Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Agents Inhibitors of cell wall synthesis
Document related concepts
Transcript
Drugs /Agents Inhibitors of cell wall synthesis Inhibitors of bacterial cell wall biosynthesis In principle, drugs that inhibit bacterial cell wall synthesis will exhibit selective toxicity, because the drug targets are unique to bacteria and are not present in human cells. In practice,this principle is valid, and inhibitors of cell wall synthesis such as the B-lactams are drugs of choice for many bacterial infections. The availability of B-lactam drugs with distinct antimicrobial spectra permits their use in a wide variety of clinical setting. Inhibitors of bacterial cell wall biosynthesis The B-lactam drugs are bactericidal and relatively non-toxic to human cells. This attractive pharmacological property has led to overuse and misuse, resulting in the emergence of drug-resistant bacteria. Resistance due to B-lactamase production can sometimes be overcome by using a B-lactamase inhibitors in combination with the B-lactam drug. Resistance due to an alteration in the B-lactam target often cannot be surmounted, and a different drug class must be used for treatment. MoA of PCN Penicillin-binding proteins (PBPs): Targets for B-lactam drugs Penicillin-binding proteins (PBPs = transpeptidase enzymes) differ among bacterial species. PBPs differ in their affinities for B-lactam drugs. Therefore, bacteria can differ in susceptibility to B-lactam drugs because their transpeptidase enzymes are different. Mutation in a PBP can confer resistance to B-lactam drugs examples. Example Methicillin-Resistant Staph. Aureus Penicillin-resistant Strep. Pneumoniae All β-lactam antibiotics interfere with the synthesis of the bacterial cell wall peptidoglycan. After attachment to penicillin-binding proteins on bacteria (there may be seven or more types in different organisms), they inhibit the transpeptidation enzyme that crosslinks the peptide chains attached to the backbone of the peptidoglycan. The final bactericidal event is the inactivation of an inhibitor of autolytic enzymes in the cell wall, leading to lysis of the bacterium. Enzymes that cleave B-lactam drugs B-lactamases cleave the C-N bond of the B-lactam ring, inactivating the drug. Production of B-lactamase is a major cause of resistance. There are many different Blactamases, and they vary in specificity. Development of drugs that inactivate B-lactamse has helped combat resistance. B-lactam action B-lactam drugs must: Penetrate outer membrane Escape inactivation Bind to target enzymes Resistance can be due to Lack of membrane penetration Inactivation by B-lactamase Altered target PBPs Semi-synthetic drugs have modification that: Improve penetration through porins, enhancing Gram - negative activity. Decrease B-lactames susceptibility, broadening spectrum Alter PBP binding pattern, changing spectrum. PENICILLINS Side Effects: MOA: inhibit bacterial cell wall synthesis bactericidal! Target: PBP (cell wall transpeptidase) Lactam antibiotics PCN are polar: Mostly Excreted primarily by kidneys Diarrhea: 5-10% Rash: 4-10% Fever: 4-8% Neutropenia: 1-4% Exceptions: Nafcillin, Oxacillin Thrombocytopenia: 1-2% Dose adjustment needed in renally Hypersensitivity Rxn insufficient patients Tissue penetration: good Lung, liver, kidney, muscle, bone Most common AE and PCN may be the most common cause of drug allergy. Seizures: 1% Adverse Effects of PCN Allergic reactions include various skin rashes, serum-sickness (rare), and anaphylaxis (rare). Assume cross-allergenicity among PCNs. N&V: reflect direct irritation of the GI tract and/or alterations in bowler flora. In renal failure, Na+ or K+ toxicity can produce Seizures. Natural PCNs Agents Pen G (PO), Pen VK, Benzathine PCN (long acting IM injection, used in syphilis) Coverage GRAM + Very little clinically relevant gram – Strep: Pneumo, ABCG: >60% susc. Viridans: 30-60% susc. Enterococcus: Faecalis >60% Faecium 30-60% PCN G: neisseria meningitidis Anaerobes: Actinomyces: 30-60% Clostridium (not difficile): >60% Peptostreptococcus: >60% Penicillinase Resistant PCNs (Anti-Staph PCNs) Primary Coverage Agents GRAM + Methicillin Oxacillin Staph (MSSA & Epi): >60% Nafcillin Strep: Dicloxacillin (PO) Nafcillin, oxacillin: Pneumo, ABCG: >60% susc. Viridans: 30-60% susc. NO enterococcus NO GRAM - coverage •High Na+ in IV forms, watch out in HTN patients •Hepatically eliminated, do not need renal adjustment Amino PCNs Created to add some Gram - coverage Agents Ampicillin, Amoxicillin, Bacampicillin Primary Coverage GRAM + Strep: Pneumo, ABCG: >60% susc. Viridans: 30-60% susc. Staph Epi: >60% Enterococcus (both): >60% GRAM >60%: Proteus, Neisseria meningitidis 30-60%: H. Influenzae, E. Coli, Salmonella sp., Shigella sp. - Anaerobes: >60%: Clostridium (not difficile), Peptostreptococcus 30-60%: Actinomyces Anti-Pseudomonal PCNs (Carboxypenicillins, Ureidopenicillins) Agents Piperacillin, Ticarcillin Primary Coverage: GRAM + >60%: Strep Pneumo, Strep ABCG 30-60%: Strep viridans, Enterococcus (both) Anaerobes: >60%: Clostridium (not difficile), Peptostreptococcus GRAM - >60%: Pseudomonas, Citrobacter, Enterobacter, Proteus, E. Coli, Salmonella, Shigella, Neisseria Klebsiella (Pip only), Serratia (Ticar only) 30-60%: H. Influenzae, Moraxella (Pip only) Lactamase Inhibitor PCNs Agents Augmentin: PO Amoxicillin/Clavulanate Increase coverage to Lactamase Producing: Timentin: IV Ticarcillin/Clavulanate Staph Zosyn: IV Neisseria Piperacillin/Tazobactam H. Influenzae Klebsiella Proteus Unasyn: IV Ampicillin/Sulbactam Augmentin, Unasyn do NOT cover Pseudomonas
