third-Generation Cephalosporins. Fourth-Generation Cephalosporins.

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third-Generation Cephalosporins.
Fourth-Generation Cephalosporins.
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LEARNING OBJECTIVES

• At the end of lecture students dhould be able t
  know ABOUT,
• CEFOTAXIME
• CEFPODOXIME PROXETIL
• CEFTIBUTEN
• CEFDINIR
• Third-Generation Cephalosporins with Good
  Activity Against Pseudomonas
• Fourth-Generation Cephalosporins
• CEFEPIME

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CEFOTAXIME

• Highly resistant to many (but not the
  extended-spectrum product) of the bacterial
  b-lactamases and has good activity against many
  gram-positive and gram-negative aerobic bacteria.
• Activity against B. fragilis is poor compared
  with agents such as clindamycin and
  metronidazole.
• Ceftriaxone has activity in vitro very similar to
  that of ceftizoxime and cefotaxime.

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CEFOTAXIME

• The drug is metabolized in vivo to
  desacetylcefotaxime, which is less active against
  most microorganisms than is the parent compound.
• However, the metabolite acts synergistically with
  the parent compound against certain microbes.
• Ceftizoxime has a spectrum of activity in vitro
  that is very similar to that of cefotaxime,
  except that it is less active against S.
  pneumoniae and more active against B. fragilis .
• The half-life is somewhat longer, 1.8 hours, and
  the drug thus can be administered every 8 to 12
  hours for serious infections. Ceftizoxime is not
  metabolized, and 90 is recovered in urine.

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CEFOTAXIME

• Cefotaxime has a half-life in plasma of about 1
  hour and should be administered every 4 to 8
  hours for serious infections.
• A half-life of about 8 hours is the outstanding
  feature.
• Administration of the drug once or twice daily
  has been effective for patients with meningitis,
  whereas dosage once a day has been effective for
  other infections Cefotaxime has been used
  effectively for meningitis caused by H.
  influenzae, penicillin-sensitive S. pneumoniae,
  and N. meningitides.
• The drug is metabolized in vivo to
  desacetylcefotaxime, which is less active against
  most microorganisms than is the parent compound.
• However, the metabolite acts synergistically with
  the parent compound against certain microbes.
• About half the drug can be recovered from the
  urine the remainder appears to be eliminated by
  biliary secretion.
• A single dose of ceftriaxone (125 to 250 mg) is
  effective in the treatment of urethral, cervical,
  rectal, or pharyngeal gonorrhea, including
  disease caused by penicillinase-producing
  microorganisms

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CEFPODOXIME PROXETIL

• An orally administered third-generation agent
  that is very similar in activity to the
  fourth-generation agent cefepime.
• Except that it is not more active against
  Enterobacter or Pseudomonas spp. It has a serum
  half-life of 2.2 hours.

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CEFPODOXIME PROXETIL

• A prodrug that is hydrolyzed by esterases during
  absorption to the active drug, cefditoren.
  Cefditoren has a half-life of approximately 1.6
  hours and is eliminated unchanged in the urine.
• The drug is active against methicillin-susceptible
  strains of S. aureus, penicillin-susceptible
  strains of S. pneumoniae, S. pyogenes, H.
  influenzae, H. parainfluenzae, and Moraxella
  catarrhali. Cefditoren pivoxil is only indicated
  for the treatment of mild-to-moderate
  pharyngitis, tonsillitis, uncomplicated skin and
  skin structure infections, and acute
  exacerbations of chronic bronchitis.

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CEFTIBUTEN

• Is an orally effective cephalosporin with a
  half-life of 2.4 hours.
• It is less active against gram-positive and
  gram-negative organisms than cefixime, with
  activity limited to S. pneumonia and S. pyogenes,
  H. influenzae, and M. catarrhalis. Ceftibuten is
  only indicated for acute bacterial exacerbations
  of chronic bronchitis, acute bacterial otitis
  media, pharyngitis, and tonsillitis.

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CEFDINIR

• Is effective orally, with a half-life of
  approximately 1.7 hours it is eliminated
  primarily unchanged in the urine.
• Cefdinir has a spectrum of activity similar to
  cefixime.
• It is inactive against Pseudomonas and
  Enterobacter spp.

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Third-Generation Cephalosporins with Good
Activity Against Pseudomonas.

• Ceftazidime is one-quarter to one-half as active
  by weight against gram-positive microorganisms as
  is cefotaxime.
• Its activity against the Enterobacteriaceae is
  very similar, but its major distinguishing
  feature is excellent activity against Pseudomonas
  and other gram-negative bacteria. Ceftazidime has
  poor activity against B. fragilis.
• Its half-life in plasma is about 1.5 hours, and
  the drug is not metabolized.
• Ceftazidime is more active in vitro against
  Pseudomonas than is piperacillin.

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Fourth-Generation Cephalosporins

• Cefepime and cefpirome are fourth-generation
  cephalosporins.

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CEFEPIME

• Cefepime is stable to hydrolysis by many of the
  previously identified plasmid-encoded
  b-lactamases (called TEM-1, TEM-2, and SHV-1).
• It is a poor inducer of, and is relatively
  resistant to, the type I chromosomally encoded
  and some extended-spectrum b-lactamases.
• Thus it is active against many Enterobacteriaceae
  that are resistant to other cephalosporins via
  induction of type I b-lactamases but remains
  susceptible to many bacteria expressing
  extended-spectrum plasmid-mediated b-lactamases
  (such as TEM-3 and TEM-10).
• Against the fastidious gram-negative bacteria (H.
  influenzae, N. gonorrhoeae, and N. meningitidis),
  cefepime has comparable or greater in vitro
  activity than cefotaxime.
• For P. aeruginosa, cefepime has comparable
  activity to ceftazidime, although it is less
  active than ceftazidime for other Pseudomonas
  spp. and X. maltophilia. Cefepime has higher
  activity than ceftazidime and comparable activity
  to cefotaxime for streptococci and
  methicillin-sensitive S. aureus .

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CEFEPIME

• It is not active against methicillin-resistant S.
  aureus, penicillin-resistant pneumococci,
  enterococci, B. fragilis, L. monocytogenes,
  Mycobacterium avium complex, or M. tuberculosis.
• Cefepime is excreted almost 100 renally, and
  doses should be adjusted for renal failure.
• Cefepime has excellent penetration into the CSF
  in animal models of meningitis.
• When given at the recommended dosage for adults
  of 2 g intravenously every 12 hours, peak serum
  concentrations in human beings range from 126 to
  193 mg/ml.
• The serum half-life is 2 hours.

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Adverse Reactions

• Hypersensitivity reactions to the cephalosporins
  are the most common side effects, and there is no
  evidence that any single cephalosporin is more or
  less likely to cause such sensitization.
• The reactions appear to be identical to those
  caused by the penicillins, perhaps related to the
  shared b-lactam structure of both groups of
  antibiotics.
• Immediate reactions such as anaphylaxis,
  bronchospasm, and urticaria are observed.
• More commonly, maculopapular rash develops,
  usually after several days of therapy,this may or
  may not be accompanied by fever and eosinophilia.

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Adverse Reactions

• Because of the similar structures of the
  penicillins and cephalosporins, patients who are
  allergic to one class of agents may manifest
  cross-reactivity to a member of the other class.
• Immunological studies have demonstrated
  cross-reactivity in as many as 20 of patients
  who are allergic to penicillin, but clinical
  studies indicate a much lower frequency (about
  1) of such reactions.
• There are no skin tests that can reliably predict
  whether a patient will manifest an allergic
  reaction to the cephalosporins.

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Adverse Reactions

• Patients with a history of a mild or a temporally
  distant reaction to penicillin appear to be at
  low risk of rash or other allergic reaction
  following the administration of a cephalosporin.
• However, patients who have had a recent severe,
  immediate reaction to a penicillin should be
  given a cephalosporin with great caution, if at
  all.
• A positive Coombs' reaction appears frequently in
  patients who receive large doses of a
  cephalosporin.
• Hemolysis usually is not associated with this
  phenomenon, although it has been reported.
  Cephalosporins have produced rare instancesof
  bone marrow depression, characterized by
  granulocytopenia.

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Adverse Reactions

• The cephalosporins have been implicated as
  potentially nephrotoxic agents, although they are
  not nearly as toxic to the kidney as are the
  aminoglycosides or the polymyxins.
• Renal tubular necrosis has followed the
  administration of cephaloridine in doses greater
  than 4 g/day this agent is no longer available
  in the United States.
• Other cephalosporins are much less toxic and,
  when used by themselves in recommended doses,
  rarely produce significant renal toxicity.
• High doses of cephalothin (no longer available in
  the United States) have produced acute tubular
  necrosis in certain instances, and usual doses (8
  to 12 g/day) have caused nephrotoxicity in
  patients with preexisting renal disease.

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Adverse Reactions

• There is good evidence that the concurrent
  administration of cephalothin and gentamicin or
  tobramycin act synergistically to cause
  nephrotoxicity,especially in patients older than
  60 years of age.
• Diarrhea can result from the administration of
  cephalosporins and may be more frequent with
  cefoperazone, perhaps because of its greater
  biliary excretion.
• Intolerance to alcohol (a disulfiram-like
  reaction) has been noted with cephalosporins that
  contain the MTT group, including cefamandole (no
  longer available in the United States),
  cefotetan, moxalactam, and cefoperazone.
• Serious bleeding related either to
  hypoprothrombinemia owing to the MTT group,
  thrombocytopenia,and/or platelet dysfunction has
  been reported with several b-lactam antibiotics.

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Therapeutic Uses

• The cephalosporins are used widely and are
  therapeutically important antibiotics.
• Unfortunately, a wide array of bacteria is
  resistant to their activity. Clinical studies
  have shown cephalosporins to be effective as both
  therapeutic and prophylactic agents.
• The first-generation cephalosporins are excellent
  agents for skin and soft tissue infections owing
  to S. aureus and S. pyogenes.
• A single dose of cefazolin just before surgery
  is the preferred prophylaxis for procedures in
  which skin flora are the likely pathogens.
• For colorectal surgery, where prophylaxis for
  intestinal anaerobes is desired, the
  second-generation agents cefoxitin or cefotetan
  are preferred.

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Therapeutic Uses

• The second-generation cephalosporins generally
  have been displaced by third-generation agents.
• They have inferior activity against
  penicillin-resistant S. pneumoniae compared with
  either the third-generation agents or ampicillin
  and therefore should not be used for empirical
  treatment of meningitis or pneumonia.
• The oral second-generation cephalosporins can be
  used to treat respiratory tract infections,
  although they are suboptimal (compared with oral
  amoxicillin) for treatment of penicillin-resistant
  S. pneumoniae pneumonia and otitis media.
• In situations where facultative gram-negative
  bacteria and anaerobes are involved, such as
  intra-abdominal infections, pelvic inflammatory
  disease, and diabetic foot infection, cefoxitin
  and cefotetan both are effective.

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