Cell Wall Inhibitors PDF

Pharmacology Chemotherapy Cell Wall Inhibitors Cell Wall Inhibitors Content: Penicillins ……………………………………………………..... 6 Cephalosporins ……………………………………………………..... 33 Other β-Lactam Antibiotics ……………………………………………………..... 47 β-Lactamase Inhibitors ……………………………………………………..... 52 Vancomycin ……………………………………………………...

Pharmacology Chemotherapy Cell Wall Inhibitors Cell Wall Inhibitors Content: Penicillins ……………………………………………………..... 6 Cephalosporins ……………………………………………………..... 33 Other β-Lactam Antibiotics ……………………………………………………..... 47 β-Lactamase Inhibitors ……………………………………………………..... 52 Vancomycin ……………………………………………………..... 54 Fosfomycin ……………………………………………………..... 57 Daptomycin ……………………………………………………..... 58 Polymyxins ……………………………………………………..... 60 Cell Wall Inhibitors Overview: Penicillins and cephalosporins are the major antibiotics that inhibit bacterial cell wall synthesis. They are called beta-lactams because of the unusual 4member ring that is common to all their members. The beta-lactams include some of the most effective, widely used, and well-tolerated agents available for the treatment of microbial infections Cell Wall Inhibitors Cell Wall Inhibitors Figure 1 – Summary of antimicrobial agents affecting cell wall synthesis. *Only available in oral formulation. **Available in oral and intravenous formulations. Penicillins Penicillins Classification All penicillins are derivatives of 6- aminopenicillanic acid and contain a betalactam ring structure that is essential for antibacterial activity. Penicillin subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition. Penicillins Figure 2 – Structure of β-lactam antibiotics. Penicillins Mechanisms of Action : Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps: 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. 3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall. Penicillins A. Mechanism of Action: Figure 3 – Bacterial cell wall of gram-positive bacteria. NAM = N-acetylmuramic acid; NAG = N-acetylglucosamine; PEP = cross-linking peptide. Penicillins Penicillins Mechanism of bacterial resistance: The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms. Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) are often used in combination with penicillins to prevent their inactivation. Penicillins Penicillins Mechanism of bacterial resistance: Structural change in target PBPs is responsible for: 1. methicillin resistance in staphylococci (MRSA) 2. for resistance to penicillin G in pneumococci (eg, PRSP, penicillin resistant Streptococcus pneumoniae). 3. enterococci. In some gram-negative rods (eg, Pseudomonas aeruginosa), changes in the porin structures in the outer cell wall membrane may contribute to resistance by impeding access of penicillins to PBPs. Penicillins Clinical Uses 1. Narrow-spectrum penicillinase-susceptible agents Penicillin G is the prototype of a subclass of penicillins. Clinical uses include therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes. Many strains of pneumococci (penicillin-resistant S. pneumoniae [PRSP] strains). Staphylococcus aureus and Neisseria gonorrhoeae are resistant via production of betalactamase. Penicillins Clinical Uses 1. Narrow-spectrum penicillinase-susceptible agents Penicillin G remains the drug of choice for syphilis. Activity against enterococci is enhanced by coadministration of aminoglycosides. Penicillin V is an oral drug used mainly in oropharyngeal infections. Penicillins Clinical Uses 2. Very-narrow-spectrum penicillinase-resistant drugs This subclass of penicillins includes: 1. methicillin (the prototype, but rarely used owing to its nephrotoxic potential), 2. nafcillin, and oxacillin. Their primary use is in the treatment of known or suspected staphylococcal infections. Methicillin-resistant staphylococcus aureus [MRSA] and S. epidermidis [MRSE] are resistant to all penicillins and are often resistant to multiple antimicrobial drugs. Penicillins Penicillins Clinical Uses 3. Wider-spectrum penicillinase-susceptible drugs a. Ampicillin and amoxicillin has a wider spectrum of antibacterial activity than penicillin G. 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. Penicillins Clinical Uses 3. Wider-spectrum penicillinase-susceptible drugs a. Ampicillin and amoxicillin When used in combination with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced. Note: In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides. Penicillins Penicillins Clinical Uses 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. Penicillins Clinical Uses 3. Wider-spectrum penicillinase-susceptible drugs b. Piperacillin and ticarcillin 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 B. Antibacterial Spectrum: Figure 6 – Stability of the penicillins to acid or the action of penicillinase. *Available only as parenteral preparation. Penicillins Routes of Administration: The combination of ampicillin with sulbactam, piperacillin with tazobactam, and the anti-staphylococcal penicillins nafcillin and oxacillin must be administered intravenously (IV) or intramuscularly (IM). Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations. Others are effective by the oral, IV, or IM routes. Penicillins Routes of Administration: Depot Forms: Procaine penicillin G and benzathine penicillin G are administered IM and serve as depot forms. They are slowly absorbed into the circulation and persist at low levels over a long time period. Penicillins Absorption: Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora. Food decreases the absorption of all the penicillinase-resistant penicillins because as gastric emptying time increases, The drugs are destroyed by stomach acid. Therefore, they should be taken on an empty stomach. Cell Wall Inhibitors Distribution: All the penicillins distribute well & cross the placental barrier, but none have been shown to have teratogenic effects. However, penetration into bone or (CSF) is insufficient for therapy unless these sites are inflamed Penicillins Penicillins Excretion: The primary route of excretion is by glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted. Nafcillin and oxacillin are metabolized in the liver. Probenecid inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter and, thus, can increase blood levels. Penicillins Penicillins 4. Adverse effects Allergy—Allergic reactions include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis. Methicillin causes interstitial nephritis. Nafcillin is associated with neutropenia. Complete cross-allergenicity between different penicillins should be assumed. 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 grampositive organisms or yeasts. Cephalosporins Cephalosporins The cephalosporins are β-lactam antibiotics closely related both structurally and functionally to penicillins. Most cephalosporins are produced semi-synthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid. Structural changes on the acyl side chain at the 7-position alter antibacterial activity and variations at the 3- position modify the pharmacokinetic profile (Figure 10). Cephalosporins have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the penicillins to certain β-lactamases. Cephalosporins Figure 10 – Structural features of cephalosporin antibiotics. Cephalosporins Mechanisms of Action and Resistance Cephalosporins: Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins. Cephalosporins are bactericidal against susceptible organisms. Cephalosporins less susceptible to penicillinases produced by staphylococci, but many bacteria are resistant through the production of other betalactamases that can inactivate cephalosporins. Resistance can also result from decreases in membrane permeability to cephalosporins and from changes in PBPs. Methicillin-resistant staphylococci are also resistant to cephalosporins. Cephalosporins Cephalosporins 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. Note: Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis in selected conditions Cephalosporins 2. Second-generation have slightly less activity against gram-positive organisms than the first-generation drugs but have an extended gram-negative coverage. Marked differences in activity occur among the drugs in this subgroup. Examples of clinical uses include infections caused by : 1. Anaerobe Bacteroides fragilis (cefotetan, cefoxitin). 2. Sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor). Cephalosporins 3. Third-generation drugs: (ceftazidime, cefoperazone, cefotaxime) include increased activity against gramnegative organisms resistant to other betalactam drugs and ability to penetrate the blood-brain barrier (EXCEPT cefoperazone and cefixime). Most are active against : 1. Providencia 2. Serratia marcescens 3. beta-lactamase producing strains of H influenzae and Neisseria. Cephalosporins 3. Third-generation drugs: Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains) Also have activity against Pseudomonas (cefoperazone, ceftazidime) and B fragilis (ceftizoxime) Ceftriaxone (parenteral) and cefixime (oral), currently drugs of choice in gonorrhea 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. Cephalosporins 5. Advanced Generation: Ceftaroline is a broad-spectrum, advanced-generation cephalosporin. It is the only β-lactam in the United States with activity against MRSA, and it is indicated for the treatment of complicated skin and skin structure infections and community-acquired pneumonia. The unique structure allows ceftaroline to bind to PBPs found in MRSA and penicillinresistant Streptococcus pneumoniae. In addition to its broad gram-positive activity, it also has similar gram-negative activity to the third-generation cephalosporin ceftriaxone. Cephalosporins Pharmacokinetics: Several cephalosporins are available for oral use, but most are administered parenterally. Cephalosporins with side chains may undergo hepatic metabolism, but the major elimination mechanism for drugs in this class is renal excretion via active tubular secretion. Cefoperazone and ceftriaxone are excreted mainly in the bile. Most first- and second-generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed. Cephalosporins Cephalosporins Adverse effects : Allergy—Cephalosporins cause a range of allergic reactions from skin rashes to anaphylactic shock. These reactions occur less frequently with cephalosporins than with penicillins. Complete cross-hypersensitivity between different cephalosporins should be assumed. Cross-reactivity between penicillins and cephalosporins is incomplete (5–10%) Cephalosporins may cause pain at intramuscular injection sites and phlebitis after I.V administration. Note: They may increase the nephrotoxicity of aminoglycosides when the two are administered together. Other β-Lactam Antibiotics Other β-Lactam Antibiotics 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. Aztreonam is 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, skin rash (NO cross allergenicity with penicillins). Other β-Lactam Antibiotics B. Imipenem, Doripenem, Meropenem, and Ertapenem: parenterally These drugs are carbapenems (chemically different from penicillins but retaining the beta-lactam ring structure) They have wide activity against gram-positive cocci (including some penicillin resistant pneumococci), gram-negative rods, and anaerobes. For pseudomonal infections, they are often used in combination with an aminoglycoside. MRSA strains of staphylococci are resistant. Other β-Lactam Antibiotics B. Imipenem, Doripenem, Meropenem, and Ertapenem: parenterally Imipenem is rapidly inactivated by renal dehydropeptidase-I and is administered in fixed combination with cilastatin, an inhibitor of this enzyme. Cilastatin increases the plasma half life of imipenem and inhibits the formation of potentially nephrotoxic metabolite. Other β-Lactam Antibiotics B. Imipenem, Doripenem, Meropenem, and Ertapenem: parenterally Adverse effects of imipenem-cilastatin include : 1. gastrointestinal distress 2. skin rash 3. At very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures). 4. There is partial cross allergenicity with the penicillins β-Lactamase Inhibitors β-Lactamase Inhibitors A. Clavulanic acid, sulbactam, and tazobactam Are used in fixed combinations with certain hydrolyzable penicillins. They are most active against plasmid-encoded beta-lactamases 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, Pseudomonas, and Serratia. Vancomycin 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. This action prevents elongation of the peptidoglycan chain and interferes with crosslinking. Resistance in strains of enterocci (vancomycin-resistant enterococci [VRE]) and staphylococci (vancomycin-resistant S aureus [VRSA]) involves a decreased affinity of vancomycin for the binding site. Vancomycin Vancomycin has a narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin resistant staphylococci (MRSA) and in combination with ceftriaxone for treatment of (PRSP). Vancomycin is a backup drug for treatment of infections caused by Clostridium difficile. Toxic effects of vancomycin include chills, fever, phlebitis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) from histamine release Fosfomycin Fosfomycin Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase. This action prevents the formation of N-acetylmuramic acid, an essential precursor molecule for peptidoglycan chain formation. Fosfomycin is excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MICs) ,So It is indicated for urinary tract infections caused by E. coli or E. faecalis. It maintains high concentrations in the urine over several days, allowing for a one-time dose Adverse effects include diarrhea, vaginitis, nausea, and headache. Daptomycin Daptomycin is a bactericidal, a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci. Daptomycin is indicated for the treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus. Daptomycin is inactivated by pulmonary surfactants; thus, it should never be used in the treatment of pneumonia. Creatine phosphokinase should be monitored since daptomycin may cause myopathy. Polymyxins Polymyxins The polymyxins are cation polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria. They have a detergent-like effect that disrupts cell membrane integrity, leading to leakage of cellular components and cell death. Polymyxins are concentration-dependent bactericidal agents with activity against most clinically important gram-negative bacteria, including P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter spp., and Enterobacter spp. However, alterations in the cell membrane, lipid polysaccharides allow many species of Proteus and Serratia to be intrinsically resistant. Only two forms of polymyxin are in clinical use today, polymyxin B and colistin (polymyxin E). Polymyxins Polymyxin B is available in parenteral, ophthalmic, otic, and topical preparations. Colistin is only available as a prodrug, colistimethate sodium, which is administered IV or inhaled via a nebulizer. The use of these drugs has been limited due to the increased risk of nephrotoxicity and neurotoxicity (for example, slurred speech, muscle weakness) when used systemically.