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Antibiotic OverviewAntibiotic OverviewNathan P. Samsa,Nathan P. Samsa, Pharm.D., R.Ph.Pharm.D., R.Ph.

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ObjectivesObjectives

• Briefly discuss pharmacokinetics• Review basic pharmacology of the

various antibiotics • Address indications and side effects• Provide helpful mnemonics• Correlate infectious diseases with

appropriate pharmacological therapy

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““Basic” PharmacokineticsBasic” Pharmacokinetics

• “ADME”– Adsorption– Distribution– Metabolism– Excretion

• Pharmacokinetics:– “How the body acts on the drug”

• Pharmacodynamics:– “How the drug acts on the body”

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How Can We Inhibit How Can We Inhibit Bacteria?Bacteria?

• Bacteristatic– Inhibits a vital pathway used in the

growth of the bacteria, but does not directly cause death

• Bactericidal– Disrupts bacterial function so much that

death will occur

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What Manner Can We Kill?What Manner Can We Kill?

• Time-dependent– Drug concentration must remain

constantly above the minimum inhibitory concentration (MIC)• β-lactams, vancomycin

• Concentration-dependent– Drug concentration must reach a certain

concentration, many times based on the area under the curve (AUC)• Fluoroquinolones

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What Can We Disrupt?What Can We Disrupt?

• Cell Wall• Folic Acid Synthesis• Nucleic Acid Synthesis• Ribosome• Cell Membrane

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Cell Wall InhibitorsCell Wall Inhibitors

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Cell Wall AgentsCell Wall Agents

• β-Lactams– Penicillins– Cephalosporins– Monbactams– Carbapenems

• Glycopeptides

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β-Lactamsβ-Lactams

• Bacterial cell walls have 5-peptide chains (L-ala—D-glu—L-lys—D-ala—D-ala) cross- linked by penicillin binding proteins (PBP)

• The β-lactam ring system looks like D-ala—D-ala, where the PBPs will use the β-lactam instead

• The β-lactam “pops open,” destroying the PBP and halting further crosslinkingcell wall weakenslysis

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β-Lactam Subtypesβ-Lactam Subtypes

• All share a β-lactam ring, thereby having the same mechansim of action (and explaining the cross-sensitivity between classes)– Penicillins– Cephalosporins– Monobactams– Carbapenems

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Penicillin Classifications Penicillin Classifications

• Narrow-spectrum penicillins• Penicillinase-resistant penicillins • Extended-spectrum penicillins

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Narrow-Spectrum PenicillinsNarrow-Spectrum Penicillins

• Penicillin G (Pfzierpen®)-IM, IV, PO– More active against Neiserra and

anaerobes

• Penicillin V (Pen-Vee K®, Veetids®)-PO– Keep it straight: V is not IV

• Good activity against Gram {+} cocci• Anaerobic activity (except Bacteroides)• Drug of choice for syphilis, gas

gangrene, and meningococcus• No activity against aerobic Gram {-}

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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

• Chemicals with no antibacterial activity that irreversibly inactivate β-lactamase– Sulbactam

• With ampicillin (Unasyn®)

– Tazobactam• With pipercillin (Zosyn®)

– Clavulanate/Clavulanic acid• With amoxicillin (Augmentin®) • With ticarcillin (Timentin®)

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CephalosporinsCephalosporins

• Spectra of activity (generation)• Anaerobic activity (Cephamycins)• 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 Generation Cephalosporins Cephalosporins

• Cefepime (Maxipime®)– 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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CephamycinsCephamycins

• Cephamycins are a special subset of 2nd generation cephalosporins with great 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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GlycopeptidesGlycopeptides

• Vancomycin (Vancocin®)• Teicoplanin (Targocid®)

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VancomycinVancomycin

• Vancomycin makes five hydrogen bonds to the D-Ala-D-Ala amino acids at the end of the peptide cross-bridges

• It prevents them from being accessible to the active site of the transpeptidases (where the β-lactams work)

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Vancomycin SpectrumVancomycin Spectrum

• Gram {+} aerobes• MRSA • Penicillin-resistant pneumococcus

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Vancomycin SEVancomycin SE

• Renal clearance– Ototoxicity– Nephrotoxicity

• These are points of contention as they are normally seen in conjunction with aminoglycosides…is it the aminoglycoside, or additive effect?

• Infusion related reactions:– “Red Man Syndrome”– Fever/chills– Phlebitis

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VREVRE

• Vancomycin Resistant Enterococcus• Few options left:

– Quinopristin/Dalfopristin (Sinercid®)• Coverage only against Enterococcus

faecium, none against Enterococcus faecalis • Tip: Faecalis has a “hard c”, so it is harder to

treat

– Linezolid (Zyvox®)• Covers both faecium and faeacalis

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Folic Acid Synthesis Folic Acid Synthesis InhibitorsInhibitors

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Folic Acid InhibitorsFolic Acid Inhibitors

• “Sulfas”– Inhibit dihydropteroate synthetase, an

enzyme involved in the synthesis of bacterial folic acid

• Trimethoprim– Inhibit dihydrofolate reductase, an

enzyme necessary for thymidine synthesis

• Both are bacteriostatic

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Folic Acid Inhibitor Folic Acid Inhibitor SpectrumSpectrum

• Enterobacter• Chlamydia• Nocardia• Pneumocystis carnii

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Folic Acid Inhibitor SEFolic Acid Inhibitor SE

• Rashes– Stevens-Johnson syndrome

• Angioedema• Hemolytic anemia• Nephrotoxicity

– Via precipitation of crystals of the inactive metabolite

• Crosses the placenta– Kernicturus – Should be avoided in pregnancy and in children

under 2 months of age

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Nucleic Acid Nucleic Acid Synthesis InhibitorsSynthesis Inhibitors

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Nucleic Acid InhibitorsNucleic Acid Inhibitors

• Fluoroquinolones

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FluoroquinolonesFluoroquinolones

• Inhibit DNA topoisomerase II (DNA gyrase)

• Bacteriostatic• Divided into generations; reverse of

the reverse of cepholosporins (actual classification varies between sources)– Cephalosporins progress from Gram {+}

to Gram {-} activity, but loses Gram {+}– Fluoroquinolones progress from Gram {-}

to Gram {+} activity, but retains Gram {-}

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11stst Generation FQs Generation FQs

• Nalidixic Acid (NegGram®)• Gram {-} coverage only

– Enterobacteraceae– E. Coli– Klebsiella– Proteus

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22ndnd Generation FQs Generation FQs

• Agents– Cinoxacin (Cinobac®)– Enoxacin (Penetrex®)

• Pulled from market

– Lomefloxacin (Maxaquin®)– Norfloxacin (Noroxin®)

• Increased Gram {-} spectrum

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Advanced 2Advanced 2ndnd Generation Generation FQsFQs

• Agents– Ciprofloxacin (Cipro®)– Ofloxacin (Floxin®)

• Has increased Gram {-} coverage along with atypicals

• Cipro has good Pseudomonas coverage

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33rdrd Generation FQ Agents Generation FQ Agents

• Agents– Gatifloxacin (Tequin®)– Grepafloxacin (Raxar®)

• Pulled from market

– Levofloxacin (Levaquin®)• L-isomer of Ofloxacin

– Sparfloxacin (Zagam®)– Temafloxacin (Omniflox®)

• Pulled from market

• Same coverage as 2nd generation with moderate Gram {+} activity

• Used in community acuquired pneumonia

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44thth Generation FQ Agents Generation FQ Agents

• Agents– Alatrofloxacin (Trovan® IV)

• Limited market availability d/t toxicity

– Gemifloxacin (Factive®)– Moxifloxacin (Avelox®)– Trovafloxacin (Trovan® PO)

• Limited market availability d/t toxicity

• Same as 3rd generation with anaerobic coverage

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FQ Side EffectsFQ Side Effects

• Complexes with cations• Photosensitivity• CYP450 interactions• Renal elimination• QT prolongationTorsades de Pointes• Hepatic failure (Trovan®)• Tendon rupture

– Do not give if <18yo

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Ribosomal InhibitorsRibosomal Inhibitors

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Anti-Ribosomal AgentsAnti-Ribosomal Agents

• Ribosomal Subunits– 30s Subunit (Prokaryotic)≈40s (Eukaryotic)

• Tetracyclines• Aminoglycosides

– 50s Subunit (Prokaryotic)≈60s (Eukaryotic)• Macrolides• Lincomycins• Chloramphenicol

• Miscellaneous– Streptogramins– Oxazolidinones

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Anti-Ribosomal MnemonicAnti-Ribosomal Mnemonic

• Mnemonic:– @30, Amina cycles

• (Aminoglycocide & Tetracycline)

– @50, Mac likes Nicole• (Macrolide & Lincomycin & Chloramphenicol)

• Hey, they’re cheesy, but I’m desperate for ideas!

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30s Inhibitors30s Inhibitors

• Tetracyclines:– Bind to amino acyl t-RNA portion of the

mRNA-ribosome complex– Bacteriostatic

• Aminoglycosides– Bind to the separated 30s subunit causing

misreading– Bacteriocidal

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TetracyclinesTetracyclines

• Demeclocycline (Declomycin®)• Doxycycline (Vibramycin®)• Minocycline (Minocin®)• Tetracycline (Sumycin®)

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Tetracycline SpectrumTetracycline Spectrum

• Gram {+} Bacilli• Gram {-} Rods• Gram {-} Bacilli

– H. influenzae, Vibrio cholera

• Spirochetes– Borrelia burgdorferi (Lyme dz), treponema

pallidum (syphilis)

• Chlamydia• Rickettsia rickettsii (Rocky Mt. Spotted

Fever)

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Tetracycline SETetracycline SE

• Chelates with cations– Decreased absorption with dairy, calcium– Deposition on calcified tissues

• GI upset• Phototoxicity• Demeclocycline

– Never used as an antibiotic because it can induce nephrogenic diabetes insipidus

– Used in treatment of SIADH

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AminoglycocidesAminoglycocides

• Amikacin (Amikin®)• Gentamicin (Garamycin®)• Netilmycin (Netromycin®)• Neomycin (Mycifradin®) • Kanamycin (Kantrex®)• Streptomycin • Tobramycin (Nebcin®)

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Aminoglycocide SpectrumAminoglycocide Spectrum

• Gram {-} Bacteria– Pseudomonas aeruginosa– Vibrio cholerae– Yersinia pestis (PLAGUE! )– Enterobacter aerogenes– E. coli– Klebsiella pneumoneae– Proteus– Serratia

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Aminoglycocide SEAminoglycocide SE

• Highly polar (cationic) molecules, usually prevents GI absorption

• Renally eliminated– Ototoxicity– Nephrotoxicity

• Neomycin-used topically, orally for hepatic failure

• Streptomycin-used in TB

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50s Inhibitors50s Inhibitors

• All 50s inhibitors binds irreversibly to 50s subunit, inhibiting translocation (peptidyl transferase– Therefore, giving ≥2 of these agents is

redundant

• Generally bacteriostatic (cidal @ high doses)

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MacrolidesMacrolides

• Azalides:– Azithromycin (Zithromax®)

• Ketolides:– Telithromycin (Ketek®)

• Macrolides:– Clarithromycin (Biaxin®)– Dirithromycin (Dynabac®)– Erythromycin (Ery-Tab®)

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Macrolide SpectrumMacrolide Spectrum

• Chlamydia (Erythro drug of choice in pregnancy)

• Mycoplasma pneumoniae– Ureaplasma urealyticum

• Legionella pneumophila• Treponema pallidum (Syphillis)• Gram (+) cocci• Gram (+) bacilli

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Macrolide SpectrumMacrolide Spectrum

• Clarithro>erythro– Chlamydia, Legionella, Ureaplasma H.

flu

• Azithro<erythro– Staph, Strep

• Azithro>erythro– H. flu, moraxella catarrhalis (why used

for pneumonia)

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Macrolide SEMacrolide SE

• Erythro destroyed by gastric acid– Enteric coated or esterified forms

• Azithro concentrates in neutrophils, macrophages, fibroblasts

• Erythro Azithro=hepatic; clarithro=renal

• SE:– NVD, cholestatic jaundice (estolate salt-

erythro), Erythro & clarithro go through CYP450

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LincomycinsLincomycins

• Clindamycin (Cleocin®)• Lincomycin (Lincocin®)

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Lincomycin SpectrumLincomycin Spectrum

• Gram {+} aerobes• Gram {+} anaerobes• Gram {-} anaerobes• NO gram {-} aerobic coverage• Think of these as 2nd-line penicillins

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Lincomycin SELincomycin SE

• Rash• Neutropenia• Thrombocytopenia• Erythema multiforme (rare)• Pseudomembranous colitis

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ChloramphenicolChloramphenicol

• Broad spectrum against Gram {+}, Gram {-}, and anaerobes.

• Can be extremely toxic– Dose-related revesible anemia– Hemolytic anemia in G6PD deficiency– Dose-independent aplastic anemia– “Grey baby syndrome” caused by drug

accumulation leading to cyanosis, cardiovascular collapse and eventual death

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StreptograminsStreptogramins

• Quinupristin/Dalfopristin (Synercid®)– Dalfopristin inhibits early phase of protein

synthesis– Quinupristin inhibits late phase of protein

synthesis– Ratio 70% dalfopristin/30% quinupristin

• Major use is for VRE Enterococcus faecium (NO coverage against enterococcus faecalis)

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OxazolidinonesOxazolidinones

• Linezolid (Zyvox®)

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LinezolidLinezolid

• Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex

• Monoamine Oxidase Inhibition– Linezolid is a reversible, nonselective

inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.

• Used in VRE and other severe infections

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Cell Membrane Cell Membrane InhibitorsInhibitors

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Cell Membrane InhibitorsCell Membrane Inhibitors

• Daptomycin (Cubicin®)• Unique mechanism of action that it binds

to bacterial membranes and causes a rapid depolarization of membrane potential which leads to inhibition of protein, DNA, and RNA synthesis

• Used in antibiotic resistant MRSA, VRE, and linezolid-resistant strains

• Can cause myalgias

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Take Home MessagesTake Home Messages

• Regarding mechanism of action: Know its major effect (cell wall vs. ribosomal)

• Regarding side effects: Know what will kill (or maim) a person, or something totally unique to that drug

• Regarding coverage: Know broad classes (Gram, anaerobic)

• Regarding drugs: You will NEVER know everything about pharmacology, so don’t try to!

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The End