Cell Wall Synthesis Inhibitor (II) PDF

CELLWALL SYNTHESIS INHIBITOR (II) PENICILLINS & CEPHALOSPORINS ARE THE MAJOR ANTIBIOTICS THAT INHIBIT; The beta-lactams include some of the most effective, widely used and well tolerated agents available for the treatment of microbial infections. The cephalosporins are derivatives of 7-aminocephal...

CELLWALL SYNTHESIS INHIBITOR (II) PENICILLINS & CEPHALOSPORINS ARE THE MAJOR ANTIBIOTICS THAT INHIBIT; The beta-lactams include some of the most effective, widely used and well tolerated agents available for the treatment of microbial infections. The cephalosporins are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. Many members of this group are in clinical use. They vary in their antibacterial lactivity and are designated into generation drugs according to the order of their introduction into clinical use.  BETA-LACTAM ANTIBIOTICS ARE BATERICIDAL DRUGS : They act to inhibit cell wall synthesis by:  Binding of the drug to specific enzymes ( penicillin binding proteins [PBPs] )located in the bacterial cytoplasmic membrane; Inhibition of trans peptidase reaction that cross link the linear peptidoglycan chain constituents of the cell wall & activation of autolytic enzymes  Although the cephalosporin mechanism of action (MOA) and bactericidal effects are similar among all generations, each generation differs in regard to their coverage for gram positive and/or gram negative organisms. CEPHALOSPORINS & CEPHAMYCINS  Cephalosporins are more stable than Penicillin to many bacterial β- lactamases and therefore have a broader spectrum of activity.  First generation cephalosporins have better activity against gram positive organisms and the later compounds exhibit improved activity against gram negative aerobic organisms. FIRST-GENERATION CEPHALOSPORIN  These agents have good activity against some gram-positive organisms (streptococci) and some gram-negative organisms. First-generation cephalosporins are used mainly for E. coli, Klebsiella infections, and penicillin- and sulfonamideresistant urinary tract infections.  They are also used prophylactically in various surgical procedures.  These agents do not penetrate CSF SECOND-GENERATION CEPHALOSPORINS These agents have a somewhat broader spectrum of activity than first-generation drugs. They are used in treatment of streptococcal infections as well as infections caused by E. coli, Klebsiella, and Proteus spp. Most anaerobes (with exception of C. difficile) are covered as well. Second-generation cephalosporins are used primarily in the management of urinary and respiratory tract, bone, and soft-tissue infections and prophylactically in various surgical procedures. With the exception of cefuroxime, these agents do not penetrate CSF THIRD-GENERATION CEPHALOSPORINS  These agents have enhanced activity against gram-negative organisms.  They demonstrate high potency against Haemophilus influenzae, N. gonorrhoeae, N. meningitides, Enterobacter, Salmonella, indole-positive Proteus, and Serratia spp., and E. coli; and moderate activity against anaerobes.  Cefoperazone and ceftazidime have excellent activity against P. aeruginosa.  Ceftriaxone is used for sexually transmitted infections caused by gonorrhea, as well as in empiric therapy for community-acquired meningitis.  THIRD-GENERATION CEPHALOSPORINS  With the exception of cefoperazone, third-generation cephalosporins penetrate the CSF.  These agents are excreted by the kidney, except cefoperazone and ceftriaxone, which are excreted through the biliary tract, thus enabling the use of these agents for infections of the biliary tree.  Third-generation cephalosporins are used to treat gonorrhea, Lyme disease, meningitis, and serious hospital-acquired gram-negative infections, alone or in combination with an aminoglycoside 4TH GENERATION CEPHALOSPORINS  Cefepime is the example of so called 4th generation cephalosporin.  It is more resistant to hydrolysis by chromosomal β- lactamases that inactivate many of the 3rd generation cephalosporins.  It has good activity against P aeruginosa, enterobacteriaceae , S. aureus and pneumoniae. ADVERSE EFFECTS AND DRUG INTERACTIONS  Cephalosporins most commonly cause hypersensitivity reactions (2%–5%); 5%–10% of penicillin-sensitive persons are also hypersensitive to cephalosporins.  Alcohol intolerance (disulfiram-like) is seen with cefamandole and ceftriaxone.  may cause bleeding disorders; these disorders can be prevented by vitamin K administration. (4) Cephalosporins may be nephrotoxic when administered with diuretics.  may cause superinfection with gram-positive organisms or fungi.  Cephalosporins are the number one cause of hospital-acquired C. difficile colitis, a potentially life-threatening infection. THERAPEUTIC USES OF CEPHALOSPORINS  The 1st.generation cephalosporins; cefazolin ( parenteral ) & cephalexin (oral) are excellent agents for skin & soft tissue infections due to S. aureus and S. pyogenes  A single dose of cefazolin just before surgery is the preferred prophylaxis for procedures in which skin flora are likely the pathogens. 2ND. GENERATION DRUGS  Cefoxitin, cefotitan, cefamandole, cefaclor; this group of drugs have extended gram- negative coverage.  3rd. Generation ; ceftazimide, cefoperazone, cefotaxime include increased activity against negative organisms resistant to other beta-lactam drugs. CEFTRIAXONE AND CEFOTAXIME  Are currently the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains), but resistance has been reported.  Ceftriaxone (parenteral) & cefixime (oral), drugs of choice in gonorrhea, are exceptions. USES  For colorectal surgery, where prophylaxis for intestinal anaerobes is desired, the 2 nd. Generation agents cefoxitin or cefotetan are preferred.  The oral 2nd. Generation cephalosporins can be used to treat R.T.I though AMOXICILLIN may be better. USES – CONTD-  The 3rd. Generation cephalosporins with or without aminoglycosides have been considered to be the drugs of choice for serious infections caused by klebsiella, Enterobacter, proteus, serratia & haemophilus spp.  Ceftriaxone is the therapy of choice for all forms of gonorrhea & lyme disease(sever) C 1st 2nd 3rd 4th 5th Cefazolin Cefotetan Cefuroxime Ceftriaxone Cefepime (P) Ceftrolozone (P) Cephalexin Intraabdominal Ceftazidime (P) Tazozolactam Skin Cefotaxim Ceftaroline(MRSA infections Lung infection ) ØAnaerobic +Anaerobi ØAnaerob ØAnaerob +Anaerob c ic ic ic Gm+ve Gm+ve Pneumococcal Strong STAPH Staph+/Ve STAPH STREP STREP Gm-ve Same Better Strong Ecoli Neisseria ,Gon Proteus orhea serratia Klebsiella Psuedomonas Glycopeptide antibiotics OTHER CELL WALL OR MEMBRANE- ACTIVE AGENTS  Ristocetin, avoparcin, complestatin, vancomycin, and teicoplanin are representative molecules of these class VANCOMYCIN “DRUG OF LAST RESORT”  Vancomycin is a bactericidal glycoprotein that binds peptidoglycan pentapeptide side chain and inhibits transglycosylation.  This action prevents elongation of the peptidoglycan chain and interferes with crosslinking.  Vancomycin has a narrow spectrum of activity.  It demonstrates no cross-resistance with other antibiotics VANCOMYCIN -USES  It is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin-resistant staphylococci (MRSA)  In combination with a third-generation cephalosporin such as ceftriaxone for treatment of infections due to penicillin-resistant pneumococci (PRSP).  Vancomycin is also a backup drug for treatment of infections caused by Clostridium difficile TOXIC EFFECTS OF VANCOMYCIN  Chills, fever, phlebitis, ototoxicity, and nephrotoxicity.  Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) from histamine release.. (9) High levels of vancomycin may cause ototoxicity with permanent auditory impairment FOSFOMYCIN  It may be synergistic with beta-lactam and quinolone antibiotics in specific  Fosfomycin inhibits the enzyme enolpyruvate transferase and therby interferes downstream with the formation of bacterial cell wall specific N-acetylmuramic acid.  This oral agent is active against both gram-positive and gram-negative organisms. It is used to treat simple lower urinary tract infection  In a single dose, the drug is less effective than a 7-day course of treatment with fluoroquinolones. With multiple dosing, resistance emerges rapidly and diarrhea is common. Bacitracin  Bacitracin inhibits dephosphorylation and reuse of the phospholipid required. for acceptance of N-acetylmuramic acid pentapeptide, the building block of the peptidoglycan complex.  Bacitracin is most active against gram- positive bacteria.  Bacitracin is used only topically in combination with neomycin or polymyxin for minor infections  CYCLOSERINE  (1) Cycloserine is an amino acid analogue that inhibits alanine racemase and the incorporation of alanine into the peptidoglycan pentapeptide.  (2) Cycloserine is active against mycobacteria and gram-negative bacteria.  (3) This agent is used only as a second-line drug for treatment of urinary tract infection and tuberculosis (TB).  (4)may cause cause severe central nervous system (CNS) toxicity, including seizures and acute psychosis DAPTOMYCIN  Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci . The drug is eliminated via the kidney.  Creatine phosphokinase should be monitored since daptomycin may cause m myopathy. Other β- lactam antibiotics OTHER Β- LACTAM ANTIBIOTICS  Carbapenems – include ; imipenem ;meropenem; ertapenem ,aztreonam Carbapenems are derivatives of thienamycin that have a broad spectrum of antibacterial activity.  Imipenem is marketed in the combination product imipenem/cilastatin ;cilastatin is an inhibitor of renal dehydropeptidase I (which inactivates imipenem).  ) Carbapenems are relatively resistant to b-lactamases .Carbapenems demonstrate no cross-resistance with other antibiotics.  These agents are useful for infections caused by penicillinase- producing S. aureus, E. coli, Klebsiella spp., Enterobacter spp., and H. influenzae, among others. They are powerful agents used for Pseudomonas infections. ADVERSE EFFECTS OF IMIPENEM-CILASTATIN Gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures).  There is partial cross allergenicity with the penicillins AZTREONAM  a naturally occurring monobactam lacking the thiazolidine ring that is highly resistant to b-lactamases.  It has good activity against gram-negative organisms, but it lacks activity against anaerobes and gram-positive organisms. (  no cross-reactivity with penicillins or cephalosporins for hypersensitivity reactions.  Aztreonam is administered parenterally. (  usefulfor various types of infections caused by E. coli, Klebsiella pneumoniae, H. influenzae, P. aeruginosa, Enterobacter spp.,Citrobacter spp., andProteus mirabilis