Antimicrobial Stewardship Flashcards

Review flashcards for Antimicrobial Stewardship lecture.

Advances in Medicine related to Antimicrobials

The discovery of antimicrobials has significantly reduced morbidity and mortality worldwide.

Emergence of Resistance to Antimicrobials

Widespread antibiotic use has led to the rise of multidrug-resistant pathogens.

Adverse Effects of Antibiotic Use

Increased rates of Clostridium difficile colitis and higher medical costs due to resistance and overuse of antibiotics.

Statistics of Global Impact of Antibiotic Resistance in the U.S.

Over 2 million infections with multidrug-resistant pathogens occur annually in the U.S., resulting in 20,000 deaths.

Hospital Costs associated with Antibiotic Resistance

Antibiotic-resistant infections contribute to billions of dollars in hospital-associated infection costs.

MRSA

Methicillin-resistant Staphylococcus aureus

Common Resistant Pathogens

Extended-spectrum β-lactamase-producing Gram-negative rods (Escherichia coli, Klebsiella pneumoniae)

Reduce Inappropriate Use of Antibiotics

Prescribing antibiotics when not medically needed (e.g., viral infections).

Encourage Targeted Treatment with Narrow-Spectrum Drugs

Prompt microbiologic diagnosis and use of the most specific, safest antibiotic.

Switching Antibiotics

Switch to narrow-spectrum antibiotics as soon as possible after starting broad-spectrum empiric therapy.

Cultures Before Antibiotics

Send cultures before starting antibiotics to avoid reducing the likelihood of isolating the causative organism.

IV to Oral Antibiotics

Switching from IV to oral antibiotics can reduce catheter-associated infections.

Limit Adverse Effects by Minimizing Antibiotic Use

Minimize antibiotic use duration to reduce the risk of adverse effects.

Adjusting Antibiotic Doses

Adjust antibiotic doses in patients with reduced renal function based on their glomerular filtration rate (GFR).

Identifying Antibiotic Allergies

Identify and explore antibiotic allergies in detail to avoid unnecessary use of alternatives (e.g., penicillin).

Warning Patients About Side Effects

Warn patients about potential side effects (e.g., photosensitivity from certain antibiotics).

Reasons for Inappropriate Antibiotic Use (Physician Related)

Lack of physician knowledge or awareness.

Risk Avoidance

Risk avoidance by physicians.

Inadequate Testing

Inadequate microbiologic information.

Patient Demands

Patient demands and expectations for antibiotics.

Selective Toxicity

The key principle of antimicrobial therapy is selective toxicity, which inhibits microbial growth without harming the host.

Achieving Selective Toxicity

Achieved by targeting differences in microbial metabolism and structure compared to human cells.

Example of Selective Toxicity

Penicillins and cephalosporins inhibit bacterial cell wall synthesis without affecting human cells.

Cell Wall - Major Drug Target in Bacteria

Targeted by drugs like penicillins and cephalosporins.

Ribosomes as a Drug Target

Bacterial ribosomes differ from human ribosomes, allowing selective inhibition.

Nucleic Acids as a Drug Target

Some drugs inhibit bacterial DNA replication or RNA synthesis.

Cell Membrane as a Drug Target

Disrupting bacterial membranes can selectively kill bacteria.

Challenges in Antiviral Therapy

Fewer antiviral drugs exist because viruses rely on host cellular mechanisms for replication.

Difficulty in Antiviral Therapy

Targeting viral replication without harming host cells is difficult.

Broad-Spectrum Antibiotics

Active against multiple microorganisms (e.g., tetracyclines against gram-negative rods, chlamydiae, mycoplasmas, rickettsiae).

Narrow-Spectrum Antibiotics

Target specific bacteria (e.g., vancomycin primarily for gram-positive cocci like staphylococci and enterococci).

Bactericidal Drugs

Kill bacteria directly.

Bacteriostatic Drugs

Inhibit bacterial growth but do not kill them.

Key Characteristics of Bacteriostatic Drugs

Bacteria can resume growth once the drug is withdrawn.

Host Immune Defenses

Host immune defenses (e.g., phagocytosis) are required to eliminate bacteria.

When Bactericidal Drugs Are Essential(1)

Life-threatening infections requiring immediate bacterial elimination.

When Bactericidal Drugs Are Essential(2)

Patients with severely low immune function (polymorphonuclear leukocyte count < 500/μL).

When Bactericidal Drugs Are Essential(3)

Endocarditis, where bacteria are shielded by fibrinous vegetations, making phagocytosis ineffective.

Cephalosporins: Mechanism of Action

β-lactam drugs that inhibit peptidoglycan cross-linking, similar to penicillins.

Cephalosporins: Structure

Six-membered ring adjacent to the β-lactam ring.

Penicillins: Structure

Five-membered ring with a single substitution site.

First-generation Cephalosporins

Primarily effective against gram-positive cocci.

Second to Fifth-generation Cephalosporins

Expanded activity against gram-negative rods.

Fourth & Fifth-generation Cephalosporins

Broad-spectrum, effective against gram-positive and gram-negative bacteria.

Cephalosporins: Advantages

Broad-spectrum, well-tolerated, and cause fewer hypersensitivity reactions than penicillins.

Cephalosporins: Hypersensitivity

Cross-allergy with penicillins (~10%) due to structural similarity.

Cephalosporins: Resistance

Cephalosporins can be inactivated by β-lactamases (cephalosporinases).

β-Lactamase Inhibitors

β-lactamase inhibitors (e.g., tazobactam, avibactam) protect cephalosporins from degradation.

FDA-approved combinations for resistant infections

Ceftazidime/avibactam (Avycaz)

Uses of Ceftazidime/avibactam (Avycaz)

Used for intra-abdominal infections and complicated UTIs caused by resistant gram-negative rods.

Carbapenems: Structure & Mechanism

β-lactam drugs, structurally different from penicillins and cephalosporins.

Carbapenems: Example of Structural Difference

Imipenem has a methylene group instead of sulfur in the ring.

Carbapenems: Spectrum of Activity

Gram-positive cocci (e.g., Streptococcus, Staphylococcus). Gram-negative cocci (e.g., Neisseria). Gram-negative rods (e.g., Pseudomonas, Haemophilus, E. coli). Anaerobes (e.g., Bacteroides, Clostridium).

Carbapenems: ESBL

Effective against extended-spectrum β-lactamase (ESBL)-producing bacteria.

Carbapenems: 'Drugs of Last Resort'

Considered 'drugs of last resort' for multidrug-resistant infections in hospital settings.

Imipenem & Cilastatin Combination

Imipenem is inactivated by dehydropeptidase (kidney enzyme).

Imipenem & Cilastatin: Mechanism

Combined with cilastatin, which inhibits dehydropeptidase and prevents inactivation.

Ertapenem & Meropenem

Are not inactivated by dehydropeptidase, so they do not require cilastatin.

Carbapenemases

Can degrade imipenem and other carbapenems, posing a resistance challenge.

Monobactams

β-lactam drugs with a single β-lactam ring (monocyclic).

Aztreonam

Active against gram-negative rods (e.g., Enterobacteriaceae, Pseudomonas). Inactive against gram-positive and anaerobic bacteria. Resistant to most β-lactamases. No cross-reactivity with penicillins, making it useful for penicillin-allergic patients.

Vancomycin

Glycopeptide antibiotic, not a β-lactam drug.

Vancomycin: Mechanism

Binds D-alanyl-D-alanine of peptidoglycan, preventing transpeptidase binding. Also inhibits transglycosylase, further blocking cell wall synthesis.

Vancomycin: Uses

Treats MRSA (Methicillin-resistant Staphylococcus aureus). Used for infections caused by penicillin-resistant Streptococcus pneumoniae and enterococci.

Vancomycin: Resistance

Some strains of S. aureus, S. epidermidis, and enterococci are partially or fully resistant.

Vancomycin: Adverse Effect

'Red man syndrome' – flushing due to histamine release, not IgE-mediated.

Telavancin, Oritavancin & Dalbavancin

Synthetic derivatives of vancomycin.

Telavancin, Oritavancin & Dalbavancin: Mechanism

Inhibit peptidoglycan synthesis and disrupt bacterial membranes.

Telavancin, Oritavancin & Dalbavancin: Uses

Treat skin/soft tissue infections, including MRSA and vancomycin-resistant enterococci (VRE).

Cycloserine

Analog of D-alanine, inhibits D-alanyl-D-alanine synthesis. Used as a second-line drug for tuberculosis.

Bacitracin

Prevents phospholipid dephosphorylation, blocking peptidoglycan transport. Bactericidal, used for superficial skin infections. Too toxic for systemic use.

Inhibition of Protein Synthesis

Selective inhibition of bacterial protein synthesis is due to structural differences between bacterial (70S) ribosomes and human (80S) ribosomes.

50S subunit inhibitors

Chloramphenicol, macrolides (azithromycin, erythromycin), clindamycin, linezolid.

30S subunit inhibitors

Tetracyclines (doxycycline), aminoglycosides (gentamicin, streptomycin).

Aminoglycosides (30S inhibitors)

Bactericidal, mainly against gram-negative rods.

Aminoglycosides Key Drugs

Streptomycin – Used in tuberculosis treatment. Gentamicin – Combined with penicillin G to treat enterococcal infections.

Aminoglycosides: Mechanism of Action

Inhibits initiation complex formation, preventing protein synthesis. Causes misreading of mRNA, leading to incorrect amino acid incorporation. Disrupts bacterial membranes, resulting in bacterial death.

Aminoglycosides - Toxicity

Can cause kidney damage and hearing loss (8th cranial nerve toxicity).

Aminoglycosides - Poor GI absorption

Must be administered parenterally (not orally effective).

Aminoglycosides - Limited penetration

Poor spinal fluid penetration, requiring intrathecal administration for meningitis.

Aminoglycosides - Ineffective against anaerobes

Ineffective against anaerobes, as oxygen is required for uptake.

Tetracyclines

Bacteriostatic against gram-positive, gram-negative, mycoplasmas, chlamydiae, and rickettsiae.

Tetracyclines: Mechanism

Bind to the 30S ribosomal subunit, blocking aminoacyl-tRNA from entering the ribosome.

Tetracyclines: Selective Toxicity

Due to greater bacterial uptake, not ribosomal differences.

Common tetracyclines

Doxycycline, minocycline, oxytetracycline.

Tetracyclines: Significant Side Effects

Disrupts normal flora → Diarrhea, overgrowth of drug-resistant bacteria and fungi. Candida vaginitis due to Lactobacillus suppression. Brown tooth staining in fetuses/young children (calcium chelation). Chelates iron → Avoid iron-containing products during therapy. Photosensitivity (rash with sunlight exposure).

Tetracyclines: Contraindications

Pregnant women, children under 8 years.

Tigecycline (Glycylcycline Class)

Similar to tetracyclines in structure, mechanism, and side effects.

Tigecycline (Glycylcycline Class): Broad spectrum

Effective against MRSA, VRE, group A/B streptococci, E. coli, Bacteroides fragilis.

Tigecycline (Glycylcycline Class): Uses

Skin infections, intra-abdominal infections.

Chloramphenicol

Broad-spectrum, effective against gram-positive, gram-negative, and anaerobes.

Chloramphenicol: Bacteriostatic/Bactericidal

Bacteriostatic for most but bactericidal for H. influenzae, S. pneumoniae, and N. meningitidis (meningitis pathogens).

Chloramphenicol: Mechanism

Binds 50S ribosomal subunit, inhibiting peptidyltransferase → blocks peptide bond formation.

Chloramphenicol: Selective toxicity

Binds bacterial 50S but can affect human mitochondria (causing toxicity).

Chloramphenicol: Adverse Effects

Dose-dependent suppression (reversible). Aplastic anemia (rare, irreversible, not dose-dependent). "Gray baby" syndrome: Newborns lack glucuronyl transferase, causing toxicity, gray skin, vomiting, and shock.

Macrolides (Azithromycin, Erythromycin, Clarithromycin)

Bacteriostatic with a wide spectrum.

Azithromycin: Uses

Chlamydia trachomatis, Legionella, Mycoplasma, Chlamydia pneumoniae, S. pneumoniae.

Erythromycin: Spectrum and Half-Life

Similar spectrum, but shorter half-life and more GI side effects.

Clarithromycin: Uses

H. pylori infections, Mycobacterium avium-intracellulare (treatment & prevention).

Macrolides: Mechanism

Bind to 50S ribosomal subunit, blocking translocation. Prevent release of uncharged tRNA, halting protein synthesis.