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Unformatted text preview: Aminoglycosides Aminoglycosides and Vancomycin Streptomycin isolated from soil actinomycete in 1944 "mycins" derived directly or mycins" indirectly from Streptomyces spp. spp. "micins" " derived directly or micins indirectly from Micromonospora spp. spp. Aminoglycosides currently available agents in Canada: streptomycin (1944) gentamicin (1963) tobramycin (1968) amikacin (1972) netilmicin (1975) kanamycin (?) Aminoglycosides - Mechanism of Action Multifactorial process (bactericidal): i) passive binding to outer membrane displace Mg2+ and Ca2+ in cell wall - disruption of cell wall's permeability irreversible trapping of aminoglycoside in the cytoplasm of the bacteria ii) energy - dependent uptake iii) irreversible binding to 30s ribosomal subunit protein synthesis misreading of mRNA Aminoglycosides - Mechanism of Action
They have 3 facets of antibacterial activity:
1) Concentration- dependent killing (active at high concentrations) 2) Post a - ntibiotic effect (PAE) (activity persists after drug peak) 3) Synergism with other drugs (e.g. cell wall synthesis inhibitors) Aminoglycosides - In Vitro Antimicrobial Activity
Sensitive Enterobacteriaceae Pseudomonas aeruginosa N. gonorrhoeae (Spect.) Y. pestis (Strept.) M. tuberculosis (Strept., Amik.) H. influenzae Resistant Stenotrophomonas maltophilia Burkholderia cepacia Anaerobes Mycoplasma Pneumococcus MRSA Aminoglycosides Combination Therapy Staphylococci (Methicillin Susceptible S. aureus) aureus) Streptococci Enterococci Listeria Mycobacteria Aminoglycosides - Mechanism of Resistance 3 mechanisms: i) alteration of uptake (cross resistance) ii) synthesis of modifying enzymes (most common) acetylase adenylase phosphorylase iii) change in robosomal binding site (rare) Combined resistance mechanisms have not yet been reported in clinical isolates Epidemiology of Aminoglycoside Resistance Resistance of gram negative bacteria varies with: specific drug target organism nature of patient population and underlying disease local / regional pattern of physicians use Resistance rarely emerges during the course of aminoglycoside therapy Frequency correlates with drug usage (more- > more) Toxicity of Aminoglycosides
Adverse Reaction Nephrotoxicity Ototoxicity Cochlear Vestibular Neuromuscular blockade 0 - 62 0 - 19 Rare Estimated Frequency (%) 0 - 50 Toxicity of Aminoglycosides
1) Nephrotoxicity: Nephrotoxicity: No difference in clinical significance among Genta, Tobra, Amik Genta, Tobra, Decreased risk with younger patients, once daily dosing, normal liver function, lack of other toxic drugs, good hydration Occurs only after several days of therapy Spontaneous recovery within a few daysprogression to anuric renal failure is uncommon Serum levels are not risk factors- area under the time c - oncentration curve is a risk factor Toxicity of Aminoglycosides
2) Ototoxicity: Ototoxicity: usually irreversible, can appear after the end of treatment and repeated exposures increase risk risk factors similar to those for nephrotoxicity - cumulative dose and duration of therapy are more important than serum concentrations Aminoglycosides - Pharmacokinetics Intravenous or intramuscular injections Poor CSF penetration Excretion - 99% excreted unchanged by the kidney T1/2= 1.5 to 3.5 hours; similar for all Dosing - Multiple daily dosing vs once daily - Measurement of peak & trough levels is wise Once Daily Aminoglycoside Therapy
Rationale (explored since 1974): 1) Toxicity (renal and ear) less severe during once daily vs 2 or 3 divided doses 2) Concentration - dependent killing higher drug concentrations lead to faster bactericidal activity Once Daily Aminoglycoside Therapy Once Daily Aminoglycoside Therapy
3) Post-antibiotic effect (PAE) - continues Postfor up to 3 hours after exposure; higher concentrations lead to longer PAE Lack of adaptive resistance Efficacy - 12 studies (approx. 400 patients) Potential cost savings Patient Exclusions: Pediatrics (<18 yrs old) Pregnancy Burns Ascites Dialysis Febrile Neutropenia Renal Failure (CrCl <20 ml/min.) (CrCl 4) 5) 6) Aminoglycosides - Future Use
Continued use of aminoglycosides likely: 'd frequency of resistance of gramgramnegative bacilli to -lactams and quinolones emergence of resistance during therapy with extended spectrum cephalosporins combination therapy for multidrug resistant M. tuberculosis Vancomycin
Introduction: Introduction: glycopeptide introduced in 1956 obtained from Streptomyces orientales other glycopeptides (not yet licensed in Canada but used in Europe): teicoplanin daptomycin ramoplanin Vancomycin - Mechanism of Action bactericidal inhibits synthesis and assembly of cell wall peptidoglycan binds to D-alanyl-D-alanine precursor D- alanyl post-antibiotic effect lasting approx. 2 hours post affects only multiplying organisms Vancomycin - Antimicrobial Activity Highly susceptible: Gram positive cocci - all Staphylococci, Streptococci, most Enterococci, Corynebacterium, Enterococci, Corynebacterium, Clostridium difficile Resistant: Gram negatives, mycobacteria, fungi, mycobacteria, Bacteroides (anaerobe) Pediococcus, Leuconostoc, some Pediococcus, Leuconostoc, enterococci, S. aureus (rare) enterococci, Pharmacokinetics
Oral dosing: Poorly absorbed by g.i. tract therefore is used orally for the treatment of C. difficile colitis Vancoymcin - Toxicity & Drug Interactions Fever, chills; phlebitis at site of infusion "Red n - eck" or "red m syndrome (tingling and an" flushing of face, neck and thorax): Caused by rapid infusion of drug Neurotoxicity (auditory nerve)- >permanent hearing loss Nephrotoxicity is uncommon but reversible 'd if aminoglycosides given Incompatible with many i.v. drugs eg. heparin eg. Intravenous use: T1/2 = 6 - 8 hours; 80 - 90% excreted unchanged in urine poor CSF penetration in healthy patients; good penetration in meningitis need for routine drug level monitoring (peak and trough) not clear ...
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