Nizet-249-Abx2

Nizet-249-Abx2 - Antibacterial Therapy II Victor Nizet MD |...

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1 Antibacterial Therapy II Victor Nizet, MD | SSPPS 249 | May 25, 2011 Antibiotic Mechanisms of Action Transcription Translation Translation Alteration of Cell Membrane Polymyxins Bacitracin Neomycin
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2 Antibiotics: Protein Synthesis Inhibitors
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3 Macrolides Clarithromycin Azithromycin Erythromycin Part of the polyketide family of antibiotics – notable for a large macrocyclic lactone ring to which one or more deoxy- sugars (e.g. cladinose) are attached Active against Gram(+) bacteria and a few Gram(-) species (e.g. H. influenzae ); similar spectrum to penicillin – often choice in penicillin allergic patients Macrolides Protein synthesis inhibitors, bind to 50S ribosomal subunit, blocks the peptidyltransferase activity. Mainly bacteriostatic in action, but can be bactericidal at high doses. Accumulate in leukocytes, can be brought to site of infection
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4 Macrolides Gastrointestinal disturbances such as diarrhea, abdominal pain, nausea and vomiting are pretty common, especially with erythromycin Likely secondary to enterohepatic recycling, which leads to build-up of the drug in bile secretions/duodenum. Macrolides are potent inhibitors of the cytochrome P450 system (specifically CYP3A4) – drug:drug interaction with statins that can lead to severe and debilitating myopathy. Activity against intracellular pathogens such as Mycoplasma , Chlamydia and Legionella in addition to Staph , Strep , Pneumococcus , etc. provides utility in empiric therapy of atypical pneumonia. Azithromycin high lipid solubility, tissue concentrations 50x greater than serum, can get prolonged half-life (> 60 hours) with multiple doses ! “Z-pack”
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5 Chloramphenicol Broad-spectrum bacteriostatic antibiotic, still used in the developing world due to low cost and ready availability. In U.S. no longer a first line agent due to toxicity concerns. inhibition of protein synthesis by binding the 50S ribosomal subunit, blocking peptidyl transferase activity of the ribosome and preventing peptide bond formation Chloramphenicol Because of excellent CNS penetration and activity against the leading agents of bacterial meningitis used in low income countries in empiric therapy. Also used for brain abscess. Need to monitor levels during therapy. Neisseria meningitidis Streptococcus pneumoniae
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6 Chloramphenicol – Toxicity Neonates have an immature hepatic function and lack an effective glucoronic acid conjugation mechanism for degradation and detoxification of chloramphenicol. Even at low therapeutic levels, the drug accumulates in the body causing toxicity manifested by vomiting, flaccidity, hypothermia, gray color and ultimately shock and collapse. Gray Baby Syndrome Chloramphenicol – Toxicity The most serious adverse effect associated with chloramphenicol treatment is bone marrow toxicity, which can occur in two distinct forms: bone marrow suppression -- a direct toxic effect of the drug and usually reversible, and aplastic anemia (below), which is idiosyncratic, undrelated to dose and generally fatal.
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Nizet-249-Abx2 - Antibacterial Therapy II Victor Nizet MD |...

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