Pharmacology 2 - Antibacterial PDF

Pharmacology 2 Beta-Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors Definition of terms Bactericidal- An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria Bacteriostatic- An antimicrobial drug that inhibits antimi...

Pharmacology 2 Beta-Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors Definition of terms Bactericidal- An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria Bacteriostatic- An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the infection; does not kill bacteria Beta-lactam antibiotics- Drugs with structures containing a beta- lactam ring: includes the penicillins, cephalosporins and carbapenems. This ring must be intact for antimicrobial action Definition of terms Beta-lactamases- Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins; confer resistance Beta-lactam inhibitors-Potent inhibitors of some bacterial beta- lactamases used in combinations to protect hydrolyzable penicillins from inactivation Minimal inhibitory concentration (MIC)-Lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a defined growth medium Definition of terms Penicillin-binding proteins (PBPs)-Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillins and other beta-lactam antibiotics Peptidoglycan-Chains of polysaccharides and polypeptides that are cross-linked to form the bacterial cell wall Selective toxicity-More toxic to the invader 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 Introduction Beta-Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors Penicillins and cephalosporins are the major antibiotics that inhibit bacterial cell wall synthesis. Beta-lactams- unusual 4- member ring that is common to all their members Side chain of penicillin PENICILLINS A. Classification All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-lactam ring structure that is essential for antibacterial activity B. Pharmacokinetics Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability The plasma half-lives of most penicillins vary from 30 min to 1 h. PENICILLINS C. Mechanisms of Action and Resistance Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis : (1) binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane; (2) inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall; and (3) activation of autolytic enzymes that cause lesions in the bacterial cell wall. Resistance The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms is a major mechanism of bacterial resistance Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) are often used in combination with penicillins to prevent their inactivation PENICILLINS D. Clinical Uses 1. Narrow-spectrum penicillinase-susceptible agents— Penicillin G is the prototype of a subclass of penicillins that have a limited spectrum of antibacterial activity and are susceptible to beta-lactamases. Clinical uses include therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes Many strains of pneumococci are now resistant to penicillins (penicillin- resistant S pneumoniae [PRSP] strains). Most strains of Staphylococcus aureus and a significant number of strains of Neisseria gonorrhoeae PENICILLINS 2. Very-narrow-spectrum penicillinase-resistant drugs— This subclass of penicillins includes methicillin (the prototype, but rarely used owing to its nephrotoxic potential), nafcillin, and oxacillin. Their primary use is in the treatment of known or suspected staphylococcal infections. Methicillin-resistant (MR) staphylococci (S aureus [MRSA] and S epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs. PENICILLINS 3. Wider-spectrum penicillinase-susceptible drugs a. Ampicillin and amoxicillin—These drugs make up a penicillin subgroup that has a wider spectrum of antibacterial activity than penicillin G but remains susceptible to penicillinases. Their clinical uses include indications similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis, although resistant strains occur. When used in combination with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced. In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides. PENICILLINS 3. Wider-spectrum penicillinase-susceptible drugs b. Piperacillin and ticarcillin—These drugs have activity against several gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella species. Most drugs in this subgroup have synergistic actions with aminoglycosides against such organisms. Piperacillin and ticarcillin are susceptible to penicillinases and are often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity. PENICILLINS E. Toxicity 1. Allergy—Allergic reactions include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis Methicillin causes interstitial nephritis, and nafcillin is associated with neutropenia. Complete cross-allergenicity between different penicillins should be assumed. Ampicillin frequently causes maculopapular skin rash that does not appear to be an allergic reaction. PENICILLINS E. Toxicity 2. Gastrointestinal disturbances—Nausea and diarrhea may occur with oral penicillins, especially with ampicillin. Gastrointestinal upsets may be caused by direct irritation or by overgrowth of gram-positive organisms or yeasts. Ampicillin has been implicated in pseudomembranous colitis. CEPHALOSPORINS A. Classification The cephalosporins are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. designated first-, second-, third-, fourth or fifth generation B. Pharmacokinetics -available for oral use, but most are administered parenterally. -side chains may undergo hepatic metabolism, but the major elimination mechanism for drugs in this class is renal excretion via active tubular secretion. CEPHALOSPORINS CEPHALOSPORINS C. Mechanisms of Action and Resistance -bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins -bactericidal against susceptible organisms. -Structural differences from penicillins render cephalosporins less susceptible to penicillinases produced by staphylococci CEPHALOSPORINS D. Clinical Uses 1. First-generation drugs—Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup. They are active against gram-positive cocci, including staphylococci and common streptococci. Many strains of E coli and K pneumoniae are also sensitive. Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis in selected conditions. CEPHALOSPORINS 2. Second-generation drugs—Drugs in this subgroup usually have slightly less activity against gram-positive organisms than the first- generation drugs but have an extended gram-negative coverage. Examples of clinical uses include infections caused by the anaerobe Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor). CEPHALOSPORINS 3. Third-generation drugs—Characteristic features of third generation drugs (eg, ceftazidime, cefoperazone, cefotaxime) include increased activity against gram-negative organisms resistant to other beta-lactam drugs and ability to penetrate the blood-brain barrier (except cefoperazone and cefixime). Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains) CEPHALOSPORINS 4. Fourth-generation drugs—Cefepime is more resistant to beta- lactamases produced by gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin resistant pneumococci. Cefepime combines the gram-positive activity of first-generation agents with the wider gram-negative spectrum of third-generation cephalosporins. 5. Fifth-generation drugs-Ceftaroline has activity in infections caused by methicillin-resistant staphylococci. CEPHALOSPORINS E. Toxicity 1. Allergy—Cephalosporins cause a range of allergic reactions from skin rashes to anaphylactic shock. -occur less frequently with cephalosporins than with penicillins. -Complete cross-hypersensitivity between different cephalosporins should be assumed. CEPHALOSPORINS 2. Other adverse effects—Cephalosporins may cause pain at intramuscular injection sites and phlebitis after intravenous administration. -They may increase the nephrotoxicity of aminoglycosides when the two are administered together. OTHER BETA-LACTAM DRUGS A. Aztreonam Aztreonam is a monobactam that is resistant to beta-lactamases produced by certain gram-negative rods, including Klebsiella, Pseudomonas, and Serratia. -The drug has no activity against gram positive bacteria or anaerobes. -administered intravenously and is eliminated via renal tubular secretion. Its half-life is prolonged in renal failure. -Adverse effects include gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity. OTHER BETA-LACTAM DRUGS B. Imipenem, Doripenem, Meropenem, and Ertapenem These drugs are carbapenems (chemically different from penicillins but retaining the beta-lactam ring structure) with low susceptibility to beta-lactamases. -wide activity against gram-positive cocci (including some penicillin-resistant pneumococci), gram-negative rods, and anaerobes. -Cilastatin increases the plasma half life of imipenem and inhibits the formation of a potentially nephrotoxic metabolite. B. Imipenem, Doripenem, Meropenem, and Ertapenem -Adverse effects of imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures). -There is partial cross allergenicity with the penicillins. Meropenem -similar to imipenem except that it is not metabolized by renal dehydropeptidases and is less likely to cause seizures. Ertapenem has a long half-life but is less active against enterocci and Pseudomonas, and its intramuscular injection causes pain and irritation OTHER BETA-LACTAM DRUGS C. Beta-Lactamase Inhibitors Clavulanic acid, sulbactam, and tazobactam are used in fixed combinations with certain hydrolyzable penicillins. most active against plasmid-encoded beta-lactamases such as those produced by gonococci, streptococci, E coli, and H influenzae. OTHER CELL WALL OR MEMBRANE- ACTIVE AGENTS A. Vancomycin Vancomycin is a bactericidal glycoprotein that binds to the d-Ala-d- Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation. Vancomycin is also a backup drug for treatment of infections caused by Clostridium difficile. Teicoplanin and telavancin, other glycopeptide derivatives, have similar characteristics. Toxic effects of vancomycin include chills, fever, phlebitis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) -histamine release OTHER CELL WALL OR MEMBRANE- ACTIVE AGENTS B. Fosfomycin Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase. -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 minimal inhibitory concentrations (MICs) for many urinary tract pathogens. OTHER CELL WALL OR MEMBRANE- ACTIVE AGENTS C. Bacitracin Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall synthesis in gram-positive organisms. Because of its marked nephrotoxicity, the drug is limited to topical use. OTHER CELL WALL OR MEMBRANE- ACTIVE AGENTS D. Cycloserine Cycloserine is an antimetabolite that blocks the incorporation of d- Ala into the pentapeptide side chain of the peptidoglycan. Because of its potential neurotoxicity (tremors, seizures, psychosis), cycloserine is only used to treat tuberculosis caused by organisms resistant to first-line antituberculous drugs OTHER CELL WALL OR MEMBRANE- ACTIVE AGENTS 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. Summary