Cell wall inhibitors
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This document discusses cell wall inhibitors, specifically penicillins, cephalosporins, and carbapenems. It describes their mechanisms of action as inhibiting bacterial cell wall synthesis, their spectra of activity against gram-positive and gram-negative bacteria, and important mechanisms of resistance including beta-lactamase production. Important adverse effects and pharmacokinetics are also summarized.
![Antibacterial spectrum
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Cell wall inhibitors
- 2. Chemotherapy • Use of chemicals in infectious diseases to destroy microorganisms without demaging the host tissues
- 3. Cell Wall Inhibitors • Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wall-a structure that mammalian cells do not possess. • The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links.
- 4. Cell Wall Inhibitors • To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms; they have little or no effect on bacteria that are not growing and dividing. • The most important members of this group of drugs are the beta-lactam antibiotics (named after the beta-lactam ring that is essential to their activity) and vancomycin.
- 5. Classification of cell wall Inhibitors
- 6. I. Penicillins • The penicillins are among the most widely effective antibiotics and also the least toxic drugs known, but increased resistance has limited their use. • Members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue .
- 8. Penicillins • The nature of this side chain affects the antimicrobial spectrum,stability to stomach acid, and susceptibility to bacterial degradative enzymes (beta-lactamases).
- 9. Penicillins • Cleavage of the beta-lactum ring destroys antibiotic activity; some resistant bacteria produce beta-lactamases (pencillinases).
- 10. A. Mechanism of action • Beta lactum antibiotics inhibit transpeptidases and thus inhibit the synthesis of peptidoglycan,resulting in the formation of cell wall deficient bacteria.These undergo lysis.Thus pencillin is bactercidal.
- 11. A. Mechanism of action • The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. These drugs are thus bactericidal.
- 13. Mechanism of action • Penicillin-binding proteins: Penicillins inactivate numerous proteins on the bacterial cell membrane. These penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall and in the maintenance of the morphologic features of the bacterium. Exposure to these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria.
- 14. Mechanism of action • The number of PBPs varies with the type of organism. Alterations in some of these target molecules provide the organism with resistance to the penicillins.
- 15. Mechanism of action • Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains
- 16. B. Antibacterial spectrum • The antibacterial spectrum of the various penicillins is determined, in part, by their ability to cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space.
- 18. Antibacterial spectrum • In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins and, therefore, in the absence of resistance are susceptible to these drugs. Gram-negative microorganisms have an outer lipopolysaccharide membrane (envelope) surrounding the cell wall that presents a barrier to the water-soluble penicillins.
- 19. Antibacterial spectrum However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry. [Note: Pseudomonas aeruginosa lacks porins, making these organisms intrinsically resistant to many antimicrobial agents.]
- 20. Antibacterial spectrum 1-Natural penicillins: These penicillins, which include those classified as antistaphylococcal, are obtained from fermentations of the mold Penicillium chrysogenum. Other penicillins, such as ampicillin, are called semisynthetic.
- 21. Antibacterial spectrum • Penicillin G (benzylpenicillin) is the cornerstone of therapy for infections caused by a number of gram-positive and gram- negative cocci, gram-positive bacilli, and spirochetes . Penicillin G is susceptible to inactivation by beta-lactamases (penicillinases).
- 23. Antibacterial spectrum • Penicillin V has a spectrum similar to that of penicillin G, but it is not used for treatment of bacteremia because of its higher minimum bactericidal concentration (the minimum amount of the drug needed to eliminate the infection). Penicillin V is more acid-stable than penicillin G. It is often employed orally in the treatment of infections, where it is effective against some anaerobic organisms.
- 24. Antibacterial spectrum 2-Antistaphylococcal penicillins: Methicillin, nafcillin, oxacillin , and dicloxacillin are penicillinase-resistant penicillins. Their use is restricted to the treatment of infections caused by penicillinase-producing staphylococci.
- 25. Antibacterial spectrum 3-Extended-spectrum penicillins: Ampicillin and amoxicillin have an antibacterial spectrum similar to that of penicillin G but are more effective against gram-negative bacilli. They are therefore referred to as extended- spectrum penicillins . Ampicillin is the drug of choice for the gram- positive bacillus Listeria monocytogenes.
- 27. Antibacterial spectrum 4-Antipseudomonal penicillins: Carbenicillin, ticarcillin, and piperacillin are called antipseudomonal penicillins because of their activity against P. aeruginosa . Piperacillin is the most potent of these antibiotics. They are effective against many gram-negative bacilli. • Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam, respectively, extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms.
- 30. Antibacterial spectrum 5-Penicillins and aminoglycosides: The antibacterial effects of all the beta-lactam antibiotics are synergistic with the aminoglycosides. Because cell wall synthesis inhibitors alter the permeability of bacterial cells, these drugs can facilitate the entry of other antibiotics (such as aminoglycosides) that might not ordinarily gain access to intracellular target sites. This can result in enhanced antimicrobial activity.
- 31. C. Resistance • Natural resistance to the penicillins occurs in organisms that either • lack a peptidoglycan cell wall (for example, mycoplasma) or • have cell walls that are impermeable to the drugs.
- 32. Resistance • Acquired resistance to the penicillins by plasmid transfer has become a significant clinical problem, because an organism may become resistant to several antibiotics at the same time due to acquisition of a plasmid that encodes resistance to multiple agents. Multiplication of such an organism will lead to increased dissemination of the resistance genes.
- 33. Resistance • By obtaining a resistance plasmid, bacteria may acquire one or more of the following properties, thus allowing it to withstand beta- lactam antibiotics. • Beta-Lactamase activity • Decreased permeability to the drug • Altered PBPs
- 34. Resistance • Beta-Lactamase activity: This family of enzymes hydrolyzes the cyclic amide bond of the beta-lactam ring, which results in loss of bactericidal activity . They are the major cause of resistance to the penicillins and are an increasing problem.
- 35. Resistance • Gram-positive organisms secrete beta- lactamases extracellularly, whereas gram- negative bacteria confine the enzymes in the periplasmic space between the inner and outer membranes.
- 37. Resistance • Decreased permeability to the drug: Decreased penetration of the antibiotic through the outer cell membrane prevents the drug from reaching the target PBPs. • The presence of an efflux pump can also reduce the amount of intracellular drug.
- 38. Resistance • Altered PBPs: Modified PBPs have a lower affinity for beta-lactam antibiotics, requiring clinically unattainable concentrations of the drug to effect inhibition of bacterial growth.
- 39. D- Pharmacokinetics • Administration: The route of administration of a beta- lactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection. • Routes of administration: Ticarcillin, carbenicillin, piperacillin, and the combinations of ampicillin with sulbactam, ticarcillin with clavulanic acid, and piperacillin with tazobactam, must be administered intravenously (IV) or intramuscularly (IM).
- 40. Pharmacokinetics Penicillin V, amoxicillin, amoxicillin combined with clavulanic acid, and the indanyl ester of carbenicillin (for treatment of urinary tract infections) are available only as oral preparations. Others are effective by the oral, IV, or IM routes.
- 42. Pharmacokinetics • Absorption: Most of the penicillins are incompletely absorbed after oral administration. However, amoxicillin is almost completely absorbed.
- 43. Pharmacokinetics • Distribution: The beta-lactam antibiotics distribute well throughout the body. All the penicillins cross the placental barrier, but none has been shown to be teratogenic.
- 44. Pharmacokinetics Excretion • More than 90% of an administered dose is excreted unchanged in the urine by the glomerular filtration and active tubular secrtions.The remainder is metabolized by the liver to pencilloic acid derivatives, which may act as antigenic determinants in pencilline hypersensitivity
- 45. E. Adverse reactions • Penicillins are among the safest drugs. However, the following adverse reactions may occur. • Hypersensitivity: This is the most important adverse effect of the penicillins. The major antigenic determinant of penicillin hypersensitivity is its metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction.
- 46. Adverse reactions • Diarrhea: This effect, which is caused by a disruption of the normal balance of intestinal microorganisms, is a common problem.
- 47. Adverse reactions • Hematologic toxicities: Decreased coagulation may be observed with the antipseudomonal penicillins (carbenicillin and ticarcillin) and, to some extent, with penicillin G. • It is generally a concern when treating patients who are predisposed to hemorrhage or those receiving anticoagulants.
- 48. Adverse reactions • Cation toxicity: Penicillins are generally administered as the sodium or potassium salt. Toxicities may be caused by the large quantities of sodium or potassium that accompany the penicillin.Hyperkalemia may result from IV administration of potassium pencillin. • This can be avoided by using the most potent antibiotic, which permits lower doses of drug and accompanying cations.
- 49. Cephalosporins • The cephalosporins are beta-lactam antibiotics that are closely related both structurally and functionally to the penicillins. • Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
- 50. Cephalosporins • 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 beta-lactamases.
- 51. A. Antibacterial spectrum • Cephalosporins have been classified as first, second, third, or fourth generation, based largely on their bacterial susceptibility patterns and resistance to beta-lactamases .
- 53. Antibacterial spectrum • First generation: The first-generation cephalosporins act as penicillin G substitutes. • They are resistant to the staphylococcal penicillinase and also have activity against Proteus mirabilis, E. coli, and Klebsiella pneumoniae.
- 55. Antibacterial spectrum • Second generation: The second-generation cephalosporins display greater activity against three additional gram-negative organisms: • H. influenzae, • Enterobacter aerogenes, and • some Neisseria species, • whereas activity against gram-positive organisms is weaker
- 57. Antibacterial spectrum • Third generation: These cephalosporins have assumed an important role in the treatment of infectious disease. • Although inferior to first-generation cephalosporins in regard to their activity against gram-positive cocci, the third-generation cephalosporins have enhanced activity against gram-negative bacilli, as well as most other enteric organisms plus Serratia marcescens. Ceftriaxone or cefotaxime have become agents of choice in the treatment of meningitis.
- 58. • Klebsiella pneumonia • Proteus mirabilis • Pseudomonas aeruginosa
- 59. Antibacterial spectrum • Fourth generation: Cefepime is classified as a fourth-generation cephalosporin and must be administered parenterally. • Cefepime has a wide antibacterial spectrum, being active against streptococci and staphylococci. • Cefepime is also effective against aerobic gram- negative organisms, such as enterobacter, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa.
- 60. B. Resistance • Mechanisms of bacterial resistance to the cephalosporins are essentially the same as those described for the penicillins.
- 61. C. Pharmacokinetics • Administration: Many of the cephalosporins must be administered IV or IM because of their poor oral absorption. • Distribution: All cephalosporins distribute very well into body fluids except CSF. • Fate: Biotransformation of cephalosporins by the host is not clinically important. Elimination occurs through tubular secretion and/or glomerular filtration .
- 63. D. Adverse effects • The cephalosporins produce a number of adverse affects, some of which are unique to particular members of the group.
- 64. Adverse effects • Allergic manifestations: Patients who have had an anaphylactic response to penicillins should not receive cephalosporins. The cephalosporins should be avoided or used with caution in individuals who are allergic to penicillins (about 5- 15 percent show cross-sensitivity). • In contrast, the incidence of allergic reactions to cephalosporins is one to two percent in patients without a history of allergy to penicillins.
- 65. Adverse effects • Nephrotoxicity may develop with prolonged administration,dosages should be adjusted in the presence of renal diseases.
- 66. Adverse effects • Intolerance to alcohol (a disulfiram-like reaction) has been noted with cephalosporins that contain the methyl-acetaldehyde (MTT) group, including cefamandole (no longer available in the United States), cefotetan, moxalactam, and cefoperazone.
- 67. Adverse effects Bleeding Bleeding is also associated with agents that contain the MTT group because of anti- Vitamin k effects. Administration of the vitamin correct the problem.
- 69. Carbapenems • Carbapenems are a class of beta‐lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most beta‐lactamases.
- 71. Carbapenems • Carbapenems are one of the antibiotics of last resort for many bacterial infections, such as Escherichia coli (E. coli) and Klebsiella pneumoniae. • Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, due to production of an enzyme named NDM‐1 (New Delhi metallo‐beta‐lactamase).
- 72. Carbapenems • There are currently no new antibiotics in the pipeline to combat bacteria resistant to carbapenems
- 73. Carbapenems • The following drugs belong to the carbapenem class: • Imipenem • Meropenem • Ertapenem • Doripenem • Panipenem/betamipron • Biapenem
- 74. B. Monobactams • The monobactams, which also disrupt bacterial cell wall synthesis. • Aztreonam, which is the only commercially available monobactam, has antimicrobial activity directed primarily against the enterobacteriaceae, but it also acts against aerobic gram‐negative rods, including P. aeruginosa. • It lacks activity against gram‐positive organisms and anaerobes. This narrow antimicrobial spectrum prevent its use alone in empiric therapy.
- 76. Monobactams • Aztreonam is resistant to the action of betalactamases. • It is administered either IV or IM and is excreted in the urine. It can accumulate in patients with renal failure. Aztreonam is relatively nontoxic, but it may cause phlebitis.
- 77. Monobactams • this drug may offer a safe alternative for treating patients who are allergic to penicillins and/or cephalosporins.
- 78. V. Beta‐Lactamase Inhibitors • Hydrolysis of the beta‐lactam ring, either by enzymatic cleavage with a beta‐lactamase or by acid, destroys the antimicrobial activity of a beta‐lactam antibiotic. Beta‐Lactamase inhibitors, such as clavulanic acid, sulbactam , and tazobactam, contain a beta‐lactam ring but, by themselves, do not have significant antibacterial activity. Instead, they bind to and inactivate beta‐lactamases, thereby protecting the antibiotics that are normally substrates for these enzymes.
- 79. Beta‐Lactamase Inhibitors • The beta‐lactamase inhibitors are therefore formulated in combination with betalactamase sensitive antibiotics. • For example, the effect of clavulanic acid and amoxicillin on the growth of betalactamase producing E. coli.
- 81. VI. Vancomycin • Vancomycin is a tricyclic glycopeptide that has become increasingly important because of its effectiveness against multiple drug‐resistant organisms, such as Methicillin-resistant Staphylococcus aureus(MRSA )and enterococci.
- 82. A. Mode of action • Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization, thus weakening the cell wall and damaging the underlying cell membrane.
- 83. B. Antibacterial spectrum • Vancomycin is effective primarily against gram‐positive organisms . • It has been lifesaving in the treatment of MRSA and methicillin‐resistant Staphylococcus epidermidis (MRSE) infections as well as enterococcal infections.
- 84. Antibacterial spectrum • Vancomycin acts synergistically with the aminoglycosides, and this combination can be used in the treatment of enterococcal endocarditis.
- 85. C. Resistance • Vancomycin resistance can be caused by plasmid‐mediated changes in permeability to the drug or by decreased binding of vancomycin to receptor molecules.
- 86. D. Pharmacokinetics • Slow IV infusion is employed for treatment of systemic infections or for prophylaxis. • Metabolism of the drug is minimal, and 90 to 100 percent is excreted by glomerular filtration. • The normal half‐life of vancomycin is 6 to 10 hours
- 87. E. Adverse effects • Side effects are a serious problem with vancomycin and include local pain and/or phlebitis at the infusion site. • Flushing(red man syndrome ) results from histamine release associated with a rapid infusion. • Ototoxicity and nephrotoxicity are more common when vancomycin is administered with another drug (for example, an aminoglycoside) that can also produce these effects.