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Therapeutic Drug Monitoring and Clinical Toxicology
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Therapeutic drug monitoring of echinocandins. Has the time come?

Debbie Marriott

This month we are publishing a recent piece from our newsletter 'Compass'. The piece is a contribution from Debbie Marriott, one of our Directors of Education and chair of the Anti-infective Committee. In the piece Debbie considers therapeutic drug monitoring of echinocandins and presents three clinical cases to highlight the main take-aways from a recently published review on the topic. Congratulations to the committee for an excellent review, and a big thanks for Debbie for the piece, which helps us consider the clinical application of the findings.

 

Deborah JE Marriott

Senior Staff Specialist, Infectious Diseases and Clinical Microbiology

St. Vincent's Hospital

Sydney, Australia

 

10 am. Time for the daily antimicrobial stewardship and microbiology round in the Intensive Care Unit. The patients are the usual complex mix of medical and surgical problems, heart and lung transplantation and trauma, with management often complicated by extra-corporeal membrane oxygenation (ECMO) and renal replacement therapy (RRT). The patient in bed 6 is a 34-year-old male weighing 130 kg who suffered major trauma in an altercation with a garbage disposal truck and developed Candida glabrata fungaemia. In bed 8 is an 84-year-old frail 60 kg lady with duodenal perforation and Candida glabrata peritonitis. In the cardiothoracic Intensive Care Unit, a lung transplant recipient undergoing ECMO has a Candida albicans deep sternal wound infection and fungaemia. Product information for anidulafungin and micafungin suggest that all patients should receive a similar dose of echinocandin whilst for caspofungin a dose reduction for moderate to severe hepatic disease is suggested. Is it time to challenge these fixed dosing strategies? Should therapeutic drug monitoring (TDM) be considered?

The Anti-Infectives Committee of the IATDMCT recently developed a position statement on the potential role for TDM of echinocandin anti-fungal agents and the manuscript 'Therapeutic Drug Monitoring of the Echinocandin Antifungal Agents: is there a role in clinical practice ?'1 was recently published in the journal Therapeutic Drug Monitoring. The discussion below provides a sneak preview of the key points of the review.

The echinocandins are generally accepted to be safe drugs with minimal toxicity due to the lack of a human equivalent to the β-1,3- glucan fungal target. Pre-clinical studies, primarily undertaken in murine models, suggest that concentration dependent inhibition of fungal growth is the prime efficacy target with Cmax/MIC or AUC0-24/MIC the proposed pharmacokinetic/pharmacodynamic (PK/PD) parameters for optimal response. However, the PK/PD markers identified from pre- clinical studies are yet to be defined and validated in clinical studies and it is possible that specific patient groups are at risk of under- or over-exposure. Drug exposure-toxicity relationships have not yet been established so it is unlikely that TDM would be of benefit to prevent echinocandin toxicity.

Echinocandins in the Critical Care setting

Several recent publications suggest that the Cmax and AUC0-24 of echinocandins may be significantly reduced in critically ill patients. The DALI study2 headed by Jason Robert's group in Brisbane obtained point- prevalence data on 15 patients receiving caspofungin or anidulafungin and demonstrated that the AUC0-24 and Cmax were approximately 50% lower than general patients or healthy volunteers. Van der Elst et al3 found the caspofungin AUC0-24 was approximately 25% lower in critically ill patients than normal volunteers and approximately 50% of patients had low caspofungin exposure. Adembri et al4 studied 20 critically ill patients receiving caspofungin and divided the patients into low AUC0-24 (≤75 mg h/L) and high AUC0-24 (≥ 75 mg h/L). Substantial variability of caspofungin pharmacokinetics in critically ill septic patients was observed. For the low AUC0-24 group the probability of target attainment ≥90% occurred only for an MIC of ≤0.03 mg/L while the high AUC0-24 group had ≥90% probability of target attainment for an isolate with MIC ≤0.06mg/L. Neither group achieved ≥90% probability of target attainment when the MIC rose to the epidemiological cut-off MIC of 0.125 mg/L. van Wanrooy et al5 reported on 20 critically ill patients receiving anidulafungin who underwent extensive sampling. The overall exposure was low but considered adequate for patients where the MIC of the Candida isolate was low; however, dose escalation may be required for less susceptible isolates or Candida glabrata.

Similarly for micafungin, in a cohort of 19 critically ill patients, the reported median AUC0-24 was approximately 40% lower than healthy volunteers.6 The variability in micafungin exposure in this ICU population was primarily related to body weight with patients weighing over 100 kg at risk of under-exposure. Conclusion: Suboptimal drug exposure is now well recognised in critically ill patients suggesting a role for echinocandin TDM in this setting.

Obesity and the echinocandins

The only echinocandin for which is suggested a dose alteration for obesity, is caspofungin (70 mg loading dose followed by 50 mg/day if < 80 kg and 70mg/day for >80kg). Earlier publications where modelling was undertaken after rich sampling of healthy subjects suggested that above a weight of 66.3 kg the caspofungin AUC0-24 fell progressively as weight increased due to enhanced systemic clearance, thereby suggesting dose optimisation may improve clinical success.7 A similar finding was reported by the same group for micafungin.8

Wasmann et al9 studied 16 obese and 8 normal weight subjects receiving micafungin. Their results suggested that for a Candida species with an MIC 0.016 mg/L the standard 100 mg dose was adequate in patients weighing <125 kg but over 125 kg the dose should be increased to 200 mg or 300 mg if the MIC is 0.032mg/L. They also recommended a loading dose of twice the maintenance dose.

The same group performed a pharmacokinetic simulation study for anidulafungin in healthy and obese patients and proposed that a 25% increase in the loading and maintenance doses of anidulafungin could be considered in patients weighing more than 140 kg.10

In the setting of obesity and critical illness, Märtsonet al11 reported that standard caspofungin dosing was inadequate for 100% when weight >120 kg, over 80% of average weight (78 kg), and 25% for weight ≤50 kg and proposed weight-based caspofungin dose regimens with a loading dose of 2 mg/kg, followed by 1.25 mg/kg/day.

Conclusion: increased doses are suggested for caspofungin, micafungin and potentially for anidulafungin in obese patients. However, there is a lack of consensus on the ideal dose for weight thresholds suggesting a role for TDM.

Echinocandins and extra-corporeal membrane oxygenation

The echinocandins are all highly protein bound which suggests that circuit drug loss may occur due to sequestration. However, they are also lipophilic molecules, therefore an increased volume of distribution and decreased clearance during ECMO would be anticipated.

There is sparse and sometimes contradictory published data on echinocandin TDM and ECMO. Spriet et al12 reported that adequate caspofungin plasma concentrations were maintained during ECMO but Koch et al13 found that inadequate concentrations were maintained in a paediatric patient on ECMO. One clinical study suggested that micafungin plasma concentrations are preserved during ECMO14 despite in vitro data suggesting that, like caspofungin, micafungin is highly bound to the ECMO membranes.15 A single case report did not find anidulafungin pharmacokinetics to be altered by ECMO.16

Conclusion: the role of TDM for patients receiving echinocandins while undergoing ECMO is uncertain and future studies under a variety of clinical conditions are required.

Back to the ICU patients...

For the young obese male, TDM would be helpful but if not, available a weight-based dose adjustment would be recommended, particularly if the MIC of the organism were close to the epidemiological cut-off value.

For the frail elderly lady, no role for TDM currently recommended.

The ECMO patient – possibly! Much more data is needed before recommendations are possible.

Now that your appetite has been whet, go ahead and read our review in Therapeutic Drug Monitoring!

References

1. Hannah Yejin Kim, Sara Baldelli, Anne-Grete Märtson, Sophie Stocker, Jan-Willem Alffenaar, Dario Cattaneo, Deborah JE Marriott. Therapeutic Drug Monitoring of the Echinocandin Antifungal Agents: is there a role in clinical practice? A position statement of the Anti-Infective Drugs committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Therapeutic Drug Monitoring in press.
2. Sinnollareddy MG, Roberts JA, Lipman J et al. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study. Crit Care 2015; 19: 33.
3. van der Elst KC, Veringa A, Zijlstra JG et al. Low Caspofungin Exposure in Patients in Intensive Care Units. Antimicrob Agents Chemother 2017; 61.
4. Adembri C, Villa G, Rosi E et al. Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring? J Chemother 2020; 32: 124-31.
5. van Wanrooy MJ, Proost JH, Rodgers MG et al. Limited-sampling strategies for anidulafungin in critically ill patients. Antimicrob Agents Chemother. 2015; 59(2):1177-81.
6. Boonstra JM, van der Elst KC, Veringa A et al. Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis. Antimicrob Agents Chemother 2017; 61(12)e01398-17.
7. Hall RG, Swancutt MA, Meek C, et al. Weight drives caspofungin pharmacokinetic variability in overweight and obese people: fractal power signatures beyond two-thirds or three-fourths. Antimicrob Agents Chemother. 2013 May;57(5):2259-64.
8. Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother. 2011 Nov;55(11):5107-12.
9. Wasmann RE, Smit C, Ter Heine R et al. Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults. J Antimicrob Chemother 2019; 74: 978-85
10. Wasmann RE, Muilwijk EW, Burger DM et al. Clinical Pharmacokinetics and Pharmacodynamics of Micafungin. Clin Pharmacokinet. 2018 Mar;57(3):267-286.
11. Märtson AG, van der Elst KCM, Veringa A et al. Caspofungin Weight- Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients. Antimicrob Agents Chemother 2020
12. Spriet I, Annaert P, Meersseman P et al. Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation. J Antimicrob Chemother 2009; 63: 767-70.
13. Shekar K, Roberts JA, McDonald CI et al. Protein- bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care 2015; 19: 164.
14. Koch BC, Wildschut ED, Goede AL et al. Insufficient serum caspofungin levels in a paediatric patient on ECMO. Med Mycol Case Rep 2012; 2: 23- 4.
15. López-Sánchez M, Moreno-Puigdollers I, Rubio-López MI et al. Pharmacokinetics of micafungin in patients treated with extracorporeal membrane oxygenation: an observational prospective study. Rev Bras Ter Intensiva 2020; 32: 277-83.
16. Watt KM, Cohen-Wolkowiez M, Williams DC et al. Antifungal Extraction by the Extracorporeal Membrane Oxygenation Circuit. J Extra Corpor Technol 2017; 49: 150-9.
17. Aguilar G, Ferriols R, Carbonell JA et al. Pharmacokinetics of anidulafungin during venovenous extracorporeal membrane oxygenation. Crit Care 2016; 20: 325.

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