Antimicrobials 2 PDF

ANTIMICROBIALS 2 Beta-lactam antibiotics: Drugs with structure containing a beta-lactam ring; include the penicillins and cephalosporins. This ring must be intact for antimicrobial action. Beta-lactamases: Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the lactam ring...

ANTIMICROBIALS 2 Beta-lactam antibiotics: Drugs with structure containing a beta-lactam ring; include the penicillins and cephalosporins. This ring must be intact for antimicrobial action. Beta-lactamases: Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the lactam ring of certain penicillins and cephalosporins. Penicillin- binding proteins: Bacterial cytoplasmic membrane proteins that acts as the initial receptors for penicillins and other beta-lactam antibiotics. Peptidoglycan ,Murein: Chain of polysaccharides and polypeptides that are Cross-linked to form the bacterial cell wall. Selective Toxicity: More toxic to the invader (bacteria) than to the host ; a property of useful antimicrobial drugs. Transpeptidases: Bacterial enzymes involved in the cross-linking of linear peptidoglycan chains, the final step in cell wall synthesis. Penicillins and cephalosporins are the major antibiotics that inhibit bacterial cell wall synthesis. Vancomycin, fosfomycin, and bacitracin also inhibit cell wall synthesis but for various reasons are not nearly as important as the beta-lactam drugs. The selective toxicity of these drugs is mainly due to specific action on the synthesis of a cellular structure that is unique to the microorganism.  Penicillins A- Classification:  it has 4–membrane lactam ring , first drug in this group was pencillin G. there are many types of pencillins available like pencillin include following subtypes :- 1) narrow spectrum (natural) p :-parentral administration ( pencillin G) eg.benzyl pencillin and oral adminstration (pencillin V) eg.Phenoxymethylpencillin. 2) antistaphylococal p (B-lactamase resistance) like cloxacillin ,flucloxacillin ,methicillin. 3) Extended spectrum p like ampicillin , amoxycillin. And anti pseudomonal p eg carboxypencillin (carbencillin). – ureidopencillin (piperacillin ).  MECHANISM OF ACTION  Penicillins are bactericidal antibiotics as they kill the microorganisms when used at therapeutic dose.  The synthesis of cell wall of bacteria is completely depended upon an enzyme named as transpeptidase.  Primarily, Penicillin inhibits the cell wall of bacteria by blocking transpeptidase after binding to penicillin-binding protein (PBP) and prevents its synthesis.  Result: bacteria cells die from cell lysis.  Penicillins do not kill other cells in the body.  Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such cephamycins, as penicillins, monobactams and cephalosporins, carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase.  Examples of these bacteria: staphylococci, streptococci, Haemophilus influenzae, meningococci and gonococci.  ẞ-lactamase Inhibitors  ẞ-lactamases are a family of enzymes produced by many gram-positive and gram- negative bacteria that inactivate ẞ-lactam antibiotics by opening the ẞ-lactam ring.  Different ẞ-lactamases differ in their substrate affinities. Three Inhibitors of this enzyme:  Clavulanic Acid  Sulbactam  Tazobactam  Beta-lactamase inhibitors are drugs that are co administered with beta-lactam antimicrobials to prevent antimicrobial resistance by inhibiting serine beta lactamases, which are enzymes that inactivate the beta lactam ring, which is a common chemical structure to all beta- lactam.  Therapeutic Uses Pneumococcal Infections. Streptococcal Infections. Streptococcal A) Pneumococcal Pneumonia, Arthritis, Staphylococcal Meningitis Streptococcal Meningitis, and Infections. B) Pneumococcal Pharyngitis (including Endocarditis. Pneumonia Scarlet Fever) Meningococcal Gonococcal Syphilis. Diphtheria. Infections. Infections. Surgical Procedures in Patients with Anthrax. Clostridia Infections. Valvular Heart Disease.  ADVERSE EFFECTS  Diarrhea that is watery or bloody.  Fever, chills, body aches, flu symptoms.  Urinating less than usual or not at all.  Severe skin rash, itching, or peeling.  Agitation, confusion, unusual thoughts or behavior.  Seizure (black-out or convulsions).  Nausea, vomiting, stomach pain.  Vaginal itching or discharge.  Headache.  Thrush (white patches or inside your mouth or throat). CEPHALOSPORINS A. Classification: -  They are designated first-, second-, third-, or forth generation drugs according to the order of their introduction Into clinical use. B. Pharmacokinetics:  several are available for oral use but most administered parentally.  The major elimination is by renal excretion via active tubular secretion, some may undergo hepatic metabolism.  Cefoperazone and ceftriaxone are excreted mainly in the bile.  Most 1st & 2nd generation do not enter the CSF fluid even when the meninges are inflamed.  C. Mechanism of Action and Resistance  They bind to bacterial cell membrane to inhibit cell wall synthesis by mechanism similar to those of the penicillins.  Cephalosporins are bactericidal against susceptible organisms.  Less susceptible to staph. Penicillinases.  Some bacteria are resistant through the production of other beta-lactamases.  Resistance may resulted from decrease in membrane permeability and from changes in PBPs.  Methicillin resistant staph. are also resistant to most cephalosporins.  D. Clinical Uses 1. First generation drugs Cefazolin (parenteral) & Cephalexin (oral) are examples of this subgroups. They are active against G+ cocci, including Staph. & Strept., E. coli & K. pneumoniae. Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis in selected conditions. Have minimal activity against gram-negative cocci, enterococci, methicillin-resistant Staph, & most G-rods. 2. Second-generation drugs Less active against G+ organisms than the 1st generation drugs but have an extended G- coverage. Clinical uses include infections caused by Bacteroids fragilis (Cefotetan, cefoxitin ) and by H. fluenzae or Morexella catarrhalis ( cefuroxime , cefaclor). 3. Third Generation Drugs (Cefoperazone, Cefotaxime) increased activity against G- organisms resistant to other beta-lactam drugs and ability to penetrate the blood brain barrier (except cefoperazone & cefixime). Drugs in this subclass should usually be reserved for treatment of serious infections eg.( bacterial meningitis). Ceftriaxone (parenteral) & cefixime (oral), currently drugs of choice in gonorrhea. Likewise, in acute otitis media, a single injection of ceftriaxone is an effective as 10-days course of treatment with amoxicillin or cefaclor. 4. Fourth-generation drugs Cefepime is more resistant to beta-lactamases produced by G- organisms, including enterbacter, haemophilus, and neisseria. 5. Fifth-generation drugs Ceftaroline is used to treat some types of skin infections and pneumonia.  ADVERSE EFFECTS PAIN: i.m. or i.v. infusion is usually painful. severe pain with cephalothin is experienced. thrombophlebitis of injected vein can occur. Diarrhoea: mostly seen with cephradine and cefoperazone(due to excretion in bile). Nephrotoxicity: cephalothin, cephaloridine exhibit renal toxicity when administered. Ceftriaxone is excreted mostly in bile hence, used in patients with renal insufficiency. It also has good bone penetration.(cefazolin) Bleeding: due to hypoprothrombinemia seen commonly in patients with cancer, renal failure. Ceftazidime has been associated with neutropenia, thrombocytopenia. OTHER BETA-LACTAM DRUGS A. Aztreonam:  is a monobactam that is resistant to beta-lactamases produced by certain G- rods, including klebsiella, pseudomonas, and Serratia. - has no activity against G+ bacteria or anaerobes.  It is an inhibitor of cell wall synthesis and synergistic with aminoglycosides.  Administered iv and is eliminated via renal tubular secretion so its t ½ is prolonged in renal failure.  Adverse effect include gastrointestinal upset with possible superinfection, vertigo and headache, & rare hepatotoxicity.  Though skin rash may occur, there is no cross allergenicity with penicillins.  B. Imipenem and meropenem  They are carbapenems ( chemically different from penicillins but retaining the beta-lactam ring structure) with low susceptibility for beta-lactamases.  The drug have wide activity against G+ cocci ( including some penicillin resistant pneumococci), G- rods, & anaerobes.  It is administered parenterally and is especially useful for infections caused by organisms resistant to other antibiotics. It is currently the drug of choice for infection due to enterobacter.  C. Beta-lactamase Inhibitors  Clavulanic acid, sulbactam, and tazobactam are used in fixed combinations with certain hydrolysable penicillins.  They are most active against plasmid encoded betalactamases such as those produced by gonococci, streptococci , E coli, and H influenzae.  They are not good inhibitors of inducible chromosomal beta- lactamases formed by enterobacter and pseudomonas. OTHER INHIBITORS OF CELL WALL SYNTHESIS A. Vancomycin:  It is a bactericidal.  The action: it prevents elongation of the peptidoglycan chain and interferes with cross- linking.  Vancomycin has a narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive, including methicillin resistant staphylococci , penicillin resistant pneumococci, and c. difficile.  Vancomycin resistant enterococci have emerged recently, a potentially serious clinical problem since such organisms usually exhibit multiple drug resistance.  Vancomycin is not absorbed from the GI tract and may be given orally for bacterial enterocolitis.  Parenterally, Its given by infusion, vancomycin penetrate most tissues and is eliminated unchanged in the urine.  Dosage modification is mandatory in patients with renal impairment.  Toxic effects of vancomycin include chills, fever , phlebitis, ototoxicity.  Rapid iv infusion may cause diffuse flushing (“ red man syndrome”).  B. Fosfomycin  It is an antimetabolite inhibitor of cytosolic enolpyrovate transferase.  This action prevents the formation of N- acetylmuramic acid , an essential precursor molecule for peptidoglycan chain formation.  Resistance to fosfomycin occurs via decreased intracellular accumulation of the drug.  Fosfomycin is excreted by the kidney, with urinary levels exceeding the (MICs) for many urinary tract pathogens.  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.  Fosfomycin may be synergistic with beta- lactam and quinolone antibiotics in specific infections. C. Bacitracin:- It is a peptide antibiotic that interfere with a late stage in cell wall synthesis in G+ organisms. Have a marked nephrotoxicity so it is limited to topical use. D. Cycloserine:- Is an antimetabolite that blocks the incorporation of D- Ala into the pentapeptide side chain of the peptidoglycan. Potential neurotoxic ( tremors, seizures, Psychosis), cycloserine is only used to treat tuberculosis caused by organisms resistant to first line anti- tuberculosis drugs. E. 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 myopathy. Thank You