Bacterial Cell Wall Inhibitors -lactam antibioticslactam antibiotics Contain a beta-lactam antibioticslactam ring that is
part of their chemical structure An intact beta-lactam antibioticslactam ring is essential for antibacterial activity Include: Penicillins, Cephalosporins, Carbapenems, Carbacephems & Monobactams -lactam antibiotics The R in the structure of -lactam antibioticslactam antibiotic determines the characteristic of antimicrobial agent e.g. narrow or broad spectrum; oral
vs parenteral administration; sensitivity vs resisitence to -lactam antibiotics lactamasesetc -lactam antibiotics The -lactam antibioticslactam ring is the site of attack by gastric acidity and lactamases
Beta Lactams Mechanism of Action: Inhibit synthesis of bacterial cell walls by binding to proteins in bacterial cell membranes e.g. PBPs Binding produces a defective cell wall that allows intracellular contents to leak out (lysis) Most effective when bacterial cells are dividing
Inhibitors of Cell Wall Synthesis Bacteria that produce -lactam antibioticslactamase (hydrolyze -lactam antibioticslactam ring and hence inactivation of antimicrobial) : Staph aureus Moraxella catarrhlis Neisseria gonorrhoeae Enterobacteriaceae
Hemophilus influenzae Bacteroides species Penicillins (PNCs) -lactam antibiotics Most widely used antibiotics, most effective, least toxic and cheap -lactam antibiotics Derivatives of 6-lactam antibioticsaminopenicillanic acid (-lactam antibiotics lactam ring is important structure) -lactam antibiotics Derived from a fungus -lactam antibiotics Prototype is Penicillin G
-lactam antibiotics Widely distributed except in CSF (except if inflammation is present) and in intraocular fluid -lactam antibiotics Most serious complication is hypersensitivity -lactam antibiotics Can cause seizures and nephropathy -lactam antibiotics Natural penicillins: Benzylpenicillin=Penicillin G IM, IV Acid labile, short acting, given 4-lactam antibiotics6 times/day
Depo IM forms to penicillin G Procaine penicillin given IM twice/day, IV injection contraindicated (could lead to BP & convulsions) Benzathine penicillin given IM mainly used for rheumatic fever prophylaxis Phenoxy methylpenicillin= Penicillin V Oral Natural penicillins are narrow spectrum and penicillinase sensitive
Considered drugs of choice to treat infections with G+ve Strep., -lactam antibioticshemolytic type (most common microbe in tonsillitis) Have little effect if any against G-lactam antibioticsve bacteria -lactam antibiotics Narrow spectrum penicillinase resistant penicillins (Anti Staph penicillins): Nafcillin IM, IV Oxacillin IM, IV
Cloxacillin Oral Dicloxacillin Oral Flucloxacillin Oral & parenteral -lactam antibiotics Broad spectrum penicillinase sensitive PNCs (amino PNCs ): Ampicillin IM, IV, Oral Amoxicillin Oral More potent, better bioavailability, longer DOA These PNCs have very little effect, if any, against PNC ase producing bacteria e.g.
H. influenza and against G-lactam antibioticsve bacteria e.g. E. coli, Proteus. No effect against Pseudomonas Amino PNCs are widely used in tonsillitis, otitis media, gonorrhea, respiratory infections, shigella infections, UTIsetc Amoxicillin has good activity against Helicobacter pylori (+ PPIs + Clarithromycin +
Metronidazole) -lactam antibiotics Antipseudomonal PNCs: Piperacillin > Mezlocillin=Ticarcillin > Carbinicillin All are synergistic with aminoglycosides against Pseudomonas -lactam antibiotics Amidinopenicillins: Mecillinam (IM; IV) Pivmicillinam (oral) Most potent PNCs against enterobacteria
( Salmonella, E. coli, Klebsiella, Shigella), have little or no activity against G+ve cocci or pseudomonas; synergistic with other -lactam antibioticslactams but not with aminoglycosides MOA of Penicillins: Most bacteria have rigid cell walls that are not found in host cells (selective toxicity) PNCs act by inhibiting transpeptidases, the enzymes that catalyze the final
cross-lactam antibioticslinking step in the synthesis of peptidoglycan, thus leading to the lyses of cell wall. Disruption of the cell wall causes death of the bacterial cell (Bactericidal Effect) Pharmacokinetics of PNCs:
Bind plasma proteins, widely distributed, their concentrations in ocular fluid, joints and CSF are poor (do not cross BBB unless meninges are inflamed), do not cross the placenta Metabolized by the liver and excreted by glomerular filtration and tubular secretion Probenecid inhibits tubular secretion of PNCs (nafcillin & oxacillin are mainly excreted by the liver) Indications for Penicillins:
-lactam antibiotics More effective in treating gram+ infections -lactam antibiotics Used to treat infections of the skin, GU, GI, respiratory tract and soft tissues -lactam antibiotics Selection depends on the organism and severity of the infection e.g. anti-lactam antibioticsstaph vs. anti -lactam antibiotics pseudomonal ** Combination of PNCs or a cephalosporin with a potent inhibitor of lactamases
-lactam antibioticslactemase inhibitors: Have no antibacterial activity, increase potency and etend spectrum of activity of combined antibiotic Clavulinic acid, Sulbactam, Tazobactam (Augmentin =amoxicillin/clavulinate) (Unasyn=ampicillin/sulbactam) (Zosyn=piperacillin/tazobactam)etc
Mechanisms of resistance to PNCs: -lactam antibiotics Altered penicillin binding proteins (PBPs) -lactam antibiotics Production of beta-lactam antibioticslactamase (penicillinases) -lactam antibiotics Decreased penetration/increased efflux (pseudomonas) Preparations to PNCs : Oral, parenteral, intrathecal, topical, intra articular
Side effects to PNCs: -lactam antibiotics Allergy ( Most frequent and dangerous ) Type I allergic reactions. Early onset ( immune Ig E mediated ) Type II allergic reactions. Late onset ( 2-lactam antibiotics 10 days ). May manifest as eosinophilia, hemolytic anemia, interstitial nephritis or serum sickness
(fever; arthralgia; malaise) -lactam antibiotics Nonallergic ampicillin rash, occurs only once (more common in pts with acute leukemias; mononucleosis, lymphomas, cytomegaloviral infections) -lactam antibiotics Neurotoxicity (more common with oxacillin) -lactam antibiotics Hepatotoxicity (IV oxacillin) -lactam antibiotics Bone marrow depression (reversible)
(IV nafcillin) -lactam antibiotics Nephrotoxicity (Methicillin) -lactam antibiotics -lactam antibiotics -lactam antibiotics Other restrictions in the use of
PNCs: Na+ penicillins restricted use in pts with hypertension or heart failure K+ Penicillins restricted use in pts with renal failure Absolute contraindications to all PNCs in pts with history of allergy Cephalosporins Derivatives of 7-lactam antibioticsaminocephalosporanic
acid -lactam antibiotics lactam antibiotics, Cidal Semisynthetic Broad spectrum Inhibitors of microbial cell wall synthesis Differ in pharmacokinetic properties and spectrum of activity Classified into 1st 2nd 3rd and 4th generations * First generation Cefadroxil
Cefalexin Oral Cefazolin IM, IV Cephapirin Cephradine Cephaloridine * Second generation Cefaclor Oral Cephamandole IM, IV Cephmetazole
Cefonicid Cefotetan Cefoxitin Cefprozil Cefuroxime Cefuroxime axetil Loracarbef * Third generation Cefixime Oral Cefoperazone IM, IV
Cefdinir Cefpodoxime Cefotaxims Ceftazidime Ceftriaxone Ceftibuten Ceftizoxime * Fourth generation Cefepime IM, IV 1st generation cephalosporins have the best activity against G +ve microorganisms, less resistant to -lactam antibiotics lactamases, and do not cross readily the BBB as compared to 2nd, 3rd and
4th generations Cephalosporins never considered drugs of choice for any infection, however they are highly effective in upper and lower respiratory infection, H. influenza, UTIs, dental infections, severe systemic infection... ** Among cephalosporins: -lactam antibiotics Cefoxitin (2nd) has the best activity against Bacteroids fragilis
-lactam antibiotics Cefamandole (2nd) has the best activity against H. Influenza -lactam antibiotics Cefoperazone (3rd), Ceftazidine (3rd) and Cefepime (4th) have the best activity against P. aeruginosa infections Side effects to cephalosporins: -lactam antibiotics Allergy Cross allergy with penicillins ( 10% ) -lactam antibiotics Hepatotoxicity
-lactam antibiotics Nephrotoxicity Mostly seen with Cephaloridine (1st) with concomitant aminoglycosides use -lactam antibiotics Hemolytic anemia All cephalosporins are excreted by the kidney except Ceftriaxone (3rd) which is excreted by the liver Other -lactam antibiotics lactam antibiotics: -lactam antibiotics Carbapenems e.g. Imipenem, Meropenem
* Imipenem Has the broadest spectrum of activity of all -lactam antibiotics lactam antibiotics, effective against most G +ve & -lactam antibiotics ve bacteria and anaerobes, given IM, IV; -lactam antibioticslactamase resistant More potent against E. faecalis, B. fragilis and pseudomonas aeroginosa as compared to 3rd generation cephalosporin Some consider imipenem the drug of choice
in the management of polymicrobial pulmonary, intraabdominal and tissue infections Imipenem is metabolized and excreted by the kidney. It is metabolized in kidney by the enzyme dehydropeptidase I; so it is combined with Cilastatin (inhibitor to dehydrpeptidase I) to decrease rapid metabolic clearance of imipenem Seizures are major side effect to imipenem
* Meropenem; has similar activity to imipenem; but resistant to metabolism by dehydropeptidase I (no need to combine it with cilastatin) and incidence of seizures is less than imipenem -lactam antibiotics Carbacephems e.g. Loracarbef Oral Spectrum of activity similar to 2nd generation cephalosporin particularly cefaclor and cefprozil; effective orally; excreted renally
-lactam antibiotics Monobactams e.g. Aztreonam IM, IV Has excellent activity against G -lactam antibioticsve bacteria little if any effect against G +ve MOs -lactam antibioticslactamase resistant Considered a substitute to aminoglycosides to treat G-lactam antibioticsve infections (less toxic) Rarely, causes allergic reactions in pts with type I allergy to other -lactam antibiotics lactam antibiotics
Vancomycin & Teicoplanin Glycopeptide (Large Molecules) Prevent crosslinking of peptidoglycans Bactericidal Narrow spectrum of activity effective against G+ve bacteria especially methicillin resistant Staph aureus (MRSA) Alternatives to PNCs to treat G+ve Strep & Staph infections in pts allergic to PNCs Given IV (oral absorption is poor)
Considered drug of choice + metronidazole to treat pseudomembranous colitis=antibiotic associated colitis (Clostridium difficille colitis; Staph enterocolitis) and in this case vancomycin could be given orally (IV in life threatening cases) Teicoplanin is given IM Side effects: Rapid IV flushing, tachycardia, BP
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