Introduction to Antibiotics PDF (August 2024)

AUGUST 2024 INTRODUCTION TO ANTIBIOTICS KATHRYN G. ROSE, PHARMD, BCPS, BCPPS, BCIDP Adjunct Assistant Professor at the University of Texas at Austin College of Pharmacy Division Director of Clinical Pharmacy, HCA Central West Texas (St. David’s HealthCare and Las Palmas Del Sol Healthcare) Pre-Wo...

AUGUST 2024 INTRODUCTION TO ANTIBIOTICS KATHRYN G. ROSE, PHARMD, BCPS, BCPPS, BCIDP Adjunct Assistant Professor at the University of Texas at Austin College of Pharmacy Division Director of Clinical Pharmacy, HCA Central West Texas (St. David’s HealthCare and Las Palmas Del Sol Healthcare) Pre-Work Learning Objectives 1. Recognize the roles that ADME (absorption, distribution, metabolism, and excretion) and restricted compartments play in mediating the actions of antimicrobial drugs. 2. Describe the differences between the terms minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). 3. Explain the concept of MIC breakpoint and interpret MIC breakpoint data from clinical cases to make informed judgements about antimicrobial dosing. 4. Compare and contrast bactericidal and bacteriostatic antimicrobial agents. 5. Compare and contrast concentration dependent and concentration independent cell killing activity. 6. Explain post-antibiotic effect. 7. List the major organisms prone to development of antimicrobial drug resistance and the mechanisms by which they develop/acquire resistance. In Class Learning Objectives 1. Evaluate a clinical scenario and identify relevant patient-specific factors guiding antimicrobial drug selection. 2. Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent. 3. Organize the antibiotics by both mechanism of action and spectrum (Gram +, Gram -, Anaerobes). Overview of Today’s Class Classification of Antibiotics Principles of Treatment Antibiotic Resistance  Eukaryotes vs. Prokaryotes (Prokaryotes) Unique targets can be distinguished between eukaryotes and prokaryotes Helps minimize toxicity to the host Example shown here – Unique target = 50S & 30S ribosomes Antibiotic mechanism of action = Inhibit biosynthesis of proteins  Additional Examples of Antibiotic Targets Unique target = porin Unique target = peptidoglycan Unique target = mycolic acids LO: Organize the antibiotics by both mechanism of action and spectrum (Gram +, Gram -, Anaerobes) LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent.  Classification of Antibiotics by Mechanism of Action (Target) Cell Wall B-lactams (penicillins, cephalosporins, Synthesis carbapenems) Inhibitors Glycopeptides (vancomycin) Fluoroquinolones (levofloxacin) DNA Synthesis Nitrofurantoin Inhibitors Metronidazole Protein Aminoglycosides (gentamicin) Synthesis Tetracycline (doxycycline) Inhibitors Macrolide (azithromycin) RNA Synthesis Rifampin Inhibitor Mycolic Acid Synthesis Isoniazid Inhibitor Folic Acid Synthesis Bactrim (sulfamethoxazole/trimethoprim) Inhibitor LO: Organize the antibiotics by both mechanism of action and spectrum (Gram +, Gram -, Anaerobes).  Antibiotic Spectrum of Activity Gram Positive Coverage Gram Negative Coverage Anaerobic Coverage Clindamycin Penicillin Augmentin Oxacillin, nafcillin Clindamycin Metronidazole Vancomycin (only anaerobes) Piperacillin-tazobactam Aztreonam Moxifloxacin Aminoglycosides (gentamicin) Unasyn Amoxicillin, ampicillin Carbapenems Amoxicillin-clavulanate (Augmentin), ampicillin-sulbactam (Unasyn) Piperacillin-tazobactam (Zosyn) 1st – 5 generation cephalosporins (i.e. cefazolin, ceftriaxone, th cefepime) Carbapenems (meropenem) Fluoroquinolones (levofloxacin) Bactrim (sulfamethoxazole/trimethoprim) Tetracycline (doxycycline) LO: Organize the antibiotics by both mechanism of action and spectrum (Gram +, Gram -, Anaerobes). Antibiotic Resistance Factors contributing to the development of antibiotic resistance Treating viral and noninfectious diseases with antibiotics Treating positive cultures in asymptomatic patients with antibiotics Using antibiotics when they will not alter the patient’s clinical course Not obtaining adequate source control Not selecting the shortest effective duration of therapy Clatworthy, A., Pierson, E. & Hung, D. Targeting virulence: a new paradigm for antimicrobial therapy. Nat Chem Biol 3, 541–548 (2007). https://doi.org/10.1038/nchembio.2007.24  Resistance Prone Organisms VRE Carbapenem- MRSA resistant (methicillin- (vancomycin- Acinetobacter resistant resistant Staphylococcus enterococcus) spp. aureus) CRE MDR ESBL (carbapenem- (multi-drug (extended- resistant resistant spectrum Enterobacterale Pseudomonas cephalosporin s) aeruginosa) resistance) CDC. COVID-19: U.S. Impact on Antimicrobial Resistance, Special Report 2022. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2022. https://www.cdc.gov/drugresistance/covid19.html LO: List the major organisms prone to development of antimicrobial drug resistance and the mechanisms by which they develop/acquire resistance.  Mechanisms of Resistance Export of drug from bacterial cell Pumps drugs back out of cell (promote the active efflux of multiple classes of antibiotics) Provides resistance to – tetracyclines (doxycycline) – fluoroquinolones (levofloxacin) Example: gram negative bacteria and tetracycline AIMS Microbiol. 2018; 4(3): 482–501. doi: 10.3934/microbiol.2018.3.482 LO: List the major organisms prone to development of antimicrobial drug resistance and the mechanisms by which they develop/acquire resistance.  Mechanisms of Resistance Decreased access of drug to target site Mutation of porin proteins in outer membrane of gram-negative cell wall → decreased permeability Provides resistance to – β-lactams – aminoglycosides Example: Pseudomonas aeruginosa strains resistant to many β-lactam antibiotics AIMS Microbiol. 2018; 4(3): 482–501. doi: 10.3934/microbiol.2018.3.482 LO: List the major organisms prone to development of antimicrobial drug resistance and the mechanisms by which they develop/acquire resistance.  Mechanisms of Resistance Modify drug target in bacterial cell Resistance Modification to Mutation in penicillin-binding B-lactams proteins (PBP) Aminoglycosid Mutation in 30S subunit of es bacterial ribosome (gentamicin) Example: MRSA contains Replacement of alanine with lactate mecA gene which encodes Vancomycin in bacterial peptidoglycan additional PBP2a Fluoroquinolon AIMS Microbiol. 2018; 4(3): 482– Mutation in DNA gyrase es 501. doi: 10.3934/microbiol.2018.3.482 (levofloxacin) LO: List the major organisms prone to development of antimicrobial drug resistance and the mechanisms by which they develop/acquire resistance.  Mechanisms of Resistance Inactivate the drug with a bacterial enzyme β-lactamases cleaves β-lactam drugs – Provides resistance to penicillins cephalosporins carbapenems Aminoglycoside modifying enzymes Example: KPC-1 carbapenamase in K. pneumoniae resistant to carbapenems, broad spectrum penicillins and cephalosporins AIMS Microbiol. 2018; 4(3): 482–501. doi: 10.3934/microbiol.2018.3.482 LO: List the major organisms prone to development of antimicrobial drug resistance and the mechanisms by which they develop/acquire resistance.  Classification of Antibiotics by Spectrum of Activity Narrow Extended Broad spectrum spectrum spectrum Act primarily G+ Intermediate Act on both G+ OR G- bacteria coverage of G+ and G- bacteria Example: G+  and G- bacteria including multi- penicillin, Example: drug resistant oxacillin ceftriaxone, pathogens like ampicillin- Pseudomonas sulbactam aeruginosa (Unasyn) Example: piperacillin- tazobactam LO: Organize the antibiotics by both mechanism of action and spectrum (Gram +, Gram -, Anaerobes). Introduction to Antibiotics Pathog The right drug against the en right pathogen must be administered at the right dose to be safe and effective. Antibio tic Selecti on Spectrum of activity Antibio Pharmacokinetics Patient tic Pharmacodynamics Pai, MP, Cottrell ML, & Bertino JS. (2020). Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. In Bennett JE, Dolin R, & Blaser MJ (Eds.), Mandell, Douglas, and Bennett's Principles and In the following patient case… What are patient, pathogen, and antibiotic specific factors that should be considered to guide antibiotic selection?  61 year old female presents to the Emergency Department with shortness of breath and fever that has worsened over the past 5 days. PMH: metastatic breast cancer, hypertension, craniotomy ~2 weeks ago for tumor removal. HPI: per the patient, she began coughing five days ago and started to feel worse so she took her temperature today and upon discovering she had a fever she contacted her provider who told her to seek care immediately. Vital Signs: – Heart rate 112 Neuro Examination: normal Chest X-ray: abnormal (diffuse bilateral patchy – Blood pressure 90/54 mm Hg infiltrates) (MAP 66) WBC 10 x 109/L – Temperature 39.2°C SCr 0.87 mg/dL Bilirubin: 1.8 mg/dL – Respiratory rate 18 on room air Lactate: 2.8 mmol/L – Weight: 70 kg  Patient-Specific Factors to Guide Antibiotic Selection Severity of Illness Age Past Medical History Weight Presence of chronic co- morbidities Renal and hepatic Immunosuppression function Previous/recent antibiotic use Community vs. hospital onset Allergies Site of Infection Pregnancy & breastfeeding LO: Evaluate a clinical scenario and identify relevant patient-specific factors guiding antimicrobial drug selection.  Using Pathogens to Guide Antibiotic Selection Diagnosis of a suspected or confirmed Pathog microbial infection en Obtain tests to identify and determine pathogen susceptibility Antibio tic What pathogens are associated with Selecti the suspected or confirmed site/source of the microbial infection? on Antibio Patient tic Make antibiotic selection (empiric vs. targeted) considering patient and antibiotic factors LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent. In the following patient case… What are patient, pathogen, and antibiotic specific factors that should be considered to guide antibiotic selection?  61 year old female presents to the Emergency Department with shortness of breath and fever that has worsened over the past 5 days. PMH: metastatic breast cancer, hypertension, craniotomy ~2 weeks ago for tumor removal. HPI: per the patient, she began coughing five days ago and started to feel worse so she took her temperature today and upon discovering she had a fever she contacted her provider who told her to seek care immediately. Vital Signs: – Heart rate 112 Neuro Examination: normal Chest X-ray: abnormal (diffuse bilateral patchy – Blood pressure 90/54 mm Hg infiltrates) (MAP 66) WBC 10 x 109/L – Temperature 39.2°C SCr 0.87 mg/dL Bilirubin: 1.8 mg/dL – Respiratory rate 18 on room air Lactate: 2.8 mmol/L – Weight: 70 kg  Susceptibility Testing Laboratory methods to determine the sensitivity of the isolated pathogen to antimicrobial drugs Minimum inhibitory concentration (MIC) – the lowest concentration of an antibacterial agent that inhibits visible growth – Whether an MIC is interpreted as susceptible depends on the drug-bug combination and the set breakpoints Minimum Bactericidal Concentration (MBC) – the lowest concentration of an antibacterial agents that either totally prevents growth or results in a >99.9% decrease in the initial inoculum (could be at or above the MIC) LO: Describe the differences between the terms minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent. LO: Describe the differences between the terms minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent.  MIC Breakpoints The highest inhibitory concentration that is reached by an antibiotic with FDA dosing Standardized value by organism and antibiotic Determines: − Whether an organism will be susceptible, intermediate, or resistant − Likelihood of clinical success and/or microbiologic eradication Applies only to the immunocompetent patient whose host defenses are able to resolve the infection LO: Explain the concept of MIC breakpoint and interpret MIC breakpoint data from clinical cases to make informed judgements about antimicrobial dosing. LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent.  MIC Breakpoints Example Example: Pseudomonas aeruginosa MIC Interpretative Criteria Comments S I R Breakpoints for susceptible are based on Piperacillin/tazobactam ≤ 16/4 32/4 ≥ 64/4 a dosage regimen of 4.5 g administered every 6 h over 30 minutes or over 3 h. Breakpoints are based on a dosage Cefepime ≤8 16 ≥ 32 regimen of 1 g administered every 8 h or 2 g administered every 12 h. Breakpoints are based on a dosage Levofloxacin ≤1 2 ≥4 regimen of 750 mg administered every 24 h LO: Explain the concept of MIC breakpoint and interpret MIC breakpoint data from clinical cases to make informed judgements about antimicrobial dosing. LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent.  Application of MIC Breakpoints AN is a 60 year old male growing Pseudomonas aeruginosa from 2 sets of blood cultures. He is currently on empiric cefepime. Based on this susceptibility panel, do you believe you should change therapy? ANTIBIOTIC MIC INTERPRETATION BREAKPOI DILUTIONS FROM NT BP PIP-TAZO 16 S 16 0 CEFEPIME 2 S 8 2 LEVOFLOXAC 1 S 1 0 IN MEROPENEM Continue 2 S current therapy 4 1 Activity is defined by MIC relative to antibiotic-organism breakpoint LO: Explain the concept of MIC breakpoint and interpret MIC breakpoint data from clinical cases to make informed judgements about antimicrobial dosing. LO: Use disease-specific factors such as infecting organism and drug resistance levels to select an appropriate antimicrobial agent. Antibiotic-Specific Factors to Guide Antibiotic Selection Pathog The right drug against the en right pathogen must be administered at the right dose Antibio to be safe and effective. tic Selecti on Spectrum of activity Antibio Patient tic Pharmacokinetics Pharmacodynamics Pai, MP, Cottrell ML, & Bertino JS. (2020). Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. In Bennett JE, Dolin R, & Blaser MJ (Eds.), Mandell, Douglas, and Bennett's Principles and  Pharmacokinetics Describes the process by which a drug enters and leaves the body General goal is to ensure that the antibiotic can reach the site of action and persist until the infection is resolved Absorptio Distributi Metabolis Eliminatio n on m n Bioavailability Transfer of drug Enzymes in liver Renal clearance % of a drug’s dose from systemic that reaches circulation into systemic circulation tissue or site of action (infection) LO: Recognize the roles that ADME (absorption, distribution, metabolism, and excretion) and restricted compartments play in mediating the actions of antimicrobial drugs.  Pharmacodynamics Concentrati Concentrati Dosage Biological on in on at Regimen Effect Serum Infection Pharmacodynamic s Pharmacokine The drug’s impact tics on the body LO: Recognize the roles that ADME (absorption, distribution, metabolism, and excretion) and restricted compartments play in mediating the actions of antimicrobial drugs. (efficacy & toxicity)  Bactericidal vs. Bacteriostatic Antibiotics Mechanism of action: general goal is to eradicate or slow the growth of bacteria without harming the host Bactericidal Bacteriostatic  Kill more than  Prevent growth of 99.9% of bacteria bacteria, keeping them in the stationary  Examples: B-lactams phase of growth (i.e. penicillin, cefazolin, meropenem)  Examples: clindamycin, azithromycin Overall, there is no evidence that cidal antibiotics are intrinsically more clinically effective than static antibiotics LO: Compare and contrast bactericidal and bacteriostatic antimicrobial agents.  Pharmacodynamic Indices Pharmacodynamics combines pharmacokinetics parameters and microbiology parameters to describe drug effect in relation to some measure of exposure – Cmax / MIC – AUC / MIC – TIME / MIC Pai, MP, Cottrell ML, & Bertino JS. (2020). Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. In Bennett JE, Dolin R, & Blaser MJ (Eds.), Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Elsevier Inc. LO: Compare and contrast concentration dependent and concentration independent cell killing activity.  Concentration Dependent Activity (Cmax / MIC) Described in relation to MIC (i.e., 4 X MIC, 10 X MIC) ↑ the concentrations result in improved bacterial activity (increased killing) Post antibiotic effect (PAE) –Growth inhibition continues for a variable period after the concentration at the site of the bacteria has decreased below the MIC for the Example antibiotics: fluoroquinolones (levofloxacin), aminoglycosides antimicrobial agent. (gentamicin), metronidazole, daptomycin LO: Compare and contrast concentration dependent and concentration independent cell killing activity.  Post-antibiotic Effect Proposed Mechanisms 1. Slow recovery of bacteria after non-lethal damage to cell structures 2. Persistence of the antibiotic at its binding site (e.g. aminoglycosides bind irreversibly to ribosomes). 3. A need for bacteria to synthesize new proteins before growth can continue LO: Explain post-antibiotic effect.  Time Dependent (concentration independent) Activity (TIME / MIC) Maintaining steady serum levels above MIC over time results in maximum killing time that free (unbound) drug above MIC of infecting pathogen results in bacterial activity Effect often saturates 4-5 X MIC More ≠ better Desired percentage of time above the MIC for bacterio-STATIC and –CIDAL killing -STATIC -CIDAL Penicillins 30% 50% Example antibiotics: penicillins, Cephalosporins 35-40% 60-70% cephalosporins (cefepime), Carbapenems 20% 40% carbapenems (meropenem) LO: Compare and contrast concentration dependent and concentration independent cell killing activity. Patient Case What are patient, pathogen, and antibiotic specific factors that should be considered to guide antibiotic selection?  61 year old female presents to the Emergency Department with shortness of breath and fever that has worsened over the past 5 days. PMH: metastatic breast cancer, hypertension, craniotomy ~2 weeks ago for tumor removal. HPI: per the patient, she began coughing five days ago and started to feel worse so she took her temperature today and upon discovering she had a fever she contacted her provider who told her to seek care immediately. Vital Signs: – Heart rate 112 Neuro Examination: normal Chest X-ray: abnormal (diffuse bilateral patchy – Blood pressure 90/54 mm Hg infiltrates) (MAP 66) WBC 10 x 109/L – Temperature 39.2°C SCr 0.87 mg/dL Bilirubin: 1.8 mg/dL – Respiratory rate 18 on room air Lactate: 2.8 mmol/L – Weight: 70 kg AUGUST 2024 INTRODUCTION TO ANTIBIOTICS KATHRYN G. ROSE, PHARMD, BCPS, BCPPS, BCIDP Adjunct Assistant Professor at the University of Texas at Austin College of Pharmacy Division Director of Clinical Pharmacy, HCA Central West Texas (St. David’s HealthCare and Las Palmas Del Sol Healthcare)