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• Antibacterial Pharmacology is discussed in the presentation

Objectives of the presentation:

• Discuss the mechanisms of action (MOA) for beta-lactam, quinolone, macrolide, and other common antimicrobials
• Compare the activity spectrums of beta-lactam, quinolone, and macrolides
• Discuss allergic reactions to antimicrobials, including desensitization
• Review side effects, focusing on seizures and QT prolongation

Beta-Lactams

• Penicillin, a beta-lactam, was first discovered over 75 years ago, specifically in 1929 by Flemming
• Beta-Lactams are the largest antimicrobial class
  • Includes penicillins, cephalosporins, carbapenems, and monobactams
• Beta-lactam general structure includes fused thiazolidine and beta-lactam rings, referred as "house and garage"

Beta-Lactam Structures

• Includes penicillins, cephalosporin, clavulanate, and imipenem

Pharmacology of Beta-Lactams

• Method of Action: Inhibits cell wall synthesis by binding to Penicillin Binding Proteins (PBPs) at the active site, inhibiting transpeptidation (cross-linking)
• Typically bactericidal, except against enterococcus, and when cells are not actively growing
• Exhibits a faster kill rate compared to vancomycin for streptococcus
• Efficacy is determined by the time spent above the Minimum Inhibitory Concentration (MIC)
• Excreted renally, with exceptions such as nafcillin, oxacillin, ceftriaxone, and cefoperazone, which requires monitoring of renal function
• Exhibits poor oral absorption
• Has a short half-life (t1/2) of under 2 hours, except for ceftriaxone
• Demonstrates limited Central Nervous System (CNS) penetration, except for ceftriaxone and cefotaxime

Resistance to Beta-Lactams

• Occurs through four general mechanisms:
  • Enzymatic inactivation of the antibiotic
  • Modification of the target PBP
  • Impaired penetration into the cell
  • Efflux pumps
• Beta-lactamase production is the most common resistance mechanism
• Over 100 beta-lactamases have been identified to date
• Some beta-lactamases are specific to penicillin but not cephalosporins

Beta-Lactamase Inhibitors

• Combines a beta-lactamase inhibitor to a beta-lactam antibiotic to prevent resistance
• In case of enzymatic resistance, couple antimicrobial agent with a beta-lactamase inhibitor
• Only overcomes resistance mediated by beta-lactamase
• With overproduction of beta-lactamase, the inhibitor may have less activity
• Examples of beta-lactamase inhibitors include: Clavulanic acid, Sulbactam, Tazobactam, and Avibactam

Penicillin Classifications

• Natural penicillins have decent function against staph and strep, but causes resistance quickly
  • Examples include: Penicillin G, benzathine and VK*
• Antistaphylococcal penicillins
  • Examples include: Nafcillin, oxacillin, methicillin, dicloxacillin*
• Aminopenicillins, examples: Ampicillin*, amoxicillin*
• Carboxypenicillins, examples: Ticarcillin
• Ureidopenicillins, example: Piperacillin
• Beta-lactamase inhibitor combos
  • Examples include: Amp/clav*, amp/sulb, ticar/clav, pip/tazo
    • *Oral formulation

Classification and Activity Spectrum of Penicillins

• Penicillins are effective against Streptococci and T. pallidum
• Antistaphylococcal penicillins are effective against MSSA and strep
• Aminopenicillins cover Strep, enterococcus, Listeria, Salmonella sp., Shigella sp., and "wimpy" GNB
• Carboxypenicillins are effective against most Gram-negative bacteria including PSAE, E. coli, Proteus sp., Enterobacter sp., and some Gram-positive bacteria
• Ureidopenicillins are effective against enhanced GNB (PSAE), Serratia, streptocci, and some Gram-positive bacteria
• Beta-lactamase inhibitors combat beta-lactamase producing stains of E.coli, Proteus sp., MSSA, H.flu, Neisseria, and Bacteroides sp.

Cephalosporins

• Cephalosporins were introduced in the 1960s
• Cephalosporins are categorized into "generations," which are loose classifications based on spectrum of activity
• More resistant to beta-lactamases, resulting in a broader spectrum of activity
• Inactive against most Extended-Spectrum beta-lactamase (ESBLs), enterococci, and Listeria
  • Cefepime has some stability against ESPLs

Cephalosporin general structure includes:

• R1 acyl side chain
• Beta-lactam ring
• Dihydrothiazine ring
• R2

First Generation Cephalosporins

• Activity is narrow, mainly effective against Gram-positive cocci, mostly skin infections
• Examples: S. aureus (MSSA), streptococci, E. coli, Klebsiella
• Treats skin and skin-structure infections, surgical prophylaxis, UTI, and endocarditis
• Includes drugs like Cefazolin (Ancef), cephalexin* (Keflex), and cefadroxil* (Duricef)
  • *Oral formulation

Second Generation Cephalosporins

• Enhanced Gram-negative and anaerobic activity while maintaining some Gram-positive coverage
• Effective against H. influenza (penicillin resistant), M. catarrhalis, Neisseria sp., and Bacteroides sp. (including B. fragilis)
• Commonly used for colorectal, urogenital, and lower/upper respiratory tract infections (RTI)
• Examples include Cefotetan, cefoxitin, cefmetazole, and cefuroxime (Ceftin*)
  • Cefoxitin can cover anaerobes below the waist
• Treats Polymicrobial infections, such as Intra-abdominal and gynecologic infections
  • *Oral Formulation noted for Ceftin

Third Generation Cephalosporins

• Enhanced activity against Gram-negative bacteria, less activity against Gram-positive and anaerobic bacteria

• Variable activity against AMP-C hydrolysis, affecting Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter ("SPACE bugs")

• Treats NGPR (now DOC), meningitis (PRP), Gram-negative sepsis/UTI/RTI (HAP), and SSTI

• Ceftazidime is the only one with activity against PSAE ("Tasmanian Devil”)

• Ceftriaxone and cefotaxime are used to treat Meningitis because they have good CNS penetration

• Other third gen drugs:

  • Ceftriaxone (Rocephin)
  • Cefdinir (Omnicef*)
  • Cefixime (Suprax*)
  • Cefotaxime (Claforan)
  • Primarily broad-spectrum Gram-(negative) O * Oral formulation

Fourth and Fifth Generation Cephalosporins

• Good Gram-negative and Gram-positive activity
• Effective against MSSA, strep, Enterobacteriaceae, Citrobacter, and Enterobacter
• No activity against Stenotrophomonas and Burkholderia
• Some stability against ESBL and Amp-C producers
• Cefepime (Maxipime) is a fourth-generation cephalosporin
• Ceftaroline (Teflaro) is a fifth-generation cephalosporin that is similar to cefepime but effective against MRSA

Carbapenems

• Called "Bazooka" has wide coverage
• Broadest spectrum, covering MSSA, strep, Enterobacteriaceae, Citrobacter sp., Enterobacter sp., Stenotrophomonas, and ESBL producers
• Includes Imipenem (Primixim), meropenem (Merrem), ertapenem (Invanz), and doripenem (Doribax)
• Imipenem and meropenem have similar spectrums (mero>PSAE and imi>enterococcus)
  • Ertapenem does NOT cover Pseudomonas aeruginosa (PSAE) or enterococcus
• Considered as the drug of choice for ESBLs and inducible Amp-C producers
• Used to treat polymicrobial infections, HAP (not dori/erta), and meningitis (mero), etc.

Monobactams

-  Broad spectrum Gram-negative ONLY
- Similar Gram-negative activity to ceftazidime

• Reserved for penicillin allergic patients
  • Is structure is only the "garage” portion
• Aztreonam (Azactam) an IV drug therapy

Allergic Reactions to Antimicrobials

• Drug monitoring indicates 2.2% of cutaneous drug reactions are due to drugs like Amoxicillin, Ampicillin, or Trimethoprim/sulfamethoxazole
• Maculopapular rash is the most common reaction, occurring from day to weeks (secondary exposure)
• Onset from initial exposure occurs in minutes to hours
• Patients with HIV (20-80%) are more likely to have hypersensitivity to Bactrim
• Cystic Fibrosis results in increased immune hyper-responsiveness with repeated exposure
• Mononucleosis can also cause allergic reactions, due to unclear alteration in host immune response

Allergic Reactions to Beta-Lactams

• Cross-reactivity may be overestimated due to inaccuracy of patient reporting or impurities from manufacturing
• Cross-reactivity between different Beta-Lactams is between 1% and 10%
• Cross-reactivity appears higher in individuals with more serious reactions
• Cross reactivity increases with severity and antibody activity
• Aztreonam missing reactive "house portion", therefore reserved for those w/ serious allergy
• Meropenem safer than imipenem but caution is still advised as there are few documented cases

Antimicrobial Desensitization

• Desensitization is a safe procedure which allows administration of antibiotics to patients with severe allergic reactions, such as hives or anaphylaxis
• Works for Type I, IgE mediated hypersensitivity reactions
• Goal is to convert patients from a hyperactive state to a tolerant state
• Desensitization involves controlled degranulation of mast cells
• Typically start with abx dose generally 1/10,000 to 1/100,000 of full dose, abx concentration and rate of infusion are steadily increased over time
• Slow degranulation reduces or eliminates inflammatory mediators
• Desensitization is NOT permanent; hypersensitivity returns

Quinolones

• All are derivatives of nalidixic acid and cinoxacin
• Original compound fluorinated to improve activity
• Method of Action: Topoisomerase (gram negative) and DNA gyrase (Gram positive) inhibition
• High bioavailability
• Active against Gram-negative (all) & Gram-positive (newer agents)
• Considered cidal against susceptible bugs
• List of Quinolones: - Nalidixic acid - First - Norfloxacin – UTI - Ofloxacin (Oflox) - Ciprofloxacin (Cipro) - Levofloxacin – L isomer (Levaquin) - Lomefloxacin – gone (P) - Clinafloxacin – gone (P) - Temafloxacin – gone (G) - Grepafloxacin – gone (C) - Sparfloxacin – gone (P/C) - Trovafloxacin (Trovan) – gone (H) - Moxifloxacin (Avelox) - Gatifloxacin (Tequin)- gone (G) - Gemifloxacin (Factive) -C = QT-prolong H = hepatotoxicity - G = Glucose abn P = Phototoxicity

Activity Spectrum for Quinolones

• All cover Enterobacteriaceae, Neisseria sp., Moraxella sp., Haemophilus sp. Good Gram Negative
  • MSSA, pneumococci covered by levofloxacin, moxi, gemiflox(S. pneumonia not Cipro)
  • Ciprofloxacin is better than Levofloxacin for Pseudomonas
  • Moxi and gemiflox do not cover Pseudomonas
  • Moxifloxacin is good for anaerobes
  • Effective against Atypicals with Cipro, levo, moxi, gemiflox

Quinolones – Precautions

• Arthropathy/tendonopathy
  • juvenile animal studies (beagles)
  • Increase in renal failure/transplant, age>50, steroid use, M>F
    • Achilles' tendon most common (50% rupture)
  • Requires 1 to 2 months for rest and immobilization
  • Caution when using Steroids due to precipitate which can cause tendon rupture
• QT – prolongation
• Glucose homeostasis
• CNS – HA, dizziness, altered mental status, seizure
• Phototoxicity (<0.1% in available agents)
• Administration w/ divalent cations (physically binds)
  • esp. Mg, Fe, Ca, Zn) - Requires dose separation - Tube feeds

Macrolides versus Ketolides

• C11-C12 Carbamate:
  • Increase in potency, overcomes macrolide resistance
• Methoxy group:
  • Increase in acid stability Keto Group:
• Increase in acid stability, overcomes macrolide resistance

Macrolides and Ketolides

• Erythromycin is the prototype member of this family Targeting activity against the 50S ribosome

• Bacteriostatic

• Metabolized in the liver, with only clarithromycin requiring renal adjustment

• P450 drug interactions, except azithromycin - No CYP interactions with azithromycin

• Erythromycin (initial macrolide) features acid labile, Gl intolerance, narrow spectrum of activity

  • Low dose use as prokinetic agent
    • Clarithromycin, azithromycin and telithromycin are synthetic derivatives
  • Acid stable, greater half-life (esp. azithromycin) penetrates well into most tissues (esp. pulmonary) dump-truck theory" of distribution

• Higher Gram positive activity: Telith > clarith > eryth > azith

• Examples: MSSA, S.pneumonia (PSSP), S.pyogenes, viridans streptocci

• Higher Gram Negative activity: Azith>clarith>eryth>telith - E- Examples: M. catarrhalis, H.influenza, Neisseria sp. Is No Activity against Enterobacteriaceae (gut bugs)

  • Atypicals: All have excellent activity

• Others: Mycobacterium avuim, T. pallidum, Borellia, Bordetella

Macrolides - Monitoring Parameters

Drug interactions – All except azithro

• GI intolerance – Nausea, vomiting, diarrhea Ototoxicity – Rare, but seen with high dose erythro
• QT prolongation (erythr > clarith > telith > azith)
• Hepatic (telithro) – Seen 1-2 weeks - Increase of 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

• 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 diseas (52.6%) - Hypokalemia (30.6%) - Drug interactions / excess drug dose

• 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

Macrolides (erythromycin/clarithromycin) and

• A moxifloxacin appear at highest risk for induction of arrhythmia
• -Generally multifactorial -Watch for Dose adjustment (renal impairment, drug interactions, etc.) -Other QT agents present (class la/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 studies

• Penicillin has greatest epileptogenic of other penicillins -Large inpatient study showed incidence ar ound 0.32%. Renal insufficiency and high doses were most underlying cause of seizures

• Neonates (<7 months) appear to haveincreased risk of penicillin induced seizures

• Patients treated for meningitis may have been predisposed seized

• Frequently linked in human/animal neurotoxicity

• Incidence higher than penicillins

• Imipenem is best studied agent - incidence (0.2-6%)

• Clinical trials comparing imipenem vs. meropenem yielded similar results

• Newer carbapenems (doripenem) excluded pts w/ active seizure hx from trials 2 summary studies have listed the following risk factors for the development of risk factors include:

• Age <7 months, >60 years

• Renal insufficiency

• Pre-existing CNS dx .- -Cardiopulmonary bypass Sepsis and endocarditis Administration ·site Treatment --centers on removing offending agent. -Judiciious dosing required for continued use

Old and New Gram-Positive and Gram-Negative Antimicrobials

• Multidrug-Resistant Gram Positives: MRSA, VRE, GISA, VISA
  • Vancomycin – oldie but a goodie
  • Linezolid – “Vitamin L”
  • Daptomycin – Should be resistant? -Tigecycline – Similar to minocycline, but much more sexy.
  • Dalbavancin – Weekly dosing
• Multidrug-resistant Pseudo, Acinetobacter, ESBL's, carbapenem-resistant Klebsiella - Colistin? – Back of the hands of time! - Few new agents in trials or development for multidrug-resistant GNB. Extended spectrum cephalosporin in combination with B-lactamase inhibitor
  • Ceftolozane/Tazobactam
    • Ceftazidime/Avibactam