Transcript β-Lactam Antibiotics

β-Lactam Antibiotics
Nathan P. Samsa, Pharm.D., R.Ph., OMSII
November 17, 2004
1
Objectives
• Review basic pharmacology of β-lactam
antibiotics
• Discuss the four main classes of βlactam antibiotics
• Organize agents according to various
criteria
• Address indications and side effects
• Provide helpful mnemonics
2
Bacterial Cell Walls
• Bacterial cell walls (especially Gram {+})
contain a peptidoglycan layer made up of
repeating N-acetylglucosamine (NAG)
and N-acetylmuramic acid (NAM) units
• Each NAM is linked to an 5-peptide
chain: L-ala—D-glu—L-lys—D-ala—D-ala
• Penicillin binding proteins (PBP) crosslink
the peptidoglycan strands
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Mechanism Of β-Lactams
• Spatial arrangement of the β-lactam
ring system closely resembles the
conformation
of
the
D-ala—D-ala
segment of the peptidoglycan strand
• PBPs recognize the β-lactam as the
natural substrate
• The β-lactam ring “pops open,” thereby
destroying the PBP and halting further
crosslinkingcell wall weakenslysis
• Time-dependent killing
4
Bacterial Defenses
• β-lactamases
– Proteins that catalyze hydrolysis of the βlactam ringinactivation
• Decreased affinity of PBPs
• Reduced penetrance to the site of action
5
β-Lactam Subtypes
• Penicillins
H
N
R
O
O
S
N
CH3
CH3
O
R1
O
O
O
O
N
R2
• Carbapenems
R3
R1
S
N
R1
OH
• Cephalosporins
H
N
• Monobactams
R2
OH
O
N
O
S
R2
OH
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β-Lactam Hypersentivity
• Immediate reactions (<72 hours after
initiation) can be IgE-mediated
– IgE mediated reactions thought to be
caused by the β-lactam ring
• Delayed reactions (>3 days) in patients
with first exposure are not IgEmediated
7
Cross Sensitivity
• Cephalosporins share the β-lactam
structure of penicillin; this is the
proposed mechanism for cross-sensitivity
• A rash (type IV sensitivity) from
penicillin does not guarantee a reaction
to cephalosporins (<10% cross-reactivty)
H
N
R
O
O
S
N
O
Penicillin
CH3
CH3
OH
H
N
R1
O
O
S
N
O
R2
OH
Cephalosporin
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Penicillamine
• Penicillamine (Cuprimine®)
– Chelates copper in Wilson’s disease
– Decreases IgM Rheumatoid Factor
– Decreases
excretion
of
cystine
cystinuria
in
• Shares a common non β-lactam
component structure with penicillin, the
cause of cross-sensitivity
H
N
R
O
O
S
N
O
Penicillin
CH3
CH3
OH
HS
H2N
O
CH3
CH3
OH
Penicillamine
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β-Lactam Side Effects
• Seizures
– Especially the carbapenems
• Gastrointestinal
– Diarrhea
– Pseudomembranous collitis
• Caused by overgrowth of C. Difficile
• Positive direct Coomb’s Test
10
Penicillin Classifications
• Narrow-spectrum penicillins
• Penicillinase-resistant penicillins
• Extended-spectrum penicillins
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Narrow-Spectrum Agents
• Natural penicillin comes as two variants
– Penicillin G (Pfzierpen®)
• A.K.A. benzylpenicillin
– Penicillin V (Pen-Vee K®, Veetids®)
• A.K.A. phenoxymethyl penicillin
• Short half-lives
• As K+ or Na+ salts; follow in renal patients
– 1.7 mEq K+ per 1 million units
– 2 mEq Na+ per 1 million units
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Penicillin G Versus V
• Penicillin G (IV, PO, IM)
– Destroyed extremely rapidly by gastric acid
– More active against Neiserra and anaerobes
• Penicillin V (PO)
• Keep it straight: V is not IV
• In a severe infection, this is one of the
few times you would not want to give an
oral medication over IV
– Due to erratic absorption of penicillin V
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Narrow-Spectrum Coverage
• Good activity against Gram {+} cocci
(except penicillinase-producing staph)
• Anaerobic activity (except Bacteroides)
• Drug of choice for syphilis, gas gangrene,
and meningococcus
• No activity against aerobic Gram {-}
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Prolonging Penicillin G
• Benzathine salt (Bicillin LA®)
– Average duration is 26 days
– Benzathine adds anesthetic aspect as well
• Procaine salt (Wycillin®)
– Average duration 24 hours
– Potential for procaine allergy
– Large doses can cause procaine toxicity
• Benzathine/procaine salt (Bicillin CR®)
– Contains both salts for early and late peaks
– Usually used for syphilis
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Prolonging Penicillin V
• Probenecid (Benemid®)
– Competitively inhibits active reabsorption
of uric acid at the proximal convoluted
tubule; used for gout, especially under
excretors
– At the proximal and distal tubules,
probenecid competitively inhibits the
secretion of many weak organic acids,
including β-lactams
– Not typically used anymore for penicillins
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Penicillinase-Resistant Agents
• Cloxacillin (Cloxapen®)
• Dicloxacillin (Dynapen®)
• Methacillin (Staphcillin®)
– Discontinued in US
• Nafcillin (Nafcil®)
• Oxacillin (Prostaphlin®)
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Penicillinase-Resistant PCNs
• Originally designed solely for coverage
against S. aureus (methicillin-susceptable
S. aureus [MSSA])
• Decreased activity against other bugs
• S. aureus becoming increasingly resistant
to this class (MRSA), as well as
Staphylococcus epidermidis
– Vancomycin treatment of choice for MRSA
• Eliminated hepatically
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Extended-spectrum PCNs
• Aminopenicillins
• Carboxypenicillins
• Ureidopenicillins
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Aminopenicillins
• Agents
– Ampicillin (Omnipen®, Principen®)
– Amoxicillin (Amoxil®, Trimox®)
– Bacampicillin (Spectrobid®)
• Broader spectrum over penicillin
–
–
–
–
Gram {-} aerobes
Listeria monocytogenes
Proteus mirabilis
E. coli
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Carboxypenicillins
• Agents
– Carbenicillin (Geopen®)
– Ticarcillin (Ticar®)
• More coverage than the aminopenicillins
– Increased Gram {-} coverage
– Peudeomonas aeruginosa
• Ticarcillin 2-4× > Carbenicillin
– Enterobacter
• Carbenicillin concentrates rapidly in urine
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Ureidopenicillins
• Agents
– Azlocillin (Azlin®)
• Discontinued in the US
– Mezlocillin (Mezlin®)
– Pipercillin (Pipracil®)
• Activity
– Maintains Gram {+} coverage
– Added Gram {-}
– Anti-pseudomonal activity
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β-Lactamase Inhibitors
• Irreversibly inactivate β-lactamase
• Given in combination with β-lactamase
susceptible penicillins; this allows the
penicillins to do their job without being
destroyed
• Have no innate antibacterial activity
themselves
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Combination Drugs
• Sulbactam
– With ampicillin (Unasyn®)
• Tazobactam
– With pipercillin (Zosyn®)
• Clavulanate/Clavulanic acid
– With amoxicillin (Augmentin®)
– With ticarcillin (Timentin®)
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Cephalosporins Classifications
•
•
•
•
•
•
•
Spectra of activity (generation)
Carbacephem structure
Anaerobic activity (Cephamycin structure)
Anti-pseudomonal activity
Methyltetrazolethiomethyl side-chain
Metabolism/elimination
Cerebrospinal fluid penetrance
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1st Generation Agents
• Cefazolin (Ancef®, Kefzol®)
• Cefadroxil (Duricef®)
– Cephalosporin analog of amoxicillin
• Cephalexin (Keflex®)
– Cephalosporin analog of ampicillin
• Cephalothin (Keflin®)
• Cephapirin (Cefadyl®)
• Cephradine (Anspor®, Velosef®)
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1st Generation Cephalosporins
• Great Gram {+} activity
• No activity against enterococci
Listeria monocytogenes
or
• Mainstay of choice for uncomplicated
community acquired infections
• PEcK activity
– Proteus
– E. coli
– Klebsiella
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2nd Generation Agents
•
•
•
•
•
•
•
•
Cefaclor (Ceclor®)
Cefamandole (Mandol®)
Cefmetazole (Zefazone®)
Cefoxitin (Mefoxin®)
Cefotetan (Cefotan®)
Cefonicid (Monocid®)
Cefprozil (Cefzil®)
Cefuroxime (Ceftin®, Zinacef®, Kefurox®)
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2nd Generation Cephalosporins
• More Gram {-} activity than
generation agents
• Often used for UTIs and URIs
• HENPEcK activity
–
–
–
–
–
–
H. influenzae
Enterobacter* (rapid resistance occurs)
Neisseria
Proteus
E. coli
Klebsiella
1st
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3rd Generation Agents
•
•
•
•
•
•
•
•
•
•
Cefdinir (Omnicef®)
Cefditoren (Spectracef®)
Cefixime (Suprax®)
Cefoperazone (Cefobid®)
Cefotaxime (Claforan®)
Cefpodoxime (Vantin®)
Ceftazidime (Fortaz®, Tazidime®)
Ceftibuten (Cedax®)
Ceftizoxime (Cefizox®)
Ceftriaxone (Rocephin®)
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3rd Generation Cephalosporins
• Have even better Gram {-} coverage
than second generation agents
• Loses more Gram {+} coverage
• Extra coverage against Serratia and
Moraxella catarrhalis
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4th Generation Agents
• Cefepime (Maxipime®)
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4th Generation Cephalosporins
• Has most of the Gram {-} coverage with
Gram {+} coverage
• Anti-pseudomonal activity
• No anaerobic activity
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The Generation Progression
• As one moves up in cephalosporin
generation, more Gram {-} activity is
seen
• Consequently, Gram {+} activity is
decreased advancing in generation
• 4th generation has Gram {-} activity
without sacrificing Gram {+} activity
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Keeping Generations Straight
• How can one keep them all straight?
• 1st generation:
– If the “f” sound is spelled “ph”, it HAS to
be a 1st generation (phirst)
• 3rd generation:
– If an “f” is followed immediately by a “d” or
“t”, it HAS to be a 3rd generation (third)
• 4th generation:
– “Cefepime is supreme!”
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Carbacephems
• Carbacephems substitute a carbon in
place of sulfur
• Otherwise has same activity as a
cephalosporin
• Loracarbef (Lorabid®), the only clinically
used carbacephem, is typically classified
as a 2nd generation cephalosporin (due to
its activity)
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Cephamycins
• Cephamycins are a special subset of 2nd
generation
cephalosporins
with
excellent anaerobic activity
– Cefotetan
– Cefoxitin
• Mnemonic: Get a foxy tan on your back!
– Back is for bacteroides, a common anaeobic
bacteria
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Anti-Pseudomonal Cephalosporins
• 3rd Generation
– Cefoperazone
– Ceftazidime
• 4th Generation
– Cefepime
• The 3rd generation anti-pseduomonal
agents lose even more Gram {+} activity
than other 3rd generation agents
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MTT Side-Chain
• Methyltetrazolethiomethyl (MTT)
– Hypoprothrombinemia and
disturbing
synthesis
of
dependent clotting factors
bleeding
vitamin
by
K-
• Risk factors are renal or hepatic disease, poor
nutrition, the elderly, and cancer
– Disulfiram-like reaction
• Disulfiram is an agent that inhibits alcohol
dehydrogenase,
causing
an
increase
of
acetaldehyde, the agent that causes hangovers
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MTT-Containing Cephalosporins
• Agents
–
–
–
–
Cefamandole
Cefmetazole
Cefoperazone
Cefotetan
• Mnemonic: I met a man with a perfect tan
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Cephalosporin Elimination
• For the most part, all are renal with few
exceptions
• The “zones” are hepatic
– Cefoperazone
– Ceftriaxone
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CSF penetrance
• 2nd Generation
– Cefuroxime
• Generally not used due to decreased efficacy
• 3rd Generation
– Cefotaxime
• Q6-8° dosing
• Agent of choice in neonatal meningitis (along
with ampicillin)
– Ceftriaxone
• Q12-24° dosing
• Agent of choice for adult meningitis
• Causes kernicterus in neonates
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Monobactams
• Aztreonam (Azactam®)
• Resistant to most Gram {-} β-lactamases
• Activity
– Only Gram {-} coverage (spectrum
resembles aminoglycosides)
– Excellent activity against P. aeruginosa
– Superb Enterobacteriaceae activity
– No Gram {+} or anaerobic activity
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Carbapenems
• More resistant to hydrolysis from βlactamases
• Very broad spectrum with coverage of
Gram {+} (not MRSA), Gram {-},
anaerobes, and Pseudomonas aeruginosa
• Higher incidence of seizure than other
β-lactam agents
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Carbapenem Agents
• Agents
– Ertapenem (Invanz®)
– Imipenem (Primaxin®)
– Meropenem (Merrem®)
• Ertapenem
lacks
coverage
against
Pseudomonas
acinetobacter,
two
common nosocomial agents
45
Cilistatin
• Inhibits renal dehydropeptidase 1, an
enzyme which degrades imipenem in the
kidney brush border cells
• Given only with imipenem (Primaxin®)
• Has neither β-lactamase inhibitory
effects nor antibacterial activity
• Totally unrelated from the “statin”
cholesterol drugs (HMG-CoA Inhibitors)
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Conclusion
• β-lactam antibiotics can treat a wide
variety of bacterial infections
• Choosing an agent must be done with
care as each specific drug has its own
strengths and weaknesses
• However, members of each class share
similar characteristics that would allow
for a fairly equivalent substitution
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References
• Goodman & Gilman’s The Pharmacological Basis
of Therapeutics. 9th & 10th Ed.
• http://www.aafp.org/afp/20000801/611.html
• Mayo Clin Proc 1999:74;187-195
• Mayo Clin Proc 1999:74;290-307
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