BETALACTAM ANTIMICROBIAL AGENTS

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BETA-LACTAMANTIMICROBIAL AGENTS

• Alan M. Stamm, M.D.
• astamm_at_uabmc.edu
• October 23, 2002

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Beta-lactams

• Each agent has this 4-member ring which is
  essential for antibacterial activity.

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Outline

• Mechanism of action.
• Mechanisms of resistance.
• Pharmacology.
• Adverse effects.
• Classes of beta-lactams.
• Clinical uses.

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Mechanism of Action - 1

• Interference with cell wall synthesis prevention
  of cross-linking of linear peptidoglycan strands
  by inhibition of transpeptidase,
  carboxypeptidase, or endopeptidase.
• Inhibition occurs by competitive binding to
  enzyme located beneath cell wall on inner surface
  of cell membrane.

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Mechanism of Action - 2

• Structural weakening leads to cell death.
• Effect is bactericidal or lethal, not
  bacteriostatic or inhibitory.
• However, the effect depends on
• active multiplication/division of bacteria
• beta-lactam penetration of cell wall
• affinity of beta-lactam for enzyme, a.k.a.
  penicillin binding protein (PBP)
• activation of autolytic system of bacteria

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Mechanisms of Resistance - 1

• Production of beta-lactamase bacterial enzyme
  catalyzing hydrolysis of beta-lactam ring.
• chromosomal vs. plasmid DNA
• one vs. multiple in a single bacterium
• dozens exist with varying spectrums
• e.g., Staphylococcus aureus - penicillinase

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Mechanisms of Resistance - 2

• Decreased access of drug to target penicillin
  binding protein.
• exclusion by outer membrane protein channels
  porins
• augmented efflux mechanisms
• e.g., Enterobacter species
• e.g., Pseudomonas aeruginosa

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Mechanisms of Resistance - 3

• Alteration of penicillin binding protein
  decreased affinity, less effective competitive
  inhibition.
• clinical isolates are often broadly resistant to
  antibacterial agents
• e.g., drug resistant Streptococcus pneumoniae
• e.g., methicillin resistant Staph. aureus (MRSA)
• e.g., vancomycin resistant Enterococci (VRE)

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Pharmacology - 1

• Absorption some are acid stable and absorbed in
  the duodenum - peak serum level in 1-2 hours
  many are administered only intravenously.
• Half-life most are short, 1 hour with serious
  disease, these must be administered 4-6 times per
  day or as a continuous infusion.

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Pharmacology - 2

• Elimination primarily by glomerular filtration
  and tubular secretion decreased in patients with
  renal impairment reduce dose if creatinine
  clearance lt40-50 ml/min.
• Biliary excretion is predominant for nafcillin
  and significant for ureidopenicillins.

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Efficacy

• A principal determinant is TgtMIC the proportion
  of time for which beta-lactam level at the site
  of infection exceeds the minimal inhibitory
  concentration of the bacterium.

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Adverse Effects - 1

• IgM-mediated erythematous, maculopapular, trunkal
  rash.
• Diarrhea, Clostridium difficile colitis.
• Hemolytic anemia, neutropenia, thrombocytopenia,
  bleeding.
• Fever.
• Interstitial nephritis.
• Anicteric hepatitis, cholestatic jaundice.
• Seizures.

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Adverse Effects - 2

• Comparatively safe.
• Safe in pregnancy.
• Phlebitis from IV administration.
• Superinfection from alteration of normal flora.
• e.g., thrush (oral candidiasis)
• Selection of resistant bacteria.
• particularly 3rd generation cephalosporins

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Allergy

• IgE-mediated urticaria, anaphylaxis.
• From 1-10 report allergy to penicillin
• 10-30 of these have a positive skin test.
• Cross-reactivity occurs with other beta-lactams
  10 with cephalosporins.
• Detection history, skin testing -
  penicilloyl-polylysine and penicillin G.
• Management avoidance, substitution,
  desensitization - PO or IV.

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Penicillins - 1

• Natural penicillins
• for streptococci, normal oral flora,
  meningococci, anaerobes
• benzylpenicillin penicillin G
• aqueous Na or K crystalline IV
• procaine IM
• benzathine (Bicillin) IM
• phenoxymethylpenicillin penicillin V PO

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Penicillins - 2

• Penicillinase resistant penicillins
• for methicillin susceptible Staphylococcus aureus
  (MSSA)
• nafcillin IV
• cloxacillin PO
• dicloxacillin PO

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Penicillins - 3

• Extended spectrum penicillins
• more broadly active against gram-negatives
• aminopenicillins
• ampicillin IV
• amoxicillin PO
• ureidopenicillins (acylaminopenicillins)
• piperacillin IV

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Penicillins - 4

• Penicillin beta-lactamase inhibitor
  combinations
• even more active against gram-negatives
• ampicillin sulbactam (Unasyn) IV
• piperacillin tazobactam (Zosyn) IV
• amoxicillin clavulanate (Augmentin) PO

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Cephalosporins - 1

• 1st generation
• active against streptococci, methicillin
  susceptible staphylococci, some gram-negatives
• cephapirin (Cefadyl) IV
• cefazolin (Ancef, Kefzol) IM, IV
• cephalexin (Keflex) PO

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Cephalosporins - 2

• 2nd generation
• more broadly active against gram-negatives
• cefuroxime (Kefurox, Zinacef) IV, (Ceftin) PO

• 2nd generation
• added activity against anaerobes
• cefotetan (Cefotan) IV

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Cephalosporins - 3

• 3rd generation
• much broader and better activity against
  gram-negatives (but less vs. staphylococci)
• ceftriaxone (Rocephin) IV
• cefotaxime (Claforan) IV
• few have added activity against Pseudomonas
  aeruginosa, e.g., ceftazidime (Ceptaz, Fortaz,
  Tazicef, Tazidime) IV

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Cephalosporins - 4

• 4th generation
• activity against a broader range of gram-negative
  bacilli better penetration of outer membrane and
  less affinity for beta-lactamases
• cefepime (Maxipime) IV

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Cephalosporins - 5

• Cephalosporins are not useful in the treatment of
  infections due to methicillin resistant
  Staphylococcus aureus (MRSA), Enterococci, or
  Listeria monocytogenes.

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Carbapenems

• The most broadly active of antibacterial agents -
  streptococci, MSSA, gram-negatives, anaerobes
• imipenem/cilastatin (Primaxin) IV
• meropenem (Merrem) IV
• Induce production of beta-lactamases by
  gram-negative bacilli.
• Hold in reserve do not use routinely.

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Carbacephems

• Greater chemical stability in solution.
• Activity similar to 2nd generation cephalosporin
  cefuroxime
• lorcarbef (Lorabid) PO
• No need to use this class.

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Monobactams

• Active against aerobic gram-negative bacilli
  resistant to hydrolysis
• aztreonam (Azactam) IV
• An alternative to an aminoglycoside.
• Do not induce production of beta-lactamases.
• Minimal risk of reaction in those allergic to
  penicillins.

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Selection of Antibiotics - 1

• Patient factors
• history of antibiotic allergy
• pharmacogenomic profile
• recent antibiotic exposure
• age and organ dysfunction
• status of host defenses
• disposable income

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Selection of Antibiotics - 2

• Infectious disease factors
• source of acquisition - community, travel,
  occupation, nosocomial
• site of infection - likely pathogens and their
  usual susceptibility patterns
• severity of infection

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Selection of Antibiotics - 3

• Antibiotic factors
• cidal vs. static
• route of administration schedule of dosing
• tissue penetration
• spectrum of antimicrobial activity
• local pattern of antimicrobial resistance or
  proven susceptibility
• potential adverse effects drug interactions

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Selection of Antibiotics - 4

• Public health considerations
• prevention of transmission
• induction of resistance
• cost

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Respiratory Infections

• Pharyngitis due to Streptococcus pyogenes (Group
  A streptococci)
• penicillin V or amoxicillin 250 mg PO tid x 10
  days
• Community acquired pneumonia
• ceftriaxone 2 g IV qd (often with a macrolide)
  initially if hospitalized

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Urinary Tract Infections

• Pyelonephritis
• ceftriaxone 2 g IV qd initially if hospitalized

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Sexually Transmitted Diseases

• Gonorrhea
• ceftriaxone 125 mg IM once
• Syphilis
• early stages - benzathine penicillin G 2.4
  million units IM once
• neurosyphilis - aqueous penicillin G 3 million
  units IV q 4 hours x 10 days

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Skin / Soft Tissue Infections

• Cellulitis
• nafcillin 1 g IV q 4 hours initially if
  hospitalized or cephalexin 500 mg PO qid
• Diabetic foot infection
• cefotetan 2 g IV q 12 hours or piperacillin/tazoba
  ctam 3.375 g IV q 6 hours

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Central Nervous System Infections

• Meningitis
• ampicillin 2 g IV q 4 hours
• ceftriaxone 2 g IV q 12 hours
• vancomycin initially pending results
• of cultures and susceptibility tests

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Endocarditis

• Due to viridans Streptococci
• ceftriaxone 2 g IV qd
• gentamicin x 2 weeks
• Due to Enterococcus fecalis
• ampicillin 2 g IV q 4 hours
• gentamicin x 4-6 weeks

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Surgery - Prophylaxis

• Cardiovascular
• cefazolin 1 g IV once 30-60 minutes prior to
  procedure

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Summary

• Beta-lactam antibiotics are often the treatment
  of choice because of their efficacy and safety.
• Learn how to use one agent from each of the
  classes.
• Adjust your practice in accordance with changes
  in susceptibility.