Lecture 13 - Bactericidal Inhibitors of Protein & Folic Acid Synthesis

‭ actericidal Inhibitors of Protein Synthesis‬ B ‭Aminoglycosides‬ ‭Prototype(s)‬ ‭‬ G ● ‭ entami‬‭cin‬ ‭●‬ ‭Tobramy‬‭cin‬‭, streptomy‬‭cin‬‭, amika‬‭cin‬ ‭MOA‬ ‭●‬ ‭Inhibit translation of the mRNA by binding to the 30s subunit of the ribosome, causing:‬ ‭○‬ ‭Inhibition of protein synthesis‬ ‭○‬ ‭Premature termination of protein synthesis‬ ‭○‬ ‭Production of abnormal proteins = abnormal cell membrane‬ ‭●‬ ‭Bactericidal:‬‭“Cell kill” is‬‭concentration-dependent‬ ‭●‬ ‭Post-antibiotic effect:‬‭Bactericidal activity continues‬‭after serum level has dropped‬ ‭Gentamicin‬ ‭Bacterial Resistance‬ ‭●‬ ‭Produces enzymes that can inactivate‬ ‭Indications‬ ‭●‬ ‭Narrow spectrum‬ ‭●‬ ‭Some gram-positive‬ ‭●‬ ‭Primarily used in a narrow capacity against‬‭aerobic‬‭gram-negative‬‭bacilli‬ ‭○‬ ‭E. coli‬ ‭○‬ ‭K. pneumoniae‬ ‭○‬ ‭P. aeruginosa‬ ‭●‬ ‭Ex. Severe soft tissue infections, septicemia, peritonitis, endocarditis, neonatal sepsis‬ ‭Pharmacokinetics/Dynamics‬ ‭●‬ ‭Effect is concentration-dependent‬ ‭●‬ ‭Post-antibiotic effect‬ ‭●‬ ‭Poor absorption‬ ‭●‬ ‭High affinity for renal tissue and inner ear‬ ‭●‬ ‭Pregnancy: Can cross placenta‬ ‭●‬ ‭Not metabolized; rapid renal excretion‬‭(2-3 hours)‬ ‭●‬ ‭High patient variability‬ ‭ dverse Effects‬ A ‭Ototoxicity‬ ‭●‬ ‭Largely irreversible‬ ‭‬ H ● ‭ earing impairment‬ ‭●‬ ‭Disruption of balance‬ ‭●‬ ‭S/S: Tinnitus, persistent headache‬ ‭Nephrotoxicity‬ ‭●‬ ‭Reversible‬ ‭●‬ ‭S/S due to tubular necrosis:‬ ‭○‬ ‭Proteinuria‬ ‭○‬ ‭Casts in urine‬ ‭○‬ ‭Increased serum BUN/Cr levels‬ ‭Considerations for Administration‬ ‭●‬ ‭Who is high risk‬ ‭●‬ ‭Monitor:‬ ‭○‬ ‭Serum levels to reduce the risk of toxicity‬ ‭○‬ ‭Renal function‬ ‭●‬ ‭Assess: For S/S of toxicity‬ ‭●‬ ‭Educate patient about S/S‬ ‭Managing Concentration‬ ‭Monitoring Drug Levels‬ ‭Aminoglycosides‬ ‭●‬ ‭Peak levels must be sufficiently high‬ ‭●‬ ‭Trough levels must be sufficiently low‬ ‭●‬ ‭Once daily dosing measure trough levels only‬ ‭●‬ ‭Divided doses measure peak and trough levels‬ ‭Peak‬ ‭●‬ ‭30 minutes after administration (IM/IV)‬ ‭Trough‬ ‭●‬ ‭Divided dose: Measure right before next dose‬ ‭●‬ ‭Once daily: Measure 1 hour before next dose‬ ‭Beneficial Drug-Drug Interactions‬ ‭Beta-Lactam Drugs/Drugs that Weaken the Cell Wall‬ ‭●‬ ‭Synergistic effect‬ ‭●‬ ‭Facilitate aminoglycoside entry into the cell‬ ‭Adverse Drug-Drug Interactions‬ ‭Vancomycin & Cephalosporins‬ ‭●‬ ‭Increased risk for‬‭nephrotoxicity‬ ‭Loop Diuretics‬ ‭●‬ ‭Increased risk for‬‭ototoxicity‬ ‭ acteriostatic Inhibitors of Folic Acid Synthesis:‬ B ‭Sulfonamides & Trimethoprim‬ ‭Prototype‬ ‭●‬ ‭Trimethoprim/sulfamethoxazole (TMP/SMZ) combination drug‬ ‭MOA‬ ‭‬ B ● ‭ acteriostatic, broad-spectrum antibiotics‬ ‭●‬ ‭Both groups have similar MOAs that suppress bacterial growth by inhibiting the‬ ‭synthesis of folic acid‬ ‭●‬ ‭Inhibits sequential steps in bacterial folic acid synthesis to disrupt synthesis of DNA,‬ ‭RNA, and proteins‬ ‭Bactrim‬ ‭MOA‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ wo drugs suppress synthesis of folate derivate at different site of action‬ T ‭Trimethoprim can be bactericidal or bacteriostatic‬ ‭Potentiate‬‭each other’s effects; more powerful than‬‭either as monotherapy‬ ‭Selective toxicity; mammals consume folic acid‬ ‭Broad spectrum individually and in combination; gram-negative and gram-positive‬ ‭UTI, otitis media, bronchitis‬ ‭Adverse Effects‬ ‭SMZ Related‬ ‭●‬ ‭Most common:‬‭GI upset‬ ‭●‬ ‭Hypersensitivity reactions‬ ‭○‬ ‭Primarily mild:‬‭Rash, drug fever, photosensitivity‬ ‭○‬ ‭Severe:‬‭Stevens-Johnson Syndrome‬ ‭●‬ ‭Hemolytic anemia‬‭r/t G6PD deficiency‬ ‭○‬ ‭Fever, pallor, jaundice‬ ‭●‬ ‭Kernicterus‬‭in neonates‬ ‭TMP Related‬ ‭●‬ ‭Itching/rash‬ ‭●‬ ‭Hyperkalemia‬‭:‬‭TMP suppresses renal secretion of potassium‬ ‭●‬ ‭Birth defects‬‭in the‬‭first trimester‬