بنام خداوند جان وخرد

Antimicrobial Agents 2 Murray: ch 17 Jawets: ch 28 Dr Alvandi

Resistance to aminoglycosides (1) mutation of the ribosomal binding site (1) mutation of the ribosomal binding site (2) decreased uptake of the antibiotic into the bacterial cell, (2) decreased uptake of the antibiotic into the bacterial cell, (3) increased expulsion of the antibiotic from the cell (3) increased expulsion of the antibiotic from the cell (4) enzymatic modification of the antibiotic. (4) enzymatic modification of the antibiotic. –aminoglycoside phosphotransferase [APHs] seven described), – adenyltransferases (adenine nucleotide translocases [ANTs]; four described) –acetyltransferases (acetyl-CoA carboxylases [AACs]; ]; four described

Tetracyclines

bacteriostatic binding reversibly to the 30S ribosomal subunits, thus blocking the binding of aminoacyl-tRNA to the 30S ribosome–mRNA complex

Resistance to the tetracyclines Decreased penetration Decreased penetration Active efflux Active efflux alteration of the ribosomal target site alteration of the ribosomal target site enzymatic modification of the antibiotic. enzymatic modification of the antibiotic.

Glycylclines Tigecycline has a higher binding affinity for the ribosome and is less affected by efflux or enzymatic modification has a higher binding affinity for the ribosome and is less affected by efflux or enzymatic modification broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria, broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria, although Proteus, Morganella, Providencia, and P. aeruginosa are generally resistant. although Proteus, Morganella, Providencia, and P. aeruginosa are generally resistant.

Oxazolidinones Narrow-spectrum Narrow-spectrum Linezolid Linezolid binds to the 30S ribosomal subunit and blocks initiation of protein synthesis binds to the 30S ribosomal subunit and blocks initiation of protein synthesis activity against all staphylococci, streptococci, and enterococci activity against all staphylococci, streptococci, and enterococci

Chloramphenicol broad antibacterial spectrum broad antibacterial spectrum disrupts protein synthesis in human bone marrow cells and can produce blood dyscrasias, such as aplastic anemia disrupts protein synthesis in human bone marrow cells and can produce blood dyscrasias, such as aplastic anemia binding reversibly to the peptidyl transferase component of the 50S ribosomal subunit, thus blocking peptide elongation. binding reversibly to the peptidyl transferase component of the 50S ribosomal subunit, thus blocking peptide elongation.

Resistance to chloramphenicol plasmid-encoded chloramphenicol acetyl transferase plasmid-encoded chloramphenicol acetyl transferase

Macrolides Reversible binding to the 23S ribosomal RNA (rRNA) of the 50S ribosomal subunit which blocks polypeptide elongation. Reversible binding to the 23S ribosomal RNA (rRNA) of the 50S ribosomal subunit which blocks polypeptide elongation. bacteriostatic antibiotics bacteriostatic antibiotics broad spectrum of activity broad spectrum of activity

Resistance to macrolides methylation of the 23S rRNA methylation of the 23S rRNA inactivation of the macrolides by enzymes (e.g., esterases, phosphorylases, glycosidase) inactivation of the macrolides by enzymes (e.g., esterases, phosphorylases, glycosidase) mutations in the 23S rRNA and ribosomal proteins. mutations in the 23S rRNA and ribosomal proteins.

Ketolides: Telithromycin semisynthetic derivative of erythromycin semisynthetic derivative of erythromycin binds to the 50S ribosomal subunit and blocks protein synthesis binds to the 50S ribosomal subunit and blocks protein synthesis Resistance: Mutations in 23S rRNA or the ribosomal proteins Resistance: Mutations in 23S rRNA or the ribosomal proteins

Telithromycin cont… good activity against staphylococci good activity against staphylococci S. pneumoniae, other respiratory pathogens (e.g., H. influenzae, Moraxella catarrhalis) S. pneumoniae, other respiratory pathogens (e.g., H. influenzae, Moraxella catarrhalis) gram-positive rods, gram-positive rods, some anaerobes except B. fragilis some anaerobes except B. fragilis Good activity against intracellular pathogens (e.g., Legionella, Mycoplasma, Chlamydia, Chlamydiophila ), Rickettsia, Bartonella, Coxiella, Francisella, and M. avium. Good activity against intracellular pathogens (e.g., Legionella, Mycoplasma, Chlamydia, Chlamydiophila ), Rickettsia, Bartonella, Coxiella, Francisella, and M. avium.

lincosamide: Clindamycin blocks protein elongation by binding to the 50S ribosome by inhibiting peptidyl transferase blocks protein elongation by binding to the 50S ribosome by inhibiting peptidyl transferase interfering with the binding of the amino acid–acyl-tRNA complex. interfering with the binding of the amino acid–acyl-tRNA complex. Clindamycin is active against staphylococci and anaerobic gram-negative rods Clindamycin is active against staphylococci and anaerobic gram-negative rods Methylation of the 23S rRNA is the source of bacterial resistance Methylation of the 23S rRNA is the source of bacterial resistance.

cyclic peptides: group A and B Streptogramins quinupristin-dalfopristin quinupristin-dalfopristin Dalfopristin binds to the 50S ribosomal subunit and induces a conformational change that facilitates binding of quinupristin. Dalfopristin binds to the 50S ribosomal subunit and induces a conformational change that facilitates binding of quinupristin. Dalfopristin prevents peptide chain elongation, and quinupristin initiates premature release of peptide chains from the ribosome. Dalfopristin prevents peptide chain elongation, and quinupristin initiates premature release of peptide chains from the ribosome.

INHIBITION OF NUCLEIC ACID SYNTHESIS

Quinolones and Fluoroquinolones: Mechanism of activity inhibit bacterial DNA topoisomerase type II (gyrase) or topoisomerase type IV, which are required for DNA replication, recombination, and repair inhibit bacterial DNA topoisomerase type II (gyrase) or topoisomerase type IV, which are required for DNA replication, recombination, and repair

Resistance Resistance to the quinolones is mediated by chromosomal mutations in the structural genes for DNA gyrase and topoisomerase type IV Resistance to the quinolones is mediated by chromosomal mutations in the structural genes for DNA gyrase and topoisomerase type IV decreased drug uptake decreased drug uptake Overexpression of efflux pumps that actively eliminate the drug Overexpression of efflux pumps that actively eliminate the drug

Fluoroquinolones Adverse Effects Gastrointestinal – 5 % Gastrointestinal – 5 %  Nausea, vomiting, diarrhea, dyspepsia Central Nervous System Central Nervous System  Headache, agitation, insomnia, dizziness, rarely, hallucinations and seizures (elderly) Hepatotoxicity Hepatotoxicity  LFT elevation (led to withdrawal of trovafloxacin) Phototoxicity (uncommon with current FQs) Phototoxicity (uncommon with current FQs)  More common with older FQs (halogen at position 8) Cardiac Cardiac  Variable prolongation in QTc interval  Led to withdrawal of grepafloxacin, sparfloxacin

Fluoroquinolones Adverse Effects Articular Damage Articular Damage  Arthopathy including articular cartilage damage, arthralgias, and joint swelling  Observed in toxicology studies in immature dogs  Led to contraindication in pediatric patients and pregnant or breastfeeding women  Risk versus benefit Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity

Rifampin and Rifabutin binds to DNA dependent RNA polymerase and inhibits the initiation of RNA synthesis. binds to DNA dependent RNA polymerase and inhibits the initiation of RNA synthesis. Rifampin is bactericidal for Mycobacterium tuberculosis Rifampin is bactericidal for Mycobacterium tuberculosis mutation in the beta subunit of RNA pol mutation in the beta subunit of RNA pol Rifabutin: particularly active against M. avium Rifabutin: particularly active against M. avium

Metronidazole effective in the treatment of amebiasis, giardiasis, and serious anaerobic bacterial infections (including those caused by B. fragilis). effective in the treatment of amebiasis, giardiasis, and serious anaerobic bacterial infections (including those caused by B. fragilis).

Metronidazole: Mechanisms of activity The antimicrobial properties of metronidazole stem from the reduction of its nitro group by bacterial nitroreductase, thereby producing cytotoxic compounds that disrupt the host DNA. The antimicrobial properties of metronidazole stem from the reduction of its nitro group by bacterial nitroreductase, thereby producing cytotoxic compounds that disrupt the host DNA.

Metronidazole: Resistance Resistance results either from decreased uptake of the antibiotic Resistance results either from decreased uptake of the antibiotic elimination of the cytotoxic compounds before they can interact with bacterial DNA. elimination of the cytotoxic compounds before they can interact with bacterial DNA.

Clofazimine Clofazimine: lipophilic antibiotic that binds to mycobacterial DNA. It is highly active against M. tuberculosis, Clofazimine: lipophilic antibiotic that binds to mycobacterial DNA. It is highly active against M. tuberculosis, first-line drug for the treatment of Mycobacterium leprae first-line drug for the treatment of Mycobacterium leprae

Pyrazinamide (PZA) Pyrazinamide (PZA) is active against M. tuberculosis at a low pH, such as that found in phagolysosomes Pyrazinamide (PZA) is active against M. tuberculosis at a low pH, such as that found in phagolysosomes The mechanism by which PZA exerts its effect is unknown.