BETA-LACTAM
ANTIMICROBIAL AGENTS
Alan M. Stamm, M.D.
astamm@uabmc.edu
October 23, 2002
Beta-lactams
• Each agent has this 4-member ring
which is essential for antibacterial
activity.
Outline
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Mechanism of action.
Mechanisms of resistance.
Pharmacology.
Adverse effects.
Classes of beta-lactams.
Clinical uses.
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.
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
Mechanisms of Resistance - 1
• Production of beta-lactamase: bacterial
enzyme catalyzing hydrolysis of betalactam ring.
– chromosomal vs. plasmid DNA
– one vs. multiple in a single bacterium
– dozens exist with varying spectrums
• e.g., Staphylococcus aureus - penicillinase
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
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)
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.
Pharmacology - 2
• Elimination: primarily by glomerular
filtration and tubular secretion;
decreased in patients with renal
impairment; reduce dose if creatinine
clearance <40-50 ml/min.
• Biliary excretion is predominant for
nafcillin and significant for
ureidopenicillins.
Efficacy
• A principal determinant is T>MIC =
the proportion of time for which betalactam level at the site of infection
exceeds the minimal inhibitory
concentration of the bacterium.
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.
Adverse Effects - 2
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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
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 betalactams: 10% with cephalosporins.
• Detection: history, skin testing - penicilloylpolylysine and penicillin G.
• Management: avoidance, substitution,
desensitization - PO or IV.
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
Penicillins - 2
• Penicillinase resistant penicillins:
– for methicillin susceptible
Staphylococcus aureus (MSSA)
– nafcillin IV
– cloxacillin PO
– dicloxacillin PO
Penicillins - 3
• Extended spectrum penicillins:
– more broadly active against gramnegatives
– aminopenicillins
• ampicillin IV
• amoxicillin PO
– ureidopenicillins (acylaminopenicillins)
• piperacillin IV
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
Cephalosporins - 1
• 1st generation:
– active against streptococci, methicillin
susceptible staphylococci, some gramnegatives
– cephapirin (Cefadyl) IV
– cefazolin (Ancef, Kefzol) IM, IV
– cephalexin (Keflex) PO
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
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
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
Cephalosporins - 5
• Cephalosporins are not useful in the
treatment of infections due to
methicillin resistant Staphylococcus
aureus (MRSA), Enterococci, or
Listeria monocytogenes.
Carbapenems
• The most broadly active of antibacterial
agents - streptococci, MSSA, gramnegatives, anaerobes:
– imipenem/cilastatin (Primaxin) IV
– meropenem (Merrem) IV
• Induce production of beta-lactamases
by gram-negative bacilli.
• Hold in reserve – do not use routinely.
Carbacephems
• Greater chemical stability in solution.
• Activity similar to 2nd generation
cephalosporin cefuroxime:
– lorcarbef (Lorabid) PO
• No need to use this class.
Monobactams
• Active against aerobic gram-negative
bacilli; resistant to hydrolysis:
– aztreonam (Azactam) IV
• An alternative to an aminoglycoside.
• Do not induce production of betalactamases.
• Minimal risk of reaction in those
allergic to penicillins.
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
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
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
Selection of Antibiotics - 4
• Public health considerations:
– prevention of transmission
– induction of resistance
– cost
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
Urinary Tract Infections
• Pyelonephritis:
– ceftriaxone 2 g IV qd initially if
hospitalized
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
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/tazobactam 3.375 g IV q 6
hours
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
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
Surgery - Prophylaxis
• Cardiovascular:
– cefazolin 1 g IV once 30-60 minutes
prior to procedure
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.