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Understanding Antibiotic Use in Critically Ill Surgical Patients
- 1. Understanding Antibiotics in Critically Ill Surgical Patients Allison N. Boyd, PharmD, BCCCP Clinical Pharmacist Specialist – Trauma/Burn Cell: 401.500.9663 | Office: 401.444.3295 aboyd1@lifespan.org
- 2. Outline 1. Antibiotic stewardship principles 2. Pharmacokinetic/pharmacodynamics changes in trauma and burn 3. Vancomycin dosing 4. Pneumonia treatment 5. Urinary tract infections
- 4. Antibiogram • Located on the Intranet • Susceptibilities provided over the previous year Goal: > 90%
- 5. Culture and Susceptibility Timeline Data Time Period Gram stain Minutes Initial positive culture 12-48 hours Identification of species 24-48 hours Anti-infective susceptibilities 48-72 hours Stein SM. Boh’s pharmacy practice manual: a guide to the clinical experience. Third edition. Lippincott Williams & Wilkins. 2009
- 6. Keys to Success with Stewardship 48 hour assessment and documentation Patient meets criteria for broad spectrum antibiotic coverage until cultures result Planned duration and day of therapy Ex: Cefazolin for MSSA bacteremia day # 4/14 De-escalation Broad to narrow: carbapenem to cephalosporin to penicillin IV to PO Is the patient appropriate for a more narrow PO option in the same therapeutic class? Infectious Disease order sets include: Adult SIRS/Fever Focused, General Adult Pneumonia Treatment Focused
- 7. Comparative Serum Concentration-Time Profiles Time (hours) Log Conc (mcg/mL) Zosyn 3.375g Ceftriaxone 1 g Imipenem 500mg Levofloxacin 750mg 50 100 200
- 8. Example Sensitivity Data Antibiotic MIC Susceptibility Breakpoint Pip:Tazo 8 S < 16 Cefepime < 2 S < 8 Meropenem > 16 R < 2 Amikacin < 2 S < 16 Gentamicin < 1 S < 4 Tobramycin < 1 S < 4 Ciprofloxacin 2 I < 1 Levofloxacin 4 I < 2 Pseudomonas aeruginosa – BAL
- 9. Why Do You Sometimes Tell Us The Susceptibilities Are Wrong? • Many Enterobacteriaceae species possess changes that confer high- level resistance to quinolones (e.g. Klebsiella pneumoniae, Escherichia coli, Enterobacter spp) • Intrinsically resistant to aminopenicillins, cefazolin, and cefoxitin • β-lactam exposure is capable of inducing expression of AmpC β- lactamases • Can also possess extended spectrum beta-lactamase (ESBL) resistance • Third-generation cephalosporins (i.e. ceftriaxone) should be avoided as treatment for serious infection with Enterobacter spp • Alternatives: Cefepime, Ertapenem, Meropenem, Sulfamethoxazole/trimethoprim, (?) piperacillin/tazobactam Gram-Negative Bacteria: Enterobacter spp Paterson, DL. Am J Med 2006 Jun;119(6 Suppl 1):S20-8. Jacoby GA. Clin Microbiol Rev 2009 Jan;22(1):161-82.
- 10. Pharmacokinetic and Pharmacodynamic Changes in Trauma and Burn
- 11. Pharmacokinetics (PK) Pharmacodynamics (PD) • Absorption • Distribution • Metabolism • Elimination PK: What the body does to a drug PD: What a drug does to the body
- 12. Augmented Renal Clearance in Trauma Patients Systemic inflammation Increased organ blood flowIntravenous fluids Vasoactive medications Increased GFR Altered tubular function Renal reserve Augmented renal clearance Barletta JF, et al. J Trauma Acute Care Surg 2017;82:665-71. • ↓ clinical cure • ↑ length of stay • ↑ mortality
- 13. Augmented Renal Clearance in Trauma Intensive Care (ARCTIC) Score Barletta JF, et al. J Trauma Acute Care Surg 2017;82:665-71. ARCTIC Score Variable Points SCr < 0.7 mg/dL 3 Male sex 2 Age < 56 years 4 Age 56 – 75 years 3 ARCTIC score > 6 indicates likely presence of augmented renal clearance
- 14. Inflammatory Response in Burn Patients Initial vasoconstriction: thermal injury causes decreased blood flow Profound vasodilation: release of histamine from mast cells, basophils, and platelets Increased microvascular permeability: breakdown of hyaluronate/collagen results in increased extravascular osmotic activity Further vasodilation & permeability: caused by substance P, histamine, bradykinin, prostacyclin, leukotrienes Yogaratnam D, et al. Pharmacotherapy 2004;24(12):1793-1799.
- 15. Metabolic Alterations in Burn Patients • Gluconeogenesis (catecholamines, glucagon, cortisol) • Stress hormones (ACTH, vasopressin, corticotropin-releasing hormone) • Cytokines/oxidants (protein degradation, metabolic rate, temperature) • Anabolic hormones (growth hormone, testosterone) HYPERMETABOLIC Yogaratnam D, et al. Pharmacotherapy 2004;24(12):1793-1799.
- 16. Physiologic Changes in Burn Injury ACUTE PHASE (First 48 hours) • Vasodilation • Capillary integrity loss • Fluid diffuses from vasculature • Decreased cardiac output • Tissue HYPOperfusion HYPERMETABOLIC PHASE (After 48 hours) • Vasoconstriction • Enhanced hepatic and renal perfusion and clearance • Accentuated cardiac output • Tissue HYPERperfusion Yogaratnam D, et al. Pharmacotherapy 2004;24(12):1793-1799.
- 17. Pharmacokinetics in Trauma and Burn Shorter T1/2 • Increased renal blood flow ↓ Bioavailability • Peripheral perfusion changes, increased edema ↑ Vd • Volume resuscitation, capillary leak, increased extravascular volume Ortwine JK, et al. J Burn Care Res 2015;36:e72-84. Barletta JF, et al. J Trauma Acute Care Surg 2017;82:665-71.
- 18. PK Changes Affecting Dosing in Trauma and Burn Patients • Shorter T1/2 more frequent dosing • Reduced bioavailability increased doses • Increased Vd increased doses • Hypermetabolic increased doses NORMAL TRAUMA/BURN Vancomycin Q12h or Q24h Vancomycin Q8h or Q12h Linezolid Q12h Linezolid Q8h Tobramycin Q24h Tobramycin Q12h or Q18h Ortwine JK, et al. J Burn Care Res 2015;36:e72-84. Barletta JF, et al. J Trauma Acute Care Surg 2017;82:665-71.
- 19. PK Literature for Antibiotics in Burn Drug Vd T1/2 CLT Penicillins ↑ ↑ ↓ Cephalosporins ↑ ↑ ↑ Meropenem ↑ ↑ ↑ Aztreonam ↑ ↑ ↑ Aminoglycosides - to ↑ ↓ ↑ Vancomycin - to ↑ ↓ ↑ Daptomycin ↑ - ↑ Linezolid - ↓ ↑ Colistin ↑ ↑ - Ortwine JK, et al. J Burn Care Res 2015;36:e72-84.
- 20. Additional Considerations • Therapeutic window • Narrow = more monitoring • Drug levels • Individual considerations • Volume status/resuscitation • Presence of TBI • %TBSA • CrCl • Albumin (protein binding)
- 22. Determining Vancomycin Dose • Adult Patients • Goal trough 10-15 mcg/mL: SSTI, UTI, bacteremia, intra- abdominal infection • Goal trough 15-20 mcg/mL: pneumonia, endocarditis, meningitis, osteomyelitis, neutropenic fever due to MRSA • Loading dose (optional) • 25 mg/kg (range 20-30 mg/kg) • Consider for young patients with large burns (> 20% TBSA) or TBI • Max empiric dose: 3000 mg • Maintenance dose • 15 – 20 mg/kg per dose • 40 – 45 mg/kg total daily dose Ortwine JK, et al. J Burn Care Res 2015;36:e72-84. Carter BL, Damer KM, Walroth TA, et al. J Burn Care Res 2015;36:641-50.
- 23. Vancomycin Dosing Interval Creatinine Clearance Interval > 100 mL/min and < 35 years of age Q8 hours > 60 mL/min Q12 hours 40-59 mL/min Q24 hours 25-39 mL/min Q48 hours < 25 mL/min Intermittent Additional Considerations: • Elderly patients (> 70 years) should not be empirically started on an interval more frequent than Q24H regardless of CrCl calculation • Troughs should not be collected sooner than the fourth dose to be accurate and must be drawn on time (e.g. immediately prior to fourth dose) • Once a patient has had 2 troughs within goal range, can reduce frequency to once weekly if no major changes in renal function Note: CrCl is calculated using ideal body weight
- 24. Pneumonia
- 25. Disease State Definitions CAP • Occurs within 48 hours of admission HAP • Episode of pneumonia not associated with mechanical ventilation • Not incubating at the time of hospital admission and occurring > 48 hours after admission VAP • Occurs > 48 hours after endotracheal intubation Mandell LA, et al. Clin Infect Dis 2007;44:S27-72. Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111.
- 26. Community-Acquired Pneumonia Inpatient Treatment Most likely to be caused by Streptococcus pneumonia, Haemophilus influenzae, or atypical organisms Recommended Treatment Alternative Treatment Ceftriaxone + Azithromycin Levofloxacin Pseudomonas Risk Piperacillin-Tazobactam + Azithromycin (+/- Tobramycin or Ciprofloxacin) Cefepime + Azithromycin (+/- Tobramycin or Ciprofloxacin) OR Aztreonam + Levofloxacin Mandell LA, et al. Clin Infect Dis 2007;44:S27-72.
- 27. CAP Duration of Therapy • Treat for a minimum of 5 days • Patients should be afebrile for 48-72 hours before discontinuation of therapy • A longer duration of therapy may be needed if initial therapy was not active against identified pathogen or if it was complicated by extrapulmonary infection, such as meningitis or endocarditis Mandell LA, et al. Clin Infect Dis 2007;44:S27-72.
- 28. Empiric HAP/VAP Coverage Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111. HAP or VAP suspected Risk factors for MDR pathogens or high risk for mortality? No Yes
- 29. Risk Factors for MDR Pathogens HAP • IV antibiotics within 90 days • Ventilatory support (mortality risk) • Septic shock (mortality risk) VAP • ARDS prior to VAP • Septic shock at time of VAP • IV antibiotics within 90 days • Acute renal replacement prior to VAP • > 5 days in hospital prior to VAP Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111.
- 30. Empiric HAP/VAP Coverage Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111. HAP or VAP suspected Risk factors for MDR pathogens or high risk for mortality? No Yes Add MRSA coverage Structural lung disease? > 10% pseudomonal resistance? Abundance of GNR on gram stain? No Yes 1 anti-pseudomonal agent 2 anti-pseudomonal agents MRSA coverage Plus 2 anti-pseudomonal agents of different classes • VAP: • ARDS prior to VAP • Septic shock at time of VAP • IV antibiotics within 90 days • Acute renal replacement prior to VAP • > 5 days in hospital prior to VAP • HAP: • IV antibiotics within 90 days • Ventilatory support (mortality risk) • Septic shock (mortality risk)
- 31. HAP/VAP – Early Onset < 5 days of hospitalization, no risk for MDR pathogens Most likely to be caused by Streptococcus pneumoniae, Haemophilus influenzae, MSSA, or antibiotic sensitive Gram- negative bacilli Recommended Treatment Alternative Treatment Ceftriaxone + Azithromycin Levofloxacin Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111.
- 32. HAP/VAP – Late Onset > 5 days of hospitalization or risk for MDR pathogens Most likely to be caused by the same organisms as early onset plus Pseudomonas aeruginosa, Klebsiella pneumoniae, or MRSA Recommended Treatment Alternative Treatment Piperacillin-Tazobactam +/- Tobramycin or Ciprofloxacin + Vancomycin Cefepime +/- Tobramycin or Ciprofloxacin + Vancomycin OR Aztreonam + Vancomycin + Tobramycin or Ciprofloxacin Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111.
- 33. HAP/VAP Duration of Therapy • For patients with HAP and VAP, recommend a 7 day course of antimicrobial therapy over a longer regimen (strong recommendation, moderate-quality evidence) • There exist situations which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement in clinical, radiologic, and laboratory parameters • Guideline Meta-Analysis: • No differences between short-course (7-8 days) and long-course (10-15 days) regimens in terms of mortality, clinical cure, and recurrent pneumonia • Short-course regimens associated with reduced recurrent VAP due to MDR pathogens compared to long-course regimens • Subpopulation of VAP due to non-fermenting gram-negative bacilli (including Pseudomonas and Acinetobacter): no differences in pneumonia recurrence or mortality Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111.
- 34. Common Doses of Antibiotics for Pneumonia Gram-Positive Antibiotics with MRSA Activity Gram-Negative Antibiotics with Antipseudomonal Activity: β-Lactam-Based Agents Gram-Negative Antibiotics with Antipseudomonal Activity: Non-β-Lactam-Based Agents Vancomycin 15 mg/kg IV q8-12h *Consider loading dose of 25-30 mg/kg x 1 for severe illness Piperacillin-tazobactam 4.5 g IV q6h Amikacin 15-20 mg/kg IV q24h Gentamicin 5-7 mg/kg IV q24h Tobramycin 5-7 mg/kg IV q24h Linezolid 600 mg IV q12h Cefepime 2 g IV q8h Ciprofloxacin 400 mg IV q8h Levofloxacin 750 mg IV q24h Meropenem 1 g IV q8h *Consider 2 g IV q8h for obesity, TBI, or burns > 20% TBSA Aztreonam 2 g IV q8h Antibiotics that Target Community-Acquired Pneumonia (No Antipseudomonal/MRSA activity) Ceftriaxone 1 g IV q24h *Consider 2 g IV q24h for obesity, TBI, or burns > 20% TBSA Azithromycin 500 mg IV/PO q24h x 3 days ***Recommended dosing for patients with normal renal function (CrCl > 60 mL/min) Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-111.
- 36. Community-Acquired UTIs Most likely to be caused by Escherichia coli or Proteus mirabilis Recommended Treatment Alternative Treatment Nitrofurantoin 100 mg PO BID x 5 days Trimethoprim- Sulfamethoxazole 160-800 mg PO BID x 3 days Cephalexin 500 mg PO BID x 3 days Ciprofloxacin 250 mg PO BID x 3 days+ Levofloxacin 250 mg PO daily x 3 days+ Gupta K, et al. Clin Infect Dis 2011;52(5):e103-20. ***Recommended dosing for patients with normal renal function (CrCl > 60 mL/min) +Fluoroquinolones discouraged due to increasing resistance with E. coli
- 37. Catheter-Associated UTIs Most likely to be caused by Escherichia coli, Enterobacter spp., Serratia marcescens, or Pseudomonas aeruginosa Recommended Treatment Alternative Treatment Ceftriaxone 1 g IV q24h Cefepime 2 g IV q8h Pip/tazo 3.375 g IV q6h Aztreonam 1 g IV q8h CAUTI Treatment Duration Prompt Resolution: 7 days Delayed Resolution: 10-14 days Hooten TM, et al. Clin Infect Dis 2010;50:625-63. May consider 3 days for patients < 65 years if catheter removed ***Recommended dosing for patients with normal renal function (CrCl > 60 mL/min)
- 38. Understanding Antibiotics in Critically Ill Surgical Patients Allison N. Boyd, PharmD, BCCCP Clinical Pharmacist Specialist – Trauma/Burn Cell: 401.500.9663 | Office: 401.444.3295 aboyd1@lifespan.org