ANTIBAC ORGMED

• Ertapenem


  Similar structure to meropenem, has an extra substituent on the carbapenem ring which provides further stability against dehydropeptidases

  
• Ertapenem


  • Treatment of abdominal infections, acute gynecological infections, CAP(community-acquired pneumonia), and diabetic foot infections of the skin and soft tissue; prophylactic for colorectal surgery
• Higher doses of ertapenem provokes seizures
• Adverse effects of carbapenems

  • Nausea and Vomiting
  • Diarrhea
  • High doses may provoke seizures
• β-lactamase inhibitors


  Not stand-alone drugs, added because they have weak or little antibacterial activity
• Clavulanic acid


  Isolated from Streptomyces clavuligerus, exhibits very weak antibacterial activity, but a potent inhibitor of S. aureus β-lactamases, has a B-lactam ring fused to an oxazolidine ring with S replaced by O, acts as a "suicide substrate"

  
• β-lactamase inhibitor products


  • Co-amoxiclav (Amoxicillin + Clavulanic Acid)
  • Ticarcillin clavulanate (Ticarcillin + Clavulanic Acid)
  • Ampicillin + Sulbactam (Unasyn)
  • Piperacillin + Tazobactam (Piptaz)

  
• Sulbactam


  Potent inhibitor of S. aureus β-lactamase as well as many β–β-lactamases elaborated by Gram-negative bacilli, has weak intrinsic antibacterial activity but potentiates the activity of ampicillin and carbenicillin against β–lactamase–producing S. aureus and members of the Enterobacteriaceae family
• Tazobactam


  More potent β-lactamase inhibitor than sulbactam and has a slightly broader spectrum of activity than clavulanic acid
• Cephalosporins are cell wall inhibitors
• Cephalosporins C


  1st cephalosporin derived from a fungus, similarities to that of penicillin, 7-amino-cephalosporanic acid vs penicillin's 6-amino-cephalamic acid, source is Cephalosporium acrelnonium (now known as Acremonium chrysogenum)
• Cephalosporins


  • Antibacterial activity that is more evenly directed against Gram (+) and (-) bacteria, greater resistance to acid hydrolysis and B-lactamase enzymes, less likely to cause allergic reactions
• Cephalosporin nucleus


  1. aminocephalosporinic Acid (A-ACA), dihydrothiazine ring + B-Lactam (6 sides attached vs. 5 sides attached in penicillin)

  
• Structure activity relationship of cephalosporins

  Variations of the 7-acylamino side chain affects antimicrobial activity, variations of the 3-acetoxymethyl side chain affect metabolic and pharmacokinetic activity, change in 3 also affects 7, variation in metabolic/pharmacokinetic properties decreases/affects antimicrobial activity, methyl group enhances oral absorption, extra substitution at carbon 7 usually adds methyl group

  
• 1st generation cephalosporins


  • They have lower activity than comparable penicillin but a better range, poorly absorbed through gut wall and have to be injected, appearance of resistant organism has posed a problem, particularly Gram-negative organism, activity against Proteus mirabilis, E.coli and Klebsiella pneumoniae (PEcK)
• Cephalotin


  Most commonly used first generation cephalosporin, spectrum of activity is broader than that of penicillin G, absorbed poorly in GI tract, pain in IM and IV route, targets B-lactamase producing S. aureus strain, acetyloxy group is important to the mechanism of inhibition and acts as a good leaving group

  
• Cephaloridine


  Exists as zwitterion and is soluble in water but poorly absorbed through the gut wall, replacement of ester with metabolically stable pyridinium group, pyridine is a good leaving group for the inhibition mechanism

  
• Cephalexin


  Has a methyl substituent at position 3, presence of α-carbon of 7- acylamino side chain helps restore its activity, treatment of UTI, respiratory tract, ear, skin and mouth infections, good oral absorption due to the methyl group in R3

  
• Cefazolin


  First generation cephalosporin, used for prophylaxis to prevent infection on surgical procedures

  
• 2nd generation cephalosporins


  • Display greater activity against three additional gram-negative organism: Haemophilus influenzae, Enterobacter aerogenes, Neiserria species, activity in gram-positive is weaker, target: HENPEcK
• Cephamycin


  Contain a methoxy substituent at position 7 which improves stability, first B-lactam isolated from a bacterial source (Streptomyces clavuligerus)

  
• Cefoxitin


  Showed a broader spectrum of activity than most first generation cephalosphorins, active against bowel flora and was once recommended for peritonitis, modification that still contributes to Beta-lactamase forms resistance

  
• Cefuroxime


  Penetrates inflamed meninges in high enough concentrations susceptible organism due to presence of iminomethoxy group, wide spectrum of activity; against organisms which have become resistant to penicillin; used for surgical prophylaxis as well as for the treatment of Lyme disease
• Oximinocephalosporins


  Cephalosporins with iminomethoxy group, the iminomethoxy group increases the stability of the drug against beta-lactamases

  
• 3rd generation cephalosporins


  • Good activity against gram (-) bacteria with varying activity against gram (+) cocci, lack activity against the MRSA organisms and Enterobacter species, enhanced activity against gram (-) bacilli including those mentioned previously plus Serratia marcescens, target: HEN PEcK S cefa fac man L
• Cefotaxime


  First 3rd generation cephalosporin introduced, excellent broad-spectrum activity against G(+) and G(-) aerobic and anaerobic bacteria, offers good penetration to the cerebrospinal fluid (CSF)
• Ceftriaxone


  Most commonly used 3rd generation cephalosporin, used for surgical prophylaxis and as a prophylactic for meningococcal meningitis, exhibit excellent broad-spectrum antibacterial activity against both G(+) and G(-) organism
• Cefixime


  First orally active 3rd generation cephalosporin, used for the treatment of various respiratory tract infections and otitis media, used to treat uncomplicated urinary tract infection and gonorrhea
• 4th generation cephalosporins


  • Enhanced ability of these agents to penetrate outer membrane of gram (-) bacteria, good affinity for transpeptidase and low affinity for B-lactamases, target: HEN PEcK S Pi
• 5th generation cephalosporins


  Ceftaroline, Ceftobiprole, importance of 1,3 – thiazole ring is for targeting MRSA, target: Fta fto

  
• Ceftaroline fosamil


  Prodrug of Ceftaroline, fifth-generation cephalosporin that has activity against various strains of MRSA and multiresistant Streptococcus pneumonia (MDRSP), used for treatment of bacterial pneumonia and acute bacterial skin infections
• Cephalosporins contain a strained B-lactam ring fused to a dihydrothiazine ring

  
• Semisynthetic cephalosporin can be prepared from 7-amino-cephalosporanic acid (7-ACA), which is obtained from the chemical hydrolysis of cephalosporin

  
• Deacetylation of cephalosporin occurs metabolically to produce inactive metabolites

  
• Metabolism can be blocked by replacing the susceptible group with metabolically stable group
• Methyl substituent at position 3 is good for oral absorption but bad for activity unless a hydrophilic group is present at the position α-position of the acyl side chain

  
• Cephamycins are cephalosporin containing a methoxy group at position 7

  
• Oximinocephalosporins have resulted in several generations of cephalosporin with increased potency and a broader spectrum of activity, particularly G(-) bacteria
• Cephalosporin generation mnemonic


  • 1st: Dr. Zol sa Ph

  2nd: Fo, fu, fp, fac-man, L

  3rd: "money"

  4th: "pi"

  5th: Fto, fta
• Monobactams


  Disrupt bacterial cell wall synthesis, unique because the B-lactam ring is not fused to another ring