Pharmacology III-Lecture (2) PDF

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Cell Wall Inhibitors...

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Cell Wall Inhibitors Lecture(2)  Cephalosporins Includes the true cephalosporins (produced from Cephalosporium spp.) and cephamycins (produced from Streptomyces spp.). The cephalosporins are β-lactam antibiotics closely related both structurally and functionally to penicillins. They tend to be more resistant than the penicillins to certain β- lactamases. Most cephalosporins are produced semisynthetically 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.  Cephalosporins v Antibacterial spectrum Cephalosporins have been classified as first, second, third, fourth, and advanced ge n e rat i o n , b a s e d l a rge l y o n t h e i r bacterial susceptibility patterns and resistance to β-lactamases. Note: Commercially available cephalosporins are ineffective against L. monocytogenes, C. difficile, and the enterococci.  Cephalosporins v Antibacterial spectrum 1. First generation (Cefazolin, Cephalexin) The first-generation cephalosporins act as penicillin G substitutes. They are resistant to the staphylococcal penicillinase (that is, they cover MSSA). Agents in this generation also have modest activity against Proteus mirabilis, E. coli, and K. pneumoniae Most oral cavity anaerobes like Peptostreptococcus are sensitive, but the Bacteroides fragilis group is resistant. Isolates of S. pneumoniae resistant to penicillin are also resistant to first-generation cephalosporins.  Cephalosporins v Antibacterial spectrum 2. Second generation (Cefotetan, Cefoxitin, Cefuroxime) The second-generation cephalosporins display greater activity against gram-negative organisms, such as H. influenzae, Klebsiella species, Proteus species, Escherichia coli, and Moraxella catarrhalis, whereas activity against gram-positive organisms is weaker. Antimicrobial coverage of the cephamycins (cefotetan and cefoxitin) also includes anaerobes (for example, Bacteroides fragilis). They are the only cephalosporins commercially available with appreciable activity against gram-negative anaerobic bacteria. However, neither drug is first line because of the increasing prevalence of resistance among B. fragilis.  Cephalosporins v Antibacterial spectrum 3. Third generation (Cefotaxime, Ceftriaxone, Ceftazidime, Cefixime) A l t h o u g h t h ey a re l e s s p o te nt t h a n f i rst - ge n e rat i o n c e p h a l o s p o r i n s a ga i n s t M S S A , t h e t h i rd - g e n e ra t i o n cephalosporins have enhanced activity against gram-negative bacilli, including β-lactamase producing strains of H. influenzae and Neisseria gonorrhoeae. The spectrum of activity of this class includes enteric organisms, such as Serratia marcescens and Providencia species.  Cephalosporins v Antibacterial spectrum 3. Third generation Ceftriaxone and cefotaxime have become agents of choice in the treatment of meningitis. Ceftazidime has activity against P. aeruginosa; however, resistance is increasing and use should be evaluated on a case-by-case basis. Third-generation cephalosporins must be used with caution, as they are associated with significant “collateral damage,” including the induction of antimicrobial resistance and development of Clostridium difficile infection. Note: Fluoroquinolone use is also associated with collateral damage.  Cephalosporins v Antibacterial spectrum 4. Fourth generation (Cefepime) Cefepime is classified as a fourth-generation cephalosporin and must be administered parenterally. Cefepime has a wide antibacterial spectrum, with activity against streptococci and staphylococci (but only those that are methicillin susceptible). Cefepime is also effective against aerobic gram-negative organisms, such as Enterobacter species, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. When selecting an antibiotic that is active against P. aeruginosa, clinicians should refer to their local antibiograms (laboratory testing for the sensitivity of an isolated bacterial strain to different antibiotics) for direction.  Cephalosporins v Antibacterial spectrum 5. Advanced or fifth generation (Ceftaroline) Ceftaroline is a broad-spectrum, advanced-generation cephalosporin. It is the only β-lactam 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 penicillin-resistant Streptococcus pneumoniae. In addition to its broad gram-positive activity, it also has similar gram- negative activity to the third-generation cephalosporin ceftriaxone. Important gaps in coverage include P. aeruginosa, extended-spectrum β- lactamase (ESBL)-producing Enterobacteriaceae, and Acinetobacter baumannii.  Cephalosporins v Resistance Resistance to the cephalosporins is either due to the hydrolysis of the beta-lactam ring by β-lactamases or reduced affinity. v Pharmacokinetics 1. Administration Many of the cephalosporins must be administered IV or IM because of their poor oral absorption.  Cephalosporins v Pharmacokinetics 2. Distribution All cephalosporins distribute very well into body fluids. However, adequate therapeutic levels in the CSF, regardless of inflammation, are achieved with only a few cephalosporins. For example, ceftriaxone and cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by H. influenzae. Cefazolin is commonly used for surgical prophylaxis due to its activity against penicillinase-producing S. aureus, along with its good tissue and fluid penetration. 3. Elimination Cephalosporins are eliminated through the kidney. Therefore, doses must be adjusted in renal dysfunction to guard against accumulation and toxicity. One exception is ceftriaxone, which is excreted through the bile into the feces and, therefore, is frequently employed in patients with renal insufficiency.  Cephalosporins v Adverse effects Like the penicillins, the cephalosporins are generally well tolerated. However, allergic reactions are a concern. Cephalosporins should be avoided or used with caution in individuals with penicillin allergy. Current data suggest that the cross-reactivity between penicillin and cephalosporins is around 3% to 5%. The highest rate of allergic cross-sensitivity is between penicillin and first-generation cephalosporins. 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. Some cephalosporins may cause hypoprothrombinemia and disulfiram-like reactions with ethanol.  Cephalosporins v Cephalosporin and β-lactamase inhibitor combinations Ceftolozane is a third-generation cephalosporin combined with the β-lactamase inhibitor, tazobactam. Ceftazidime, a third-generation cephalosporin is combined with the β-lactamase inhibitor avibactam. Both of these combinations are indicated for the treatment of intra-abdominal infections (in combination with metronidazole) and for the management of complicated urinary tract infections. Given the extensive antimicrobial activity, ceftolozane–tazobactam and ceftazidime–avibactam are reserved for the treatment of infections due to multidrug-resistant pathogens. These combinations have narrow gram-positive and very limited anaerobic activity.  Other β-Lactam Antibiotics Carbapenems Carbapenems are synthetic β-lactam antibiotics that differ in structure from the penicillins in that the sulfur atom of the thiazolidine ring has been externalized and replaced by a carbon atom. Imipenem, meropenem, doripenem, and ertapenem are drugs in this group.  Other β-Lactam Antibiotics Carbapenems v Antibacterial spectrum Imipenem resists hydrolysis by most β-lactamases, but not the metallo-β-lactamases. This drug plays a role in empiric therapy because it is active against β-lactamase–producing gram-positive and gram- negative organisms, anaerobes, and P. aeruginosa. Meropenem and doripenem have antibacterial activity similar to that of imipenem. Doripenem may retain activity against resistant isolates of Pseudomonas. Unlike other carbapenems, ertapenem lacks coverage against P. aeruginosa, Enterococcus species, and Acinetobacter species.  Other β-Lactam Antibiotics Carbapenems v Pharmacokinetics Imipenem, and doripenem are administered IV and penetrate well into body tissues and fluids, including the CSF when the meninges are inflamed. Meropenem is known to reach therapeutic levels in bacterial meningitis even without inflammation. These agents are excreted by glomerular filtration, so doses of these agents must be adjusted in patients with renal insufficiency. Imipenem undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule. Compounding imipenem with cilastatin protects the parent drug from renal dehydropeptidase and, thus, prolongs its activity in the body. Now, imipenem is available as a coformulation with the β-lactamase inhibitor relebactam (imipenem/cilastatin/relebactam), which extends its spectrum against organisms producing carbapenemases. The other carbapenems do not require coadministration of cilastatin. Ertapenem is administered IV once daily.  Other β-Lactam Antibiotics Carbapenems v Adverse effects Imipenem/cilastatin can cause nausea, vomiting, and diarrhea. Eosinophilia and neutropenia are less common than with other β- lactams. High levels of imipenem may provoke seizures; however, the other carbapenems are less likely to do so. While those with true penicillin allergy should use carbapenems cautiously, the cross-reactivity rate seen in studies is very low (less than 1%).  Other β-Lactam Antibiotics Carbapenems v Carbapenem/β-lactamase inhibitor combination Meropenem-vaborbactam is a combination of a carbapenem and a β- lactamase inhibitor. It is approved for the treatment of complicated urinary tract infections including pyelonephritis. This combination agent has activity against Enterobacteriaceae producing a broad spectrum of β-lactamases, except metallo-β- lactamases.  Other β-Lactam Antibiotics Monobactams The monobactams, which also disrupt bacterial cell wall synthesis, are unique because the β-lactam ring is not fused to another ring. Aztreonam, which is the only commercially available monobactam, has antimicrobial activity directed primarily against gram-negative pathogens, including the Enterobacteriaceae and P. aeruginosa. It lacks activity against gram- positive organisms and anaerobes. Aztreonam is administered either IV or IM and can accumulate in patients with renal failure. Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash, and, occasionally, abnormal liver function tests. This drug has a low immunogenic potential, and it shows little cross-reactivity with antibodies induced by other β-lactams. Thus, this drug may offer a safe alternative for treating patients who are allergic to other penicillins, cephalosporins, or carbapenems.  Vancomycin Vancomycin is a tricyclic glycopeptide active against aerobic and anaerobic gram-positive bacteria, including MRSA, methicillin- resistant Staphylococcus epidermidis (MRSE), Enterococcus spp., and Clostridium difficile. Following cell entry, it binds to peptidoglycan precursors, disrupting polymerization and cross-linking required for maintenance of cell wall integrity. This interaction results in bactericidal activity. Due to an increase in MRSA, vancomycin is commonly used in patients with skin and soft tissue infections, infective endocarditis, and nosocomial pneumonia. Frequency of administration is dependent on renal function. Therefore, monitoring of creatinine clearance is required to optimize exposure and minimize toxicity.  Vancomycin Common adverse events include nephrotoxicity, infusion-related reactions (red man syndrome and phlebitis), and ototoxicity. Emergence of resistance is uncommon within Streptococcus and Staphylococcus spp., but frequently observed in Enterococcus faecium infections. Resistance is driven by alterations in binding affinity to peptidoglycan precursors. Due to the prevalence of resistance, prudent use of vancomycin is warranted. Lastly, vancomycin has poor absorption after oral administration, so use of the oral formulation is limited to the management of Clostridium difficile infection in the colon (after metronidazole).  Lipoglycopeptides Telavancin, oritavancin, and dalbavancin are bactericidal concentration-dependent semisynthetic lipoglycopeptide antibiotics with activity against gram-positive bacteria. The lipoglycopeptides maintain a spectrum of activity similar to vancomycin, affecting primarily staphylococci, streptococci, and enterococci. Because of structural differences, they are more potent than vancomycin and may have activity against vancomycin-resistant isolates. The lipid tail is essential in anchoring the drug to the cell walls to improve target site binding. Additionally, telavancin and oritavancin disrupt membrane potential. In combination, these actions improve activity and minimize selection of resistance. Telavancin is considered an alternative to vancomycin in treating acute bacterial skin and skin structure infections (ABSSSIs) and hospital-acquired pneumonia caused by resistant gram-positive organisms, including MRSA. The use of telavancin in clinical practice may be limited by its adverse effect profile, which includes nephrotoxicity, risk of fetal harm, and interactions with medications known to prolong the QTc interval (for example, fluoroquinolones, macrolides). Prior to initiation, assessment of renal function, pregnancy status, and current medications is needed to ensure safe administration.  Daptomycin Daptomycin is a bactericidal concentration-dependent cyclic lipopeptide antibiotic that is an alternative to other agents, such as vancomycin or linezolid, for treating infections caused by resistant gram-positive organisms, including MRSA and vancomycin-resistant enterococci (VRE). Daptomycin is indicated for the treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus, including those with right-sided infective endocarditis. Additionally, daptomycin is inactivated in the lung; thus, it should never be used in the treatment of pneumonia. Daptomycin is dosed IV once daily.  Fosfomycin Fosfomycin is a bactericidal synthetic derivative of phosphonic acid. It blocks cell wall synthesis by inhibiting the enzyme enolpyruvyl transferase, a key step in peptidoglycan synthesis. It is indicated for urinary tract infections caused by E. coli or E. faecalis and is considered first-line therapy for acute cystitis. Due to its unique structure and mechanism of action, cross-resistance with other antimicrobial agents is unlikely. Fosfomycin is rapidly absorbed after oral administration and distributes well to the kidneys, bladder, and prostate. The drug is excreted in its active form in the urine and maintains high concentrations over several days, allowing for a one-time dose. The most commonly reported adverse effects include diarrhea, vaginitis, nausea, and headache.  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 orally (diarrhea), IV (UTI) or inhaled via a nebulizer (pneumonia). 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. However, with increasing gram-negative resistance, they are now commonly used as salvage therapy for patients with multidrug-resistant infections. Careful dosing and monitoring of adverse effects are important to maximize the safety and efficacy of these agents.  Bacitracin Bacitracin inhibits cell wall peptidoglycan synthesis by blocking the regeneration of C55-isoprenyl phosphate (bactroprenol phosphate), the lipid carrier molecule. Bacitracin is active against gram-positive cocci, including staphylococci and streptococci, and it is primarily used for the topical treatment of minor skin and ocular infections. It is often combined with polymyxin or neomycin in ointments and creams. Bacitracin is very nephrotoxic and is not used systemically.  Summary β-lactam antibiotics, vancomycin, bacitracin, and fosfomycin are drugs that inhibit bacterial cell wall synthesis. The β-lactam antibiotics inhibit the transpeptidase reaction that cross-links the peptidoglycan component of the cell wall. These antibiotics include penicillins, cephalosporins, aztreonam, and carbapenems. β-lactamase inhibitors (avibactam, clavulanate, sulbactam, or tazobactam) are administered in combination with a β-lactam antibiotic to prevent degradation of the antibiotic by bacteria. Narrow-spectrum penicillins (e.g., penicillin G) are primarily active against gram- positive cocci and spirochetes; penicillinase-resistant penicillins (e.g., dicloxacillin and nafcillin) are used to treat staphylococcal infections; and extended-spectrum penicillins (e.g.,amoxicillin) are active against various gram-negative bacilli.  Summary Acid-stable penicillins (e.g., penicillin V, amoxicillin, and dicloxacillin) can be given orally, whereas acid-labile drugs (piperacillin) must be given parenterally. Most penicillins are eliminated primarily by renal tubular secretion, a process that is inhibited by probenecid. Two long-acting forms of penicillin G (procaine and benzathine penicillin G) are available for intramuscular administration. Penicillins can elicit any of the four types of hypersensitivity reactions, including anaphylactic shock and other immediate hypersensitivity reactions mediated by immunoglobulin E. Cephalosporins are semisynthetic antibiotics that are subdivided into four generations on the basis of their antimicrobial spectrum. The activity against gram-negative organisms increases from the first to the fourth generation.  Summary Some cephalosporins (e.g., cefazolin) are eliminated by renal tubular secretion, whereas others (e.g., ceftriaxone) are eliminated in the bile. Ceftriaxone has a much longer half-life than other cephalosporins, enabling it to be used as single-dose treatment for certain infections, including gonorrhea. Carbapenems (e.g., imipenem and meropenem) are active against a broad spectrum of bacteria, including many strains of gram-negative bacteria resistant to other antibiotics. Aztreonam is a monobactam antibiotic that is active against aerobic gram-negative bacilli. It does not show cross-sensitivity with other β-lactam drugs. Vancomycin is a glycopeptide antibiotic that is active against gram-positive organisms, including methicillin resistant staphylococci (MRSA), enterococci, and Clostridiodes difficile. Q1: Which generation of cephalosporins is most effective against Pseudomonas aeruginosa? A) First generation (e.g., cephalexin) B) Second generation (e.g., cefuroxime) C) Third generation (e.g., ceftriaxone) D) Fourth generation (e.g., cefepime) Q2: Which of the following is a characteristic feature of monobactams, such as aztreonam? A) Broad-spectrum activity against gram-positive bacteria B) Exclusively active against gram-negative bacteria, including Enterobacteriaceae C) High risk of cross-reactivity with penicillin allergies D) Effective against MRSA infections Q3: Which of the following carbapenems is associated with a risk of seizures, especially in patients with renal impairment or CNS disorders? A) Ertapenem B) Meropenem C) Imipenem D) Doripenem Q4: Vancomycin is used as a first-line treatment for which of the following infections? A) Methicillin-resistant Staphylococcus aureus (MRSA) B) Pseudomonas aeruginosa C) Escherichia coli D) Mycoplasma pneumoniae Q5: Why is daptomycin not suitable for treating pneumonia? A) It has a narrow spectrum of activity. B) It is rapidly metabolized in the liver. C) It is inactivated by surfactant in the lungs. D) It causes severe nephrotoxicity. Q6: What is the primary mechanism of action of polymyxins (e.g., polymyxin B and colistin)? A) Inhibition of protein synthesis B) Disruption of cell membrane integrity C) Inhibition of DNA synthesis D) Inhibition of cell wall synthesis Q7: Why is bacitracin mainly used topically and not systemically? A) Poor absorption in the gastrointestinal tract B ) H i g h r i s k o f n e p h ro tox i c i t y w h e n u s e d systemically C) Rapid inactivation by hepatic enzymes D) Limited spectrum of activity Q8: Which of the following cephalosporins has activity against methicillin-resistant Staphylococcus aureus (MRSA)? A) Cefazolin B) Cefepime C) Ceftaroline D) Cefotaxime Q9: Which carbapenem is unique in lacking activity against Pseudomonas aeruginosa? A) Ertapenem B) Imipenem C) Meropenem D) Doripenem Q10: Which of the following adverse effects is associated with rapid infusion of vancomycin? A) Red man syndrome B) Stevens-Johnson syndrome C) Hemolytic anemia D) Torsades de pointes thank you