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BETALACTAM ANTIMICROBIAL AGENTS

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active multiplication/division of bacteria. beta-lactam penetration of cell wall ... activation of autolytic system of bacteria. Mechanisms of Resistance - 1 ... – PowerPoint PPT presentation

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Title: BETALACTAM ANTIMICROBIAL AGENTS


1
BETA-LACTAMANTIMICROBIAL AGENTS
  • Alan M. Stamm, M.D.
  • astamm_at_uabmc.edu
  • October 23, 2002

2
Beta-lactams
  • Each agent has this 4-member ring which is
    essential for antibacterial activity.

3
Outline
  • Mechanism of action.
  • Mechanisms of resistance.
  • Pharmacology.
  • Adverse effects.
  • Classes of beta-lactams.
  • Clinical uses.

4
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.

5
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

6
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

7
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

8
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)

9
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.

10
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.

11
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.

12
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.

13
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

14
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.

15
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

16
Penicillins - 2
  • Penicillinase resistant penicillins
  • for methicillin susceptible Staphylococcus aureus
    (MSSA)
  • nafcillin IV
  • cloxacillin PO
  • dicloxacillin PO

17
Penicillins - 3
  • Extended spectrum penicillins
  • more broadly active against gram-negatives
  • aminopenicillins
  • ampicillin IV
  • amoxicillin PO
  • ureidopenicillins (acylaminopenicillins)
  • piperacillin IV

18
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

19
Cephalosporins - 1
  • 1st generation
  • active against streptococci, methicillin
    susceptible staphylococci, some gram-negatives
  • cephapirin (Cefadyl) IV
  • cefazolin (Ancef, Kefzol) IM, IV
  • cephalexin (Keflex) PO

20
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

21
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

22
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

23
Cephalosporins - 5
  • Cephalosporins are not useful in the treatment of
    infections due to methicillin resistant
    Staphylococcus aureus (MRSA), Enterococci, or
    Listeria monocytogenes.

24
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.

25
Carbacephems
  • Greater chemical stability in solution.
  • Activity similar to 2nd generation cephalosporin
    cefuroxime
  • lorcarbef (Lorabid) PO
  • No need to use this class.

26
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.

27
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

28
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

29
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

30
Selection of Antibiotics - 4
  • Public health considerations
  • prevention of transmission
  • induction of resistance
  • cost

31
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

32
Urinary Tract Infections
  • Pyelonephritis
  • ceftriaxone 2 g IV qd initially if hospitalized

33
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

34
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

35
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

36
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

37
Surgery - Prophylaxis
  • Cardiovascular
  • cefazolin 1 g IV once 30-60 minutes prior to
    procedure

38
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.
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