Alternative Dosing for IV Antibiotics

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in January 2018 ~ Resource # Alternative Dosing for IV Antibiotics Intravenous medications are commonly diluted in small volumes of normal saline or dextrose 5% to permit intermittent IV piggy-back administration. 1 An ongoing shortage of small volume parenteral solutions is making it necessary to conserve existing supplies of these 25 to 100 ml premade IV bags. 1-3 Alternative administration methods, such as IV push or continuous infusion, may be an option for some IV antibiotics and assist with conservation efforts. 1 This chart provides mixing recommendations and administration rates for antibiotics that can be given safely IV push or via continuous infusion. More information about how to manage the shortage and further conserve small volume parenterals is available from ASHP: conservation.ashx?la=en&hash=d6bb06db8ad5891e7eae628e3b b75. Abbreviations: CrCl = creatinine clearance; D5W = Dextrose 5% in Water; IM = intramuscular; IV = intravenous; IVPB = intravenous piggy back; NS = normal saline; SWFI = sterile water for injection What are some considerations for administering IV antibiotics via alternative methods? Purchase ready-to-use preparations, such as frozen minibags or pre-made syringes from a compounding supplier. 1 Reconstitute with sterile water for injection (SWFI), unless otherwise instructed by package insert labeling. 4 o Use of D5W or NS increases final preparation osmolality, potentially increasing risk for phlebitis. 4,5 o Peripherally administered IV meds with osmolarities >600 mosmol/l are more likely to cause soft tissue irritation. 6 Likewise, extravasation of high-osmolarity meds may result in local tissue damage. 6 Consider batching the most commonly used antibiotics in unit-of-use syringes for IV push administration. 1 Make kits containing antibiotic powder vial and the appropriate vial size of SWFI to permit nurse mixing. 4,7 o Load these into automated dispensing cabinets in high volume areas, such as the ED and OR. 4 o Educate nurses to label syringes appropriately, and administer doses immediately following preparation. 7 IV syringe pumps can be used to administer IV medications that cannot be given IV push. 1 o Weigh benefits of this strategy with risk of accidental IV push administration of these medications. o Label and/or otherwise differentiate the appearance of these pre-made syringes to help avoid mistakes. 7,23 Use positive wording, such as for syringe pump use only. 23

2 (Clinical Resource #340121: Page 2 of 7) Which antibiotics can be given IV push? Drug Dose Diluent Rate of IV Push Administration Ampicillin-sulbactam (Unasyn) 1.5 grams At least 3.2 ml SWFI 8,13 Over 10 to 15 minutes. 8 3 grams At least 6.4 ml SWFI 8,13 Too-rapid administration of ampicillin may cause seizures. 13,40 Consider using syringe pump. 1 Aztreonam 1 gram 10 ml SWFI 5,13,41 Over 2 to 4 minutes. 5 2 grams Over 5 minutes. 9 Cefazolin 1 gram 10 ml SWFI 4,5 Over 1 to 2 minutes. 4,5 2 grams 10 to 20 ml SWFI 4,5,13,42 Cefepime 1 gram 10 ml SWFI 5 Over 2 to 4 minutes. 5 2 grams 10 to 20 ml SWFI 4,13,43 Over 5 minutes. 4,9 Cefoxitin 1 gram 10 ml SWFI 4,5 Over 2 to 4 minutes. 5 2 grams 10 to 20 ml SWFI 13 Over 5 minutes. 4 Cefotaxime 1 gram 10 ml SWFI 5,13 Over 1 to 2 minutes. 5 2 grams Ceftazidime 1 gram 10 ml SWFI 5 Over 1 to 2 minutes. 5 2 grams 20 ml SWFI 4 Over 5 minutes. 4 Ceftriaxone 1 gram 10 ml SWFI 4,5 Over 1 to 2 minutes. 4,5 2 grams 20 ml SWFI 13,44 Daptomycin (Cubicin, generics) 10 ml NS 14,15 Over 2 minutes mg Daptomycin (Cubicin RF) 10 ml SWFI 16 Ertapenem 1 gram 10 ml SWFI 12 Over 5 minutes. 10 Meropenem 500 mg 10 ml SWFI 13 Over 3 to 5 minutes. 5 1 gram 20 ml SWFI 13 Oxacillin 500 mg 5 ml SWFI or NS 13 Over 10 minutes gram 10 ml SWFI or NS 13 Consider using syringe pump. 1

3 (Clinical Resource #340121: Page 3 of 7) Which antibiotics can be given via continuous infusion, and how are they dosed? Continued Continuous infusion of IV antibiotics offers the advantage of steady drug concentrations in the blood This may improve efficacy for time above MIC-dependent bactericidal antibiotics, such as beta-lactams and vancomycin ,28-31 Disadvantages include need for a dedicated IV line, IV incompatibilities, and stability concerns. 17 Antibiotics that may be given via continuous infusion include: o Meropenem Continuous infusion is associated with reduced mortality in comparison to intermittent dosing in patients with sepsis [Evidence level A-2] mg IV loading dose is followed by three 1-gram infusions administered over 8 hours each. 25,26,28 Preparation: dilute each dose in 100 to 500 ml of NS, and set to infuse over 8 hours. 13,26,31 Continuous infusion meropenem has not been adequately studied in renal impairment. 25,26,28 o Piperacillin-tazobactam (Zosyn) Continuous infusion is associated with improved rates of clinical cure and reduced mortality as compared with intermittent infusion [Evidence level A-2]. 25,26,29,30,45 Loading dose 2.25 to 4.5 grams is infused over 30 minutes before continuous infusion is begun. 25,27,30,32 Continuous infusion dosing varies, and depends on site of infection and renal function to 18 grams/day, infused over 24 hours. 27,29,30 o Intermittent dose (determined based on site of infection and renal function) is converted to the equivalent total daily dose and administered over 24 hours. 11,32 o Example: an intermittent regimen of grams IV every 6 hours would be converted to 13.5 grams IV infused over 24 hours. 11,32 Preparation: dilute total daily dose in 250 ml NS and infuse over 24 hours. 26,31 o Vancomycin Dosing, monitoring, and therapeutic concentration range differ from intermittent dosing, and no consensus exists regarding which continuous infusion regimen is preferred. 13,17 Most published nomograms use a loading dose of 15 to 20 mg/kg, based on actual body weight. 17,19,20,46 A higher loading dose of 35 mg/kg has been used for critically ill patients with normal renal function [Evidence level B-3]. 20,21 Continuous infusion dosing (over 24 hours) varies and can be either weight-based or clearance-based. 17 Weight-based: o 30 mg/kg/day for patients with normal renal function. 17,19 o Ranges from 7 mg/kg/day for patients with renal impairment, to as much as 45 mg/kg/day for patients with augmented renal function. 20,21 Clearance-based: calculated using estimated vancomycin clearance and desired vancomycin steady state concentration. 17

4 (Clinical Resource #340121: Page 4 of 7) Continuous infusion, continued What other strategies can be considered to promote conservation of small volume parenterals? Preparation: dilute total daily dose in 250 to 1000 ml D5W or NS, to a maximum concentration of 10 mg/ml. 13,17,20 Titrate dose to maintain vancomycin steady state concentrations of 17.5 to 30 mcg/ml. 17,21 Steady state vancomycin levels can be drawn 18 to 48 hours after infusion is started in patients with normal renal function. 17,19,22 Additional levels may be needed to confirm steady state attainment in renal impairment. 17 No clear efficacy advantage for continuous infusion over intermittent infusion has been consistently demonstrated. 17,18,21,22,46 Potential advantages with continuous infusion include quicker achievement of therapeutic vancomycin levels, lower risk of nephrotoxicity [Evidence level A-2], 46 and lower cost. 19,21,22,46 Consider extended interval dosing of aminoglycosides in appropriate (see below) patients. o This reduces the total number of IV admixture gentamicin or tobramycin bags from 3 to 1 per day ,47 o Extended interval dosing allows the total daily aminoglycoside dose to be given at one time. 33,36 This achieves higher peak concentrations, and allows for very low trough concentrations (<1 mcg/ml), limiting nephrotoxicity [Evidence level A-2]. 34,36,37,47 Dosing Methods: 7 mg/kg gentamicin or tobramycin IV x 1 infused over 30 minutes. 13,33,35,36,47 o The interval between subsequent doses is determined using the Hartford nomogram. 35,47 A serum level is obtained 6 to 14 hours after the first dose. 35,47 Result is plotted on the nomogram to determine appropriate dosing interval. 35,47 Dosing interval of every 24, 36, or 48 hours depending on plotted result. 33,35,47 5 mg/kg gentamicin or tobramycin IV once daily, infused over 30 minutes. 36 o The interval between subsequent doses is empiric and is based on estimated CrCl. 36 o Dose adjustments can then be made to achieve goal trough levels (<1 mcg/ml). 36 Should not be used in patients with ascites, CrCl <20 ml/min, extensive burns (>20% body), or pregnancy. 36 Not indicated for synergy dosing in endocarditis. 36 Promote conversion from IV to PO antibiotics as soon as clinically appropriate. 1 Encourage shorter courses of antibiotic therapy when appropriate. 38,39 o For example, consider stopping antibiotics on day 5 in clinically improved community-acquired pneumonia patients, rather than completing a 7- to 10-day course. 38,39

5 (Clinical Resource #340121: Page 5 of 7) Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Levels of Evidence In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish. Level Definition Study Quality A B C Good-quality patient-oriented evidence.* Inconsistent or limited-quality patient-oriented evidence.* 1. High-quality RCT 2. SR/Meta-analysis of RCTs with consistent findings 3. All-or-none study 1. Lower-quality RCT 2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings 3. Cohort study 4. Case control study Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. *Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life). RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69: Project Leader in preparation of this clinical resource (340121): Leslie Gingo, PharmD, BCPS References 1. ASHP. Small-volume parenteral solutions shortages suggestions for management and conservation. October 18, /media/assets/drug-shortages/docs/drug-shortagessvp-shortages-suggestions-for-management conservation.ashx?la=en&hash=d6bb06db8ad589 1E7EAE628E3B B75. (Accessed November 28, 2017). 2. Personal communication (written). Luce, Scott P. General Manager, U.S. Hospital Products. Baxter Healthcare Corporation. Deerfield, IL October 27, FDA. Statement by FDA Commissioner Scott Gottlieb, MD, updating on Puerto Rico related medical product shortages. November 30, nnouncements/ucm htm. (Accessed November 30, 2017). 4. McLaughlin JM, Scott RA, Koenig SL, Mueller SW. Intravenous push cephalosporin antibiotics in the emergency department: a practice improvement project. Adv Emerg Nurs J 2017;39: Spaulding A. Trick of the trade: IV-push antibiotics in the ED. May 11, Academic Life in Emergency Medicine. (Accessed November 29, 2017.) 6. Clinical Resource, Management of Non-Chemo Extravasation. Pharmacist s Letter/Prescriber s Letter. October ISMP. Safe practice guidelines for adult IV push medications vpushmedguidelines.pdf. (Accessed November 29, 2017). 8. Product information for Unasyn. Pfizer. New York, NY August Butterfield-Cowper JM, Burgner K. Effects of i.v. push administration on beta-lactam pharmacodynamics. Am J Health Syst Pharm 2017;74:e Wiskirchen DE, Housman ST, Quintiliani R, et al. Comparative pharmacokinetics, pharmacodynamics, and tolerability of ertapenem 1 gram/day administered as a rapid 5-minute infusion versus the standard 30-minute infusion in healthy adult volunteers. Pharmacotherapy 2013;33: Paul M, Theuretzbacher U. Beta-lactam prolonged infusion: it s time to implement! Lancet Infect Dis doi: /S (17)30614-X. 12. Product information for Invanz. Merck & Co. Whitehouse Station, NJ August Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; (Accessed November 30, 2017.) 14. Product information for Cubicin. Merck & Co. Whitehouse Station, NJ September Product information for Daptomycin. Fresenius Kabi USA. Lake Zurich, IL August Product information for Cubicin RF. Merck & Co. Whitehouse Station, NJ September Waineo MF, Kuhn TC, Brown DL. The pharmacokinetic/pharmacodynamics rationale for administering vancomycin via continuous infusion. J Clin Pharm Therapeut 2015;40: DiMondi VP, Rafferty K. Review of continuousinfusion vancomycin. Ann Pharmacother 2013;47: Cataldo MA, Tacconelli E, Grilli E, et al. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother 2012;67:17-24.

6 (Clinical Resource #340121: Page 6 of 7) 20. Roberts JA, Taccone FS, Udy AA, et al. Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother 2011;55: Cristallini S, Hites M, Kabtouri H, et al. New regimen for continuous infusion of vancomycin in critically ill patients. Antimicrob Agents Chemother 2016;60: Alvarez R, Lopez Cortes LE, Molina J, et al. Optimizing the clinical use of vancomycin. Antimicrob Agents Chemother 2016:60; ISMP Medication Safety Alert! Affirmative warnings (do this) may be better understood than negative warnings (do not do that). August 12, asp. (Accessed December 5, 2017.) 24. Bates A, Joffe AR. Is there a role for continuous infusion of beta-lactam antibiotics in severe sepsis? J Thorac Dis 2016;8:E Dulhunty JM, Roberts JA, Davis JS, et al. A multicenter randomized trial of continuous versus intermittent beta-lactam infusion in severe sepsis. Am J Respir Crit Care Med 2015;192: Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013;56: Goncalves-Pereira J, Olivieira BS, Janeiro S, et al. Continuous infusion of piperacillin/tazobactam in septic critically ill patients a multicenter propensity matched analysis. PLOS One 2012;7:e Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, et al. Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics. Minerva Anesthesiol 2012;78: Yang H, Zhang C, Zhou Q, et al. Clinical outcomes with alternative dosing strategies for piperacillin/tazobactam: a systematic review and meta-analysis. PLOS One 2015;10:e Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis 2013;56: Dulhunty JM, Roberts JA, Davis JS, et al. A protocol for a multicentre randomized controlled trial of continuous beta-lactam infusion compared with intermittent beta-lactam dosing in critically ill patients with severe sepsis: the BLING II study. Crit Care Resusc 2013;15: Lau WK, Mercer D, Itani K, et al. Randomized, open-label, comparative study of piperacillintazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intraabdominal infection. Antimicrob Agents Chemother 2006;50: Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 1997;39: Pagkalis S, Mantadakis E, Mavros MN, et al. Pharmacological considerations for the proper clinical use of aminoglycosides. Drugs 2011;71: Nicolau D, Quintiliani R, Nightingale CH. Once-daily aminoglycosides. Conn Med 1992;56: Stankowicz MS, Ibrahim J, Brown DL. Once-daily aminoglycoside dosing: an update on current literature. Am J Health Syst Pharm 2015;72: Drusano GL, Louie A. Optimization of aminoglycoside therapy. Antimicrob Agents Chemother 2011;55: Professional Resource, Antibiotic Therapy: When Are Shorter Courses Better? Pharmacist s Letter/ Prescriber s Letter. November Spellberg B. The new antibiotic mantra shorter is better. JAMA Intern Med 2016;176: Product information for ampicillin. Fresenius Kabi USA. Lake Zurich, IL October Product information for aztreonam. Fresenius Kabi USA. Lake Zurich, IL March Gura KM. Parenteral drug administration guidelines for the pediatric patient: one hospital s recommendations. Hosp Pharm 1993;28:221-23,227-8, Product information for Cefepime. Hospira, Inc. Lake Forest, IL April Product information for Ceftriaxone. West-Ward Pharmaceuticals. Eatontown, NJ October Vardakas KZ, Voulgaris GL, Maliaros A, et al. Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis doi: /S (17) Hao JJ, Chen H, Zhou JX. Continuous versus intermittent infusion of vancomycin in adult patients: a systematic review and meta-analysis. J Antimicrob Agents 2016;47: Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995;39: Cite this document as follows: Clinical Resource, Alternative Dosing for IV Antibiotics. Pharmacist s Letter/Prescriber s Letter. January 2018.

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