In this article two infectious diseases pharmacists interview a pharmacist with high-level expertise in the area of antibiotic dose optimization in critical care.
Interviewee: Professor Jason Roberts
[Last Updated: 21 January 2020]
Selecting a dose for an antimicrobial drug is complicated, because it requires consideration for pharmacokinetics (i.e., how the body effects drugs), pharmacodynamics (i.e., how drugs effect the body), and microbial factors (e.g., minimum inhibitory concentration). Change one aspect in a patient case and all three items must be reconsidered.
When it comes to dosing antimicrobials in special populations, there is inevitably less published data to guide decision making. This of course translates into more difficulty identifying treatment plans most likely to lead to a successful outcome. In critical care populations at high risk for mortality there is considerable interest in learning how to make smarter antibiotic dosing decisions.
One of the leaders in the area of antibiotic dosing in critical care is Professor Jason Roberts who serves as the Director of the Centre of Research Excellence (REDUCE). REDUCE aims to develop optimised antibiotic dosing regimens to improve patient outcomes and minimise the emergence of antibiotic-resistant superbugs. Dr. Roberts has published 24 book chapters and over 400 peer-reviewed articles. He is on Twitter @JasonRoberts_pk where we were able to connect with him as one of his recent articles was being discussed. We inquired with Dr. Roberts about interest in letting us pick his brain about antibiotic dose optimization in critical care and he graciously accepted our interview request.
The following is the result of our correspondence. We hope you enjoy reading this as much as we enjoyed constructing it!
1. What prompted your interest in antimicrobial dosing in critical care?
When I finished pharmacy and first went to an intensive care unit (ICU), I noted how strong the mechanistic knowledge was for all the physicians, but how they all came to different conclusions when it came to antibiotic dosing. At that time I felt I would like to develop my knowledge of pharmacokinetics and pharmacodynamics (PK/PD) and antibiotics because I could see there was an area of need, and at that time I did not have the knowledge or skills to fill that gap and so I undertook a PhD on that topic. More specifically my focus was on a PK-characterisation of continuous versus intermittent infusions of beta-lactams in critically ill patients with sepsis. Anytime a person sees uncertainty, I think natural curiosity aims to address it and that was my main driver for getting into this area of work that I now find fascinating, rewarding, and a pleasure to contribute to.
2. Can you briefly summarize the goal and take home points of one of your recent publications?
Hmmm… I am going to choose a ‘lower level’ study for this one because I think the scenario of being confronted with a case study where there is no prior data to inform treatment (in this case dosing), is surprisingly common.
This was a case study we wrote up about a patient who required IV amoxicillin-clavulanate for a aspiration pneumonia, but in whom he had normal renal function, but was also being treated with continuous renal replacement therapy (CRRT) to help remove toxic levels of carbamazepine associated with an intentional overdose by the patient. So the question was, what dose of antibiotic should be used (other drugs of course as well) and with no prior data to inform the additional effect of CRRT in combination with apparent ‘normal renal function.’ We obtained patient and ethics committee approval to collect some blood samples and confirm that a higher dose should be used in this scenario. This demonstrated the tremendous value of having beta-lactam therapeutic drug monitoring (TDM) available to solve challenges like this during clinical practice!
- Lonsdale D, Lipman J, Livermore A, Ungerer JP, McWhinney BC, Roberts JA. Amoxicillin-clavulanate dosing in the ICU: the additive effect of renal replacement therapy in a patient with normal kidney function. Chemotherapy 2019; Epub Ahead of Print]
3. If you had to pick one drug for developing a dosing algorithm, which do you expect could provide the greatest utility to clinicians?
Piperacillin. I think it is surprisingly difficult to dose with high inter-patient PK variability that is quite difficult to explain. So whilst I think a nomogram for this would be great, I am not sure how easy it would be to develop one.
My observations of TDM levels of piperacillin thus far is such that two patients can have apparently the same age, weight, creat and GFR, but when given the same dose can have trough concentrations that are 3-5 fold different. This variability leads me to have limited enthusiasm for development of such a nomogram… but continue to watch this space though, we are trying!
4. In assessing the literature, what have you found to be “low hanging fruit” for antimicrobial dosing in critical care?
Case studies of interesting problems are very much low hanging fruit from my perspective and they address challenges that are commonly confronted. Additional to this, I think that there are many groups around the world wanting to undertake PK studies and each have their own patient case-mix, drug-treatment challenges that need to be addressed, and so linking with those clinical groups and supporting their most interesting challenges is also important!
Some recent publications on this topic that readers may be interested in include:
- Fox E, et al. Pharmacokinetics of flucloxacillin during prolonged intermittent renal replacement therapy in a 76-year-old man. Journal of Chemotherapy. 2019; 31 (7-8): 419-423.
- Rawlins M, et al. Pharmacokinetics of Ceftolozane-Tazobactam during Prolonged Intermittent Renal Replacement Therapy. Chemotherapy. 2018; 63(4).
- Cheng V, et al. Pharmacokinetics of Benzylpenicillin (Penicillin G) during Prolonged Intermittent Renal Replacement Therapy. Chemotherapy. 2019; 64(1): 17-21.
5. Under what circumstances do you recommend vancomycin dosing based upon AUC:MIC in a critically ill patient.
Great question! In Brisbane, Australia, we have dramatically decreased our use of vancomycin associated with a major lower incidence of methicillin-resistant Staphylococcus aureus infections over the last 15 years and so it is quite rare we end up using vancomycin for a treatment course. However, ventilator associated pneumonia or sepsis, particularly in the context of shock, would be classical scenarios where the level of sickness severity would drive me to use AUC-based monitoring
6. Some people have argued to err on the side of larger doses when it comes to beta-lactams due to their relatively favorable safety profile. Do you agree with this notion?
Generally speaking yes, but interestingly we have been advocating for this for a while now and I suspect that there is a general change in prescribing globally because of the different work in this area, and corresponding to this, over the last 5 years more papers on beta-lactam toxicity have emerged, particularly for cefepime, but also others.
I think our current approach is generally too blunt and we do need to be more personalised in our approach, a classical area for clinical pharmacists to contribute of course. In sepsis/ obesity and other scenarios of PK uncertainty, my approach has always been to use higher than standard doses for the first 24 to 48 hours and then align dosing more with predicted organ function/ drug clearance. We are fortunate to have beta-lactam TDM at my institution (for 10 years now!) and so this can always guide choices in challenging patients. In terms of doses that we choose, it would be very rare to use a dose exceeding a licensed dose for a drug, but with TDM, it is not uncommon to exceed this and as we collect data as we practice, we have been able to establish an evidence base for safety for our approach.
7. The BLING III study is ongoing to investigate continuous versus intermittent beta-lactam infusions strategies for sepsis. What do you anticipate we are likely to learn from this trial?
Tough question again! I think a lot of this depends on the sickness severity of the patients and susceptibility of the pathogens causing infections. If both are high, then I think an advantage in favour of continuous infusion is highly likely. But, we will have to wait until 2022 or 2023 to find out!
8. Many pharmacy departments have dosing algorithms for antimicrobials and renal function. How can lessons you have learned from critical care be applied enhance these practice tools?
I think there is a lot of duplication of activity in this regard across hospitals/ units and if people more commonly published their dosing guidelines, it would be helpful for all of us. We recently published one developed by a member of our team (Paul Williams who is a PhD student, but more importantly a senior clinical pharmacist and critical care pharmacist) and we agreed it was important to publish/ share so others could benefit from the time that he, and his colleague Gareth Beale, had put into the guideline. The citation is as follows:
- Williams P, et al. Antimicrobial dosing in Critical Care: a pragmatic adult dosing nomogram. International Journal of Antimicrobial Agents. 2019. ePub Ahead of Press.
9. What resources do you recommend to people who want to learn more about antimicrobial dosing in critical care?
I really like Antimicrobial Agents and Chemotherapy (AAC), Journal of Antimicrobial Chemotherapy (JAC), and International Journal of Antimicrobial Agents (IJAA), as they tend to get many of the PK and PK/PD articles I am most interested in.
In terms of papers I think have been most impactful recently, I would select these ones which I think have not been widely seen because are not in traditional antimicrobial journals:
- Hagel S, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam to improve outcome in patients with sepsis (TARGET): a prospective, multi-centre, randomised controlled trial. Trials. 2019; 6;20(1): 330.
- Bouglé A, eta al. PHARMECMO: Therapeutic drug monitoring and adequacy of current dosing regimens of antibioticsin patients on Extracorporeal Life Support. Anaesth Crit Care Pain Med. 2019; 38(5): 493-497.
- Timsit JF, et al. Rationalizing antimicrobial therapy in the ICU: a narrative review. Intensive Care Med. 2019; 45(2): 172-189.
- Roggeveen LF, et al. Right Dose Right Now: bedside data-driven personalized antibiotic dosing in severe sepsis and septic shock – rationale and design of a multicenter randomized controlled superiority trial. Trials. 2019; 18;20(1): 745.
We would like to express our utmost gratitude to Professor Roberts for entertaining our questions and taking the time to complete this interview. He has certainly provided us with a lot to think about as well as a nice list of reading to review! We would also like to thank him for his work in this space and helping to lead the charge on such an important topic.
ABOUT THE INTERVIEWEE
Professor Jason Roberts is a Clinical Pharmacist at Royal Brisbane and Women’s Hospital and National Health and Medical Research Council Practitioner Fellow at The University of Queensland. He is Director of the Centre of Research Excellence REDUCE which aims to develop optimised antibiotic dosing regimens to improve patient outcomes and minimise the emergence of antibiotic-resistant superbugs.
TPG and and BG note that the views expressed in this interview represent that of the individuals only and do not necessarily reflect the position or policy of their previous, current, or potential future employers or other organizations in which they serve. JR reports nothing to disclose.
RECOMMENDED TO YOU