β-Lactam Antibiotics

Transcript β-Lactam Antibiotics

Antibiotic Overview

Nathan P. Samsa, Pharm.D., R.Ph.

Objectives

• 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 2

“Basic” Pharmacokinetics

• “ADME” – Adsorption – Distribution – Metabolism – Excretion • Pharmacokinetics: – “How the body acts on the drug” • Pharmacodynamics: – “How the drug acts on the body” 3

How Can We Inhibit 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 4

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 5

What Can We Disrupt?

• Cell Wall • Folic Acid Synthesis • Nucleic Acid Synthesis • Ribosome • Cell Membrane 6

Cell Wall Inhibitors

Cell Wall Agents

• β-Lactams – Penicillins – Cephalosporins – Monbactams – Carbapenems • Glycopeptides 8

β-Lactams

• Bacterial cell walls have 5-peptide chains (

-ala—

-glu—

-lys—

-ala—

-ala) cross linked by penicillin binding proteins (PBP) • The β-lactam ring system looks like

ala—

-ala, where the PBPs will use the β lactam instead • The β-lactam “pops open,” destroying the PBP and halting further crosslinking  cell wall weakens  lysis 9

β-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 10

Penicillin Classifications

• Narrow-spectrum penicillins • Penicillinase-resistant penicillins • Extended-spectrum penicillins 11

Narrow-Spectrum Penicillins

• Penicillin G (Pfzierpen • Penicillin V (Pen-Vee K ® ® )-IM, IV, PO – More active against Neiserra and anaerobes , 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 {-} 12

Penicillinase-Resistant Agents

• Cloxacillin (Cloxapen ® ) • Dicloxacillin (Dynapen ® ) • Methacillin (Staphcillin ® ) – Discontinued in US • Nafcillin (Nafcil ® ) • Oxacillin (Prostaphlin ® ) 13

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 14

Extended-spectrum PCNs

• Aminopenicillins • Carboxypenicillins • Ureidopenicillins 15

Aminopenicillins

• Agents – Ampicillin (Omnipen ® , Principen ® ) – Amoxicillin (Amoxil ® , Trimox ® ) – Bacampicillin (Spectrobid ® ) • Broader spectrum over penicillin – Gram {-} aerobes – Listeria monocytogenes – Proteus mirabilis – E. coli 16

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 17

Ureidopenicillins

• Agents – Azlocillin (Azlin ® ) • Discontinued in the US – Mezlocillin (Mezlin ® ) – Pipercillin (Pipracil ® ) • Activity – Maintains Gram {+} coverage – Added Gram {-} – Anti-pseudomonal activity 18

β-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 ® ) 19

Cephalosporins

• Spectra of activity (generation) • Anaerobic activity (Cephamycins) • Anti-pseudomonal activity • Methyltetrazolethiomethyl side-chain • Metabolism/elimination • Cerebrospinal fluid penetrance 20

1 Generation Agents

• Cefazolin (Ancef ® , Kefzol ® ) • Cefadroxil (Duricef • Cephalexin (Keflex • Cephalothin (Keflin • Cephapirin (Cefadyl ® • Cephradine (Anspor ® ® ® ) ® ) ) ) – Cephalosporin analog of amoxicillin – Cephalosporin analog of ampicillin , Velosef ® ) 21

1 Generation 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 22

2 Generation Agents

• Cefaclor (Ceclor ® ) • Cefamandole (Mandol ® ) • Cefmetazole (Zefazone ® ) • Cefoxitin (Mefoxin ® ) • Cefotetan (Cefotan ® ) • Cefonicid (Monocid ® ) • Cefprozil (Cefzil ® ) • Cefuroxime (Ceftin ® , Zinacef ® , Kefurox ® ) 23

2 Generation Cephalosporins

• More Gram {-} activity than 1 st generation agents • Often used for UTIs and URIs • HENPEcK activity – H. influenzae – Enterobacter * (rapid resistance occurs) – Neisseria – Proteus – E. coli – Klebsiella 24

3 Generation Agents

• Cefdinir (Omnicef ® ) • Cefditoren (Spectracef ® ) • Cefixime (Suprax ® ) • Cefoperazone (Cefobid ® ) • Cefotaxime (Claforan ® ) • Cefpodoxime (Vantin ® ) • Ceftazidime (Fortaz ® , Tazidime ® ) • Ceftibuten (Cedax ® ) • Ceftizoxime (Cefizox ® ) • Ceftriaxone (Rocephin ® ) 25

3 Generation Cephalosporins

• Have even better Gram {-} coverage than second generation agents • Loses more Gram {+} coverage • Extra coverage against Serratia and

Moraxella catarrhalis

4 Generation Cephalosporins

• Cefepime (Maxipime Gram {+} coverage – No anaerobic activity ® ) – Has most of the Gram {-} coverage with – Anti-pseudomonal activity 27

The Generation Progression

• As one moves up in cephalosporin generation, more Gram {-} activity is seen • Consequently, Gram {+} activity is decreased advancing in generation • 4 th generation has Gram {-} activity without sacrificing Gram {+} activity 28

Keeping Generations Straight

• How can one keep them all straight?

• 1 st generation: – If the “f” sound is spelled “ph”, it HAS to be a 1 st generation (phirst) • 3 rd generation: – If an “f” is followed immediately by a “d” or “t”, it HAS to be a 3 rd generation (third) • 4 th generation: – “Cefepime is supreme!” 29

Cephamycins

• Cephamycins are a special subset of 2 anaerobic activity – Cefotetan – Cefoxitin • Mnemonic: Get a foxy tan on your back!

bacteria nd generation cephalosporins with great – Back is for bacteroides, a common anaeobic 30

Anti-Pseudomonal Cephalosporins

• 3 rd Generation – Cefoperazone – Ceftazidime • 4 th Generation – Cefepime • The 3 rd generation anti-pseduomonal agents lose even more Gram {+} activity than other 3 rd generation agents 31

MTT 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 32

MTT-Containing Cephalosporins

• Agents – Cefamandole – Cefmetazole – Cefoperazone – Cefotetan • Mnemonic: I met a man with a perfect tan 33

Cephalosporin Elimination

• For the most part, all are renal with few exceptions • The “zones” are hepatic – Cefoperazone – Ceftriaxone 34

CSF penetrance

• 2 nd Generation – Cefuroxime • Generally not used due to decreased efficacy • 3 rd 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 35

Monobactams

• Aztreonam (Azactam • Activity – Only Gram {-} ® ) • Resistant to most Gram {-} β-lactamases coverage (spectrum resembles aminoglycosides) – Excellent activity against P. aeruginosa – Superb Enterobacteriaceae activity – No Gram {+} or anaerobic activity 36

Carbapenems

• 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 37

Carbapenem Agents

• Agents – Ertapenem (Invanz®) – Imipenem (Primaxin®) – Meropenem (Merrem®) • Ertapenem lacks coverage

Pseudomonas

acinetobacter, common nosocomial agents against two 38

Cilistatin

• Inhibits renal dehydropeptidase 1, an enzyme which degrades imipenem in the kidney brush border cells • Given only with imipenem (Primaxin effects nor antibacterial activity ® ) • Has neither β-lactamase inhibitory • Totally unrelated from the “statin” cholesterol drugs (HMG-CoA Inhibitors) 39

Glycopeptides

• Vancomycin (Vancocin ® ) • Teicoplanin (Targocid ® ) 40

Vancomycin

• 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) 41

Vancomycin Spectrum

• Gram {+} aerobes • MRSA • Penicillin-resistant pneumococcus 42

Vancomycin 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 43

VRE

• Vancomycin Resistant Enterococcus • Few options left: – Quinopristin/Dalfopristin (Sinercid none against Enterococcus faecalis treat – Linezolid (Zyvox ® ) • Covers both faecium and faeacalis ® ) • Coverage only against Enterococcus faecium, • Tip: Faecalis has a “hard c”, so it is harder to 44

Folic Acid Synthesis Inhibitors

Folic 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 46

Folic Acid Inhibitor Spectrum

• Enterobacter • Chlamydia • Nocardia • Pneumocystis carnii 47

Folic 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 48

Nucleic Acid Synthesis Inhibitors

Nucleic Acid Inhibitors

• Fluoroquinolones 50

Fluoroquinolones

• Inhibit DNA topoisomerase II (DNA gyrase) • Bacteriostatic • Divided into generations; reverse of the reverse of cepholosporins Gram {-} activity, but loses Gram {+} Gram {+} activity, but retains Gram {-} (actual classification varies between sources) – Cephalosporins progress from Gram {+} to – Fluoroquinolones progress from Gram {-} to 51

1 Generation FQs

• Nalidixic Acid (NegGram ® ) • Gram {-} coverage only – Enterobacteraceae – E. Coli – Klebsiella – Proteus 52

2 Generation FQs

• Agents – Cinoxacin (Cinobac ® ) – Enoxacin (Penetrex ® ) • Pulled from market – Lomefloxacin (Maxaquin ® ) – Norfloxacin (Noroxin ® ) • Increased Gram {-} spectrum 53

Advanced 2

Generation FQs

• Agents – Ciprofloxacin (Cipro ® ) – Ofloxacin (Floxin ® ) • Has increased Gram {-} coverage along with atypicals • Cipro has good Pseudomonas coverage 54

3 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 2 nd generation with moderate Gram {+} activity • Used in community acuquired pneumonia 55

4 Generation FQ Agents

• Agents – Alatrofloxacin (Trovan • Limited market availability d/t toxicity – Gemifloxacin (Factive – Moxifloxacin (Avelox – Trovafloxacin (Trovan ® ® ) ® ® ) IV) PO) • Limited market availability d/t toxicity • Same as 3 coverage rd generation with anaerobic 56

FQ Side Effects

• Complexes with cations • Photosensitivity • CYP450 interactions • Renal elimination • QT prolongation 

Torsades de Pointes

• Hepatic failure (Trovan ® ) • Tendon rupture – Do not give if <18yo 57

Ribosomal Inhibitors

Anti-Ribosomal Agents

• Ribosomal Subunits – 30s Subunit (Prokaryotic)≈40s (Eukaryotic) • Tetracyclines • Aminoglycosides – 50s Subunit (Prokaryotic)≈60s (Eukaryotic) • Macrolides • Lincomycins • Chloramphenicol • Miscellaneous – Streptogramins – Oxazolidinones 59

Anti-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!

30s 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 61

Tetracyclines

• Demeclocycline (Declomycin ® ) • Doxycycline (Vibramycin ® ) • Minocycline (Minocin ® ) • Tetracycline (Sumycin ® ) 62

Tetracycline 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) 63

Tetracycline 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 64

Aminoglycocides

• Amikacin (Amikin ® ) • Gentamicin (Garamycin ® ) • Netilmycin (Netromycin ® ) • Neomycin (Mycifradin ® ) • Kanamycin (Kantrex ® ) • Streptomycin • Tobramycin (Nebcin ® ) 65

Aminoglycocide Spectrum

• Gram {-} Bacteria – Pseudomonas aeruginosa – Vibrio cholerae – Yersinia pestis (PLAGUE!

– Enterobacter aerogenes – E. coli – Klebsiella pneumoneae – Proteus – Serratia  ) 66

Aminoglycocide SE

• Highly polar (cationic) molecules, usually prevents GI absorption • Renally eliminated – Ototoxicity – Nephrotoxicity • Neomycin-used topically, orally for hepatic failure • Streptomycin-used in TB 67

50s 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) 68

Macrolides

• Azalides: – Azithromycin (Zithromax ® ) • Ketolides: – Telithromycin (Ketek ® ) • Macrolides: – Clarithromycin (Biaxin ® ) – Dirithromycin (Dynabac ® ) – Erythromycin (Ery-Tab ® ) 69

Macrolide Spectrum

• Chlamydia (Erythro drug of choice in pregnancy) • Mycoplasma pneumoniae – Ureaplasma urealyticum • Legionella pneumophila • Treponema pallidum (Syphillis) • Gram (+) cocci • Gram (+) bacilli 70

Macrolide Spectrum

• Clarithro>erythro – Chlamydia, Legionella, Ureaplasma H. flu • Azithroerythro – H. flu, moraxella catarrhalis (why used for pneumonia) 71

Macrolide 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 72

Lincomycins

• Clindamycin (Cleocin ® ) • Lincomycin (Lincocin ® ) 73

Lincomycin Spectrum

• Gram {+} aerobes • Gram {+} anaerobes • Gram {-} anaerobes • NO gram {-} aerobic coverage • Think of these as 2 nd -line penicillins 74

Lincomycin SE

• Rash • Neutropenia • Thrombocytopenia • Erythema multiforme (rare) • Pseudomembranous colitis 75

Chloramphenicol

• 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 76

Streptogramins

• Quinupristin/Dalfopristin (Synercid synthesis synthesis faecium (NO coverage ® ) – Dalfopristin inhibits early phase of protein – Quinupristin inhibits late phase of protein – Ratio 70% dalfopristin/30% quinupristin • Major use is for VRE Enterococcus against enterococcus faecalis) 77

Oxazolidinones

• Linezolid (Zyvox ® ) 78

Linezolid

• 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 79

Cell 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 81

Take 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!