Beta-Lactams II - Miscellaneous Peptide Antibiotics PDF

Beta-Lactams II Miscellaneous Peptide Antibiotics Lecture Objectives 1. Review the indications, contraindications, and interactions for the use of b-lactam and other cell wall- and membrane-active antibiotics. 2. Discuss the mechanism of physiological action and most common unintended effects of b-l...

Beta-Lactams II Miscellaneous Peptide Antibiotics Lecture Objectives 1. Review the indications, contraindications, and interactions for the use of b-lactam and other cell wall- and membrane-active antibiotics. 2. Discuss the mechanism of physiological action and most common unintended effects of b-lactam and other cell wall- and membraneactive antibiotics. 3. Relate the mechanisms of acquired drug resistance for b-lactam and other cell wall- and membrane-active antibiotics. Penicillins 1. Standard penicillins 2. Antistaphylococcal penicillins 3. Extended-spectrum penicillins 4. Antipseudomonal penicillin Penicillins Standard penicillins Penicillin G (Pfizerpen) i.v., i.m. Benzathine penicillin G suspension (Bicillin L-A) i.m. depot Penicillin V → Only p.o. for oropharyngeal infections (streptococci/pneumococci) Spectrum of activity (Pen G) Non-penicillinase producing gram-positive bacteria, spirochetes, meningococci Neisseria meningitidis, Treponema pallidum, Leptospira Syphilis, endocarditis, bacteremia, meningitis, anthrax, gas gangrene, actinomycosis Penicillins Antistaphylococcal penicillins Nafcillin Oxacillin Dicloxacillin Spectrum of activity Staphylococci & streptococci Bacteremia, endocarditis, meningitis, RTIs UTIs, RTIs, skin and soft tissue infections, bone infections Penicillins Extended-spectrum penicillins Amoxicillin (Moxatag) Amoxicillin/potassium clavulanate (Augmentin, Augmentin XR) Ampicillin Ampicillin/sulbactam sodium (Unasyn) Spectrum of Pen G (plus) Increased gram-negative activity Proteus mirabilis, E. coli, Haemophilus influenzae, Moraxella, Shigella, Salmonella & Helicobacter pylori UTIs, RTIs, endocarditis prophylaxis, meningitis, gastroenteritis, peptic ulcer Penicillins Antipseudomonal penicillin Piperacillin/tazobactam sodium (Zosyn) Broadest spectrum penicillin Spectrum of aminopenicillins (plus) Increased gram-negative activity Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter, Serratia & Bacteroides fragilis UTIs, RTIs, bacteremia, intra-abdominal infections Bacterial Cell Wall Inhibitors b-Lactams Target site PBPs → Transpeptidase → Inhibit transpeptidation reaction Bactericidal Time-dependent killing Synergistic with aminoglycosides Cephalosporins 1st generation Cephalexin (Keflex) Cefazolin Spectrum of activity Staphylococci (penicillinase-resistant), streptococci & pneumococci Proteus mirabilis, E. coli & Klebsiella pneumoniae UTIs, RTIs, skin and soft tissue infections Surgical prophylaxis, bone infections, endocarditis Cephalosporins 2nd generation Cefprozil (Cefzil) Cefuroxime axetil (Ceftin) Spectrum of 1st generation (plus) Haemophilus influenzae and Moraxella catarrhalis RTIs, UTIs, skin and soft tissue infections Cephalosporins Cephamycins (subclass of 2nd generation) Cefoxitin (Mefoxin) Cefotetan (Cefotan) Spectrum of cefprozil (plus) Neisseria gonorrhoeae, Bacteroides fragilis, Clostridium perfringens Mixed anaerobic infections Intra-abdominal infections Cephalosporins 3rd generation Ceftriaxone Cefotaxime (Claforan) Ceftazidime (Fortaz, Tazicef) Cefdinir (Omnicef) Cefixime (Suprax) Spectrum of cefprozil (plus) Extended gram-negative activity Cephalosporins 3rd generation Ceftriaxone Gonorrhea, chancroid, typhoid fever, Lyme disease (disseminated) Ceftriaxone Cefotaxime (Claforan) Meningitis, penicillin-resistant pneumococci, RTIs, UTIs Bacteremia, bone infections, skin & soft tissue infections Cephalosporins 3rd generation Ceftazidime (Fortaz, Tazicef) Cefdinir (Omnicef) Pseudomonas aeruginosa (w/ tobramycin) UTIs, meningitis, bacteremia, pneumonia RTIs, skin & soft tissue infections Cefixime (Suprax) Neisseria gonorrhoeae Cephalosporins 4th generation Cefepime (Maxipime) Spectrum of activity Broadest spectrum cephalosporin Pseudomonas, Enterobacter & Bacteroides UTIs, meningitis, bacteremia, pneumonia Intra-abdominal infections Cephalosporins 5th generation Ceftaroline fosamil (Teflaro) Spectrum of activity MRSA, VISA, VRSA, enterococci, pneumococci, streptococci PEcK, Haemophilus influenzae, Moraxella Skin and soft tissue infections, CAP Cephalosporins Adverse effects Hypersensitivity reactions Disulfiram reaction Nephrotoxicity Superinfections Mechanisms of Resistance to b-Lactam Antibiotics 1. 2. Inactivation by b-lactamase a. Penicillinase b. Cephalosporinase Decreased accumulation 3. Reduced permeability or Efflux pump Modification of target PBPs MRSA & PRSP Interactions Probenecid Inhibits renal tubular secretion of penicillins/cephalosporins Except for nafcillin, ceftriaxone Contraindications Previous b-lactam allergy Reduced renal function Except for nafcillin, ceftriaxone Other b-Lactam Antibiotics Carbapenems Imipenem/cilastatin (Primaxin IM, Primaxin IV) Meropenem (Merrem IV) Broad spectrum Empiric therapy, UTIs, RTIs Carbapenems Unintended effects Hypersensitivity reactions Diarrhea Infusion site reactions Seizures Other b-Lactam Antibiotics Monobactam Aztreonam (Azactam, Cayston) Aerobic gram-negative activity UTIs, bacteremia, intra-abdominal infections Not cross-allergenic with other b-lactams Cell Wall Inhibitors/Membrane Disruptors Peptides Vancomycin Bacitracin Polymyxin B Daptomycin Others Cycloserine Fosfomycin Bacterial Cell Wall Inhibitors Vancomycin Inhibits cell wall synthesis Damages cell membranes Inhibits peptidoglycan polymerization Inhibits transpeptidation reaction Inhibits synthesis of cell membrane phospholipids Bactericidal Peptide Antibiotics Vancomycin (Vancocin, First-Vancomycin) Tricyclic glycopeptide Spectrum of activity Gram-positive activity MRSA, penicillin-resistant pneumococci & enterococci b-lactam resistant infections, penicillin-allergic patients Slow i.v. infusion → Systemic gram-positive infections Oral → C. difficile and Staph. aureus Ab-associated enterocolitis Mechanisms of Resistance to Vancomycin Decreased drug permeability VISA Modification of vancomycin binding site VRSA Vancomycin Unintended effects Infusion phlebitis Flushing and shock Ototoxicity Peptide Antibiotics Daptomycin (Cubicin) Cyclic lipopeptide i.v. Depolarizes bacterial cell membrane potential Spectrum of activity Gram-positive cocci MRSA, VISA & VRSA VRE & streptococci Skin & skin structure infections Bacteremia & endocarditis Daptomycin Pharmacokinetics Inactivated by pulmonary surfactant Majority eliminated by glomerular filtration Unintended effects Myopathy Rhabdomyolysis w/ & w/out renal failure Jaundice and elevated hepatic enzymes Bacterial Cell Wall Inhibitors Bacitracin Inhibits incorporation of amino acids into bacterial cell wall Cycloserine Fosfomycin Inhibit peptidoglycan polymerization Bactericidal Peptide Antibiotics Bacitracin Cyclic peptide mixture → Cell wall inhibitor Gram-positive activity (topical ointments) Nephrotoxicity Polymyxin B Cationic basic peptide Disrupts bacterial cell membranes Aerobic gram-negative activity (topical ointments) Nephrotoxicity & neurotoxicity Miscellaneous Antibiotics Cycloserine Analog of D-alanine → Cell wall inhibitor Second-line tuberculostatic agent Dose-related CNS toxicities & peripheral neuropathies Fosfomycin (Monurol) Analog of phosphoenolpyruvate → Cell wall inhibitor Acute cystitis/UTIs E. coli & Enterococcus faecalis