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

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

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

What Manner Can We Kill? Time-dependent Concentration-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

What Can We Disrupt? Cell Wall Folic Acid Synthesis Nucleic Acid Synthesis Ribosome Cell Membrane

Cell Wall Inhibitors

Cell Wall Agents β-Lactams Glycopeptides Penicillins Cephalosporins Monbactams Carbapenems Glycopeptides

β-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 crosslinkingcell wall weakenslysis

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

Penicillin Classifications Narrow-spectrum penicillins Penicillinase-resistant penicillins Extended-spectrum penicillins

Narrow-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 {-}

Penicillinase-Resistant Agents Cloxacillin (Cloxapen®) Dicloxacillin (Dynapen®) Methacillin (Staphcillin®) Discontinued in US Nafcillin (Nafcil®) Oxacillin (Prostaphlin®)

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

Extended-spectrum PCNs Aminopenicillins Carboxypenicillins Ureidopenicillins

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

Carboxypenicillins Agents More coverage than the aminopenicillins Carbenicillin (Geopen®) Ticarcillin (Ticar®) More coverage than the aminopenicillins Increased Gram {-} coverage Peudeomonas aeruginosa Ticarcillin 2-4× > Carbenicillin Enterobacter Carbenicillin concentrates rapidly in urine

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

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®)

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

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®)

1st 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

2nd Generation Agents Cefaclor (Ceclor®) Cefamandole (Mandol®) Cefmetazole (Zefazone®) Cefoxitin (Mefoxin®) Cefotetan (Cefotan®) Cefonicid (Monocid®) Cefprozil (Cefzil®) Cefuroxime (Ceftin®, Zinacef®, Kefurox®)

2nd Generation 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

3rd Generation Agents Cefdinir (Omnicef®) Cefditoren (Spectracef®) Cefixime (Suprax®) Cefoperazone (Cefobid®) Cefotaxime (Claforan®) Cefpodoxime (Vantin®) Ceftazidime (Fortaz®, Tazidime®) Ceftibuten (Cedax®) Ceftizoxime (Cefizox®) Ceftriaxone (Rocephin®)

3rd Generation Cephalosporins Have even better Gram {-} coverage than second generation agents Loses more Gram {+} coverage Extra coverage against Serratia and Moraxella catarrhalis

4th Generation Cephalosporins Cefepime (Maxipime®) Has most of the Gram {-} coverage with Gram {+} coverage Anti-pseudomonal activity No anaerobic activity

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

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!”

Cephamycins 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

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

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

MTT-Containing Cephalosporins Agents Cefamandole Cefmetazole Cefoperazone Cefotetan Mnemonic: I met a man with a perfect tan

Cephalosporin Elimination For the most part, all are renal with few exceptions The “zones” are hepatic Cefoperazone Ceftriaxone

CSF penetrance 2nd Generation 3rd Generation Cefuroxime Cefotaxime 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

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

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

Carbapenem Agents Agents Ertapenem (Invanz®) Imipenem (Primaxin®) Meropenem (Merrem®) Ertapenem lacks coverage against Pseudomonas acinetobacter, two common nosocomial agents

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)

Glycopeptides Vancomycin (Vancocin®) Teicoplanin (Targocid®)

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)

Vancomycin Spectrum Gram {+} aerobes MRSA Penicillin-resistant pneumococcus

Vancomycin SE Renal clearance Infusion related reactions: 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

VRE 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

Folic Acid Synthesis Inhibitors

Folic Acid Inhibitors “Sulfas” Trimethoprim Both are bacteriostatic 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

Folic Acid Inhibitor Spectrum Enterobacter Chlamydia Nocardia Pneumocystis carnii

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

Nucleic Acid Synthesis Inhibitors

Nucleic Acid Inhibitors Fluoroquinolones

Fluoroquinolones 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 {-}

1st Generation FQs Nalidixic Acid (NegGram®) Gram {-} coverage only Enterobacteraceae E. Coli Klebsiella Proteus

2nd Generation FQs Agents Increased Gram {-} spectrum Cinoxacin (Cinobac®) Enoxacin (Penetrex®) Pulled from market Lomefloxacin (Maxaquin®) Norfloxacin (Noroxin®) Increased Gram {-} spectrum

Advanced 2nd Generation FQs Agents Ciprofloxacin (Cipro®) Ofloxacin (Floxin®) Has increased Gram {-} coverage along with atypicals Cipro has good Pseudomonas coverage

3rd Generation FQ Agents Gatifloxacin (Tequin®) Grepafloxacin (Raxar®) Pulled from market Levofloxacin (Levaquin®) L-isomer of Ofloxacin Sparfloxacin (Zagam®) Temafloxacin (Omniflox®) Same coverage as 2nd generation with moderate Gram {+} activity Used in community acuquired pneumonia

4th Generation FQ Agents Alatrofloxacin (Trovan® IV) Limited market availability d/t toxicity Gemifloxacin (Factive®) Moxifloxacin (Avelox®) Trovafloxacin (Trovan® PO) Same as 3rd generation with anaerobic coverage

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

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

Anti-Ribosomal 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: Aminoglycosides Bind to amino acyl t-RNA portion of the mRNA-ribosome complex Bacteriostatic Aminoglycosides Bind to the separated 30s subunit causing misreading Bacteriocidal

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

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)

Tetracycline SE Chelates with cations GI upset Phototoxicity 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

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

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

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

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)

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

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

Macrolide Spectrum Clarithro>erythro Azithro<erythro Chlamydia, Legionella, Ureaplasma H. flu Azithro<erythro Staph, Strep Azithro>erythro H. flu, moraxella catarrhalis (why used for pneumonia)

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

Lincomycins Clindamycin (Cleocin®) Lincomycin (Lincocin®)

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

Lincomycin SE Rash Neutropenia Thrombocytopenia Erythema multiforme (rare) Pseudomembranous colitis

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

Streptogramins 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)

Oxazolidinones Linezolid (Zyvox®)

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

Cell Membrane Inhibitors

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

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!

The End