β-Lactam Antibiotics

• The presentation discusses antibacterial pharmacology.
• Specifically B-Lactams, Quinolones, Macrolides
• The presentation reviews the adverse effects associated with commonly used antimicrobials
• Adverse effects include seizure and QT prolongation.

B-Lactams

• First discovered over 75 years ago by Flemming in 1929.
• The largest antimicrobial class
• Includes penicillins, cephalosporins, carbapenems, and monobactams.
• General structure is fused thiazolidine and ẞ-lactam rings (aka. "house and garage").
• Inhibits cell wall synthesis by binding to Penicillin Binding Proteins (PBPs) at active site.
• Binding to PBPs inhibits transpeptidation (cross-linking).
• Bactericidal, except for enterococcus, and is effective when cells are not actively growing.
• Quicker kill rate than vancomycin for streptococcus.
• Time above the minimum inhibitory concentration (MIC) determines efficacy.
• Primarily eliminated renally, except for nafcillin, oxacillin, ceftriaxone, and cefoperazone.
• Most have poor oral absorption.
• Short half-life (< 2 hours); ceftriaxone is an exception.
• Poor CNS penetration, except for ceftriaxone and cefotaxime.
• Resistance occurs by 4 general mechanisms.
  • Enzymatic inactivation of antibiotic
  • Modification of target PBP
  • Impaired penetration into cell
  • Efflux pumps.
• B-Lactamase production is the most common mechanism of resistance.
• Over 100 B-lactamases have been identified to date.
• Some are specific to penicillin and not cephalosporins.

B-Lactamase Inhibitors

• Strategy: Add beta lactamase inhibitor to beta lactam antibiotic to prevent resistance.
• The bacteria cannot deactivate the antibiotic being administered
• Couple antimicrobial to a B-lactamase inhibitor where there is enzymatic resistance.
• Only overcomes resistance mediated by B-lactamase.
• If there's overproduction of B-lactamase, the inhibitor may have less activity.

Penicillin Classification

• Natural penicillins include Penicillin G, benzathine and VK.
  • These are decent against staph/strep; resistance rates quick.
• Antistaphylococcal penicillins include nafcillin, oxacillin, methicillin, and dicloxacillin.
• Aminopenicillins include ampicillin and amoxicillin.
• Carboxypenicillins include ticarcillin.
• Ureidopenicillins include piperacillin.
• Beta-lactamase inhibitor combinations include Amp/clav, amp/sulb, ticar/clav, and pip/tazo.
• Oral formulations exist for VK, dicloxacillin, amoxicillin, and Amp/clav,

Classification Spectrum of Activity

• Penicillins are effective against Streptococci and T. pallidum.
• Antistaphylococcal penicillins are effective against MSSA and strep.
• Aminopenicillins are effective against Strep, enterococcus, Listeria, Salmonella sp., and Shigella sp.
• Considered effective against “wimpy” Gram-Negative Bacteria (GNB).
• Carboxys are effective against Gram(-) bacteria.
• Includes PSAE, E. coli, and Proteus sp.
• Considered effective against Enterobacter sp.
• Less effective against Gram(+) bacteria
• Ureidopenicillins are effective against Enhanced GNB (PSAE) and Serratia.
• Streptococci and Gram(+) are not as effective against it.
• Beta-lactamase inhibitors are effective against B-lactamase producing strains such as E.coli, Proteus sp., MSSA, H.flu, Neisseria, and Bacteroides sp.

Cephalosporins

• Introduced in 1960's
• Categorized into “generations”
• "Generations" are loose classifications for spectrum of activity
• More stable against B-lactamases.
• Therefore have a broader spectrum of activity.
• Not active against most Extended-Spectrum B-lactamase (ESBL's), enterococci AND Listeria.
  • Cefepime has some stability against ESPLs

First Generation Cephalosporins

• Activity is narrow; primarily gram-positive cocci.
• These cocci mostly cause skin infections
• Effective against S. aureus (MSSA), streptococci, E. coli, and Klebsiella
• Used for skin/skin-structure treatment, surgical prophylaxis, UTI, and endocarditis.
• Includes cefazolin (Ancef®) cephalexin* (Keflex®), and cefadroxil* (Duricef®)
• Oral formulation

Second Generation Cephalosporins

• Have enhanced gram-negative and anaerobic activity while retaining some gram-positive activity
• Effective against H. influenza and M. catarrhalis
• Effective against Neisseria sp. and Bacteroides sp., including B. frag.
• Treats colorectal and urogenital infections
• Can treat lower/upper Respiratory Tract Infections (RTI)
• Includes Cefotetan, cefoxitin, cefmetazole, and cefuroxime (Ceftin®*).
• Cefoxitin can cover anaerobes below the waist.
• Treats polymicrobial infections: Intra-abdominal, gynecologic.

Third Generation Cephalosporins

• Have enhanced gram-negative activity with less gram-positive and anaerobic activity.
• Variable activity to AMP-C hydrolysis.
  • Includes Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter.
  • Can treat NGPR meningitis, gram(-) sepsis/UTI/RTI (HAP), and SSTI
• Only caftazidime has activity against PSAE (“Tasmanian Devil").
• Treats Meningitis
  • Ceftriaxone and cefotaxime
  • Good CNS penetration
• Have primarily broad-spectrum gram(-) activity.
• Drugs include ceftriaxone (Rocephin®), ceftazidime (Fortaz®), cefdinir (Omnicef®), cefixime (Suprax®), and cefotaxime (Claforan®).
  • Ceftazidime offers more stability versus "SPACE bugs”.

Fourth and Fifth Generation Cephalosporins

• Good gram(-) AND gram (+) 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 4th generation
• Ceftaroline (Teflaro®) – 5th generation
  • Like cefepime BUT can treat MRSA

Allergic Reactions to Antimicrobials

• Drug surveillance data indicated 2.2% of cutaneous drug reactions are due to amoxicillin, ampicillin, or trimethoprim/sulfamethoxazole.
• Maculopapular rash is the most common reaction, occurring days to weeks later.
• Reactions appear in minutes to hours.
• Patients have a higher frequency of allergic reactions:
• HIV - (20 to 80%) hypersensitive to Bactrim.
• CF – Immune hyperresponsiveness and repeated exposure.
• Mononucleosis – Unclear alteration in host IR.

Allergic Reactions to B-Lactams

• May overestimate allergic frequency based on patient reporting accuracy.
• Caused by impurities in the manufacturing process.
• Cross-reactivity between different B-Lactams appears to be between 1 and 10%.
• Closer to 1% in reality.
• Cross-reactivity appears higher in individuals with more serious reactions.
• Cross-reactivity increases with severity; more antibody activity.
• Aztreonam is missing reactive “house portion"
  • Reserved for those with a serious allergy.
• Meropenem may be safer than imipenem.
  • However, few documented cases exist.
  • Would use caution.
  • (Also concerns around seizure story)

Antimicrobial Desensitization

• Relatively safe procedure.
• Allows administration of antibiotics to patients with severe allergic reactions
• Effective for Type I, IgE mediated hypersensitivity.
• Converts patient from hyperactive state to a tolerant state.
• Allows controlled degranulation of mast cells
• To initiate desensitization:
• Start antibiotic dose at 1/10,000 to 1/100,000 of full dose.
• Increase antibiotic concentration and infusion rate over time.
• Slow degranulation produces low or undetectable levels of inflammatory mediators.

Quinolones

• All are derivatives of nalidixic acid and cinoxacin.
• Original compounds fluorinated to improve activity
• Mechanism of action (MOA) – Topoisomerase (gram negative) and DNA gyrase (gram positive) inhibition.
• All have high bioavailability (if gut works, use PO)
• Have activity against gram negative and gram positive.
• Newer agents perform better against gram positive
• Considered bactericidal against susceptible bugs

Quinolone Agents

• Nalidixic acid: First generation
• Norfloxacin: Used to treat UTIs.
• 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-prolongation
  • G = Glucose abnormality
  • H = Hepatotoxicity
  • P = Phototoxicity

Spectrum of Activity for Quinolones

• All cover Enterobacteriaceae, Neisseria sp., Moraxella sp., and Haemophilus sp.
  • Considered Good against Gram-Negative bacteria.
• MSSA and pneumococci are covered by levofloxacin, moxi, and gemiflox
  • Streptococcus.pneumoniae not covered by Cipro.
• Ciprofloxacin works better than Levofloxacin for Pseudomonas.
• Moxi and gemiflox do NOT work against Pseudomonas.
• Moxifloxacin considered good against anaerobes.
• Atypicals work well against Cipro, levo, moxi, and gemiflox

Spectrum and Indications for Quinolones

• Community-Acquired Pneumonia (CAP): Levo, moxi, gemi
• Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia (HAP/VAP): Levo and Cipro
  • NO MOXI OR GEMI!
• Intraabdominal: Moxifloxacin only (anaerobes)
• Skin and Soft Tissue Infections (SSTI): Levo, moxi
  • Urinary Tract Infection (UTI): Cipro, Levo – NO MOXI
• Gonorrhea: was used to be the agent of choice
• Mycobacterium tuberculosis

Precautions to Quinolone Use:

• Arthropathy/tendonopathy
  • Juvenile animal studies (beagles) show signs of this.
  • Increase in renal failure/transplant patients, age>50, steroid use, M>F -Achilles' tendon most common (50% rupture
  • Requires 1 to 2 months rest and immobilization
• QT – prolongation
• Glucose homeostasis
• CNS – Headache, dizziness, altered mental status, seizure
• Phototoxicity (<0.1% in available agents
• Do not administer with divalent cations (physically binds)
• Magnesium, Iron, Calcium, and Zinc
• Requires dose separation
• Be careful with tube feeds Separately administer cations from quinolones due to binding for medications given orally (IV not affected)

Macrolides vs Ketolides

• C11-C12 Carbamate increases potency and overcomes macrolide resistance.
• A methoxy group increases acid stability
• A Keto Group increases acid stability and overcomes macrolide resistance.

Macrolides and Ketolides

• Erythromycin is the prototype member of this family.
• Targets activity against 50S ribosome.
• Bacteriostatic.
• Metabolized in the liver.
• Adjust the dose of clarithromycin for renal impairment
• P450 drug interactions.
  • Azithromycin is an exception.
  • It does not have CYP interactions
  • a computer will still flag this because it's a macrolide.

Agents within Macrolides and Ketolides

• Erythromycin's features:
• Acid labile.
• GI intolerance
• The narrow spectrum of activity. -Low dose use as a prokinetic agent
• Clarithromycin, azithromycin, and telithromycin features:
• Synthetic derivatives.
• Stable in acid.
• Offer a longer half-life (especially azithromycin).
• Penetrate well into most tissues, especially pulmonary tissue.
• Distribute in a “dump-truck" mechanism

Activity Spectrum within Macrolides and Ketolides

• The efficacy against Gram+: Telith > clarith> eryth > azith
• Effective against MSSA, S.pneumonia (PSSP), S.pyogenes, and viridans streptococci.
• The efficacy against Gram (-): Azith > clarith > eryth > telith
• Effective against M. catarrhalis, H.influenza, and Neisseria sp.
• Not Effective against Enterobacteriaceae (gut bugs).
• Effective vs Atypicals
• Effective vs Others: Mycobacterium avium, T. pallidum, Borellia, and Bordetella.

Uses for Macrolides and Ketolides

• Respiratory tract infection
• Sinusitis/CAP/Pharyngitis
• Mycobacterium avium
• Skin and skin-structure
• STD'S
• Anti-inflammatory in treatment of CF and panbronchiolitis
• Inhibit oxidative burst in neutrophils/MØ
• Inhibit NFKB which ↓ IL-8 and other chemokines

Monitoring Parameters for Macrolides and Ketolides

• Drug interactions
• All except azithromycin
• GI intolerance Nausea, vomiting, and diarrhea
• Ototoxicity Rare, but seen with high dose erythro
• QT prolongation (erythr > clarith > telith > azith)
• Hepatic (telithro).
  • Seen in 1-2 weeks
  • Includes increased transaminases with eosinophilia (75%)

QT Prolongation with Certain Antibiotics

• Seen with macrolides, quinolones, azole antifungals, and pentamidine.
• Most information from post-marketing studies.
• Defining a QTC change is difficult:
• Some patients are more susceptible to the effects.
• Analysis of patients experiencing QT-prolongation revealed multiple risk factors.
  • Of the 69 cases of Torsades de Pointes (TdP), patients 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
• The FDA post-marketing reports showed that macrolides account for (77%) of TdP
• Multifactorial including:
  • Concurrent administration of other QT prolonging agents
  • Electrolyte abnormalities
• Advanced age -Cardiac disease
• Organ dysfunction
• Conclusions, to avoid QT prolongation
• Azithromycin appears to be the safest macrolide because it has no P450 interactions.
• Cipro appears the safest Quinolone
• Watch for dose adjustments when treating renal impairment and in the setting of drug interactions.

Seizures Resulting from Antibiotic Use

• Epileptogenic effect of antibiotics-based on alterations in GABA activity.

• Antibiotics appear to antagonize GABAA.

• Seizure activity characterized by:
• Myoclonus, confusion, twitching.
• Proconvulsant antibiotics include: -Penicillins, cephalosporins, aztreonam, carbapenems, and fluoroquinolones.
• Penicillin most extensively studied.
• Penicillin has the greatest epileptogenic effect among other penicillins.
• Large inpatient study showed incidence around 0.32%.
• Renal insufficiency and high doses were the most underlying cause of seizures.
• Neonates (<7 months) appear to have an increased risk of penicillin-induced seizures.
• Patients treated for meningitis may be predisposed to a seizure.
• Newer carbapenems (doripenem) excluded patients with active seizure from the hx trials.

Risk Factors for Antibiotic Induced Seizures

• Age <7 months, >60 years.
• Renal insufficiency.
• Pre-existing CNS diagnosis.
• Cardiopulmonary bypass.
• Sepsis and endocarditis.
• Administration site.
• Onset usually 12 to 36 hours after initiation of antibiotic administration.

Summary of Considerations for Seizures and Antibiotic Use

• Stop the drug causing a seizure
• Benzos (1st) and barbs (pheno 2nd) appear more efficacious than phenytoin (don't use).
• Remember the risk factors and adjust treatment accordingly.
• Keppra may provide some benefit because it can modulate the GABA channel.
• Allows concentration of epileptogenic agent to decline most effectively.

Treatment for Gram Positive infections

• Multidrug-Resistant Gram Positives are resistant to the classes of drugs
• Vancomycin
• Linezolid
• Daptomycin Dalbavancin
• Old and New Gram-
• New agents in clinical trials and development for multidrug-resistant GNB.

Old and New Gram- Antibiotics

• Targeting Multidrug-resistant Pseudo, Acinetobacter, and ESBL's
• Talk about using Colistin
• Extended-spectrum cephalosporins in combination with B-lactamase inhibitors.
  • Use Ceftolozane/Tazobactam
  • Use Ceftazidime/Avibactam

Explore the mechanism, spectrum of activity, and resistance mechanisms of β-lactam antibiotics. Understand their clinical use, including appropriate selection, dosing strategies, and managing resistance.