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PHARMACOLOGY Bactericidal Gram positive - thick cell wall-high CELL WALL proteoglycan...

PHARMACOLOGY Bactericidal Gram positive - thick cell wall-high CELL WALL proteoglycan Gram negative - thin wall -low INHIBITORS proteoglycan Penicillin more active against gram positive B - LACTAMS RESISTANCE ___ B lactam ring - inhibit Cell wall only present in bacteria transpeptidase Thiazolidine + B lactam ring 1. Decreasing influx, increasing efflux-gram negative 1. Penicillin (t1/2 - 30 min. To 1 hour) 2. Penicillinase-degrade penicillin or - Cross BBB when mininges B lactam ring -most common inflamed - Gram positive (Most 2. Cephalosporin staphylococci) 3. Carbapenem - Gram negative 4. Monobactam Inhibitors of B lactamases - Clavulanic acid, BACTERICIDAL Sublactam, Tazobactam Mechanism of action Penicillinase resistant Cell wall-polymer penicillin-penicillin with more side UDP-N chains, covered - Methicillin, acetylmuramic(NAM)-PENTAMER Cloxacillin, Dlicloxacillin N - acetylglucosamine(NAG) 3. Penicillin binding protein is Cross linking of NAM-NAG altered - Transpeptidase(cytoplasm) - split MRSA defends itself in this way the terminal D-alanine- energy PRSP, penicillin resistant released-used in cross linking Streptococcus pneumoniae Enterococci. B lactams - inhibit cross linking-cell wall 4. Changes in porin structures in the lost outer cell wall - PBPs access impeded Cell wall deficient bacteria - water Pseudomonas aeruginosa enter-swell-burst-bacteria die PENICILLIN  2 First antibiotic discovered by Adverse effects Alexander Fleming from fungus Local irritancy penicillium notatum and penicillium Hypersensitivity - urticaria, severe chrysogenum. pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis. Jarish-Herxheimer reaction - due to spirochetal lytic product - Syphilitic patient Methicillin- interstitial nephritis Nafcillin - neutropenia Antigenic determinants - penicilloic NATURAL PENICILLIN acid Complete cross allergenicity - Classification between penicillin (Penicillin G, Benzylpenicillin) - procaine Ampicillin - Maculopapular rash, and benzathine forms - intramuscular - Nausea and diarrhea with oral release slowly penicillins, pseudomembranous colitis Narrow spectrum GIT upset - irritation or overgrowth B lactamase susceptible of gram positive organisms or yeast 1. Acid labile-injections 2. Resistance against Uses this L - Leptospira 3. Altered PBP - Narrow spectrum (few gram A - Actinomycetes positive) S - Streptococcus,Staphylococcus(non Spectrum - Gram positive bacteria, bacilli penicillinase producing), Spirochetes RESISTANCE - PRSP, Staphylococcus T-Treponema, Tetanus (Gas gangrene) aureus, Neisseria gonorrhoeae - B lactamase production M-Meningococcus Doc for Syphilis, against enterococci with AN-Anthrax, Actinomycosis aminoglycosides D- Diphtheria  3 P-Pneumococcus 3. Expanded activity- Wider spectrum B - Bacilli - gram positive penicillinase susceptible Prophylactic - Rheumatic fever, 1. Amino - Acid stable, Penicillinase Endocarditis, Agranulocytosis susceptible SEMISYNTHETIC PENICILLIN All organisms sensitive to PnG Many gram negative bacilli 1. Artificial-acid stable(penicillin V) - H. influenza, E. coli, Proteus, oral (Phenoxymethyl penicillin) - Moraxella, L. monocytogenes oropharyngeal infections(oral) Salmonella, Shigella, Helicobacter pylori, Prototype - Ampicillin, 2. Penicillinase resistant penicillin - Amoxicillin side chain Uses similar to PenG Very narrow Used with penicillinase C - Cloxacillin inhibitors(clavulanic acid) Enterococcal and listeria O-Oxacillin infections - Ampicillin synergistic with N-Nafcillin(biliary excretion) Aminoglycosides D-Dicloxacillin 2. Carboxy - Not acid stable, not O penicillinase resistant(Carbenicillin) M-Methicillin(Rarely used - Pseudomonas and indole positive nephrotoxicity) - not resistant to Proteus gram negative bacteria Less active against Salmonella, E.coli, enterobacter - Known for susceptible Not active against Klebsiella, staphylococcal infection positive cocci - MRSA , MRSE - all penicillins resistant 3. Ureido group added to penicillin(Extended spectrum)  4 Pipperacillin, Ticeracillin, Mezlocillin Ureidocillin Mezlocillin 8 times more active against Azlocillin pseudomonas Klebsiella,Enterobacter Piperacillin enterobacteriaceae, some (injection) bacteroides AA CT MAP Gram negative rods Gram negative infections in neutropenic/ immunocompromised or burn patients Synergistic with aminoglycosides Succeptible to penicillinase (used with tazobactam, clavulanic acid) ANTIPSEUDOMONAL PENICILLINS C - Carbenicillin Tularemia - Rat bite fever T - Ticarcillin CEPHALOSPORINS M-Mezlocillin A. CLASSIFICATION A-Azlocillin 7-aminocephalosporanic acid Extended gram negative P-Piperacillin coverage EXTENDED SPECTRUM PENICILLIN B. PHARMACOKINETICS Oral, most parenterally Side chains - hepatic metabolism Aminopenicillins Ampicillin Renal excretion via tubular (injection) secretion- major (biliary excretion) Cefoperazone and Ceftriaxone - bile Amoxicillin First, Second generation - do not enter CSF even when meninges Carboxycillin Carbenicillin inflamed Ticarcillin( C. MOA injection) Bind PBPs to inhibit cell wall synthesis  5 Bactericidal Increase gram negative activity for Less susceptible to penicillinase by organisms resistant to other beta staphylococci lactam drugs Resistant to other B lactamases Penetrate BBB (except cefoperazone, D. RESISTANCE cefixime) Providencia, Serratia, beta lactamase Decrease in membrane permeability, producing H. influenzae, Neisseria changes in PBPs Less active against Enterobacter - MRSA - resistant to cephalosporins extended spectrum beta lactamase E. USE Ceftriaxone, Cefotaxime - most active against PRSP 1. First generation drugs - Cefazolin Pseudomonas(cefoperazone, (parenteral), Cephalexin(Oral) ceftazidime) Gram positive cocci - B fragilis(ceftizoxime) staphylococci, streptococci Serious infection E.coli and K pneumoniae Ceftriaxone(parenteral) and USES - Infections surgical cefixime(oral) - DOC in gonorrhea prophylaxis Acute otitis media - ceftriaxone - 10 Minimal activity against day with amoxicillin gram negative cocci, enterococci, MRSA, most 4. Fourth generation drugs - Cefepime gram negative rods Resistant to B lactamases producing 2. Second generation drugs - Cefaclor, gram negative organisms - cefuroxime, cefprozil Enterobacter, Haemophilus, Neisseria, PRSP Less activity against Gram positive Combines the Gram-positive activity Extended gram negative of first-generation agents with the Infections caused by Bacteroides wider Gram-negative spectrum of fragilis(cefotetan, cefoxitin) third-generation cephalosporins Sinus, Ear and respiratory infections Ceftaroline - MRSA - H. influenzae, M catarrhalis(cefamandole, F. TOXICITY cefuroxime, cefaclor) 1. Allergy - Skin rash, Anaphylactic 3. Third Generation drugs- Ceftazidime, shock Cefoperazone,cefotaxime Less frequent than Penicillin  6 Complete cross Renal tubular secretion - hypersensitivity elimination Cross reactivity between Prolonged T1/2 in renal penicillins and failure cephalosporins AE - GIT upset - incomplete(5-10%) superinfection, vertigo, Anaphylaxis with penicillin headache, rarely not treated with hepatotoxicity cephalosporins Skin rash 2. Other AE No cross allergenicity with Pain at intramuscular penicillins injection sites B. Imipenem, Doripenem, Phlebitis after IV Meropenem, Ertepenem Increase nephrotoxicity of Carbapenems-low susceptibility to aminoglycosides beta lactamases Drugs containing Wide activity against Gram positive methylthiotetrazole groups cocci(PRSP),gram negative rods, (cefamandole, cefoperazone, anaerobes cefotetan) - Pseudomonas infection - hypoprothrombinemia, aminoglycoside disulfiram like reactions with Parenteral - antibiotic resistant ethanol organisms MRSA resistant OTHER BETA LACTAM DRUGS Co drug for Enterobacter, Citrobacter, Serratia A. AZTREONAM Aztreonam - Monobactam Resistant to B lactamases by Ertapen Meropene Imipenem Doripene Gram negative rods em m cilastatin m Klebsiella, Pseudomonas, Aeruginosa Aeruginosa Aeruginos Serratia Acitnetoba Acitnetoba a cter cter Acitnetob Not Gram positive or acter anaerobes not not - renal not PBP3, Aminoglycoside degrade degraded dehydrope degraded d by the by the ptidase I by the synergistic kidney kidney kidney IV long not GIT l half-life metabolize distress,  7 but is d by renal skin rash, Inhibits transglycosylation less dehydrope and, at very Prevents elongation of active ptidase and high against is less plasma peptidoglycan chain and enteroco likely to levels, CNS cci and cause toxicity interferes with cross linking Pseudo seizures (confusion, VRE, VRSE - replacement of monas, encephalop and it's athy, D-Ala by D-lactate intramu seizures) Narrow spectrum scular injection Serious infection caused by causes pain and drug resistant gram positive irritatio organisms - MRSA n PRSP-Ceftriaxone Partial cross-allerg Clostridium difficile enicity infections with penicillin Teicoplanin, Teicovalcin - same VRE - MRD C. BETA LACTAMASE INHIBITOR Vancomycin intermediate Clavulanic acid, sulbactam, strains of S aureus - tazobactam treatment failures Plasmid encoded beta Not absorbed it GIT - Oral for lactamases - gonococci, bacterial enterocolitis streptococci, E coli, H. Parenterally-unchanged in influenzae urine Not good inhibitors of Renal impairment dosage inducible chromosomal adjustments beta-lactamases formed by Toxic - Chills, fever, Enterobacter, Pseudomonas, phlebitis, ototoxicity, and Serratia nephrotoxicity Rapid IV - Diffuse OTHER CELL WALL OR flushing-Red man syndrome MEMBRANE ACTIVE AGENTS from histamine release B. FOSFOMYCIN A. VANCOMYCIN Antimetabolite inhibitor of Bactericidal cytosolic enolpyruvate D-Ala-D-ALa terminal - transferase peptidoglycan pentapeptide side chain  8 Prevents formation of Cyclic lipopeptide - vancomycin N-acetyl muramic acid - similar spectrum peptidoglycan chain VRE and VRSA active Resistance via decreased Inserts into cytoplasmic membrane intracellular accumulation of causing potassium leak and cell drug death Renal excretion , exceeding Renal elimination MIC - U=urinary tract Creatinine phosphokinase pathogens monitored, can cause myopathy Single dose - less effective than a 7 day course of treatment with fluoroquinolones Multiple-Resistance rapid Diarrhea Synergistic with beta lactam and quinolone antibiotics C. BACITRACIN Peptide antibiotic Late stage in cell wall synthesis in gram positive Nephrotoxicity - topical D. CYCLOSERINE Antimetabolite - blocks incorporation of D-Ala into pentapeptide side chain of peptidoglycan Neurotoxicity (tremors, seizures, psychosis) - tuberculosis - organisms resistant to first line antitubercular drugs E. DAPTOMYCIN