Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation?

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Introduction

Invasive fungal infections are an important cause of morbidity and mortality, especially in critically ill patients Increasing resistance rates and inadequate antifungal exposure have been documented in these patients, due to clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) alterations, leading to treatment failure. Physiological changes such as third spacing (movement of fluid from the intravascular compartment to the interstitial space), hypoalbuminemia, renal failure and hepatic failure, as well as common interventions in the intensive care unit, such as renal replacement therapy and extracorporeal membrane oxygenation, can lead to these PK and PD alterations.

This review aims to describe the current evidence regarding optimal PK/PD indices associated with the clinical efficacy of the most commonly used antifungal agents in critically ill patients (azoles, echinocandins, lipid complexes of amphotericin B, and flucytosine), provide a comprehensive understanding of the factors affecting the PK of each agent, document the PK parameters of critically ill patients compared to healthy volunteers, and, finally, make recommendations for therapeutic drug monitoring (TDM) of antifungals in critically ill patients.

TDM of Azoles in Critically Ill Patients

The antifungal group of azoles is associated with two subgroups: imidazoles and triazoles; the first is formed by a two-nitrogen azole ring and the second is formed by a three-nitrogen ring. Both subgroups work by inhibiting the cytochrome P450 enzyme 14-a-sterol-demethylase, a key enzyme in the synthesis of fungal ergosterol, which is the most abundant sterol in fungi membranes and the main actor in maintaining membranes’ permeability and fluidity. The main protagonists of this subgroup of antifungals in current clinical practice are fluconazole, voriconazole, posaconazole, isavuconazole and itraconazole. Of these antifungals, only itraconazole, posaconazole and voriconazole might be candidates for TDM, primarily due to increased risk of serious adverse reactions and drug-drug interactions.

TDM of Echinocandins in Critically Ill Patients

Echinocandins are a class of antifungal drugs targeting fungal cell wall synthesis. They act through non-competitive inhibition of the b-(1,3)-D-glucan synthase, the enzyme responsible for the synthesis of b-(1,3)-D-glucan, which is an essential component of the fungal cell wall. Although all echinocandins exhibit the same mechanism of action, they differ in certain PK properties. However, they all demonstrate extensive protein binding, lack of renal Cl, and lack of oral bio availability. The only fungi susceptible to this class of antifungals are Candida and Aspergillus spp. Their clinical use has increased significantly as they are recommended by some guidelines as the first-line therapy for candidemia, and for chronic disseminated candidiasis.

Echinocandins are also used as empiric therapy in patients with neutropenic fever, and in combination with triazoles as the initial treatment for invasive aspergillosis. Due to the increased use of this class of antifungal drugs, resistance rates are increasing. For instance, Pfaller et al. documented an increase of 2.6% in the quantity of resistant candida isolates for Caspofungin and C. parapsilosis, 3.3% for micafungin and C. Krusei, and 1.4% for anidulafungin and C. gablatra, documented over a period of 9 years in 100 centres worldwide. Echinocandin resistance can occur as a result of substitution mutations in the FKS1 and FKS2 genes. These amino acid substitutions lead to decreased sensitivity of the glucan synthase to the drug, and can elevate MIC values 5- to 100-fold. The increasing resistance can be in part due to suboptimal drug exposure in critically ill patients, given that echinocandins demonstrate concentration and dose-dependent efficacy.

There are several studies addressing the PK and PD changes of echinocandins in critically ill patients, some with conflicting results but the majority showing suboptimal exposure, as well as changes in Vd and Cl and changes in PK/PD indices compared to healthy volunteers. However, there is no clear opinion on whether TDM is useful for echinocandins. An understanding of the relationship between antifungal exposure and response is necessary to adequately specify clinical thresholds that would have an impact on clinical outcomes and consequently the usefulness of TDM. In this section, we revise the available evidence to address the relationship between systemic echinocandin concentrations and efficacy, as well as inter-individual variability and covariates that may affect the drugs’ PK, before finally giving recommendations for TDM.

TDM of Amphotericin B in Critically Ill Patients

Regarding its therapeutic spectrum, amphotericin B possesses arguably the broadest coverage amongst all antifungal agents. Although some conflicting evidence exists for certain species, there is consistency regarding most of the species considered both susceptible and resistant to amphotericin B. Amongst susceptible organisms, Candida tropicalis, Candida krusei, Candida guilliermondii, Candida kefyr and Candida famata stand out from the Candida genus, while Malassezia spp., Saccharomyces cerevisiae, Aspergillus niger, Aspergillus nidulans and Cryptococcus neoformans are also considered sensitive.

Compellingly, Candida albicans and Candida parapsilosis, while still believed to be susceptible, have been reported to exhibit resistance. Regarding resistant species, Candidaauris, Candida lusitaniae, Candida haemulonii, Sporothrix schenckii and Scedosporium prolificans are the most noteworthy organisms known to cause disease in human hosts. Aspergillus fumigatus, Aspergillus flavus, Fusarim spp., Trichosporon beigelii and Scedosporium apiospermum are some of the organisms that have generated controversial results regarding amphotericin B resistance and clinical utility in spite of reports of therapeutic failure. Lastly, it should be mentioned that difficulty in culturing and testing antifungal resistance in Zygomycetes makes it difficult to obtain a clear point of reference regarding their susceptibility; nonetheless, amphotercin B remains a useful tool in severe Mucor spp., Rhizopus spp., and Rhizomucor pusillus infections.

Invasive mycoses are a common complication in critically ill patients, a population characterised by a profound comorbidity burden, and in many cases, variable states of immune deficit. Under these circumstances, treatment of fungal infection requires a precise and fine-tuned approach in order to reach optimal outcomes. TDM has recently emerged as a practice that may provide better results by optimising dosages and administration intervals through individualised approximation, maintaining adequate therapeutic concentrations and decreasing the risk of toxicity related adverse effects.

Conclusions

In conclusion, antifungal drugs are widely used in critically ill patients. Critical states can alter the PK parameters of antifungal drugs to the point of lowering the probability of treatment success and contributing to antimicrobial resistance. In general, we consider that clinicians should adopt PK/PD-based dosing as part of routine clinical practice, in order to avoid the suboptimal exposure seen with the use of standard dosing. Due to the high toxicity of azoles and the high probability of drug-drug interactions, TDM should be considered when using itraconazole, posaconazole or voriconazole as antifungal therapy.

For its part, echinocandin exposure has been shown to provide suboptimal exposure in critically ill patients and also in overweight patients, with documented high inter-individual variability, reasons that favor TDM. PK parameters are not well elucidated for amphotericin B so routine TDM is not desirable, except when toxicity is a major concern, or a narrow therapeutic range is needed. Finally, routine TDM for flucytosine is recommended due to the high variability in serum concentrations following administration and severe adverse effects when concentrations exceed the toxicity threshold. Furthermore, we consider further studies are needed to evaluate PK parameters during antifungal treatment in critically ill patients, especially those receiving amphotericin B, for which most studies to date have been conducted in immunocompromised pediatric patients.

Source:  Baracaldo-Santamaría, D.; Cala-Garcia, J.D.; Medina-Rincón, G.J.; Rojas-Rodriguez, L.C.; Calderon-Os-pina, C.-A. Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation? Antibiotics 2022, 11, 645. https://doi.org/10.3390/antibiotics11050645.