTIs.
Clinical uses of clindamycin
- Infections due to anaerobes OUTSIDE the CNS – pulmonary infections, diabetic foot infections.
- Mild-moderate skin and soft tissue infections due to CA-MRSA.
- Alternative agent for treatment of infections due to gram-positive aerobes in patients allergic to penicillin.
Clinical uses of metronidazole
- Infections due to anaerobes – brain abscesses. Many serious anaerobic infections are polymicrobial and additional antibiotics are necessary for coverage of aerobic bacteria.
- Pseudomembranous colitis due to C. diff. – alternative agent for non-severe C. diff colitis, can use oral or parenteral therapy.
- Trichomonas vaginalis; diarrhea due to giardia.
Major AEs of tetracyclines/tetracycline analogs
- GI: N/V (most with tigecycline) – recommended to sit up for 30 min after ingestion due to esophageal irritation.
- Dermatologic: photosensitivity (most with demeclocycline).
- Pregnancy category D: all tetracyclines and tetracycline analogs are not recommended to be used during pregnancy/lactation and in children <8yrs of age because they cause permanent discoloration of primary dentition (yellow/gray-brown) in children with developing teeth and form a complex in bone-forming tissue, leading to decreased bone growth.
Major AEs of TMP-SMX
- Hematologic: leukopenia; hypersensitivity reactions: rash; Renal insufficiency, crystalluria, hyperkalemia
- Pregnancy category C: should NOT be used in pregnant women or lactating women because it may cause kernicterus in the newborn due to bilirubin displacement from protein binding site.
Major AEs of polymyxins
- Nephrotoxicity and neurotoxicity
Major AEs of clindamycin
- GI: N/V, diarrhea; clostridium difficile colitis (pseudomembranous colitis or antibiotic-associated diarrhea) – clindamycin one of the worst inducers.
- Hepatotoxicity.
Major AEs of metronidazole
- GI – metallic taste.
- CNS: peripheral neuropathy, seizures.
- Mutagenicity and carcinogenicity: may be teratogenic – avoid during 1st trimester and during breastfeeding.
Major drug interactions with tetracylines
Aluminum hydroxide gels, calcium, magnesium, iron, zinc, bismuth subsalicylate –> chelation with divalent/trivalent cations.
Major drug interactions with TMP-SMX
warfarin – potentiated anticoagulant effects.
Major drug interactions with metronidazole
warfarin – increased anticoagulant effect; alcohol – disulfiram reaction.
What is the potential therapeutic advantage of the tetracycline analog antibiotics?
structural modifications impart enhanced activity against many tetracycline-resistant bacteria
