PHM 712 Final Therapeutics PDF

Introduction to Clinical Infectious Disease Dr. Joshua Garcia, PharmD Associate Professor of Pharmacy Practice Marshall B. Ketchum University College of Pharmacy [email protected] Objectives Differentiate between the d...

Introduction to Clinical Infectious Disease Dr. Joshua Garcia, PharmD Associate Professor of Pharmacy Practice Marshall B. Ketchum University College of Pharmacy [email protected] Objectives Differentiate between the different steps of the General Approach to a Patient with Infectious Disease Identify characteristics general signs, symptoms, and characteristics of an infected patient Describe the steps in the microorganism identification process Define antimicrobial stewardship List the consequences of inappropriate and/or unnecessary antibiotic use © Marshall B. Ketchum University Lecture Outline Introduction to Clinical Infections Infection Definition Signs and Symptoms General Approach to a Patient with Infectious Diseases Primary Prophylaxis Empiric Therapy Narrowed Therapy Definitive Therapy Secondary Prophylaxis © Marshall B. Ketchum University Introduction to Clinical Infections © Marshall B. Ketchum University Infectious Disease is and Important Health Concern Today! © Marshall B. Ketchum University What is an Infection? A disease caused by a pathogenic organism, overcoming a host’s defense system and invading the body Requirements for Infection Entry into host Establishment in host Defeat / avoiding host defenses Damage to host Exit and transmission to next host For humans, infections can range from minor / self-limiting harm to death © Marshall B. Ketchum University  The Body’s Defenses Constitutive Defenses (Non-specific) Induced Defenses (Specific to Physical and Chemical Barriers to Organism) Infection T-lymphocyte cells Increasing Inflammatory Response B-cells Complement Pathway Activation Phagocytosis (Neutrophils) © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Infection Prevented Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Patient Infected Pathogens Immune Cells © Marshall B. Ketchum University What Does an Infection Look Like? There are some general signs and symptoms of infection TQ Tachycardia (bpm > 100) ___________________________________ Tachypnea (bpm > 20) ___________________________________ Temperature (> 38°C / ~100°F ) ___________________________________ May be low in severe infections Hypotension (SPB < 90 mmHg) ___________________________________ More common in severe infections Other symptoms will be specific to certain infections (ie. SOB in pneumonia or dysuria in UTIs) Not all infected patients will present with all or even any generalized symptoms © Marshall B. Ketchum University Abnormal Labs Associated with Bandemia: The increase in Infections number of immature WBC (AKA bands) in response to an infection. AKA “left shift” Leukocytosis (WBC > 10,000 cells/ mcL) ___________________________________ Most common and go-to-lab to evaluate ESR (Erythrocyte Sedimentation Rate) Marker of inflammation ________________________________: ______________________: CRP (C-Reactive Protein) Marker of inflammation Procalcitonin By product of tissues in response to bacterial ____________: infection (as opposed to viral or fungal) Specific but expensive and not validated in all diseases Microbiologic cultures from specific sites © Marshall B. Ketchum University Distinguishing Infectious vs. Non- Infectious Etiology When evaluating a patient with a potential infection, it is important to determine: If symptoms are from infectious vs. non-infectious causes Non-infectious diseases with symptoms similar to infections CHF exacerbation (tachypnea, SOB) Asthma (SOB, cough) Hypothyroidism (lethargy, malaise) Dementia (confusion, altered mental status) Medications (fever, any ADRs) © Marshall B. Ketchum University Distinguishing Infectious vs. Non- Infectious Etiology 2 main methods: Microbiologic confirmation (ie. “culture results”) ________________________________________________ Obtaining samples from patient Incubating potential pathogens to determine if present Clinical judgment _____________________ Presence of numerous symptoms and history but negative culture results Symptoms present but microbiologic data pending Improvement of symptoms after administration of antibiotics (with no other reason for improvement) Can be difficult to determine Requires a thorough / systematic approach to infected patient © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Body Clears Infection Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Body Fails to Clear Infection: Pathogens Immune Cells Anti-Infectives Needed © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Pathogens Immune Cells © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells Anti-Infectives Reduce Pathogens Immune Cells Pathogen Burden © Marshall B. Ketchum University Infection Immune System Relationship Cell Levels Pathogens Immune Cells If antibiotics are needed, we must determine which organism is the culprit and which antibiotic will work best Anti-Infectives Body Immune FailsSystem Reduce to Clear Eliminates Infection: Pathogens Immune Cells Pathogenpathogens Remaining Burden Anti-Infectives Needed © Marshall B. Ketchum University Infection Immune System Relationship Commensal (Opportunistic) Organisms Cell Levels Pathogens Immune Cells Immunocompromised Normal Patient Pathogens Immune Cells Commensal (Opportunistic) Patient (IPT X) Organisms © Marshall B. Ketchum University Infection Immune System Relationship Commensal (Opportunistic) Organisms Cell Levels Pathogens Immune Cells Immunocompromised Normal Patient Pathogens Immune Cells Commensal (Opportunistic) Patient (IPT X) Organisms © Marshall B. Ketchum University Infection Immune System Relationship Commensal (Opportunistic) Organisms Cell Levels Pathogens Immune Cells Immunocompromised Normal Patient Pathogens Immune Cells Commensal (Opportunistic) Patient (IPT X) Organisms © Marshall B. Ketchum University General Approach to A Patient with Infectious Diseases © Marshall B. Ketchum University  General Approach to Patient with Infectious Disease Primary Prophylaxis TQ Infection suspected Cultures obtained Empiric Therapy Preliminary cultures return 24 – 48 hours Narrowed Therapy Final cultures and 24 – 48 hours susceptibilities return Definitive Therapy Cure Days to months Secondary Prophylaxis Years © Marshall B. Ketchum University  General Approach to Patient with Infectious Disease Primary Prophylaxis Causative pathogen Abx to use Don’t know Empiric Therapy Broad abx Think we know Narrowed Therapy Targeted Know abx Definitive Therapy exactly Secondary Prophylaxis © Marshall B. Ketchum University  General Approach to Patient with Infectious Disease No active infection Primary Prophylaxis Empiric Therapy Active infection Narrowed Therapy Definitive Therapy No active infection Secondary Prophylaxis © Marshall B. Ketchum University General Approach to Patient with Infectious Disease Empiric Therapy TQ The use of _______________ broad-spectrum antimicrobial therapy as the first agent nothing / very little about the organism when we know ____________________________________causing the infection. Antibiotics should also have great _____________________ depth of coverage Has a high percentage of getting the right organism but often causes _____________________ lots of adverse effects © Marshall B. Ketchum University  Breadth of Coverage Broad-Spectrum Antibiotic: An Narrow-Spectrum Antibiotic: An antibiotic that is effective against antibiotic that is only effective against many organisms a few organisms Useful when: Useful when: Causal organism is UNKNOWN Causal organism is KNOWN Risk of not covering causal organism is HIGH Risk of not covering causal organism is LOW Problematic due to: Problematic due to: Higher rate of antibiotic resistance to multiple “Holes” in coverage organisms Potentially severe adverse effects Bacterial superinfection (C. difficile) © Marshall B. Ketchum University  Gram Positive Enterococcus Breadth of Coverage Gram Negative CRE faecium (VRE) Strep & Enterococci Enterobacteriaceae ESBL Enterococcus Serratia Klebsiella faecalis Atypicals pneumoniae L/M/C S. pneumoniae E. coli Proteus Strep pyogenes mirabilis GN H. influenzae coccobacilli Drug N. meningitidis Citrobacter spp Staph aureus Enterobacter spp Amp C (MSSA) Bacteroides Producers Staph aureus fragilis Pseudomonas (MRSA) Anaerobes Staphylococci © Marshall B. Ketchum University Enterococcus CRE faecium (VRE) ESBL Enterococcus Serratia Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus mirabilis Strep pyogenes H. influenzae Cefazolin N. meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides Staph aureus fragilis Pseudomonas (MRSA) © Marshall B. Ketchum University Enterococcus CRE faecium (VRE) ESBL Enterococcus Serratia Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus mirabilis Strep pyogenes Piperacillin/ H. influenzae tazobactam N. meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides Staph aureus fragilis Pseudomonas (MRSA) © Marshall B. Ketchum University Enterococcus CRE faecium (VRE) ESBL Enterococcus Serratia Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus mirabilis Strep pyogenes Piperacillin/ H. influenzae Cefazolin tazobactam N. meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides Staph aureus fragilis Pseudomonas (MRSA) © Marshall B. Ketchum University TQ Cons of “Big Gun” Antibiotic Use Antibiotic Resistance Super infection Various Toxicities Allergic Reactions Anaphylaxis Steven Johnson Syndrome © Marshall B. Ketchum University General Approach to Patient with Infectious Disease Empiric Therapy The use of _______________ broad-spectrum antimicrobial therapy as the first agent nothing / very little about the organism when we know ____________________________________causing the infection. Antibiotics should also have great _____________________ depth of coverage Has a high percentage of getting the right organism but often causes _____________________ lots of adverse effects antibiogram of the Antibiotic chosen based on ____________ specific hospital and most likely pathogen © Marshall B. Ketchum University Empiric Therapy: Discussion on Breadth vs. Depth of Coverage Number of different organisms Breadth of coverage = ____________________________ _______________________ covered by an antibiotic Percentage chance that an antibiotic will Depth of coverage = __________________________________ ___________________________________________________ cover a particular organism (based on variability of organism ___________ resistance) Breadth and Depth of Coverage often go together © Marshall B. Ketchum University Enterococcus CRE faecium (VRE) ESBL Enterococcus Serratia Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus mirabilis Strep pyogenes H. influenzae Cefazolin N. meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides Staph aureus fragilis Pseudomonas (MRSA) © Marshall B. Ketchum University Enterococcus CRE faecium (VRE) ESBL Enterococcus Serratia Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus mirabilis Strep pyogenes Piperacillin/ H. influenzae tazobactam N. meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides Staph aureus fragilis Pseudomonas (MRSA) © Marshall B. Ketchum University Enterococcus CRE faecium (VRE) ESBL Enterococcus Serratia Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus mirabilis Strep pyogenes Piperacillin/ H. influenzae Cefazolin tazobactam N. meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides Staph aureus fragilis Pseudomonas (MRSA) © Marshall B. Ketchum University  Depth of Coverage Piperacillin / Cefazolin tazobactam 0% % E. coli 50% Covered 70% ~30% risk of treatment failure 90% 99% MDR E. coli ~3% risk of treatment failure © Marshall B. Ketchum University  Thinking About Spectrum of Activity for Empiric Therapy Use narrowest Predictable Etiology spectrum drugs Pharyngitis Common Cold Primary peritonitis Cellulitis Acute bronchitis Osteomyelitis Pyelonephritis Necrotizing Cystitis fasciitis Endocarditis Otitis Media Acute exacerbation Meningitis of COPD No benefit of Severe Consequence of Consequence of Failure - antibiotics Failure - Minimal Secondary Severe peritonitis Diabetic foot Sinusitis infection CAP HAP Febrile Sepsis of neutropenia unknown origin Variable Etiology Use broadest spectrum drugs © Marshall B. Ketchum University How to Determine Depth of Coverage Can vary widely from hospital to hospital Medication E. coli E. coli % at E. coli % at E. coli % at Approximation Hospital A Hospital B Hospital C Pip/tazo +++ 99% 98% 88% Cefazolin ++ 70% 90% 40% Ceftriaxone +++ 91% 95% 80% Levofloxacin ++ 86% 95% 75% antibiogram Determined by individual hospital, annual _______________ © Marshall B. Ketchum University  Antibiograms TQ Report effectiveness of antibiotics for a hospital during “Best percentage chance” 95 Cefepime worked against 95% (1733/1825) of all organisms Therefore, cefepime would be a good choice for empiric therapy © Marshall B. Ketchum University Depth Comparison Rule of Thumb Enterobaceriaceae 1st Gen Cephs Less deep TMP/SMX 2nd Gen Cephs Aminoglycosides Levo/cipro 3rd Gen Cephs Aztreonam Cefepime Pip/tazo Carbapenems Deeper Polymyxins *Ceftolozane/tazobactam, ceftazidime/avibactam, New meropenem/vaborbactam, plazomicin, antibiotics* © Marshall B. Ketchum University Depth Comparison Rule of Thumb Pseudomonas aeruginosa Less deep Levo/cipro Aminoglycosides Aztreonam Ceftazidime Cefepime Pip/tazo Carbapenems Polymyxins New Deeper antibiotics* *Ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, plazomicin, © Marshall B. Ketchum University Depth Comparison Rule of Thumb MRSA Less deep Clindamycin Doxycycline TMP/SMX Vancomycin Ceftaroline Dalba/orita Deeper Linezolid Daptomycin Tedizolid © Marshall B. Ketchum University Common Empiric Regimens A patient with a history of multiple hospitalizations is admitted with fever, leukocytosis, and general infection symptoms (unsure cause). Piperacillin/tazobactam + ____________ _____________________ Vancomycin TQ Cefepime + ____________ _________ Vancomycin ___________ Meropenem + ____________ Vancomycin (if ESBL concern) A patient is admitted to the hospital from home with fever and SOB requiring oxygen Ceftriaxone + _____________ ___________ Azithromycin Fluoroquinolones (levofloxacin or ciprofloxacin) __________________________________________ © Marshall B. Ketchum University General Approach to Patient with Infectious Disease Narrowed Therapy The use of __________________antimicrobial narrower-spectrum therapy as a step know a little bit about the organism down agent when we ________________________________causing the infection Example: Gram stain or preliminary identification of organism Less adverse effects and resistance TQ © Marshall B. Ketchum University Microorganism Detection Overview Agar Disk Samples collected Gram Staining Microbiological Incubator © Marshall B. Ketchum University  Once we know = Example of Narrowed Therapy Organism is a gram (+) Meropenem Vancomycin vs. Gram (-) Gram (+) E. coli S. pyogenes Gram (+) K. pneumoniae S. pneumoniae S. pyogenes P. mirabilis E. faecalis S. pneumoniae S. marcescens MSSA E. faecalis C. freundii MSSA E. cloacae MRSA P. aeruginosa © Marshall B. Ketchum University General Approach to Patient with Infectious Disease Definitive Therapy The use of ___________________ narrowest-spectrum antimicrobial therapy as a step down agent when we know the organism causing the infection and exactly which antibiotics will work _______________________________ Example: Culture and sensitivity results Least adverse effects and least resistance © Marshall B. Ketchum University  What we know = Example of Definitive Therapy Organism is MSSA Susceptibility Profile Vancomycin Antibiotics Staphylococcus aureus Penicillin Resistant Erythromycin Resistant Clindamycin Susceptible Tetracycline Susceptible Trimethoprim Sulfamethoxazole Susceptible Nafcillin Nafcillin Susceptible Cefoxitin Susceptible Vancomycin Susceptible © Marshall B. Ketchum University Microorganism Detection Overview Agar Disk Samples collected Gram Staining Broth Dilution Microbiological Incubator Useful in determining MIC © Marshall B. Ketchum University What is an MIC? MIC = Minimum Inhibitory Measure of More clinical Concentration antibiotic relevance than Lowest amount of effectiveness MBC (Minimum drug needed to against an Bactericidal inhibit growth of an organism Concentration) organism © Marshall B. Ketchum University  Determining the MIC Bacteria Enrichment broth Incubate 24-48 hours 0.25mcg/mL 0.5mcg/mL 1 mcg/mL 2 mcg/mL 4 mcg/mL Antibiotic Concentrations © Marshall B. Ketchum University MIC Reporting Example MICs Antibiotics Interpretation © Marshall B. Ketchum University  MIC Interpretation In MOST CASES, the interpretation of the MIC is more important than the TQ actual MIC number For example, both cefepime and ciprofloxacin will work equally well against this E. coli since they are both sensitive Cipro is not better than cefepime just because it has a “smaller MIC” © Marshall B. Ketchum University Rapid Diagnostic Tests (RDTs) shorten the time to identify “Next generation” tests used to ________ organisms and/or __________________________ resistance genes/phenotypes Equals less time on “big gun” empiric therapy or unnecessary antibiotics No need to wait for large colony growth Examples include: Mass spectrometry: MALDI-TOF 1 to 12 hours PCR: BioFire Microsphere Identification: Verigene “Next Gen Sequencing” Not all hospitals will have them and $$$ © Marshall B. Ketchum University  Rapid Diagnostic Tests (RDTs) MALDI-TOF BioFire Verigene © Marshall B. Ketchum University General Approach to Patient with Infectious Disease Primary Prophylaxis BEFORE a patient is actively The use of antimicrobial therapy ________ infected in order to __________ PREVENT infections Ex. Antibiotics before surgery and immunocompromised patients (ie. Chemotherapy/cancer patients, HIV/AIDS, or transplant) © Marshall B. Ketchum University General Approach to Patient with Infectious Disease Secondary Prophylaxis AFTER a patient has been cured The use of antimicrobial therapy _____________________________ PREVENT further infections of an infection in order to __________ Ex. Antibiotics for recurring urinary tract infections or SBP (spontaneous bacterial peritonitis) Not all patients will need secondary prophylaxis © Marshall B. Ketchum University  Antimicrobial Stewardship TQ “A set of coordinated strategies to improve the use of antimicrobial medications with the goal of _______________ enhancing patient ______________, health outcomes ______________________________, reducing resistance to antibiotics and _________________________.” decreasing unnecessary costs Consists of multidisciplinary team of physicians, infection control preventionists, and pharmacist! Effective Jan 1st, 2017: All hospitals MUST have an antimicrobial stewardship program in place in order to pass Joint Commission accreditation. Antimicrobial Stewardship - SHEA. https://www.shea-online.org/index.php/practice-resources/priority-topics/antimicrobial-stewardship. Accessed January 31, 2018. © Marshall B. Ketchum University  Questions © Marshall B. Ketchum University Clinical PK/PD of Cell Wall Inhibitors Dr. Joshua Garcia, PharmD Associate Professor of Pharmacy Practice Marshall B. Ketchum University College of Pharmacy [email protected] Objectives Describe the PK/PD parameters of beta-lactams and glycopeptides Compare and contrast 2009 and 2020 vancomycin dosing guidelines Recommend an initial dosing regimen (maintenance and loading) and monitoring approach for vancomycin based on patient characteristics and infection type using various dosing methodologies. Evaluate the results of assays for therapeutic drug monitoring of vancomycin and provide a recommendation regarding dosage adjustment (if necessary). Provide recommendations as to the appropriate therapeutic drug monitoring approach for a patient for a selected dosing strategy, including timing of the samples and serum concentration target(s). © Marshall B. Ketchum University Lecture Outline Review PK/PD Beta-lactams PK/PD Vancomycin Exposure-Response Relationships Initial Dose Selection Monitoring Strategy Design Interpretation of Monitoring Results and Dosage Adjustment © Marshall B. Ketchum University  Let’s Take a Second to Review Cell Wall Inhibitors Glycopeptides Vancomycin Oritavancin Beta-lactam Dalbavancin Telavancin Penicillins Cephalosporins Carbapenems Monobactams Penicillin G/V Cefazolin/cephalexin Ertapenem Aztreonam Naf/Oxa/Diclox Cefuroxime Imipenem/cilistatin Amp/Amox + sul/clav Ceftriaxone/ceftazidime Imi/cili/relebactam Pip/tazo Cefepime Meropenem Ceftaroline Mero/vaborbactam Ceftaz/avibactam Doripenem Ceftolozane/tazo Cefiderocol © Marshall B. Ketchum University Concentration vs Time Killing Peak Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 10 8 6 4 Area Under the Curve Trough 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University Concentration Dependent Killing Peak Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 10 Peak:MIC Ratio 8 6 4 MIC 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  Time Dependent Killing Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 10 8 Time Above MIC 6 4 MIC 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  AUC Dependent Killing Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 AUC24:MIC Ratio 10 8 6 4 MIC Area Under the Curve (24 hrs) 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  BacteriSTATIC vs BacteriCIDAL No Antibiotics Bacteristatic Bactericidal © Marshall B. Ketchum University  Periodic Table of Antibiotics BC Time BC Time BC Time BC Time BC AUC Penicillins Cephalosporins Carbapenems Monobactams Glycopeptides Aminoglycosides Macrolides Tetracyclines Oxazolidinones Lincosamides Sulfonamides Fluoroquinolones Urinary Nitroimidazoles Lipopeptides Polymyxins Other Antibiotics Antibiotics Cell Wall Inhibitors Cell Membrane Interactions Protein Synthesis Inhibitors Miscellaneous DNA / Replication Inhibitors © Marshall B. Ketchum University Clinical PK/PD Beta-lactams © Marshall B. Ketchum University  Let’s Take a Second to Review Cell Wall Inhibitors Glycopeptides Vancomycin Oritavancin Beta-lactam Dalbavancin Telavancin Penicillins Cephalosporins Carbapenems Monobactams Penicillin G/V Cefazolin/cephalexin Ertapenem Aztreonam Naf/Oxa/Diclox Cefuroxime Imipenem/cilistatin Amp/Amox + sul/clav Ceftriaxone/ceftazidime Imi/cili/relebactam Pip/tazo Cefepime Meropenem Ceftaroline Mero/vaborbactam Ceftaz/avibactam Doripenem Ceftolozane/tazo Cefiderocol © Marshall B. Ketchum University  Time-Dependent Killing Beta-Lactams Exhibit ____________________ Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 How can we increase 10 the efficiency of 8 beta-lactams? Time Above MIC 6 4 MIC 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  Increase Frequency Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 10 8 6 4 MIC 2 0 Time Above MIC 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  Prolonged Infusion Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 10 8 6 4 MIC 2 0 Time Above MIC 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  Continuous Infusion Drug Levels to MIC 16 Drug Concentration (mg/L) 14 12 10 Time Above MIC 8 6 4 MIC 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University Antibiotics with Increased Efficacy with Prolonged Infusions Agent Standard (intermittent) Dosing Prolonged-Infusion Dosing Cefepime 2g IV Q8h over 30 mins 2g IV Q8h over 3-4 hours Meropenem 1g IV Q8h over 3 hours 1g IV Q8h over 30 mins 500mg IV Q6h over 3 hours Piperacillin/tazobactam 2.275-4.5g IV Q6h over 30 mins 3.375g IV Q8h over 4 hours Various amounts of data for continuous infusion over 24 hours for various beta-lactams (PCN G, nafcillin, oxacillin, etc.) Beta-lactam prolonged / continuous infusions are pharmacokinetically more effective than standard intermittent infusions ______________ Limitations: Line _________________________________ access, IV compatibility, and stability Prolonged infusion vs. standard intermittent infusion decision should be based on risk/ benefit of individual patients © Marshall B. Ketchum University Clinical Case #1 CT is a 39 year old female with a PMH of breast cancer (on erlotinib) suffering from an endocarditis. While in the hospital, she was placed on empiric piperacillin/tazobactam 3.375g IV q6h and azithromycin 500mg IV daily, both over 30 minutes. Sputum cultures were taken and Staphylococcus aureus (MSSA) was isolated in 2/2 of the cultures. Despite the sensitivity profile showing sensitivity to piperacillin/tazobactam, the MD thinks that we may not utilizing the maximum potential of the antibiotics. © Marshall B. Ketchum University Knowing what you know about the PK/PD parameters of piperacillin/tazobactam and azithromycin, what can we do to maximize efficacy? Justify your answer. a. Increase the dose of piperacillin/tazobactam to 4.5g b. Increase the dose of azithromycin to 1000mg c. Prolong the infusion of piperacillin/tazobactam to over 3 hours d. Prolong the infusion of azithromycin to over 3 hours Vivian Le Thanh Ngo © Marshall B. Ketchum University The resident is concerned that the piperacillin/tazobactam might not be enough and isn’t sold on just changing the dose. “Can’t we just use vancomycin? It works for MRSA so it should work better on MSSA right?” What do you what to do regarding therapy. Justify your answer. Youjin Han Angelica Maddatu © Marshall B. Ketchum University Clinical PK/PD Vancomycin © Marshall B. Ketchum University Vancomycin Basic Info Glycopeptide used as large gram-positive “workhorse” Mainly available in two forms: IV and PO IV: Systemic gram-positive infections PO: C. difficile infections Redman’s Increments of 250mg Main ADRs of concern: Nephrotoxicity Redman’s syndrome (infusion too fast) © Marshall B. Ketchum University Vancomycin Basic Info Narrow therapeutic window Levels required First order (linear) kinetics Dosing based off _______ weight and ___________ renal function Best predictor of antibacterial effect is __________ AUC24:MIC Ratio © Marshall B. Ketchum University  Vancomycin Spectrum of Activity Enterococcus CRE faecium (VRE) ESBL Serratia Enterococcus faecalis Klebsiella pneumoniae S. pneumoniae E. coli L/M/C Proteus Strep pyogenes mirabilis H. influenzae N. meningitidis Vancomycin Citrobacter spp Staph aureus (MSSA) Bacteroides Enterobacter spp fragilis Staph aureus (MRSA) Pseudomonas Reused and modified with permission from Conan MacDougall, PharmD © Marshall B. Ketchum University  AUC Dependent Killing Drug Levels to MIC 4 Drug Concentration (mg/L) 3.5 3 AUC:MIC Ratio Vancomycin AUC:MIC Ratio 2.5 400-600mg *hr/L = Better 2 likelihood of success 1.5 1 MIC Area Under the Curve (24 hrs) 0.5 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  The S. aureus MICs Matter 400 for S. aureus Regimen 500mg IV infections MIC: 1.0 mg/L MIC 2.0 mg/L with Non-ICU MIC >ICU2 15% 0.7% 3% 10% Q12h 1000mg IV 57% 15% 6% 16% Q12h High doses 1500mg IV need for MIC 2 MIC 2 Q12h has very 79% 38% 9% 25% low chance of have high 2000mg IV 90% being effective Q12h 57% 14% 35% chance of nephrotoxicity Patel N, et al. Clin Infect Dis 2011;52:969-974 © Marshall B. Ketchum University Dosing Vancomycin © Marshall B. Ketchum University The Difficulty Learning Vancomycin Dosing There are MANY different ways to dose vancomycin For class, Hospitals differ in we will recognize protocols, and procedures, and apply available the technology Variation importantin dosing practices from equations individual that pharmacists are the calculators Expectations basedfor APPE on. Westudents vs.practice will also practical dosing various expectations in practice methods of calculation that you may see on MD’s WILL TRUST YOURAPPEs. DOSING RECOMMENDATIONS BLINDLY! © Marshall B. Ketchum University Dosing Vancomycin: Step By Step Overview 1. Select Vancomycin Target (ie. AUC vs. trough) 2. Record weight and calculate renal function 3. Select initial dosing regimen (loading + maintenance dose) 4. Order and evaluate vancomycin levels 5. Adjust vancomycin dose as needed based on levels © Marshall B. Ketchum University Step 1. Select Vancomycin Target (ie. AUC vs. trough) © Marshall B. Ketchum University  Measuring AUC Used to Be Very Difficult Troughs were used as a surrogate marker for AUC24:MIC Ratio > 400-600 40 Drug Concentration (mg/L) Trough levels of 15- 35 20 mg/L ~ AUC 400- 30 600mg *hr/L 25 New Vancomycin Guidelines Many hospitals still use troughs 20 (2020) recommend against 15 10 trough monitoring 5 0 0 5 10 15 20 Time (hours) Kullar R, et al. Clin Infect Dis 2012;52:975-981 © Marshall B. Ketchum University Old vs. New Vancomycin Guidelines 2009 Guidelines 2020 Guidelines Vancomycin troughs should be Vancomycin AUC:MIC should be obtained for efficacy and safety monitored (by calculation or Trough goal for patients was 10- Bayesian software) for efficacy 20mg/L for non-serious infection and safety and 15-20mg/L for serious Trough-based monitoring infections alone no longer recommended Troughs should be drawn 30 More recommendations on mins before 4th dose to ensure obese, pediatrics, loading doses, achievement of steady state and continuous infusion concentrations vancomycin Many hospitals have not implemented the new guidelines so it is important to know both © Marshall B. Ketchum University Summary of Old Practices Vancomycin trough levels should be obtained prior to the next dose at steady state concentrations (just before 4th) Major change in renal function or dose required time to re-achieve new steady state Serious Infections Goal trough was 15-20mg/L for Bacteremia Meningitis serious MRSA infections and 10- Endocarditis Pneumonia due to S. aureus Osteomyelitis Any S. aureus w/ MIC > 1mg/L 20mg/L for routine use (SSTIs, surgical ppx, etc.) Vancomycin nomograms and calculators used to achieve and maintain appropriate levels © Marshall B. Ketchum University The Drastic Shift to AUC Monitoring AUC:MIC of 400-600mg *hr/L Vancomycin dosing based on ______________________has been shown to be efficacious and reduced nephrotoxicity Monitoring of AUC can be achieved in 2 ways: Manual calculations Bayesian dosing software _______________________________ Statistical theorem (Bayes’ Theorem) that uses population PK and real-time collected patient data to predict the most accurate dose to achieve the desired drug level “The more data you feed the model, the smarter the system gets” – Jonathan Faldasz, PharmD © Marshall B. Ketchum University © Marshall B. Ketchum University Step 2. Record Weight and Calculate Renal Function © Marshall B. Ketchum University  Estimating Renal Function 140 − 𝑎𝑔𝑒 𝑊 x0.85 if woman Weight for CrCl equation: 𝑆𝑐𝑟𝑋72 Use ABW when TBW/IBW > 125% Ideal Body Weight (IBW) Use TBW when TBW/IBW < 125% IBW (men) = 50kg + 2.3kg * (every inch > 60 inches) SCr for CrCl equation: IBW (women) = 45.5kg + 2.3kg * If SCr < 0.8mg/dL and age > 65 or (every inch > 60 inches) emaciated, round SCr to 0.8 mg/dL Adjusted Body Weight (ABW) ABW = IBW + 0.4(TBW-IBW) TBW: Total Body Weight ABW: Adjusted Body Weight IBW: Ideal Body Weight © Marshall B. Ketchum University  Picking Which Weight to Use Vancomycin dose is calculated from __________________ total body weight Renal function is calculated from total or adjusted body weight __________________________ Use ABW when TBW/IBW > 125% Use TBW when TBW/IBW < 125% You may be using different weights for the same patient! (i.e. TBW for vancomycin dose but ABW for CrCl) TBW: Total Body Weight ABW: Adjusted Body Weight IBW: Ideal Body Weight © Marshall B. Ketchum University Step 3. Select Initial Dosing Regimen (Loading + Maintenance Dose ) © Marshall B. Ketchum University  Vancomycin Initial Dose Selection: Loading Dose Loading dose: Large initial dose to ensure rapid therapeutic concentrations Guidelines recommend a loading dose of: 20 – 35 mg/kg in severely ill and not _______________ exceed __________ 3,000 mg Vancomycin dosing based on Total body weight (TBW) ______________________ Rybak M, et al. Am J Health Syst Pharm. 2009;66(1):82-98. doi:10.2146/ajhp080434 DeRyke, Alexander D. Hosp Pharm. 2009;44(9):751-765. doi:10.1310/hpj4409-751 © Marshall B. Ketchum University Vancomycin Initial Dose Selection: Maintenance Dose General rule of thumb for initial doses in normal renal function: 15 to 20 mg/kg every 8 to 12 hrs ____________________________ If renal dysfunction, consider lower dose Once dose is determined, make sure estimated AUC:MIC achieved Doses can be calculated by several different methods (nomograms, online calculators, manual, etc.) © Marshall B. Ketchum University A Small Note on Special Populations Obesity 20-25 mg/kg Loading dose of ________________ 3000 mg with maximum of ____________ 4500 mg Total daily maintenance dose not to exceed ______________ Intermittent hemodialysis: Maintain pre-dialysis concentrations 15-20 mg/L Depending on filter, some vancomycin is lost during dialysis but stays at constant level otherwise Recommendations also exist for pediatrics, continuous infusion, CRRT, and SLED © Marshall B. Ketchum University  Important Equations: Substep Equation Estimate AUC24=TDD/Clvanco Substep Equation AUC24 from Estimate 𝑘𝑒 = 𝐶𝑟𝐶𝑙 × 0.00083 + 0.0044 vancomycin ke total daily Estimate 𝑉𝑑 = 0.7 × 𝑊𝑡 dose/CL vancomycin Vd -or- Derive 𝐶𝑙𝑣𝑎𝑛𝑐𝑜 = 𝑘𝑒 × 𝑉𝑑 Substep Equation estimated Clvanco Estimate peak Derive T1/2= 0.693/ke and trough estimated T1/2 from total daily dose/CL Tinf = Infusion Time Tau = Dosing Interval © Marshall B. Ketchum University Step 4. Order and Evaluate Vancomycin Levels © Marshall B. Ketchum University Vancomycin Levels Peak 16 Drug Concentration (mg/L) 14 12 Random 10 8 6 4 Trough 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University  Old Guideline Trough Monitoring Troughs should be drawn: Immediately before the next dose Acceptable to draw within 30 minutes before next dose Why After steadydostatewe have before is achieved: to waitthe 4until right th dose of a new regimen before Including switching th dose the of4dose to get a trough or frequency Subject to nursing error level? What does steady state mean? Trough taken here 1st Dose 2nd Dose 3rd Dose 4th Dose © Marshall B. Ketchum University  Current Guidelines AUC Monitoring Manual AUC calculation: after steady state Peak (1 hour post-infusion) and trough must be drawn ____________ is achieved Peak taken here Trough taken here 1st Dose 2nd Dose 3rd Dose 4th Dose Bayesian Dosing (preferred): Do not have to wait for steady state 1 or 2 levels needed (at least one trough) Potential other Potential other Trough taken level level here ©1Marshall st Dose B.other Potential Ketchum University 2nd Dose 3rd Dose 4th Dose Step 5. Adjust Vancomycin Dose as Needed Based on Levels © Marshall B. Ketchum University  Old Guidelines: Interpretation of Results and Dose Adjustment Recall: Vancomycin exhibits first order (linear) kinetics Therefore, we can use algebra and proportions as a rough double check method Ex. A regimen of vancomycin 1000mg IV Q8h for osteomyelitis returns with a true steady state of 12 mg/L Dose Current Dose New Css Current Css New 3000mg (daily) Dose New 12mg/L 15mg/L Dose New 3750mg (daily) (Dose New) x 12mg/L 45000 L Dose New 1250mg IV Q8h © Marshall B. Ketchum University Current Guidelines AUC Interpretation and Adjustment Bayesian Dosing: Software will provide estimates for doing as more data is acquired AUC Manual calculation: If AUC is too high or low, plug back into equations to find new clearance and re-calculate *will not need recalculate clearance from new AUC for exam* © Marshall B. Ketchum University © Marshall B. Ketchum University Clinical Case 2 AS is a 56 year old male who was admitted 13 days ago for coronary artery bypass surgery. Post CABG the patient had slow recovery and remained in the ICU. Two days ago, AS developed a fever (T-38.9 C), hypoxemia requiring intubation, WBC= 14.2, abundant purulent tracheal secretions, and a CXR revealing localized infiltrate in RLL. Scr 1.2mg/dL, Weight = 98kg, height=170cm. A mini-BAL has been sent to the lab. The team would like to initiate empiric antibacterial therapy; to cover for potential multidrug-resistant pathogens, the team would like to initiate vancomycin + cefepime + tobramycin. © Marshall B. Ketchum University  Select your initial target concentration goal of vancomycin for AS, based on old guidelines. Justify your answer a. AUC: 400-600 L*hr b. AUC: 200-400 L*hr c. 10 – 20 mg/L d. 15 – 20 mg/L Anthony Vu Alexus Reyes e. There is inadequate information © Marshall B. Ketchum University  Select your initial target concentration goal of vancomycin for AS, based on current guidelines. Justify your answer a. AUC: 400-600 L*hr b. AUC: 200-400 L*hr c. 10 – 20 mg/L d. 15 – 20 mg/L Darryl Ngadjou Adam Ibrahim e. There is inadequate information © Marshall B. Ketchum University  Calculate AS’s CrCl using the Cockcroft-Gault equation. a. 64.3 mL/min b. 76.7 mL/min c. 92.0 mL/min d. 95.2 mL/min Thanh Ngo Elika Ghoreishi © Marshall B. Ketchum University Ht: 170cm / 2.54 = 67inches TBW: 98 kg IBW= 50 + 2.3(inches above 5 feet) IBW= 50 +2.3(7) IBW= 66.1kg – if female would’ve done 45.5kg Do I need to use ABW? TBW/IBW= 98/66.1 x 100% TBW/IBW=142% Yes, I need to use ABW ABW = IBW + 0.4(TBW-IBW) ABW = 66.1 + 0.4(98-66.1) ABW = 78.86 (140-age) x weight (x0.85 if female) 72 x SCr (140-56) X 78.86 kg 72 X 1.2 mg/dL CrCl = 76.7 © Marshall B. Ketchum University  The team decides to start AS on a vancomycin regimen of 1500mg IV Q12h. Using the equations provided, it this an appropriate dose of vancomycin to achieve our therapeutic goal? Justify your answer Substep Equation Estimate AUC24 AUC24=TDD/Clvanco from total daily dose/CL Estimate 𝑘𝑒 = 𝐶𝑟𝐶𝑙 × 0.00083 + 0.0044 vancomycin ke Estimate 𝑉𝑑 = 0.7 × 𝑊𝑡 vancomycin Vd Derive estimated 𝐶𝑙𝑣𝑎𝑛𝑐𝑜 = 𝑘𝑒 × 𝑉𝑑 Clvanco Ellie Kosaka Alai Qudus Derive estimated T1/2= 0.693/ke T1/2 © Marshall B. Ketchum University  No the suggested dose is too high by estimates. Ke = (CrCl x 0.00083) +0.0044 Ke= (76.7 x 0.00083) +0.0044 Ke= 0.068061 VD = 0.7 x Wt. VD= 0.7 x 98kg VD= 68.6 CLvanc= ke x VD Clvanc= 0.068061 x 68.6 Clvanc= 4.6689846 AUC= TDD/Clvanc AUC= 3000mg/4.6689846 AUC= 642.53 too high © Marshall B. Ketchum University Despite your recommendation, the physician decides to start AS on a regimen of 1000mg IV Q12h. The electronic medical record below shows the administrations and vancomycin troughs for AS. You are on rounds on 12/6 with the medical student and he is asking you what he should do with the vancomycin dose given this level. How do you respond? Your hospital has not implemented current vancomycin guidelines yet. Dose Date/Time Vancomycin Level 1000mg 12/1 – 0910 12/1 – 2035 8 mg/L 1000mg 12/1 – 2045 Jaswinder Gill Darryl Ngadjou © Marshall B. Ketchum University Vancomycin vs. Beta-lactams for MSSA © Marshall B. Ketchum University  Vancomycin vs. Beta-lactams for MSSA and MRSA Vancomycin Cefazolin Nafcillin Piperacillin/tazobactam Vancomycin covers both MRSA Why can’t we use and MSSA, but most beta- vancomycin for both lactams don’t cover MRSA just to be safe? © Marshall B. Ketchum University  Vancomycin vs Beta-lactams for MSSA unnecessarily broad compared to cefazolin 1. Vancomycin ___________________ or nafcillin worse ADRs compared to cefazolin or 2. Vancomycin has ____________ nafcillin more effective treatments than 3. Cefazolin and nafcillin are _______________________ vancomycin for MSSA 1. Beta-lactams are more rapidly cidal 2. Vancomycin associated with higher rate of relapse for MSSA bacteremia Chang FY, et al. Medicine (Baltimore). 2003 Sep;82(5):333-9. © Marshall B. Ketchum University  Evidence for Worse Outcomes with Vancomycin for MSSA Small PM Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users, Antimicrob Agents Chemother, 1990, vol. 34 (pg. 1227-31) Martin E. Stryjewski, et al. Use of Vancomycin or First-Generation Cephalosporins for the Treatment of © Marshall B. Ketchum University Hemodialysis-Dependent Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia, Clinical Infectious Diseases, Volume 44, Issue 2, 15 January 2007, Pages 190–196, https://doi- org.eproxy.ketchum.edu/10.1086/510386  Vancomycin vs Beta-lactams for MSSA unnecessarily broad compared to cefazolin 1. Vancomycin ___________________ or nafcillin worse ADRs compared to cefazolin or 2. Vancomycin has ____________ nafcillin more effective treatments than 3. Cefazolin and nafcillin are _______________________ vancomycin for MSSA 1. Beta-lactams are more rapidly cidal 2. Vancomycin associated with higher rate of relapse for MSSA bacteremia Main point: Beta-lactams such as nafcillin and cefazolin are preferred Chang FY, et al. Medicine (Baltimore). 2003 Sep;82(5):333-9. over vancomycin when treating MSSA © Marshall B. Ketchum University The resident is concerned that the piperacillin/tazobactam might not be enough and isn’t sold on just changing the dose. “Can’t we just use vancomycin? It works for MRSA so it should work better on MSSA right?” What do you what to do regarding therapy. Justify your answer. Ellie Kosaka Richard Liou © Marshall B. Ketchum University  Questions © Marshall B. Ketchum University Additional Dosing Practice © Marshall B. Ketchum University Clinical PK/PD of Protein Synthesis Inhibitors Dr. Joshua Garcia, PharmD Associate Professor of Pharmacy Practice Marshall B. Ketchum University College of Pharmacy [email protected] Objectives Identify clinically pharmacotherapeutic and pharmacodynamic properties of aminoglycosides Recall the initial dosing and target ranges for various aminoglycosides for HDEI, traditional dosing, and gram-positive synergy in normal renal function Based on patient characteristics and infection type, select the most appropriate aminoglycoside dosing strategy and monitoring approach Evaluate the results of assays for therapeutic drug monitoring of aminoglycosides and provide a recommendation regarding dosage adjustment (if necessary) © Marshall B. Ketchum University Lecture Outline Review of Aminoglycoside Characteristics Aminoglycosides Exposure-Response Relationships and Dosing Strategies Initial Dose Selection Monitoring Strategy Design Interpretation of Monitoring Results and Dosage Adjustment © Marshall B. Ketchum University Aminoglycoside Review © Marshall B. Ketchum University  Periodic Table of Antibiotics BC Time BC Time BC Time BC Time BC AUC BC Conc Penicillins Cephalosporins Carbapenems Monobactams Glycopeptides Aminoglycosides +/- +/- +/- - + +(synergy)/- BS AUC BS AUC BS AUC BC/BS AUC BS Conc BC Conc Macrolides Tetracyclines Oxazolidinones Lincosamides Sulfonamides Fluoroquinolones +/- +/- + + +/- +/- BC Conc BC Conc BC AUC BC Variable Variable Variable Urinary Nitroimidazoles Lipopeptides Polymyxins Other Antibiotics Antibiotics +/- + - +/- +/- Cell Wall Inhibitors Cell Membrane Interactions Protein Synthesis Inhibitors Miscellaneous DNA / Replication Inhibitors © Marshall B. Ketchum University Recall: Aminoglycosides Basic Info 3 main that we will deal with: Gentamicin, Tobramycin, Amikacin Plazomicin is newer aminoglycoside that is not yet used commonly Primary use: Gram negative organisms and “synergy” for gram positive organisms in endocarditis (only) Main ADRs of concern: Nephrotoxicity Ototoxicity post-antibiotic effect Exhibits ___________________ Gentamicin & Tobramycin Peak:MIC Amikacin Best predictor of antibacterial effect is __________ © Marshall B. Ketchum University  Gram Positive Gram Negative Enterococcus CRE faecium (VRE) ESBL Serratia Enterococcus Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus Strep pyogenes mirabilis N. H. influenzae Tobramycin meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides fragilis Staph aureus Pseudomonas (MRSA) © Marshall Reused B. Ketchum University and modified with permission from Conan MacDougall, PharmD  Gram Positive Gram Negative Enterococcus CRE faecium (VRE) ESBL Serratia Enterococcus Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus Strep pyogenes mirabilis N. H. influenzae Gentamicin Amikacin meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides fragilis Staph aureus Pseudomonas (MRSA) © Marshall Reused B. Ketchum University and modified with permission from Conan MacDougall, PharmD  Gram Positive Gram Negative Enterococcus CRE faecium (VRE) ESBL Serratia Enterococcus Klebsiella faecalis pneumoniae L/M/C S. pneumoniae E. coli Proteus Strep pyogenes mirabilis N. H. influenzae Plazomicin meningitidis Citrobacter spp Staph aureus Enterobacter spp (MSSA) Bacteroides fragilis Staph aureus Pseudomonas (MRSA) © Marshall Reused B. Ketchum University and modified with permission from Conan MacDougall, PharmD Concentration Dependent Killing Peak Higher peak = Better Higher trough = 20 likelihood of success Higher chance of ADR Drug Concentration (mg/L) 18 16 14 Post antibiotic effect 12 Peak:MIC Ratio (PAE) 10 8 6 MIC 4 2 0 0 5 10 15 20 Time (hours) © Marshall B. Ketchum University Aminoglycoside ADRs Nephrotoxicity and ototoxicity are biggest clinically relevant ADRS Nephrotoxicity: Increase in SCr, decrease urine output, decrease in GFR Ototoxicity: Permanent hearing loss accumulation of aminoglycoside ADRs are due to _________________________ Toxicity Less Toxicity © Marshall B. Ketchum University Aminoglycosides: 3 Different Dosing Strategies High-Dose, Extended Interval (HDEI) Traditional Gram- Gram- Positive Negative Synergy Dosing Dosing © Marshall B. Ketchum University Traditional Gram-Negative Dosing © Marshall B. Ketchum University Traditional Gram-Negative Dosing Multiple daily dosing based on _______ weight and renal ____________ function Q8h interval Generally dosed at _______ Traditional Gram-Negative Dosing Peak ~ 10 Toxicity (More exposure = more toxicity) © Marshall B. Ketchum University  Aminoglycosides: Initial Dose Selection Weight Aminoglycoside dosing weights: Use TBW Underweight patients (TBW < IBW): ___________ Use IBW Normal patients (TBW > IBW & TBW/IBW < 125%):____________ Use ABW Overweight patients (TBW/IBW > 125%):_______________ TBW: Total Body Weight ABW: Adjusted Body Weight IBW: Ideal Body Weight © Marshall B. Ketchum University  Aminoglycosides: Initial Dose Selection (Tobramycin and Gentamicin) Gram-Positive CrCl Traditional Gram-Negative HDEI Synergy > 60 mL/min 1.5 – 1.7 mg/kg IV Q8h 5 – 7 mg/kg IV Q24h 1 mg/kg IV Q8h 40 – 60 mL/min 1.2 – 1.5 mg/kg IV Q12h 1 mg/kg IV Q12h Frequency may be adjusted 20 – 40 mL/min 1.2 – 1.5 mg/kg IV Q24h based on nomogram or avoided 1 mg/kg IV Q24h entirely 2 mg/kg IV load x1, then dose by 1 mg/kg IV load x1, < 20 mL/min levels then dose by levels Doses for gentamicin / tobramycin *Amikacin typically dosed at 15 – 20 mg/kg †Amikacin typically dosed at 5-7.5 mg/kg (5mg load) Make sure to use the correct weight! © Marshall B. Ketchum University  Aminoglycosides: Initial Dose Selection (Amikacin) Gram-Positive CrCl Traditional Gram-Negative HDEI Synergy Please note the dose of > 60 mL/min 5 – 7.5 mg/kg IV Q8h 15 – 20 mg/kg IV Q24his much higher amikacin 40 – 60 mL/min 5 – 7.5 mg/kg IV Q12h than gentamicin and is not Amikacin tobramycin (1.5 -1.7 Frequency may be adjusted mg/kg) for recommended 20 – 40 mL/min 5 – 7.5 mg/kg IV Q24h gram-positive based on nomogram or avoided entirely synergy