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 B- lactamases, 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: Diarrhea: 5-10% Rash: 4-10% Fever: 4-8% Neutropenia: 1-4% Thrombocytopenia: 1-2% Hypersensitivity Rxn Most common AE and PCN may be the most common cause of drug allergy. Seizures: 1% MOA: inhibit bacterial cell wall synthesis - bactericidal! Target: PBP (cell wall transpeptidase)  Lactam antibiotics PCN are polar: Mostly Excreted primarily by kidneys Exceptions: Nafcillin, Oxacillin Dose adjustment needed in renally insufficient patients Tissue penetration: good Lung, liver, kidney, muscle, bone

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 + Strep: Pneumo, ABCG: >60% susc. Viridans: 30-60% susc. Enterococcus: Faecalis >60% Faecium 30-60% Very little clinically relevant gram – PCN G: neisseria meningitidis Anaerobes: Actinomyces: 30-60% Clostridium (not difficile): >60% Peptostreptococcus: >60%

Penicillinase Resistant PCNs (Anti-Staph PCNs) Agents Methicillin Oxacillin Nafcillin Dicloxacillin (PO) Primary Coverage GRAM + Staph (MSSA & Epi): >60% Strep: Pneumo, ABCG: >60% susc. Viridans: 30-60% susc. NO enterococcus NO GRAM - coverage Nafcillin, oxacillin: High Na+ in IV forms, watch out in HTN patients Hepatically eliminated, do not need renal adjustment

Created to add some Gram - coverage Amino PCNs Created to add some Gram - coverage Agents Ampicillin, Amoxicillin, Bacampicillin GRAM - >60%: Proteus, Neisseria meningitidis 30-60%: H. Influenzae, E. Coli, Salmonella sp., Shigella sp. - Anaerobes: >60%: Clostridium (not difficile), Peptostreptococcus 30-60%: Actinomyces Primary Coverage GRAM + Strep: Pneumo, ABCG: >60% susc. Viridans: 30-60% susc. Staph Epi: >60% Enterococcus (both): >60%

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 Timentin: IV Ticarcillin/Clavulanate Zosyn: IV Piperacillin/Tazobactam Unasyn: IV Ampicillin/Sulbactam Increase coverage to  Lactamase Producing: Staph Neisseria H. Influenzae Klebsiella Proteus Augmentin, Unasyn do NOT cover Pseudomonas