Pharma - Other Beta Lactams (MQ) PDF

1 461151 I Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Cephalosporins/Carbapenems Fall 2024 Introduction to cephalosporins The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Cephalosporium acremonium  They are li...

1 461151 I Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Cephalosporins/Carbapenems Fall 2024 Introduction to cephalosporins The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Cephalosporium acremonium  They are like penicillins, but more stable to many bacterial β-lactamases → broader spectrum of activity  Some strains of E. coli and Klebsiella species express extended-spectrum β -lactamases that can hydrolyze most cephalosporins x x Acinetobacter, & MRSA (Exceptx  Not active against enterococci,xListeria monocytogenes, ceftaroline is active against MRSA) Mechanism of Action Like penicillins and β-lactam antibiotics, cephalosporins:  IS Inhibit bacterial growth by interfering with the transpeptidation step of bacterial cell wall synthesis.  50 Are bactericidal and kill bacteria only when they are actively growing and synthesizing cell wall, thus their bactericidal effect is time dependent. Classification 1st sthsamtonly an.at They are classified into generations (1st, 2nd, 3rd & 4th) loosely according to their antimicrobial spectrum of activity From 1st → 3rd generation, there is broader activity against Gram (-) bacteria with a slight decrease in Gram (+) activity 4th generation cephalosporins have the broadest Gram (-) activity without sacrificing Gram (+) activity A. 1st Generation Cephalosporins Fee 6 Drugs: Cefadroxil (po), cephalexin (po), cephradine (po), Cefazolin perentral  All are β-lactamases sensitive I 1 Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Cephalosporins/Carbapenems Fall 2024 Antibacterial spectrum:  Gram (+) cocci such as most of the Streptococci strains (not penicillin-resistant strains) & S. aureus (but Not MRSA)  Gram (-) rods such as E coli, K. pneumoniae, and Proteus mirabilis  Anaerobic G (+) Peptostreptococci, but Not B. fragilis (Gram negative) e Indications:  Drug of choice for uncomplicated community-acquired infections such as UTI and upper respiratory tract infections  Cellulitis and other skin infections  Prophylaxis before surgery (mainly cephazolin) B. 2nd Generation Cephalosporins Drugs: Cefoxitin, cefuroxime axetil (po), cefprozil (po) and cefaclor (po)  More resistant to β-lactamases than 1st generation cephalosporins senstive Antibacterial spectrum: Tiggy  Like 1st generation cephalosporins plus:  Gram (-) rods such as H. influenzae, Moraxella catarrhalis, and K. pneumoniae (including β-lactamase producing K. pneumoniae)  Not active against P. aeruginosa or penicillin-resistant S. pneumonia  Cefoxitin is also active against anerobic bacteria including B. fragilis  Cefuroxime is also highly active against beta-lactamase-producing Moraxella catarrhalis. Indications: Isp  URTI (sinusitis, otitis, pharyngitis), UTI, & pneumonia (the last is mainly cefuroxime)  Intra-abdominal infection, peritonitis, diverticulitis (Mainly cefoxitin) 2 Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Cephalosporins/Carbapenems Fall 2024 C. 3rd Generation Cephalosporins Drugs: Cefotaxime, ceftazidime, ceftriaxone, cefdinir (po), cefixime (po) Antibacterial spectrum:  Active against Serratia, & beta-lactamase strains of Neisseria & H. influenzae. Enterobacter species are not reliably sensitive.  Less active against Gram + cocci (vs 1st generation) except S. pneumoniae  Ceftazidime is the ONLY third generation cephalospoarin active against P. aeruginosa  Anti-pseudomonal drugs (Ceftazidime) as well as the oral drugs (cefdinir and cefixime) have decreased Gram (+) activity compared to the other 3rd generation agents Indications:  Sepsis of unknown cause, UTI, P. aeruginosa pneumonia  Bacterial meningitis (Cefotaxime and ceftriaxone)  Gonorrhea (ceftriaxone only) D. 4th Generation Cephalosporins Drugs: Cefepime (im/iv); cefpirome (im/iv) Antibacterial spectrum:  Comparable to 3rd-gen but more resistant to some β-lactamases. But are sensitive to extended spectrum beta lactamases (ESBL)  Extended Gram (-) coverage to Enterbacter & Citrobacter species  Similar activity to Gram (+) coverage (S. aureus & S. pneumoniae)  Have anti-pseudomonal activity  No anaerobic activity Indications:  Septicemia secondary to Enterobacteriaceae resistant to other drugs  Empiric therapy in febrile neutropenia, UTI, pneumonia, & meningitis 3 Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Cephalosporins/Carbapenems Fall 2024 0 Cephalosporins with good CSF permeability Nsr  2nd generation: Cefuroxime  Generally, not used due to decreased efficacy against N. meningitidis and resistant strains of H. influenza  3rd generation  Cefotaxime: Agent of choice in neonatal meningitis (along with ampicillin) lead to high bilirubin levels a It  Ceftriaxone: Agent of choice for adult meningitis but not in neonates, as it may  4th generation: Cefepime Cephalosporins active against MRSA Ceftaroline is currently classified as an advanced or a 5th generation cephalosporin. It has increased binding to PBP 2a, which mediates methicillin resistance in staphylococci cause (bactericidal)  Similar activity to ceftriaxone (3rd generation) but with improved Gram-positive activity against MRSA, penicillin-resistant S. pneumonia  Not active against enterococci, P. aeruginosa, ESBL-producing Enterobacterales bacteria, Acinetobacter baumannii, or B. fragilis Indications:  Treatment of acute bacterial skin and skin structure infections  Treatment of community acquired pneumonia Carbapenems Drugs: Ertapenem, imipenem, and meropenem Antibacterial spectrum:  Highly resistant to hydrolysis from β-lactamases as they cover extended-spectrum beta- lactamase (ESBL)-producing bacteria 4 Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Cephalosporins/Carbapenems Fall 2024  However, they are susceptible to hydrolysis by bacteria that produce metallo-β- lactamases and carbapenemases  Very broad spectrum with coverage of most Gram (+) bacteria (but not MRSA), most Gram (-) bacteria including P. aeruginosa, & anaerobes  Ertapenem is the least active against Pseudomonas or Acinetobacter species, two common nosocomial agents (usually avoided for their treatment)  Associated with higher incidence of seizure than other β-lactam agents Indications:  Treatment of mixed aerobic and anaerobic or resistant infections  Infections caused by Enterobacter, Penicillin-susceptible strains of pneumococci, or extended spectrum beta-lactamase producing Gram (-) bacteria Combination with other drugs A. Cilastatin is a peptidase inhibitor that blocks renal degradation of imipenem  Given only with imipenem (Primaxin®)  Has neither β-lactamase inhibitory nor antibacterial activity B. Vaborbactam (A beta-lactamase inhibitor) is combined with meropenem (Vabomere)  Vaborbactam ia a new ß-lactamase inhibitor (others include avibactam and relebactam) that is structurally different from the older generation with a broader spectrum of inhibition  Good inhibitor of class C ß-lactamases (chromosomally encoded) that are produced by Gram (-) pathogens such as Enterobacter, Citrobacter, Serratia, and P. aeruginosa  Resistant to hydrolysis by carbapenemases produced by K. pneumoniae  Is given with meropenem for the treatment of complicated UTI including pyelonephritis 5  Cell Wall Inhibitors Cephalosporins & Carbapenems Pharmacology ha 0 I Is.IE att Mohammad fiction Qaddoumi, Ph.D. onetime Case study – Clinical scenario 1 ▪ A 37-year-old woman comes to your office with a 5-day history of worsening purulent nasal discharge, headache, and nasal congestion. She complains of feeling stuffed head and frequent headaches when she lowers her head. She has no other significant medical history. On examination, her temperature is 38°C with a higher pulse, 82 beats per minute; and blood pressure, 120/75 mm Hg. Her lungs are clear. Ultrasound shows a right-sided infiltrate in her right cheek side. Culture results of her nasal discharge reveals gram-negative bacilli suggesting the diagnosis of acute bacterial rhinosinusitis caused by M. catarrhalis. You treat her with Cefuroxime axetil. treatedby2nd Id gen What is the mechanism of action of Cefuroxime axetil? 2nd gen ceph that's more resistant to B lactamas  MOA of cefuroxime ▪ Just like all beta-lactams o ▪ Bind and inactivate bacterial transpeptidases and prevent Iff cross-linking of peptidoglycan polymers necessary for cell- wall integrity, resulting in cell lysis and inhibition of cell-wall synthesis. What type of cephalosporin is cefuroxime core axetil? 2nd What are other examples of cephalosporins within the same generation as cefuroxime axetil? Type of Cephalosporin a ▪ 2nd generation cephalosporins Other Cephalosporins in the same class ▪ Cefoxitin ___ Pros 2 Fru Foxs tan Faces like ▪ Cefprozil 2nd ▪ Cefaclor see  What is the antibacterial spectrum of cefuroxime axetil? Antibacterial spectrum for cefuroxime a of ▪ Gram (+) cocci (staphylococci and streptococci but Not enterococci) ▪ Not MRSA or PR-S. pneumoniae ▪ Gram (-) bacilli E. coli, Proteus and K. pneumonia (1st generation) + H. influenzae, M. catarrhalis,& β-lactamases producing K. pneumonia ▪ Anerobic gram (+) peptostreptococci ▪ But not against B. fragilis What are other clinical indications for cefuroxime axetil? Other clinical indications ▪ UTI ▪ URTI (otitis media, pharyngitis) ▪ Pneumonia ▪ Peritonitis, pelvic inflammatory disease, diverticulitis (mixed anaerobic infections). Is it indicated here !! No. Clinical Scenario 2 What if the Culture results of her nasal discharge revealed instead a gram-negative bacilli such as β- lactamases producing H. influenzae as being the main causative pathogen for her acute bacterial rhinosinusitis. Would you still treat her with Cefuroxime axetil? NO No ! Why?  Since 2nd Generation cephalosporins are not active against β-lactamases e producing H. influenzae What other cephalosporins would you recommend? Any 3rd generation cephalosporins ▪ Cefixime why ▪ Cefdinir imelone ▪ Cefotaxime ▪ Ceftriaxone I ▪ Ceftazidime  What is the antibacterial spectrum of cefixime or 3rd generation cephalosporins? Antibacterial Spectrum of cefixime ▪ Gram (+) cocci: same as 2nd generation but slightly less active e ▪ Gram (-) bacteria: ▪ Neisseria ▪ H. influenzae (β-lactamases producing) ▪ Serratia ▪ P. aeruginosa (only ceftazidime) ▪ Anaerobes: None What are the clinical uses of 3rd generation cephalosporins?  Clinical uses of 3rd generation cephalosporins ▪ UTI and URTI (As 1st and 2nd generation) ▪ Skin and soft tissue infections (As 1st and 2nd generation) ▪ Septicemia ▪ Gonorrhea (Mainly ceftriaxone) ▪ Pneumonia due to P. aeruginosa (Ceftazidime only) ▪ Bacterial meningitis ▪ Ceftriaxone - adults ▪ Cefotaxime - neonate Clinical Scenario 2 What if the culture results of her nasal discharge revealed instead a gram-positive cocci such as Streptococci pneumoniae as being the main causative pathogen for her acute bacterial rhinosinusitis. You also realize that the culture sensitivity assay showed the bacteria to be resistant to penicillin. Would you still treat her with Cefixime. No Which antibacterial drug is suitable in this case?  Penicillin-resistant S. pneumoniae treatment ▪Can I use cephalosporin or carbapenem antibacterial drug? and which one? Treatment of Penicillin-resistant S. pneumoniae ▪ We know carbapenems: ▪ Have similar antibacterial spectrum to cefepime/cefpirome (4th Gen) plus ▪ ESBL produced by Gram (-) bacteria including pseudomonas ▪ Anaerobes ▪ So not suitable ▪ Most cephalosporin generations are not active against penicillin-resistant S. pneumoniae except: ▪ Ceftaroline (5th Gen or advanced generation) is active against: ▪ MRSA ▪ PR-S. pneumoniae ▪ But Not active against enterococci, pseudomonas, B. fragilis, or ESBL- producing bacteria