Antibiotic Principles and Beta-Lactams

Antibiotics Overview

• Broad-spectrum antibiotics are not a substitute for thoughtful antibiotic selection
• Objectives for antibiotic lectures include: describing key characteristics of antibiotic classes, including spectra of activity, pharmacokinetic profiles and major adverse effects; explaining mechanisms of action for antibiotic classes; and determining the most appropriate antibiotic for a given clinical scenario.
• Students should be able to choose appropriate antibiotics based on the organism causing the infection and potential toxicity to the patient.
• The important information to know are the key characteristics of antibiotic classes, and typical infection causing organisms, with the use of a spectrum chart.
• Information on uses, and structures are not necessary.

Glossary

• IV - intravenous
• PO - per os (oral)
• GI - gastrointestinal
• AE - adverse effect
• PUD - peptic ulcer disease
• t 1/2 - half-life
• BP - blood pressure
• PMH - past medical history
• SICU - surgical intensive care unit
• UTI - urinary tract infection
• MOA - mechanism of action
• MDR - multidrug resistant
• CYP450 - cytochrome P450
• N/V/D - nausea/vomiting/diarrhea
• CNS - central nervous system

Glossary of Specific Terms

• SSTI - skin and soft tissue infection
• SSSI - skin and skin structure infection
• URI/URTI - upper respiratory tract infection
• PBP - penicillin-binding protein
• PCN - penicillin
• MSSA/MRSA - methicillin-susceptible/resistant Staphylococcus aureus
• VRE - vancomycin-resistant Enterococcus
• CAP - community-acquired pneumonia
• HAP - hospital-acquired pneumonia

The Key

• Important antibiotics to know should be highlighted in a chart.
• Crossed-off antibiotics are not commonly used but might be historically relevant.
• Underlined antibiotics can be administered orally
• Italicized antibiotics are intravenous.

General Approach to Infectious Diseases

• Process of diagnosing and treating infectious diseases
• Suspect infection -> Culture suspected sites (for likely pathogens) -> Stain sample -> Identification -> Determine susceptibilities -> Definitive therapy

Fundamental Antibiotic Mechanisms of Action

• Types of antibiotic mechanisms exist: cell wall synthesis, cell membrane function, nucleic acid synthesis, and protein synthesis

Spectrum of Activity Chart

• Chart showing which antibiotics are effective against specific groups of microorganisms. Different types of organisms (e.g. VR-E, MRSA, other bacterial species) are on the chart.
• Understanding the 'S' and 'R' (susceptible and resistant) categories is important.

Beta-Lactams

• Types include penicillins and cephalosporins.
• Penicillins: include natural, antistaphylococcal, aminopenicillins, and penicillin + beta-lactamase inhibitor combinations
• Cephalosporins: include 1st, 2nd, 3rd, 4th generations
• Other types include Carbapenems and Monobactams
• Key characteristic of beta-lactams is the "beta-lactam" ring structure.
• Substitutions modify drug properties.

Natural Penicillins

• Penicillin G, Penicillin V, Penicillin G benzathine: important for their properties in relation to oral/IV administration, spectrum, and pharmacokinetics
• Important to identify when these are best used, or not used.

Aminopenicillins

• Ampicillin and Amoxicillin: key advantages like good bioavailability and broader activity against Gram-negative organisms
• Important to consider their activity in relation to different organisms.

Anti-pseudomonal Penicillins

• Types: Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin
• Carboxypenicillins: Carbenicillin, Ticarcillin
• Important for Pseudomonas infection.
• Key characteristics when comparing to other types of penicillins,

Penicillin/Beta-Lactamase Inhibitor Combinations

• Combinations improve spectrum and reduce resistance.
• TZP (tazobactam) and Sulbactam are important examples to consider.

Glycopeptides

• Vancomycin and Teicoplanin: important for their activity against Gram-positive bacteria like MRSA.
• Important because they do not inhibit the beta-lactams quickly.
• Important to recognize common adverse effects

Lipoglycopeptides

• Telavancin, Oritavancin, and Dalbavancin: additional important drugs for treating infections.
• These all have long half-lives.
• The mechanism of action uses the principle of binding to the terminal D-ala-D-ala chain and interferes with the peptide cross-linking.

Fosfomycin

• MOA: It inhibits the formation of the peptidoglycan monomers.
• It is renally eliminated, is usually a one time dose for UTIs
• It is used as a moderate bioavailable, and topical drug, usually administered IV in Europe

Cyclic Lipopeptides

• Daptomycin: An important drug for treating gram-positive infections, such as those caused by MRSA.
• It has bacteriocidal activity.
• It inserts into cell membranes, leading to leakage of cations, depolarization and cell death.

Polymyxins

• Examples include Colistin and Polymyxin B: effective against Gram-negative bacteria; particularly useful for multi-drug resistant strains of Pseudomonas aeruginosa.
• Important to understand the side effects (nephrotoxicity.)

Nitroimidazoles

• Metronidazole and Tinidazole: effective against anaerobic bacteria and have good tissue penetration.
• Nitroimidazoles interact with DNA, leading to strand breakage, having good bioavailability and tissue penetration.
• Adverse effects include: GI (NVD), CNS (dizziness.)

Fluoroquinolones

• Ofloxacin, Ciprofloxacin, Levofloxacin, Moxifloxacin: act on DNA gyrase; effective against many Gram-negative bacteria and some Gram-positive. The mechanism of action involves binding to DNA gyrase and topoisomerase IV, leading to DNA breaks and preventing replication.

Trimethoprim and Sulfonamides

• Trimethoprim and Sulfamethoxazole: important to have good knowledge of the combination for some organisms including MRSA.
• Mechanism of action involves inhibition of folic acid synthesis by affecting specific pathways in bacteria. Bacterial synthesis of folic acid is needed for growth/replication, so the effect on bacterial enzyme inhibition leads to their bacteriostatic affect.

Fidaxomicin

• Non-absorbed macrolide antibiotic used for C. difficile infections
• Spectrum is very narrow.
• Well-tolerated.
• Good for C.difficile recurrence.

Nitrofurantoin

• Primarily used for UTIs; useful for E. coli and other Gram-positive organisms.
• Important to have knowledge of the typical dose/elimination.

Other Antibiotics

• Information on other antibiotics like the broader spectrum tetracyclines is presented.
• Specifics about tigecycline, eravacycline, omadacycline, and quinupristin/dalfopristin: broader spectrum used in specific conditions.
• Information on the spectrum and resistance specifics relevant to other bacterial pathogens.

Cases

• Medical cases are presented; the most crucial information in medical case summaries is the patient's diagnosis, symptoms, history (including their medical history, allergies and relevant information), and any tests conducted.

Summary

• Review of antibiotic characteristics