1 β-Lactam Antibiotics Nathan P. Samsa, Pharm.D., R.Ph., OMSII November 17, 2004.

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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