Antibacterial Pharmacology Phar506 Lecture PDF

Antibacterial Pharmacology Phar506 CHRIS SCHRIEVER PHARM.D., M.S. CLINICAL ASSOCIATE PROFESSOR SECTION OF INFECTIOUS DISEASES PHARMACOTHERAPY Objectives u Discuss the MOA of β-lactam, quinolone, macrolide and other commonly encountered antimicrobials u Compare the spectrum of...

Antibacterial Pharmacology Phar506 CHRIS SCHRIEVER PHARM.D., M.S. CLINICAL ASSOCIATE PROFESSOR SECTION OF INFECTIOUS DISEASES PHARMACOTHERAPY Objectives u Discuss the MOA of β-lactam, quinolone, macrolide and other commonly encountered antimicrobials u Compare the spectrum of activities of β-lactam, quinolone, macrolides u Discuss allergic reactions to antimicrobials and the concept of desensitization u Review the adverse side effects including seizure and QT prolongation among commonly use antimicrobials β-Lactams u Penicillin first discovered over 75 years ago; Flemming in 1929 u Largest antimicrobial class u Penicillins, cephalosporins, carbapenems, and monobactams u General structure is fused thiazolidine and β- lactam rings (aka. “house and garage”) β-Lactam Structures β-Lactam Structures Pharmacology MOA - Inhibit cell wall synthesis by binding to Penicillin Binding Proteins (PBPs) at active site – transpeptidation (cross- linking) is inhibited Bactericidal (except enterococcus) AND when cells are not actively growing Has quicker kill rate than vanco for strep Time above the MIC determinate for efficacy (this is why you may see cont. infusion) MOA (β-Lactams) Different bacteria have different affinities for the penicillin binding protein - explains spectrum of activity Pharmacology (cont.) u Mostly renally eliminated, EXCEPT – nafcillin, oxacillin, ceftriaxone, and cefoperazone. Watch renal function u Most have poor oral absorption u Short t1/2 (< 2 hrs), exception is ceftriaxone Dosed frequently due to short T1/2 u Poor CNS penetration, except ceftriaxone and cefotaxime Resistance Occurs by 4 general mechanisms Enzymatic inactivation of antibiotic Modification of target PBP Impaired penetration into cell Efflux pumps β-Lactamase production is most common mechanism of resistance More than 100 identified to date Some are specific to penicillin and not cephalosporins β-lactamase inhibitors Strategy: Add beta lactamase inhibitor to beta lactam antibiotic to prevent resistance (bacteria can’t chew up the antibiotic we are administering) u With enzymatic resistance, couple antimicrobial with β- lactamase inhibitor u Only overcomes resistance mediated by β-lactamase u With over production of β-lactamase, inhibitor may have less activity Citation: Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics, Katzung BG. Basic & Clinical Pharmacology, 14e; 2017. Available at: https://accesspharmacy.mhmedical.com/content.aspx?sectionid=175222792&bookid=2249&jumpsectionid=175222847&Resultclick=2 Accessed: January 11, 2020 Copyright © 2020 McGraw-Hill Education. All rights reserved  Penicillin Classification Natural penicillins Carboxypenicillins Decent against staph/strep - resistance came quick Penicillin G, Ticarcillin benzathine and VK* Ureidopenicillins Antistaphylococcal penicillins Piperacillin Nafcillin, oxacillin, β-lactamase methicillin, inhibitor combos dicloxacillin* Amp/clav*, Aminopenicillins amp/sulb, ticar/clav, pip/tazo Ampicillin*, amoxicilliin* *Oral formulation Classification and Spectrum of Activity Penicillins – Streptococci, T.pallidum Antistaphylococcal – MSSA and strep Aminopenicillins – Strep, enterococcus, Listeria, Salmonella sp., Shigella sp., “wimpy” GNB Carboxy – More gram(-) including PSAE, E. coli, Proteus sp., Enterobacter sp., less gram(+) Ureidopenicillins – Enahanced GNB (PSAE), Serratia, streptocci, gram(+) not as good β-lactamase inhibitor – β-lactamase producing stains of E.coli, Proteus sp., MSSA, H.flu. Neisseria, Bacteroides sp. Cephalosporins Introduced in 1960’s Categorized into “generations” “Generations” are loose classifications for spectrum of activity More stable against β-lactamases, therefore have broader spectrum of activity NOT active against most Extended- Spectrum β-lactamase (ESBL’s), enterococci AND Listeria Cefepime DOES have some stability against ESPLs Cephalosporins First Generation u Activity narrow, mostly gram(+) cocci (mostly skin infections) u S. aureus (MSSA), streptococci, E. coli, Klebsiella u Skin / skin-structure, surgical prophylaxis, UTI, endocarditis u Cefazolin (Ancef®) cephalexin* (Keflex®), cefadroxil* (Duricef®) *Oral formulation Community acquired pneumonia, ear infections, etc. Anaerobes: think GI infection Second generation u Enhanced gram(-) and anaerobic activity while retaining some gram(+) u H. influenza (pen resist.), M.catarralis, and Neisseria sp., Bacteroides sp. (including B. frag.) u Colorectal, urogenital, lower/upper RTI, u Cefotetan, cefoxitin, cefmetazole, cefuroxime (Ceftin®*) u Cefoxitin will cover anaerobes below the waist u Polymicrobial infections – Intra-abdominal, gynecologic, etc. *Oral formulation Third generation u Enhanced gram(-) activity, less gram(+) and anaerobic. u Variable activity to AMP-C hydrolysis (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter – “SPACE bugs” u NGPR (now DOC), meningitis (PRP), gram(-) sepsis/UTI/RTI (HAP),SSTI u Only caftazidime have activity against PSAE (“Tasmanian Devil”) u Meningitis – Ceftriaxone and cefotaxime. Good CNS penetration  Third generation Activity against Primarily broad- MSSA/strep/ gram(-) spectrum gram(-) Ceftriaxone Ceftazidime (Fortaz®) (Rocephin®) More stability against Cefdinir (Omnicef®*) “SPACE bugs” Cefixime (Suprax®*) Cefotaxime (Claforan®) * Oral formulation Fourth and Fifth Generations u Good gram(-) AND gram (+) activity. u MSSA, strep, Enterobacteriaceae, Citrobacter, Enterobacter, bla, bla, bla. u No Stenotrophomonas, Burkholderia, u Some stability ESBL and Amp-C producers u Cefepime (Maxipime®) – 4th u Ceftaroline (Teflaro®) – 5th - Like cefepime BUT MRSA  Cephalosporin Spectrum a..All cephalosporins lack clinically useful activity against enterococci, Listeria monocytogenes, and atypical respiratory pathogens (Legionella, Myco plasma, Chlamydophila spp.). b. b Except for penicillin-resistant strains Carbapenems “Bazooka” - wide coverage Broadest Spectrum – MSSA, strep, Enterobacteriaceae, Citrobacter sp., Enterobacter sp., Stenotrophomonas, Burkholderia sp., ESBL producers Imipenem (Primixim®), meropenem (Merrem®), ertapenem (Invanz®) doripenem (Doribax®) Imipenem and meropenem - similar spectrums (mero>PSAE, imi>enterococcus) Ertapenem does NOT cover Psedomonas aeruginosa (PSAE) or enterococcus All are “drug of choice” for ESBL’s and inducible Amp-C producers Polymicrobial, HAP (not dori/erta), meningitis (mero), etc. Monobactams u Broad-spectrum gram(-) ONLY u Similar gram(-) activity to ceftazidime (suscept. reports should mirror each other) u Reserved for penicillin allergic patients u “Garage” only structure u Aztreonam (Azactam®) – IV only Aztreonam ONLY has activity against gram(-) bacteria Allergic reactions - antimicrobials Crossreactivity % - percentage likelihood that an allergy to one agent will also mean allergy to another agent u Drug surveillance data indicated 2.2% of cutaneous drug reactions are due to amoxicillin, ampicillin, or Trimethoprim/sulfamethoxazole u Maculopapular rash most common reaction occurring day to weeks (secondary exp. appears in min to hrs) Higher incidence of allergic reactions in patients with immune dysfunctions: u Pts have higher frequency of allergic reactions u HIV – (20 to 80%) hypersensitive to Bactrim u CF – Immune hyperresponsiveness and repeated exp. u Mononucleosis – Unclear, alteration in host IR Gruchalla, RS and Pirmohamed M. Antibiotic Allergy. N ENG J Med. 2006;354:601-9. Allergic reactions – β Lactams Crossreactivity was overestimated, partially due to contamination resulting from manufacturing practices u May overestimate based on accuracy of patient reporting allergy u Impurities in manufacture product? u Cross-reactivity between different β-Lactams appears to be between 1 and 10% Closer to 1% in reality u Cross-reactivity appears higher in those individuals w/ more serious reactions Allergic reactions – β-Lactams Cross reactivity increases with severity - more Cross-reactivity antibody activity, etc. 10% in those with rash 20% in those with Hives 40 to 50% in those with anaphylaxis Aztreonam is missing reactive “house portion”, therefore reserved for those w/ serious allergy ?Meropenem safer than imipenem - Few documented cases. Would use caution. (same as seizure story) Antimicrobial desensitization u Relatively safe procedure, which allows administration of abx to patients with severe allergic reactions (i.e. hives, anaphylaxis) u Type I, IgE mediated hypersensitivity u Converts patient from hyperactive state to tolerant state u Controlled degranulation of mast cells Desensitization can be performed provided the reaction is a type I IgE mediated hypersensitivity reaction Antimicrobial desensitization (cont.) u Starting abx dose generally 1/10,000 to 1/100,000 of full dose. u Abx conc. and infusion rate increased over time u Slow degranulation produces low or undetectable levels of inflammatory mediators Desensitization is NOT a permanent state. Stopping the drug for a period of time resotres hypersensitivity Quinolones All are derivatives of nalidixic acid and cinoxacin Original compound fluorinated to improve activity MOA – Topoisomerase (gram -) and DNA gyrase (gram +) inhibition All have high bioavailability (if gut works, use po) Activity gram (-) all, gram (+) newer agents Considered cidal against susceptible bugs Quinolone structure Quinolones – Going, going, gone Quinolones as a class tend to have a lot of side effects.Effects vary between agents Nalidixic acid - First Temafloxacin – gone (G) Norfloxacin – UTI Grepafloxacin – gone (C) Ofloxacin (Oflox®) Sparfloxacin – gone (P/C) Ciprofloxacin (Cipro®) Trovafloxacin (Trovan®) – gone (H) Levofloxacin – L isomer (Levaquin®) Moxifloxacin (Avelox®) Lomefloxacin – gone (P) Gatifloxacin (Tequin)- gone (G) Clinafloxacin – gone (P) Gemifloxacin (Factive®) C = QT-prolong H = Hepatotoxicity G = Glucose abn P = Phototoxicity Spectrum of Activity All cover Enterobacteriaceae , Neisseria sp., Moraxella sp., Haemophilus sp. Good Gram Negative MSSA, pneumococci covered by levofloxacin, moxi, gemiflox(S. pneumonia not Cipro) Ciprofloxacin >Levofloxacin for Pseudomonas Moxi and gemiflox – NO Pseudomonas Moxifloxacin – Good anaerobes Atypicals - Cipro, levo, moxi, gemiflox Cipro DOES NOT cover strep pneumo  Spectrum and Indications CAP – Levo, moxi, gemi HAP/VAP – Levo and Cipro – NO MOXI OR GEMI Intraabdominal – Moxifloxacin only (anaerobes) SSTI – Levo, moxi UTI – Cipro, Levo – NO MOXI Gonorrhea – Used to be agent of choice Mycobacterium tuberculosis  Quinolones – Precautions u Arthropathy/tendonopathy u juvenile animal studies (beagles) u Increase in renal Steroids can precipitate failure/transplant, age>50, (cause) tendon rupture steroid use, M>F u Achilles' tendon most common (50% rupture) u Requires 1 to 2 months rest and immobilization  Quinolones – Precautions u QT – prolongation u Glucose homeostasis u CNS – HA, dizziness, altered mental status, seizure u Phototoxicity (clarith>eryth>azith MSSA, S.pneumonia (PSSP), S.pyogenes, viridans streptocci Gram (-): Azith>clarith>eryth>telith M. catarrhalis, H.influenza, Neisseria sp. NO Activity against Enterobacteriaceae (gut bugs) Atypicals: All have excellent activity Others: Mycobacterium avuim, T. pallidum, Borellia, Bordetella  Places in Therapy Respiratory tract infection Sinusitis/CAP/Pharyngitis Mycobacterium avuim Skin and skin-structure STD’s Anti-inflammatory – CF/panbronchiolitis Inhibit oxidative burst in neutrophils/MØ Inhibit NFΚB which ↓ IL-8 and other chemokines Monitoring Parameters u Drug interactions – All except azithro u GI intolerance – Nausea, vomiting, diarrhea u Ototoxicity – Rare, but seen with high dose erythro u QT prolongation (erythr>clarith>telith>azith) u Hepatic (telithro) – Seen 1-2 weeks u ↑ transaminases, eosinophilia (75%)  QT prolongation Seen with macrolides, quinolones, azole antifungals, pentamidine Most of information from post-marketing studies. Defining a QTC change difficult since some patients are more susceptible to the effects QT prolongation Analysis of patients experiencing QT- prolongation revealed multiple risk factors Of the 69 cases of TdP, pts had on average at least 2 risk factors including: Female sex (64.5%) Heart disease (52.6%) Hypokalemia (30.6%) Drug interactions / excess drug dose Zelter D et al. Torsades de pointes due to noncardiac drug: most patients have easily identifiable risk factors. Medicine (Baltimore) 2003;82:282-90.  QT prolongation FDA post-marketing reports showed that macrolides account for (77%) of Torsades de Pointes Multifactorial including concurrent administration of other QT prolonging agents Electrolyte abnormalities Advanced age Cardiac disease Organ dysfunction Owens, RC and Nolin TD. Antimicrobial-Associated QT Interval Prolongation: Pointes of Interest. Clin Infect Dis. 2006;43:1603-11 Conclusions - QT prolongation Azithromycin appears to be safest macrolide (no P450 interactions), Quinolones – Moxifloxacin has most testing, Moxifloxacin>levofloxacin Cipro appears the safest Watch for Dose adjustment (renal impairment, drug interactions, etc.) Other QT agents present (class Ia/III antiarrhymics – i.e. sotalol, quinidine, dofetilide) Antimicrobials appear to play a combine role with other factors Seizures Epileptogenic effect of antibiotics based on alterations in GABA activity. Antibiotics appear to antagonize GABAA Seizure activity characterized by: Myoclonus, confusion, twitching, etc. Proconvulsant antibiotics include: Penicillins, cephalosporins, aztreonam, carbapenems, fluoroquinolones Penicillin most extensively studied Seizures – Penicillins (cont.) Penicillin has greatest epileptogenic of other penicillins Large inpatient study showed incidence around 0.32%. Renal insufficiency and high doses were most underlying cause of seizures Neonates (