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Antimicrobial dosing in critical care: A pragmatic adult dosing nomogram
Critical Care Antimicrobial Dosing Nomogram
Journal Pre-proof
Antimicrobial dosing in Critical Care: A pragmatic adult dosing nomogram Paul Williams , Gareth Beall , Menino Osbert Cotta , Jason A. Roberts PII: DOI: Reference:
S0924-8579(19)30298-5 https://doi.org/10.1016/j.ijantimicag.2019.10.018 ANTAGE 5837
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
11 February 2019 27 October 2019
Please cite this article as: Paul Williams , Gareth Beall , Menino Osbert Cotta , Jason A. Roberts , Antimicrobial dosing in Critical Care: A pragmatic adult dosing nomogram, International Journal of Antimicrobial Agents (2019), doi: https://doi.org/10.1016/j.ijantimicag.2019.10.018
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Antimicrobial dosing in Critical Care: a pragmatic adult dosing nomogram Paul Williamsa,b; Gareth Beallb; Menino Osbert Cottaa,c; Jason A. Robertsa,c,d,e a. University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, Brisbane, Queensland, Australia b. Pharmacy Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia c. School of Pharmacy, Centre for Translational Anti-infective Pharmacodynamics, The University of Queensland, Brisbane, Queensland, Australia d. Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia e. Pharmacy Department, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
Short Title: Critical Care Antimicrobial Dosing Nomogram Keywords: nomogram, guideline, beta-lactam, vancomycin, critically ill Corresponding author: Paul Williams; Pharmacy Department, Sunshine Coast University Hospital, 6 Doherty St, Birtinya, Queensland 4575, Australia; Email: [email protected]; Tel +61 7 5202 2678; Fax: +61 7 5202 0844 Word Count: Abstract = 97; Main Body = 2599
Abstract Standard dosing of antimicrobials derived from product information (PI) is considered to have limited application in critically ill patients given the pharmacokinetic (PK) and pharmacodynamic (PD) changes often seen in these patients relative to other groups in the hospital. Dosing nomograms that account for the altered needs of critically ill patients are needed to minimise the likelihood of antimicrobial underdosing (risks treatment failure) and overdosing (risks toxicity) in these patients. The aim of this paper is to present a pragmatic, evidence-based, adultdosing nomogram for a selection of antimicrobials frequently prescribed to treat infections in critically ill patients.
1.
Introduction
Optimising dosing of antimicrobials in critically ill patients requires an understanding of both the pharmacokinetic (PK) changes that can occur in these patients, and the pharmacodynamics (PD) of the antimicrobial agent prescribed. Standard dosing of drugs derived from the Product Information (PI) have limited application in critically ill patients given the PK/PD changes often seen in these patients relative to other groups in the hospital. (1) There is a growing body of literature which demonstrates from observational PK studies as well as therapeutic drug monitoring (TDM) reports, that contemporary dosing approaches risks suboptimal dosing in a large fraction of critically ill patients. (2-5)
TDM provides a robust method to individualise and optimise antimicrobial dosing. Contemporary research is applying more emphasis on utilising TDM, especially in the face of decreasing antimicrobial susceptibility and in cohorts of patients who exhibit large fluctuations in PK such as critically ill patients. (5, 6) Despite the promise of TDM-based dosing, studies in critically ill patients have highlighted that many patients still do not achieve the desired target concentration at steady state. (5, 6) It remains to be clarified whether a nomogrambased dosing strategy would impact the frequency of achieving target concentrations. Nomogram-based dosing is certainly highly feasible, something which is not the case with TDM which requires much infrastructure.
The evidence supporting the use of nomogram-based dosing of antimicrobials in the critically ill is limited. (7-9) Previous studies do not provide definitive outcome data, and most nomogram-based studies are presented as part of a ‘bundle of care’ which may confound the interpretation of their value. However, a lack of evidence-based policies and user-friendly
guidelines have been identified as factors that influence a clinician’s antibiotic prescribing behaviour. (10) Additionally, results from survey studies highlighted that clinicians frequently do not have appropriate access to resources to guide antimicrobial prescribing and that TDM is either not readily available or results are not timely. (11)
In collaboration with key stakeholders, clinicians from a 12-bed closed mixed adult Intensive Care Unit (ICU) in Australia developed an adult antimicrobial dosing nomogram as a solution to overcome the aforementioned challenges. Herewith, we present the process for dosing nomogram development and the final product.
2.
Methods
2.1 Dosing nomogram development The development of the dosing nomogram commenced in 2015 and sought to provide clinicians with a dosing nomogram based on renal function, continuous renal replacement therapy (CRRT), and suspected augmented renal clearance (ARC; defined as a creatinine clearance >130 mL/min). To align with the CRRT mode and default setting used at our ICU, the dosages were selected for continuous veno-venous haemofiltration (CVVH) and assumed an ultrafiltration rate of 2000 mL/hr. The antimicrobials for inclusion in the dosing nomogram were flucloxacillin, cefepime, ceftazidime, meropenem, piperacillin/tazobactam, and vancomycin. These antimicrobials were included due to being commonly prescribed in the ICU and in which dose modification was frequently required in critically ill patients.
In 2015, a literature review was conducted to establish the dosing nomogram, and data included was identified by searches of Medline, Embase, and references from relevant original articles. Secondary and tertiary literature was also reviewed, including: The electronic Therapeutic Guidelines complete, and The Sandford Guide to Antimicrobial therapy. Search terms for each antimicrobial included: pharmacokinetics, pharmacodynamics, penetration, augmented renal clearance, obesity, critically ill, intensive care, continuous infusion, extended infusion, prolonged infusion, Monte Carlo, renal impairment, hepatic impairment, acute kidney injury (AKI), mortality, outcome, minimum inhibitory concentration, Bayesian, and dosing software. A follow-up literature review was conducted in 2017.
Literature review and extraction was performed by PW and GB. Relevant data in the domains to be included in the dosing nomogram were populated after interpreting all relevant data obtained for methodological rigour (sample size, population PK analysis with dosing simulations performed) and consistency of results between eligible studies. The dosages in the nomogram were selected to maximise the likelihood of achieving pre-defined target concentrations as supported by the primary literature. For beta-lactam antimicrobials the target concentration was defined as 100% of time which the ‘free’ antimicrobial remains above the MIC during the dosing interval (100% fT>MIC). (2, 12) The vancomycin target concentration was defined as a steady state trough concentration of 15-20 mg/L. (13)
The draft dosing nomogram was presented to key stakeholders [ICU consultants, ID consultants, and the Antimicrobial Stewardship (AMS) team]. Clinicians were provided with electronic access to all original articles and were encouraged to review key papers identified
by the ICU pharmacists. An expert external to the host hospital (JR) also reviewed the content of the dosing nomogram. All feedback was collated, and the first iteration of the dosing nomogram was endorsed by the medicines committee in 2016.
2.1.1 Papers omitted during dosing nomogram development Papers which provided evidence to support dosages for the dosing nomogram were excluded based on the following principles: non-systematic review articles, case-studies, sample size < 10, non-IV administration of the antibiotics studied, or where the dosages were clinician’s choice and achieved target concentrations could not be correlated to the dosage. When comparing Monte Carlo simulation studies, papers were favoured where the population PK data was derived from critically ill patients, and where the model was validated using a similar cohort of patients not included in creating the population PK model. Papers were also omitted where the beta-lactam target concentration was < 100% fT>MIC or the vancomycin target trough concentration was < 15 mg/L, or where no pathogen was identified and the highest MIC for susceptible bacteria to the antibiotic was not used. Results from vancomycin nomogram-based studies were excluded when dosages were not weight based or included a dose cap in obesity. In situations where the supporting evidence was not clear, expert opinion determined the dosing nomogram recommendation.
2.2 Dosing nomogram versus Product Information (PI) dosing A comparison of total daily dosing between the dosing nomogram and PI dosing was performed. Where specified in the PI, dosages for ‘very severe or life-threatening infections’ were selected for the comparison. In instances where weight-based dosing was recommended, a 70kg individual was assumed for comparative purposes. Dose variations
between the dosing nomogram and PI were presented as a percentage variation from PI for equivalent levels of renal function. 3.
Results
A total of 227 relevant articles were obtained and considered for the development of the adult dosing nomogram with 36 articles used in the final document. Table 1 and Table 2 present the beta-lactam and vancomycin dosing nomograms showing the relationship between recommended dosage and renal function. The nomogram included doses for the breadth of renal function, including ARC, AKI, and for CRRT.
A flowchart of extraction of included papers and papers included in the dosing nomogram development can be found in the supplementary material in the online version of this article.
The variation between nomogram dosing and PI dosing are shown in Figure 1.
4.
Discussion
This pragmatic adult dosing nomogram offers clinicians up-to-date dosing recommendations for a selection of antimicrobial agents frequently prescribed to treat infections in critically ill patients. The dosing regimens included in the nomogram were developed to maximise the likelihood of achieving pre-defined concentrations associated with improved clinical outcomes. (4, 13) To the best of our knowledge, there is no comparable dosing nomogram covering this range of antimicrobials presented in the literature.
4.1 Why a different dosing approach is needed? Contemporary dosing approaches risks suboptimal antimicrobial dosing in a large fraction of critically ill patients. (2-4) There is debate over which PD target exposure is the most suitable in clinical practice, with a wide variation in target concentrations described for beta-lactams in the literature. (4, 6, 14) Improved clinical outcomes have been observed when higher target concentrations are achieved (100% fT>MIC). (4, 14)
Recently, Wong et al. reported in 330 critically ill patients that only 66.9% and 36.6% of beta-lactam dosing achieved a target trough concentration of 100% fT>MIC and 100% fT>4xMIC respectively, following at least 4 prior antimicrobial doses. (2) Empiric dosing regimens were determined by the treating physician in consultation with the clinical pharmacist in this study. These findings reflect those of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study in 2014 in which beta-lactam dosing was determined by the clinician. (4) A total of 361 patients were evaluated and 16% failed to reach concentrations of 50% fT>MIC; a positive clinical outcome was 32% less likely in these patients (OR, 0.68 [95% CI,.52–.91]; P = .009). (4) Analysis of piperacillin/tazobactam and meropenem data demonstrated that a target trough concentration of 100% fT>MIC and 100% fT>4xMIC was achieved in 63.2% (115/182) and 27.5% (50/182) of patients respectively. (15)
In 2014, Blot et al. examined whether contemporary vancomycin dosing (clinician’s choice) in 42 patients from 26 ICUs in 8 countries resulted in trough concentrations ≥15 mg/L or AUC0– 24/MIC
of 400 mg.h/L (assuming an MIC of 1 mg/L). The target trough concentration was
achieved in only 57% of patients and only 71% of patients achieved the target AUC0–24/MIC. (3)
Our dosing nomogram provides clinicians with an alternative to dosing derived from the PI. The dosing regimens in the nomogram were selected to maximise the likelihood of achieving either a beta-lactam concentration of 100% fT>MIC or a vancomycin steady state trough concentration of 15-20 mg/L. It remains to be determined how consistently the dosing nomogram achieves the pre-defined concentrations in clinical practice.
4.2 Variation of dosing between dosing nomogram and PI dosing. Figure 1. presents the variation between daily dosages from the dosing nomogram compared with those from the PI. The largest variation was observed with vancomycin. The nomogram loading dose (LD) for vancomycin recommended a 100% increase in dose compared to the PI, and a 250% increase in maintenance dose in patients with a CrCl of 20 mL/min. The nomogram vancomycin maintenance dosages are presented in mg/kg as compared to the PI which recommends daily vancomycin maintenance doses of 15 times the CrCl in mg (e.g. a patient with a CrCl of 50 mL/min would receive 750 mg daily) The vancomycin PI does not consider actual body weight. (16)
There was less variation between the dosing nomogram and PI dosages for beta-lactam antibiotics. Nomogram dosing was 0-100% higher than PI dosing and this variation was more pronounced in dosages for patients with a reduced CrCl. Furthermore, the dosing nomogram recommends full dosing for the first 24-48 hours to maximise the likelihood of achieving 100% fT>MIC at steady state.
4.3 Comparison of nomogram dosing regimens in the literature Our dosing nomogram is unique in terms of the method of development when compared to other dosing nomograms described in the literature. Dosing nomograms in critically ill patients commonly determine dosing regimens using PK/PD modelling and simulation approaches; which is a robust and appropriate approach. (7-9, 17) Our nomogram however, was compiled from the primary literature and dosing regimens were selected by author consensus based on the available evidence. Variability in dosing between our nomogram and others in the literature is apparent.
Nicasio et al. conducted an interrupted time-series study in 2010 to observe the impact of a dosing nomogram to empirically treat patients with ventilator-associated pneumonia (VAP). (7) Local MIC distributions and Monte Carlo simulations were used to recommend empiric antimicrobial agents and dosing regimens. Combination therapy of a beta-lactam with tobramycin and vancomycin was included in the regimen. Infection-related mortality was 21.6% vs 8.5% (P = 0.029) in the before and after groups, respectively, although the study was not powered for this endpoint. (7) The meropenem dosages recommended in this nomogram vary to that of our nomogram. In patients with a CrCl >50 mL/min, the Nicasio nomogram recommends meropenem 2 g three times daily infused over 3 hours which is double the daily dose recommended in our nomogram. However, in patients with a CrCl of 30-50 mL/min the Nicasio nomogram recommends 0.5 g every 6 hours (2 g daily) as compared to 1 g three times daily (3 g daily) in our nomogram. In contrast, the cefepime dose recommendations are similar between the Nicasio nomogram and our nomogram.
In 2013, Golenia et al. developed an ICU-specific vancomycin dosing nomogram, providing clinicians with loading and maintenance doses based on actual body weight and estimated renal function. (17) An initial vancomycin trough concentration of 15 mg/L or higher increased with nomogram dosing compared to the pre-implementation ‘clinicians choice’ dosing (72% vs 39%, P = 0.0004). (17) There are some differences in dosing between the Golenia nomogram and our nomogram. The Golenia nomogram recommends a LD of 15-25 mg/kg and is capped at 2250 mg for patients weighing ≥120 kg. Our nomogram recommends a LD of 25-30 mg/kg of actual body weight with no dose cap. In patients with a CrCl >60 mL/min, the maintenance dosages in the Golenia nomogram are more aggressive than our nomogram. To illustrate this point, a patient weighing 60 kg with a CrCl of 65 mL/min would receive a total daily maintenance dose of 4500mg and 2000 mg with the Golenia nomogram and our nomogram respectively. Although the Golenia nomogram is more aggressive than our nomogram, there was no observed difference in rates of nephrotoxicity in their study. Dosages that maximise the likelihood of achieving therapeutic concentrations must be balanced with the risk of exceeding a toxicity threshold when developing dosing nomograms.
Pea and colleagues have reported a correlation between observed vancomycin and meropenem concentrations, both administered by continuous infusion, in critically ill patients with suspected severe infection. (8, 9) The dosing nomograms of Pea et al. were based on the correlation between CrCl and drug clearance. In comparison to our nomogram, the Pea vancomycin nomogram recommends continuous infusions (CI) for all patients, whereas our nomogram only recommends CI in patients with suspected ARC. The vancomycin maintenance nomogram dosing of Pea et al. is based on CrCl and does not consider weight. Our nomogram is also based on CrCl, however provides weight-based dosing. To illustrate the variation in maintenance dosing, a 70 kg patient with a CrCl of 50 mL/min would receive
approximately 1000 mg daily with the Pea nomogram as compared to 1000 mg twice daily with our nomogram.
Patient outcomes related to nomogram-based dosing in the critically ill are not well described in the literature. Validation of our nomogram should include a prospective, observational study in which patient outcomes would also be assessed.
There are two main limitations to our dosing nomogram. Firstly, our nomogram requires clinicians to estimate creatinine clearance (CrCl) before selecting an appropriate dose, and the nomogram does not specify the equation to use to estimate CrCl. Estimating CrCl can be achieved using a range of equations including Cockcroft and Gault, the Modified Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). (18) All equations require a steady state serum creatinine concentration, which rarely occurs in critically ill patients due to their dynamic physiological state. (19) Furthermore, these tools have not been validated in critically ill patients and have been shown to perform poorly when estimating CrCl in critically ill patients with AKI. (18, 19) The preferred method of determining CrCl in critically ill patients is to perform a timed urinary creatinine clearance (8 to 24 hours), however this technique may have poor precision in critically ill patients with AKI. (18, 19)
The second limitation is the nomogram has not been validated, and this remains a future important area of research. Dosing nomogram validation studies are currently in progress, including a Monte Carlo simulation study and a prospective observational study measuring
drug concentrations and patient outcomes achieved when therapy is guided by our dosing nomogram.
5.
Conclusion
This pragmatic, evidence-based adult dosing nomogram summarises dosing recommendations for a selection of antimicrobials frequently prescribed to treat infections in critically ill patients. The evidence supporting the use of nomogram-based dosing in the critically ill is limited. However, given the challenges of introducing TDM-based dosing, nomogram-based dosing offers an alternative approach to optimise therapy.
6.
Acknowledgements
We would like to acknowledge the ICU, ID, Pharmacy, and AMS staff at the Sunshine Coast University Hospital for their contribution to the development of this dosing nomogram.. Jason Roberts would like to recognize funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065). 7.
Supplementary materials
Supplementary material associated with this article can be found, in the online version. 8.
Competing interest declarations
None to declare for all authors. 9.
Funding
No funding sources
10.
Ethical Approval
Not required
11.
References
1. Roberts JA. Using PK/PD to optimize antibiotic dosing for critically ill patients. Current Pharmaceutical Biotechnology. 2011;12(12):2070-9. 2. Wong G, Briscoe S, McWhinney B, Ally M, Ungerer J, Lipman J, et al. Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. The Journal of antimicrobial chemotherapy. 2018;73(11):3087-94. 3. Blot S, Koulenti D, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Critical Care (London, England). 2014;18(3):R99-R. 4. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: Defining antibiotic levels in intensive care unit patients: Are current ß-lactam antibiotic doses sufficient for critically ill patients? Clinical Infectious Diseases. 2014;58(8):1072-83. 5. De Waele JJ, Carrette S, Carlier M, Stove V, Boelens J, Claeys G, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: A randomised controlled trial. Intensive Care Medicine. 2014;40(3):380-7. 6. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, et al. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36(4):332-9. 7. Nicasio AM, Eagye KJ, Nicolau DP, Shore E, Palter M, Pepe J, et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care. 2010;25(1):69-77. 8. Pea F, Furlanut M, Negri C, Pavan F, Crapis M, Cristini F, et al. Prospectively Validated Dosing Nomograms for Maximizing the Pharmacodynamics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients. Antimicrobial Agents and Chemotherapy. 2009;53(5):1863-7. 9. Pea F, Viale P, Cojutti P, Furlanut M. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gramnegative infections: a pharmacokinetics/pharmacodynamics-based approach. Antimicrob Agents Chemother. 2012;56(12):6343-8. 10. De Souza V, MacFarlane A, Murphy AW, Hanahoe B, Barber A, Cormican M. A qualitative study of factors influencing antimicrobial prescribing by non-consultant hospital doctors. The Journal of antimicrobial chemotherapy. 2006;58(4):840-3. 11. Charmillon A, Novy E, Agrinier N, Leone M, Kimmoun A, Levy B, et al. The ANTIBIOPERF study: a nationwide cross-sectional survey about practices for β-lactam administration and therapeutic drug monitoring among critically ill patients in France. Clinical Microbiology and Infection. 2016;22(7):625-31. 12. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet Infectious diseases. 2014;14(6):498-509. 13. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC, Craig WA, Billeter M, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of
Infectious Diseases Pharmacists. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009;49(3):325-7. 14. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345-51. 15. Abdul-Aziz MH, Lipman J, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. Journal of Antimicrobial Chemotherapy. 2016;71(1):196-207. 16. Vancomycin Product Information [Internet]. 2018 [cited 09/11/2018]. Available from: https://www.mimsonline.com.au/Search/FullPI.aspx?ModuleName=Product%20Info&searchKeywor d=vancomycin&PreviousPage=~/Search/QuickSearch.aspx&SearchType=&ID=9610001_2#anDosageAdministration573. 17. Golenia BS, Levine AR, Moawad IM, Yeh DD, Arpino PA. Evaluation of a vancomycin dosing nomogram based on the Modification of Diet in Renal Disease equation in intensive care unit patients. J Crit Care. 2013;28(5):710-6. 18. Bragadottir G, Redfors B, Ricksten S-E. Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations. Critical Care. 2013;17(3):R108-R. 19. Ulldemolins M, Roberts JA, Lipman J, Rello J. Antibiotic dosing in multiple organ dysfunction syndrome. Chest. 2011;139(5):1210-20.
Table 1. Beta-lactam dosing-nomogram excerpt Ceftazidime/Cefepime* Suspected ARC#
2g q8h (4h extended infusion)
First 24-48 hours (all non-ARC)
2g q8h
CrCl >50 mL/min
2g q8h
CrCl 10-50 mL/min
2g q12h
CrCl <10 mL/min
2g q24h
CRRT
1g q8h
Flucloxacillin* Suspected ARC#
2g q4h (continuous infusion)
First 24-48 hours (all non-ARC)
2g q4h
CrCl ≥10 mL/min
2g q4h
CrCl <10 mL/min
1g q4h
CRRT
2g q6h
Meropenem* Suspected ARC#
1g q8h (3h extended infusion)
First 24-48 hours (all non-ARC)
1g q8h
CrCl >30 mL/min
1g q8h
CrCl 10-30 mL/min
1g q12h
CrCl <10 mL/min
500mg q24h
CRRT
1g q8h
Piperacillin/Tazobactam* Suspected ARC#
4.5g q6h (3h extended infusion)
First 24-48 hours (all non-ARC)
4.5g q6h
CrCl >40 mL/min
4.5g q6h
CrCl 20-40 mL/min
4.5g q8h
CrCl <20 mL/min
4.5g q12h
CRRT
4.5g q8h
*
Infuse over 30 mins except for extended or continuous infusions
#
ARC should be considered in trauma, burns, febrile neutropenia, CNS infections, SrCr <62 μmol/L,
<50 years of age with no comorbidities, males, and pregnancy.
Abbreviations: ARC, Augmented renal clearance; CrCl, Creatinine Clearance; CRRT, Continuous Renal Replacement Therapy; SrCr, Serum Creatinine Concentration, q8h; every eight hours, q12h; every twelve hours, q24h; every twenty-four hours, q4h; every four hours, q6h; every six hours.
Table 2. Vancomycin dosing nomogram excerpt Vancomycin – intermittent infusion Loading dose
25 – 30 mg/kg actual body weight with no dose cap
Initial maintenance dose Suspected ARC#
Continuous infusion
CrCl >90 mL/min
15 mg/kg q8h
CrCl 50-90 mL/min
15 mg/kg q12h
CrCl 20-50 mL/min
15 mg/kg q24h
CrCl ≤20 mL/min
15 mg/kg q48h
CRRT
10 mg/kg q12h
Vancomycin – continuous infusion Loading dose
15 mg/kg actual body weight with no dose cap
Initial maintenance dose CrCl >90 mL/min #
30 mg/kg over 24 hours
ARC should be considered in trauma, burns, febrile neutropenia, CNS infections, SrCr <62μmol/L,
<50 years of age with no comorbidities, males, and pregnancy. Abbreviations: ARC, Augmented renal clearance; CrCl, Creatinine Clearance; CRRT, Continuous Renal Replacement Therapy; SrCr, Serum Creatinine Concentration, q8h; every eight hours, q12h; every twelve hours, q24h; every twenty-four hours, q48h; every forty-eight hours, q6h.
Figure 1. Dosing nomogram versus Product Information (PI) dosing – percentage (%) increase in daily dose#
Meropenem (CrCl 20 mL/min)
100%
Meropenem (CrCl 50 mL/min)
50%
Meropenem (CrCl 90 mL/min)
0%
Cefepime/Ceftazidime (CrCl 20 mL/min)
100%
Cefepime/Ceftazidime (CrCl 50 mL/min)
0%
Cefepime/Ceftazidime (CrCl 90 mL/min)
0%
Flucloxacillin (CrCl 20 mL/min)
50%
Flucloxacillin (CrCl 50 mL/min)
50%
Flucloxacillin (CrCl 90 mL/min)
50%
Piperacillin/Tazobactam (CrCL 20 mL/min)
0%
Piperacillin/Tazobactam (CrCl 50 mL/min)
33%
Piperacillin/Tazobactam (CrCl 90 mL/min)
33%
Vancomycin MD (CrCl 20 mL/min)
250%
Vancomycin MD (CrCl 50 mL/min)
100%
Vancomycin MD (CrCL 90 mL/min)
5%
Vancomycin LD (CrCl 90 mL/min)
100% 0%
50%
100%
150%
200%
250%
300%
Percentage increase in daily dose from PI #
Dose calculations based on a 70 kg individual
Abbreviations: CrCl, Creatinine Clearance; MD, Maintenance Dose; LD, Loading Dose.
Journal Pre-proof
Antimicrobial dosing in Critical Care: A pragmatic adult dosing nomogram Paul Williams , Gareth Beall , Menino Osbert Cotta , Jason A. Roberts PII: DOI: Reference:
S0924-8579(19)30298-5 https://doi.org/10.1016/j.ijantimicag.2019.10.018 ANTAGE 5837
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
11 February 2019 27 October 2019
Please cite this article as: Paul Williams , Gareth Beall , Menino Osbert Cotta , Jason A. Roberts , Antimicrobial dosing in Critical Care: A pragmatic adult dosing nomogram, International Journal of Antimicrobial Agents (2019), doi: https://doi.org/10.1016/j.ijantimicag.2019.10.018
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Antimicrobial dosing in Critical Care: a pragmatic adult dosing nomogram Paul Williamsa,b; Gareth Beallb; Menino Osbert Cottaa,c; Jason A. Robertsa,c,d,e a. University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, Brisbane, Queensland, Australia b. Pharmacy Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia c. School of Pharmacy, Centre for Translational Anti-infective Pharmacodynamics, The University of Queensland, Brisbane, Queensland, Australia d. Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia e. Pharmacy Department, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
Short Title: Critical Care Antimicrobial Dosing Nomogram Keywords: nomogram, guideline, beta-lactam, vancomycin, critically ill Corresponding author: Paul Williams; Pharmacy Department, Sunshine Coast University Hospital, 6 Doherty St, Birtinya, Queensland 4575, Australia; Email: [email protected]; Tel +61 7 5202 2678; Fax: +61 7 5202 0844 Word Count: Abstract = 97; Main Body = 2599
Abstract Standard dosing of antimicrobials derived from product information (PI) is considered to have limited application in critically ill patients given the pharmacokinetic (PK) and pharmacodynamic (PD) changes often seen in these patients relative to other groups in the hospital. Dosing nomograms that account for the altered needs of critically ill patients are needed to minimise the likelihood of antimicrobial underdosing (risks treatment failure) and overdosing (risks toxicity) in these patients. The aim of this paper is to present a pragmatic, evidence-based, adultdosing nomogram for a selection of antimicrobials frequently prescribed to treat infections in critically ill patients.
1.
Introduction
Optimising dosing of antimicrobials in critically ill patients requires an understanding of both the pharmacokinetic (PK) changes that can occur in these patients, and the pharmacodynamics (PD) of the antimicrobial agent prescribed. Standard dosing of drugs derived from the Product Information (PI) have limited application in critically ill patients given the PK/PD changes often seen in these patients relative to other groups in the hospital. (1) There is a growing body of literature which demonstrates from observational PK studies as well as therapeutic drug monitoring (TDM) reports, that contemporary dosing approaches risks suboptimal dosing in a large fraction of critically ill patients. (2-5)
TDM provides a robust method to individualise and optimise antimicrobial dosing. Contemporary research is applying more emphasis on utilising TDM, especially in the face of decreasing antimicrobial susceptibility and in cohorts of patients who exhibit large fluctuations in PK such as critically ill patients. (5, 6) Despite the promise of TDM-based dosing, studies in critically ill patients have highlighted that many patients still do not achieve the desired target concentration at steady state. (5, 6) It remains to be clarified whether a nomogrambased dosing strategy would impact the frequency of achieving target concentrations. Nomogram-based dosing is certainly highly feasible, something which is not the case with TDM which requires much infrastructure.
The evidence supporting the use of nomogram-based dosing of antimicrobials in the critically ill is limited. (7-9) Previous studies do not provide definitive outcome data, and most nomogram-based studies are presented as part of a ‘bundle of care’ which may confound the interpretation of their value. However, a lack of evidence-based policies and user-friendly
guidelines have been identified as factors that influence a clinician’s antibiotic prescribing behaviour. (10) Additionally, results from survey studies highlighted that clinicians frequently do not have appropriate access to resources to guide antimicrobial prescribing and that TDM is either not readily available or results are not timely. (11)
In collaboration with key stakeholders, clinicians from a 12-bed closed mixed adult Intensive Care Unit (ICU) in Australia developed an adult antimicrobial dosing nomogram as a solution to overcome the aforementioned challenges. Herewith, we present the process for dosing nomogram development and the final product.
2.
Methods
2.1 Dosing nomogram development The development of the dosing nomogram commenced in 2015 and sought to provide clinicians with a dosing nomogram based on renal function, continuous renal replacement therapy (CRRT), and suspected augmented renal clearance (ARC; defined as a creatinine clearance >130 mL/min). To align with the CRRT mode and default setting used at our ICU, the dosages were selected for continuous veno-venous haemofiltration (CVVH) and assumed an ultrafiltration rate of 2000 mL/hr. The antimicrobials for inclusion in the dosing nomogram were flucloxacillin, cefepime, ceftazidime, meropenem, piperacillin/tazobactam, and vancomycin. These antimicrobials were included due to being commonly prescribed in the ICU and in which dose modification was frequently required in critically ill patients.
In 2015, a literature review was conducted to establish the dosing nomogram, and data included was identified by searches of Medline, Embase, and references from relevant original articles. Secondary and tertiary literature was also reviewed, including: The electronic Therapeutic Guidelines complete, and The Sandford Guide to Antimicrobial therapy. Search terms for each antimicrobial included: pharmacokinetics, pharmacodynamics, penetration, augmented renal clearance, obesity, critically ill, intensive care, continuous infusion, extended infusion, prolonged infusion, Monte Carlo, renal impairment, hepatic impairment, acute kidney injury (AKI), mortality, outcome, minimum inhibitory concentration, Bayesian, and dosing software. A follow-up literature review was conducted in 2017.
Literature review and extraction was performed by PW and GB. Relevant data in the domains to be included in the dosing nomogram were populated after interpreting all relevant data obtained for methodological rigour (sample size, population PK analysis with dosing simulations performed) and consistency of results between eligible studies. The dosages in the nomogram were selected to maximise the likelihood of achieving pre-defined target concentrations as supported by the primary literature. For beta-lactam antimicrobials the target concentration was defined as 100% of time which the ‘free’ antimicrobial remains above the MIC during the dosing interval (100% fT>MIC). (2, 12) The vancomycin target concentration was defined as a steady state trough concentration of 15-20 mg/L. (13)
The draft dosing nomogram was presented to key stakeholders [ICU consultants, ID consultants, and the Antimicrobial Stewardship (AMS) team]. Clinicians were provided with electronic access to all original articles and were encouraged to review key papers identified
by the ICU pharmacists. An expert external to the host hospital (JR) also reviewed the content of the dosing nomogram. All feedback was collated, and the first iteration of the dosing nomogram was endorsed by the medicines committee in 2016.
2.1.1 Papers omitted during dosing nomogram development Papers which provided evidence to support dosages for the dosing nomogram were excluded based on the following principles: non-systematic review articles, case-studies, sample size < 10, non-IV administration of the antibiotics studied, or where the dosages were clinician’s choice and achieved target concentrations could not be correlated to the dosage. When comparing Monte Carlo simulation studies, papers were favoured where the population PK data was derived from critically ill patients, and where the model was validated using a similar cohort of patients not included in creating the population PK model. Papers were also omitted where the beta-lactam target concentration was < 100% fT>MIC or the vancomycin target trough concentration was < 15 mg/L, or where no pathogen was identified and the highest MIC for susceptible bacteria to the antibiotic was not used. Results from vancomycin nomogram-based studies were excluded when dosages were not weight based or included a dose cap in obesity. In situations where the supporting evidence was not clear, expert opinion determined the dosing nomogram recommendation.
2.2 Dosing nomogram versus Product Information (PI) dosing A comparison of total daily dosing between the dosing nomogram and PI dosing was performed. Where specified in the PI, dosages for ‘very severe or life-threatening infections’ were selected for the comparison. In instances where weight-based dosing was recommended, a 70kg individual was assumed for comparative purposes. Dose variations
between the dosing nomogram and PI were presented as a percentage variation from PI for equivalent levels of renal function. 3.
Results
A total of 227 relevant articles were obtained and considered for the development of the adult dosing nomogram with 36 articles used in the final document. Table 1 and Table 2 present the beta-lactam and vancomycin dosing nomograms showing the relationship between recommended dosage and renal function. The nomogram included doses for the breadth of renal function, including ARC, AKI, and for CRRT.
A flowchart of extraction of included papers and papers included in the dosing nomogram development can be found in the supplementary material in the online version of this article.
The variation between nomogram dosing and PI dosing are shown in Figure 1.
4.
Discussion
This pragmatic adult dosing nomogram offers clinicians up-to-date dosing recommendations for a selection of antimicrobial agents frequently prescribed to treat infections in critically ill patients. The dosing regimens included in the nomogram were developed to maximise the likelihood of achieving pre-defined concentrations associated with improved clinical outcomes. (4, 13) To the best of our knowledge, there is no comparable dosing nomogram covering this range of antimicrobials presented in the literature.
4.1 Why a different dosing approach is needed? Contemporary dosing approaches risks suboptimal antimicrobial dosing in a large fraction of critically ill patients. (2-4) There is debate over which PD target exposure is the most suitable in clinical practice, with a wide variation in target concentrations described for beta-lactams in the literature. (4, 6, 14) Improved clinical outcomes have been observed when higher target concentrations are achieved (100% fT>MIC). (4, 14)
Recently, Wong et al. reported in 330 critically ill patients that only 66.9% and 36.6% of beta-lactam dosing achieved a target trough concentration of 100% fT>MIC and 100% fT>4xMIC respectively, following at least 4 prior antimicrobial doses. (2) Empiric dosing regimens were determined by the treating physician in consultation with the clinical pharmacist in this study. These findings reflect those of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study in 2014 in which beta-lactam dosing was determined by the clinician. (4) A total of 361 patients were evaluated and 16% failed to reach concentrations of 50% fT>MIC; a positive clinical outcome was 32% less likely in these patients (OR, 0.68 [95% CI,.52–.91]; P = .009). (4) Analysis of piperacillin/tazobactam and meropenem data demonstrated that a target trough concentration of 100% fT>MIC and 100% fT>4xMIC was achieved in 63.2% (115/182) and 27.5% (50/182) of patients respectively. (15)
In 2014, Blot et al. examined whether contemporary vancomycin dosing (clinician’s choice) in 42 patients from 26 ICUs in 8 countries resulted in trough concentrations ≥15 mg/L or AUC0– 24/MIC
of 400 mg.h/L (assuming an MIC of 1 mg/L). The target trough concentration was
achieved in only 57% of patients and only 71% of patients achieved the target AUC0–24/MIC. (3)
Our dosing nomogram provides clinicians with an alternative to dosing derived from the PI. The dosing regimens in the nomogram were selected to maximise the likelihood of achieving either a beta-lactam concentration of 100% fT>MIC or a vancomycin steady state trough concentration of 15-20 mg/L. It remains to be determined how consistently the dosing nomogram achieves the pre-defined concentrations in clinical practice.
4.2 Variation of dosing between dosing nomogram and PI dosing. Figure 1. presents the variation between daily dosages from the dosing nomogram compared with those from the PI. The largest variation was observed with vancomycin. The nomogram loading dose (LD) for vancomycin recommended a 100% increase in dose compared to the PI, and a 250% increase in maintenance dose in patients with a CrCl of 20 mL/min. The nomogram vancomycin maintenance dosages are presented in mg/kg as compared to the PI which recommends daily vancomycin maintenance doses of 15 times the CrCl in mg (e.g. a patient with a CrCl of 50 mL/min would receive 750 mg daily) The vancomycin PI does not consider actual body weight. (16)
There was less variation between the dosing nomogram and PI dosages for beta-lactam antibiotics. Nomogram dosing was 0-100% higher than PI dosing and this variation was more pronounced in dosages for patients with a reduced CrCl. Furthermore, the dosing nomogram recommends full dosing for the first 24-48 hours to maximise the likelihood of achieving 100% fT>MIC at steady state.
4.3 Comparison of nomogram dosing regimens in the literature Our dosing nomogram is unique in terms of the method of development when compared to other dosing nomograms described in the literature. Dosing nomograms in critically ill patients commonly determine dosing regimens using PK/PD modelling and simulation approaches; which is a robust and appropriate approach. (7-9, 17) Our nomogram however, was compiled from the primary literature and dosing regimens were selected by author consensus based on the available evidence. Variability in dosing between our nomogram and others in the literature is apparent.
Nicasio et al. conducted an interrupted time-series study in 2010 to observe the impact of a dosing nomogram to empirically treat patients with ventilator-associated pneumonia (VAP). (7) Local MIC distributions and Monte Carlo simulations were used to recommend empiric antimicrobial agents and dosing regimens. Combination therapy of a beta-lactam with tobramycin and vancomycin was included in the regimen. Infection-related mortality was 21.6% vs 8.5% (P = 0.029) in the before and after groups, respectively, although the study was not powered for this endpoint. (7) The meropenem dosages recommended in this nomogram vary to that of our nomogram. In patients with a CrCl >50 mL/min, the Nicasio nomogram recommends meropenem 2 g three times daily infused over 3 hours which is double the daily dose recommended in our nomogram. However, in patients with a CrCl of 30-50 mL/min the Nicasio nomogram recommends 0.5 g every 6 hours (2 g daily) as compared to 1 g three times daily (3 g daily) in our nomogram. In contrast, the cefepime dose recommendations are similar between the Nicasio nomogram and our nomogram.
In 2013, Golenia et al. developed an ICU-specific vancomycin dosing nomogram, providing clinicians with loading and maintenance doses based on actual body weight and estimated renal function. (17) An initial vancomycin trough concentration of 15 mg/L or higher increased with nomogram dosing compared to the pre-implementation ‘clinicians choice’ dosing (72% vs 39%, P = 0.0004). (17) There are some differences in dosing between the Golenia nomogram and our nomogram. The Golenia nomogram recommends a LD of 15-25 mg/kg and is capped at 2250 mg for patients weighing ≥120 kg. Our nomogram recommends a LD of 25-30 mg/kg of actual body weight with no dose cap. In patients with a CrCl >60 mL/min, the maintenance dosages in the Golenia nomogram are more aggressive than our nomogram. To illustrate this point, a patient weighing 60 kg with a CrCl of 65 mL/min would receive a total daily maintenance dose of 4500mg and 2000 mg with the Golenia nomogram and our nomogram respectively. Although the Golenia nomogram is more aggressive than our nomogram, there was no observed difference in rates of nephrotoxicity in their study. Dosages that maximise the likelihood of achieving therapeutic concentrations must be balanced with the risk of exceeding a toxicity threshold when developing dosing nomograms.
Pea and colleagues have reported a correlation between observed vancomycin and meropenem concentrations, both administered by continuous infusion, in critically ill patients with suspected severe infection. (8, 9) The dosing nomograms of Pea et al. were based on the correlation between CrCl and drug clearance. In comparison to our nomogram, the Pea vancomycin nomogram recommends continuous infusions (CI) for all patients, whereas our nomogram only recommends CI in patients with suspected ARC. The vancomycin maintenance nomogram dosing of Pea et al. is based on CrCl and does not consider weight. Our nomogram is also based on CrCl, however provides weight-based dosing. To illustrate the variation in maintenance dosing, a 70 kg patient with a CrCl of 50 mL/min would receive
approximately 1000 mg daily with the Pea nomogram as compared to 1000 mg twice daily with our nomogram.
Patient outcomes related to nomogram-based dosing in the critically ill are not well described in the literature. Validation of our nomogram should include a prospective, observational study in which patient outcomes would also be assessed.
There are two main limitations to our dosing nomogram. Firstly, our nomogram requires clinicians to estimate creatinine clearance (CrCl) before selecting an appropriate dose, and the nomogram does not specify the equation to use to estimate CrCl. Estimating CrCl can be achieved using a range of equations including Cockcroft and Gault, the Modified Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). (18) All equations require a steady state serum creatinine concentration, which rarely occurs in critically ill patients due to their dynamic physiological state. (19) Furthermore, these tools have not been validated in critically ill patients and have been shown to perform poorly when estimating CrCl in critically ill patients with AKI. (18, 19) The preferred method of determining CrCl in critically ill patients is to perform a timed urinary creatinine clearance (8 to 24 hours), however this technique may have poor precision in critically ill patients with AKI. (18, 19)
The second limitation is the nomogram has not been validated, and this remains a future important area of research. Dosing nomogram validation studies are currently in progress, including a Monte Carlo simulation study and a prospective observational study measuring
drug concentrations and patient outcomes achieved when therapy is guided by our dosing nomogram.
5.
Conclusion
This pragmatic, evidence-based adult dosing nomogram summarises dosing recommendations for a selection of antimicrobials frequently prescribed to treat infections in critically ill patients. The evidence supporting the use of nomogram-based dosing in the critically ill is limited. However, given the challenges of introducing TDM-based dosing, nomogram-based dosing offers an alternative approach to optimise therapy.
6.
Acknowledgements
We would like to acknowledge the ICU, ID, Pharmacy, and AMS staff at the Sunshine Coast University Hospital for their contribution to the development of this dosing nomogram.. Jason Roberts would like to recognize funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065). 7.
Supplementary materials
Supplementary material associated with this article can be found, in the online version. 8.
Competing interest declarations
None to declare for all authors. 9.
Funding
No funding sources
10.
Ethical Approval
Not required
11.
References
1. Roberts JA. Using PK/PD to optimize antibiotic dosing for critically ill patients. Current Pharmaceutical Biotechnology. 2011;12(12):2070-9. 2. Wong G, Briscoe S, McWhinney B, Ally M, Ungerer J, Lipman J, et al. Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. The Journal of antimicrobial chemotherapy. 2018;73(11):3087-94. 3. Blot S, Koulenti D, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Critical Care (London, England). 2014;18(3):R99-R. 4. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: Defining antibiotic levels in intensive care unit patients: Are current ß-lactam antibiotic doses sufficient for critically ill patients? Clinical Infectious Diseases. 2014;58(8):1072-83. 5. De Waele JJ, Carrette S, Carlier M, Stove V, Boelens J, Claeys G, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: A randomised controlled trial. Intensive Care Medicine. 2014;40(3):380-7. 6. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, et al. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36(4):332-9. 7. Nicasio AM, Eagye KJ, Nicolau DP, Shore E, Palter M, Pepe J, et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care. 2010;25(1):69-77. 8. Pea F, Furlanut M, Negri C, Pavan F, Crapis M, Cristini F, et al. Prospectively Validated Dosing Nomograms for Maximizing the Pharmacodynamics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients. Antimicrobial Agents and Chemotherapy. 2009;53(5):1863-7. 9. Pea F, Viale P, Cojutti P, Furlanut M. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gramnegative infections: a pharmacokinetics/pharmacodynamics-based approach. Antimicrob Agents Chemother. 2012;56(12):6343-8. 10. De Souza V, MacFarlane A, Murphy AW, Hanahoe B, Barber A, Cormican M. A qualitative study of factors influencing antimicrobial prescribing by non-consultant hospital doctors. The Journal of antimicrobial chemotherapy. 2006;58(4):840-3. 11. Charmillon A, Novy E, Agrinier N, Leone M, Kimmoun A, Levy B, et al. The ANTIBIOPERF study: a nationwide cross-sectional survey about practices for β-lactam administration and therapeutic drug monitoring among critically ill patients in France. Clinical Microbiology and Infection. 2016;22(7):625-31. 12. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet Infectious diseases. 2014;14(6):498-509. 13. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC, Craig WA, Billeter M, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of
Infectious Diseases Pharmacists. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009;49(3):325-7. 14. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345-51. 15. Abdul-Aziz MH, Lipman J, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. Journal of Antimicrobial Chemotherapy. 2016;71(1):196-207. 16. Vancomycin Product Information [Internet]. 2018 [cited 09/11/2018]. Available from: https://www.mimsonline.com.au/Search/FullPI.aspx?ModuleName=Product%20Info&searchKeywor d=vancomycin&PreviousPage=~/Search/QuickSearch.aspx&SearchType=&ID=9610001_2#anDosageAdministration573. 17. Golenia BS, Levine AR, Moawad IM, Yeh DD, Arpino PA. Evaluation of a vancomycin dosing nomogram based on the Modification of Diet in Renal Disease equation in intensive care unit patients. J Crit Care. 2013;28(5):710-6. 18. Bragadottir G, Redfors B, Ricksten S-E. Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations. Critical Care. 2013;17(3):R108-R. 19. Ulldemolins M, Roberts JA, Lipman J, Rello J. Antibiotic dosing in multiple organ dysfunction syndrome. Chest. 2011;139(5):1210-20.
Table 1. Beta-lactam dosing-nomogram excerpt Ceftazidime/Cefepime* Suspected ARC#
2g q8h (4h extended infusion)
First 24-48 hours (all non-ARC)
2g q8h
CrCl >50 mL/min
2g q8h
CrCl 10-50 mL/min
2g q12h
CrCl <10 mL/min
2g q24h
CRRT
1g q8h
Flucloxacillin* Suspected ARC#
2g q4h (continuous infusion)
First 24-48 hours (all non-ARC)
2g q4h
CrCl ≥10 mL/min
2g q4h
CrCl <10 mL/min
1g q4h
CRRT
2g q6h
Meropenem* Suspected ARC#
1g q8h (3h extended infusion)
First 24-48 hours (all non-ARC)
1g q8h
CrCl >30 mL/min
1g q8h
CrCl 10-30 mL/min
1g q12h
CrCl <10 mL/min
500mg q24h
CRRT
1g q8h
Piperacillin/Tazobactam* Suspected ARC#
4.5g q6h (3h extended infusion)
First 24-48 hours (all non-ARC)
4.5g q6h
CrCl >40 mL/min
4.5g q6h
CrCl 20-40 mL/min
4.5g q8h
CrCl <20 mL/min
4.5g q12h
CRRT
4.5g q8h
*
Infuse over 30 mins except for extended or continuous infusions
#
ARC should be considered in trauma, burns, febrile neutropenia, CNS infections, SrCr <62 μmol/L,
<50 years of age with no comorbidities, males, and pregnancy.
Abbreviations: ARC, Augmented renal clearance; CrCl, Creatinine Clearance; CRRT, Continuous Renal Replacement Therapy; SrCr, Serum Creatinine Concentration, q8h; every eight hours, q12h; every twelve hours, q24h; every twenty-four hours, q4h; every four hours, q6h; every six hours.
Table 2. Vancomycin dosing nomogram excerpt Vancomycin – intermittent infusion Loading dose
25 – 30 mg/kg actual body weight with no dose cap
Initial maintenance dose Suspected ARC#
Continuous infusion
CrCl >90 mL/min
15 mg/kg q8h
CrCl 50-90 mL/min
15 mg/kg q12h
CrCl 20-50 mL/min
15 mg/kg q24h
CrCl ≤20 mL/min
15 mg/kg q48h
CRRT
10 mg/kg q12h
Vancomycin – continuous infusion Loading dose
15 mg/kg actual body weight with no dose cap
Initial maintenance dose CrCl >90 mL/min #
30 mg/kg over 24 hours
ARC should be considered in trauma, burns, febrile neutropenia, CNS infections, SrCr <62μmol/L,
<50 years of age with no comorbidities, males, and pregnancy. Abbreviations: ARC, Augmented renal clearance; CrCl, Creatinine Clearance; CRRT, Continuous Renal Replacement Therapy; SrCr, Serum Creatinine Concentration, q8h; every eight hours, q12h; every twelve hours, q24h; every twenty-four hours, q48h; every forty-eight hours, q6h.
Figure 1. Dosing nomogram versus Product Information (PI) dosing – percentage (%) increase in daily dose#
Meropenem (CrCl 20 mL/min)
100%
Meropenem (CrCl 50 mL/min)
50%
Meropenem (CrCl 90 mL/min)
0%
Cefepime/Ceftazidime (CrCl 20 mL/min)
100%
Cefepime/Ceftazidime (CrCl 50 mL/min)
0%
Cefepime/Ceftazidime (CrCl 90 mL/min)
0%
Flucloxacillin (CrCl 20 mL/min)
50%
Flucloxacillin (CrCl 50 mL/min)
50%
Flucloxacillin (CrCl 90 mL/min)
50%
Piperacillin/Tazobactam (CrCL 20 mL/min)
0%
Piperacillin/Tazobactam (CrCl 50 mL/min)
33%
Piperacillin/Tazobactam (CrCl 90 mL/min)
33%
Vancomycin MD (CrCl 20 mL/min)
250%
Vancomycin MD (CrCl 50 mL/min)
100%
Vancomycin MD (CrCL 90 mL/min)
5%
Vancomycin LD (CrCl 90 mL/min)
100% 0%
50%
100%
150%
200%
250%
300%
Percentage increase in daily dose from PI #
Dose calculations based on a 70 kg individual
Abbreviations: CrCl, Creatinine Clearance; MD, Maintenance Dose; LD, Loading Dose.