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β-Lactam Antibioticsβ-Lactam AntibioticsNathan P. Samsa,Nathan P. Samsa, Pharm.D., R.Ph., OMSIIPharm.D., R.Ph., OMSII
November 17, 2004November 17, 2004
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ObjectivesObjectives
• Review basic pharmacology of β-lactam antibiotics
• Discuss the four main classes of β-lactam antibiotics
• Organize agents according to various criteria
• Address indications and side effects• Provide helpful mnemonics
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Bacterial Cell WallsBacterial 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-LactamsMechanism 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 crosslinkingcell wall weakenslysis
• Time-dependent killing
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Bacterial DefensesBacterial Defenses
• β-lactamases– Proteins that catalyze hydrolysis of the β-
lactam ringinactivation
• Decreased affinity of PBPs• Reduced penetrance to the site of
action
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β-Lactam Subtypesβ-Lactam Subtypes
• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems
N
S
O
O OH
CH3
CH3
NH
R
O
N
S
O
NH
R1
O
O OH
R2N
O
O OH
R1
S
R3
R2
NO
R1
R2
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β-Lactam Hypersentivityβ-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 IgE- mediated
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Cross SensitivityCross 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)
N
S
O
O OH
CH3
CH3
NH
R
O
Penicillin
Cephalosporin
N
S
O
NH
R1
O
O OH
R2
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PenicillaminePenicillamine
• Penicillamine (Cuprimine®)– Chelates copper in Wilson’s disease– Decreases IgM Rheumatoid Factor– Decreases excretion of cystine in
cystinuria• Shares a common non β-lactam
component structure with penicillin, the cause of cross-sensitivity
N
S
O
O OH
CH3
CH3
NH
R
O
Penicillin
SH
O OH
CH3
CH3NH2
Penicillamine
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β-Lactam Side Effectsβ-Lactam Side Effects
• Seizures– Especially the carbapenems
• Gastrointestinal– Diarrhea– Pseudomembranous collitis
• Caused by overgrowth of C. Difficile
• Positive direct Coomb’s Test
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Penicillin Classifications Penicillin Classifications
• Narrow-spectrum penicillins• Penicillinase-resistant penicillins • Extended-spectrum penicillins
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Narrow-Spectrum AgentsNarrow-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 VPenicillin 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 CoverageNarrow-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 GProlonging 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 VProlonging 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 Penicillinase-Resistant AgentsAgents
• Cloxacillin (Cloxapen®)• Dicloxacillin (Dynapen®)• Methacillin (Staphcillin®)
– Discontinued in US
• Nafcillin (Nafcil®)• Oxacillin (Prostaphlin®)
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Penicillinase-Resistant PCNsPenicillinase-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 PCNsExtended-spectrum PCNs
• Aminopenicillins• Carboxypenicillins• Ureidopenicillins
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AminopenicillinsAminopenicillins
• 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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CarboxypenicillinsCarboxypenicillins
• 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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UreidopenicillinsUreidopenicillins
• 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 Inhibitorsβ-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 DrugsCombination Drugs
• Sulbactam – With ampicillin (Unasyn®)
• Tazobactam– With pipercillin (Zosyn®)
• Clavulanate/Clavulanic acid– With amoxicillin (Augmentin®) – With ticarcillin (Timentin®)
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Cephalosporins Cephalosporins ClassificationsClassifications
• 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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11stst Generation Agents 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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11stst Generation Generation Cephalosporins Cephalosporins
• Great Gram {+} activity• No activity against enterococci or
Listeria monocytogenes• Mainstay of choice for uncomplicated
community acquired infections• PEcK activity
– Proteus– E. coli– Klebsiella
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22ndnd Generation Agents Generation Agents
• Cefaclor (Ceclor®)• Cefamandole (Mandol®)• Cefmetazole (Zefazone®)• Cefoxitin (Mefoxin®)• Cefotetan (Cefotan®) • Cefonicid (Monocid®)• Cefprozil (Cefzil®)• Cefuroxime (Ceftin®, Zinacef®,
Kefurox®)
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22ndnd Generation Generation Cephalosporins Cephalosporins
• More Gram {-} activity than 1st generation agents
• Often used for UTIs and URIs• HENPEcK activity
– H. influenzae– Enterobacter* (rapid resistance occurs)– Neisseria– Proteus– E. coli– Klebsiella
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33rdrd Generation Agents 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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33rdrd Generation Generation Cephalosporins 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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44thth Generation Agents Generation Agents
• Cefepime (Maxipime®)
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44thth Generation Generation Cephalosporins Cephalosporins
• Has most of the Gram {-} coverage with Gram {+} coverage
• Anti-pseudomonal activity• No anaerobic activity
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The Generation ProgressionThe 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 Keeping Generations StraightStraight
• 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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CarbacephemsCarbacephems
• 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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CephamycinsCephamycins
• 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 Anti-Pseudomonal CephalosporinsCephalosporins
• 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-ChainMTT Side-Chain
• Methyltetrazolethiomethyl (MTT)– Hypoprothrombinemia and bleeding by
disturbing synthesis of vitamin K-dependent clotting factors• 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 MTT-Containing CephalosporinsCephalosporins
• Agents– Cefamandole– Cefmetazole – Cefoperazone– Cefotetan
• Mnemonic: I met a man with a perfect tan
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Cephalosporin EliminationCephalosporin Elimination
• For the most part, all are renal with few exceptions
• The “zones” are hepatic– Cefoperazone– Ceftriaxone
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CSF penetranceCSF 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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MonobactamsMonobactams
• 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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CarbapenemsCarbapenems
• More resistant to hydrolysis from β-lactamases
• 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 AgentsCarbapenem Agents
• Agents– Ertapenem (Invanz®)– Imipenem (Primaxin®)– Meropenem (Merrem®)
• Ertapenem lacks coverage against Pseudomonas acinetobacter, two common nosocomial agents
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CilistatinCilistatin
• 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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ConclusionConclusion
• 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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ReferencesReferences
• 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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