Antimicrobial Therapy - Cell Wall Synthesis Inhibitors PDF

Antimicrobial Therapy Drugs That Weaken the Bacterial Cell Wall I: Penicillin and cephalosporins Dr. Zainab zaki zakaraya Al-Ahliyya Amman University Faculty of Pharmacy  Mechanism of Action Because they have a beta-lactam ring in their structure, t...

Antimicrobial Therapy Drugs That Weaken the Bacterial Cell Wall I: Penicillin and cephalosporins Dr. Zainab zaki zakaraya Al-Ahliyya Amman University Faculty of Pharmacy  Mechanism of Action Because they have a beta-lactam ring in their structure, the penicillins are known as beta-lactam antibiotics The beta-lactam family also includes the cephalosporins, carbapenems, and aztreonam All of the beta-lactam antibiotics share the same mechanism of action: disruption of the bacterial cell wall  Mechanism of Action Penicillins weaken the cell wall, causing bacteria to take up excessive amounts of water and rupture. They are considered bactericidal Penicillins weaken the cell wall by two actions: 1. Inhibition of transpeptidases-enzymes critical to cell wall synthesis 2. Activation of autolysins-bacterial enzymes that cleave bonds in the cell wall Transpeptidases and autolysins are called penicillin-binding proteins (PBPs), because penicillins must bind to them to produce antibacterial effects  Mechanisms of Bacterial Resistance to penicillins 1. Inability of penicillins to reach their targets (PBPs) 2. Inactivation of penicillins by bacterial enzymes (B- lactamases) 3. Production of PBPs that have a low affinity for penicillins. The Gram-negative And Gram Positive Cell Envelope The gram-positive bacteria: cell envelope has only two layers: the cytoplasmic membrane plus a relatively thick cell wall that can be readily penetrated by penicillins, giving them easy access to PBPs on the cytoplasmic membrane The gram-negative: cell envelope has three layers: the cytoplasmic membrane, a relatively thin cell wall, and an additional outer membrane. The outer membrane, however, is difficult to penetrate. As a result, only certain penicillins (e.g., ampicillin) are able to cross it and thereby reach PBPs on the  Bacterial Resistance Penicillinases (Beta-Lactamases): Gram-positive organisms produce large amounts of these enzymes and then export them into the surrounding medium. In contrast, gram-negative bacteria produce penicillinases in relatively small amounts and, rather than exporting them to the environment, secrete them into the periplasmic space-Staph. Aureus Altered Penicillin-Binding Proteins: Methicillin resistant Staphylococcus aureus (MRSA) production of PBPs with a low affinity for penicillins and almost all other beta-lactam antibiotics  Penicillin Class Drug Drug Clinically Useful Antimicrobial Spectrum Narrow-spectrum penicillins: Penicillin G Streptococcus species, penicillinase Penicillin V Neisseria species, many sensitive anaerobes, spirochetes, others Narrow-spectrum penicillins: Nafcillin Staphylococcus aureus penicillinase Oxacillin resistant (antistaphylococcal Dicloxacillin penicillins) Broad-spectrum penicillins Ampicillin Haemophilus influenzae, (aminopenicillins) Amoxicillin Escherichia coli, Proteus mirabilis, enterococci, Neisseria gonorrhoeae Extended-spectrum penicillin Piperacillin Same as broad-spectrum (antipseudomonal penicillin) Ticarcillin penicillins plus Pseudomonas Carbenicillin aeruginosa,  Penicillin Allergy Penicillins are the most common cause of drug allergy. Between 0.4% and 7% of patients who receive penicillins experience an allergic reaction. Severity can range from a minor rash to life-threatening anaphylaxis. Penicillin reactions are classified as immediate, accelerated, and delayed. Immediate reactions occur 2 to 30 minutes after drug administration; accelerated reactions occur within 1 to 72 hours; and delayed reactions occur within days to weeks. Immediate and accelerated reactions are mediated by immunoglobulin E (IgE) antibodies. Anaphylaxis (laryngeal edema, bronchoconstriction, severe hypotension) is an immediate hypersensitivity reaction, mediated by IgE  Penicillins Combined With a Beta-Lactamase Inhibitor By combining a betalactamase inhibitor with a penicillinase-sensitive penicillin, we can extend the antimicrobial spectrum of the penicillin Ampicillin/sulbactam Amoxicillin/clavulanate Piperacillin/tazobactam Sulbactam, tazobactam, and clavulanic acid (clavulanate) are Beta-Lactamase Inhibitors and not available alone but only in fixed-dose combinations with a penicillin  Cephalosporins The cephalosporins are beta-lactam antibiotics similar in structure and actions to the penicillins. These drugs are bactericidal, often resistant to beta- lactamases, and active against a broad spectrum of pathogens. Their toxicity is low These agents bind to penicillin-binding proteins (PBPs) and thereby (1) disrupt cell wall synthesis and (2) activate autolysins (enzymes that cleave bonds in the cell wall)  Classification and Antimicrobial Spectra 5 generations The generations differ significantly with respect to antimicrobial spectrum and susceptibility to beta- lactamases In general, as we progress from first-generation agents to fifth-generation agents, there is 1. Increasing activity against gram-negative bacteria and anaerobes 2. Increasing resistance to destruction by beta- lactamases 3. Increasing ability to reach the cerebrospinal fluid (CSF).  First Generation Cephalexin Is highly active against gram-positive bacteria The first-generation agents have only modest activity against gram-negative bacteria and do not reach effective concentrations in the CSF  Second Generation Cefoxitin Enhanced activity against gram-negative bacteria. None of the second-generation agents is active against pseudomonas aeruginosa. These drugs do not reach effective concentrations in the CSF  Third Generation Cefotaxime Have a broad spectrum of antimicrobial activity. Because of increased resistance to beta-lactamases, these drugs are considerably more active against gram-negative aerobes than are the first- and second-generation agents. Some third-generation cephalosporins (Ceftazidime) have important activity against P. Aeruginosa. Others (Cefotaxime and Cefixime) lack such activity. In contrast to first- and second-generation cephalosporins, the third-generation agents reach clinically effective concentrations in the CSF  Fourth Generation Cefepime, the only fourth-generation cephalosporin Highly resistant to beta-lactamases and has a very broad antibacterial spectrum. Activity against P. Aeruginosa equals that of ceftazidime. Penetration to the CSF is good  Fifth Generation Ceftaroline Has a spectrum like that of the third-generation agents, but with one important exception: ceftaroline is the only cephalosporin with activity against MRSA.  Pharmacokinetics Absorption. Because of poor absorption from the GI tract, many cephalosporins must be administered parenterally (IM or IV). Cefadroxil-1, Cephalexin-1, Cefaclor-2, Cefuroxime-2, Cefdinir-3, Cefixime-3 are administered orally Elimination Practically all cephalosporins are eliminated by the kidneys; excretion is by a combination of glomerular filtration and active tubular secretion. In patients with renal insufficiency, dosages of most cephalosporins must be reduced (to prevent accumulation to toxic levels). Ceftriaxone—is eliminated largely by the liver and dosage reduction is unnecessary in patients with renal impairment.  Adverse Effects Allergic Reactions: Hypersensitivity reactions are the most frequent adverse events. Maculopapular rash that develops several days after the onset of treatment is most common. Severe, immediate reactions (e.g., bronchospasm, anaphylaxis) are rare Only 1% of penicillin-allergic patients experience an allergic reaction if given a cephalosporin. Bleeding: Two cephalosporins—cefotetan and ceftriaxone— can cause bleeding tendencies. The mechanism is reduction of prothrombin levels through interference with vitamin K metabolism Thrombophlebitis: Thrombophlebitis may develop during IV infusion. This reaction can be minimized by rotating the infusion site and by administering cephalosporins slowly and in dilute solution  Carbapenems Carbapenems are beta-lactam antibiotics that have very broad antimicrobial spectra—although none is active against MRSA. Four carbapenems are available: imipenem, meropenem, ertapenem, and doripenem, all are parenteral To delay emergence of resistance, these drugs should be reserved for patients who cannot be treated with a more narrow-spectrum agent.  Imipenem Broad antimicrobial spectrum As a result, imipenem may be of special use for treating mixed infections in which anaerobes, Staph. aureus, and gram-negative bacilli may all be involved. Mechanism of Action: Imipenem binds to two PBPs, causing weakening of the bacterial cell wall with subsequent cell lysis and death. Pharmacokinetics Elimination is primarily renal Imipenem is not absorbed from the GI tract and hence must be given intravenously. Imipenem is supplied in fixed-dose combinations with cilastatin, a compound that inhibits destruction of imipenem by renal enzymes.  Imipenem-Adverse Effects Gastrointestinal effects (nausea, vomiting, diarrhea) are most common. Superinfections with bacteria or fungi develop in about 4% of patients. Rarely, seizures have occurred Cross-sensitivity with penicillins is low—only about 1%