Overview of antifungal dosing in invasive candidiasis

Overview of antifungal dosing in invasive candidiasis Abstract In the past, most antifungal therapy dosing recommendations for invasive candidiasis followed a ‘one-size fits all’ approach with recommendations for lowering maintenance dosages for some antifungals in the setting of renal or hepatic impairment. A growing body of pharmacokinetic/pharmacodynamic research, however now points to a widespread ‘silent epidemic’ of antifungal underdosing for invasive candidiasis, especially among critically ill patients or special populations who have altered volume of distribution, protein binding and drug clearance. In this review, we explore how current adult dosing recommendations for antifungal therapy in invasive candidiasis have evolved, and special populations where new approaches to dose optimization or therapeutic drug monitoring may be needed, especially in light of increasing antifungal resistance among Candida spp. Introduction A growing body of evidence suggests that antifungal therapy is frequently underdosed in treatment of invasive candidiasis, especially in critically ill patients.1 In a pharmacokinetic point prevalence study from 68 European ICUs, Sinnollareddy et al.2 found that one-third of fluconazole-treated patients failed to achieve minimum recommended pharmacokinetic/pharmacodynamic (PK/PD) target exposures, a factor previously identified in several retrospective studies as an independent risk factor for death.3–5 Drug exposures of anidulafungin and caspofungin were also variable or lower, on average, compared with exposures previously reported for healthy subjects. Recently, Jullien et al. reported that drug exposures among patients enrolled in a placebo-controlled trial of micafungin empirical therapy for invasive candidiasis were 50% lower than the values reported for healthy subjects, and 25% lower compared with hospitalized non-ICU patients.6,7 A possible silent epidemic of antifungal underdosing in hospitals among patients with invasive candidiasis is troubling for several reasons. First, the most commonly used agents, echinocandins and fluconazole, are well tolerated by patients even at much higher doses. Therefore, the risks versus benefits of using higher doses clearly favour more aggressive dosing for invasive candidiasis, where crude mortality rates still approach 40% even with effective therapy.8 Second, insufficient dosing of triazoles has been linked to the emergence of resistance,9 and Candida isolates with acquired multidrug resistance to fluconazole and echinocandins are increasing in frequency, with reported rates as high as 25%–30% when isolates are tested from deep tissue sites or mucosa after azole or echinocandin treatment.8,10–12 Finally, antifungal underdosing could theoretically favour the emergence and spread of MDR Candida glabrata and Candida auris in the critically ill and severely immunocompromised populations.13,14 In this article, we will review our current scientific rationale of antifungal dosing for invasive candidiasis, and summarize recent data concerning subpopulations of adult patients at risk for invasive candidiasis where dosing must be altered. We will also summarize adult patient-specific considerations that must be addressed when individualizing therapy and antifungal dosing for invasive candidiasis. Pharmacodynamic basis for antifungal dosing Triazoles Fluconazole was developed during the 1980s and first approved for clinical use in 1990. The drug quickly became the preferred agent for preventing and treating oral oesophageal candidiasis in patients with AIDS at a time before the availability of HAART. Fluconazole was the only available antifungal with predictable oral absorption and limited adverse effects. Intravenous fluconazole was also proved to be as effective as and less toxic than amphotericin B deoxycholate for the treatment of invasive candidiasis.15 However, long-term treatment with fluconazole, which was necessary in patients with advanced AIDS and persistently low CD4+ counts, inevitably led to relapsing oesophageal candidiasis that failed to respond to conventional fluconazole doses (100–400 mg/day).16 In some cases, fluconazole failures were linked to breakthrough infection caused by isolates with elevated MICs. However, many patients with relapsed oropharyngeal candidiasis would often still respond to higher doses of fluconazole.17 By 1997, the National Committee for Clinical Laboratory Standards (now Clinical Laboratory Standards Institute, CLSI) had developed susceptibility breakpoints for interpretation of fluconazole MICs performed using a proposed standardized broth microdilution method.18 Breakpoints for fluconazole included a novel ‘susceptible-dose dependent’ (SDD) category based on the clinical experience described above, where higher doses of fluconazole (12 mg/kg or 800 mg per day) were recommended for isolates with MICs ranging from 8 to 32 mg/L.19 The concept of a ‘pharmacodynamic’ SDD breakpoint was later supported by studies in animal models of invasive candidiasis that explored how changes in the dosing interval affected fluconazole efficacy over a wide range of doses. Andes and van Ogtrop20 and Louie et al.21 independently demonstrated that a fluconazole free-drug 24 h AUC to MIC ratio (fAUC/MIC) of 25–50 was associated with a 50% reduction in fungal tissue burden in neutropenic mice with disseminated candidiasis. This PK/PD target was roughly equivalent to maintaining fluconazole concentrations above the MIC throughout the entire dosing interval (i.e. 1 × MIC × 24 h = AUC/MIC 24) (Table 1). Subsequent studies confirmed that an fAUC/MIC target of 25–50 was predictive of efficacy for other triazoles (voriconazole, posaconazole, isavuconazole) if free (non-protein-bound) concentrations were considered.22–24 An fAUC/MIC target of 25–50 was also confirmed to produce 50% reduction in tissue fungal burden among other Candida species with different resistance profiles and/or resistance mechanisms.25 Table 1. PK/PD properties of antifungal agents for invasive candidiasis Antifungal  Activity against Candida spp.  PK/PD parameter associated with treatment efficacy  PK/PD references  Polyenes  fungicidal       DAmB    Cmax/MIC >10  Andes et al., 200157      AUC/MIC >100  Andes et al., 200656      (varies depending on tissue infection site)     LAmB    Cmax/MIC >40  Hong et al., 200660  Triazoles  fungistatic  fAUC/MIC 25–100  Andes and van Ogtrop, 199920   fluconazole      Louie et al., 199821,122   itraconazole      Andes et al., 200424   voriconazole      Andes et al., 200323   posaconazole      Lepak et al., 201322   isavuconazole      Lepak et al., 201551  Echinocandins  fungicidal  fAUC/MIC >20  Andes et al., 200337   anidulafungin    (C. albicans)  Andes et al., 200840 and 201148   caspofungin      Andes et al., 201038   micafungin            fAUC/MIC >7  Gumbo et al., 200745      (C. glabrata, C. parapsilosis)  Andes et al., 200839        Hope et al., 2007123        Petraitiene et al., 201543  Pyrimidine analogues  fungistatic  T>MIC 40%  Andes and van Ogtrop, 200061   flucytosine      Hope et al., 200762  Antifungal  Activity against Candida spp.  PK/PD parameter associated with treatment efficacy  PK/PD references  Polyenes  fungicidal       DAmB    Cmax/MIC >10  Andes et al., 200157      AUC/MIC >100  Andes et al., 200656      (varies depending on tissue infection site)     LAmB    Cmax/MIC >40  Hong et al., 200660  Triazoles  fungistatic  fAUC/MIC 25–100  Andes and van Ogtrop, 199920   fluconazole      Louie et al., 199821,122   itraconazole      Andes et al., 200424   voriconazole      Andes et al., 200323   posaconazole      Lepak et al., 201322   isavuconazole      Lepak et al., 201551  Echinocandins  fungicidal  fAUC/MIC >20  Andes et al., 200337   anidulafungin    (C. albicans)  Andes et al., 200840 and 201148   caspofungin      Andes et al., 201038   micafungin            fAUC/MIC >7  Gumbo et al., 200745      (C. glabrata, C. parapsilosis)  Andes et al., 200839        Hope et al., 2007123        Petraitiene et al., 201543  Pyrimidine analogues  fungistatic  T>MIC 40%  Andes and van Ogtrop, 200061   flucytosine      Hope et al., 200762  When the outcomes of oesophageal candidiasis treatment were analysed according to the MIC of the infecting isolate, fluconazole treatment was successful in 91%–100% of treated patients when the estimated fAUC/MIC surpassed 25, but was only 27%–35% successful in patients with a fAUC/MIC <25.26 Most patients with normal body habitus and renal function could achieve fAUC/MIC >25 up to a fluconazole MIC of 8 mg/L, but doses of 12 mg/kg/day (800 mg) were confirmed to be important for achieving this PK/PD target for SDD isolates (MIC 8–32 mg/L).19 Multiple observational studies have since documented a link between fluconazole fAUC/MIC and the outcomes of invasive candidiasis.3,5,26–31 Given the nearly 1:1 linear relationship between fluconazole dose and AUC,32 investigators have also reported that fluconazole dose/MIC >100 was an independent predictor of treatment success when MICs were determined using the EUCAST methodology.27,29,31 A fluconazole dose/MIC target of 100 was subsequently used as the basis for proposal of a EUCAST susceptibility breakpoint for fluconazole of ≤2 mg/L.33 The CLSI later adopted this same MIC susceptibility cut-off when it was shown that the lower breakpoint had improved sensitivity for detecting C. albicans that harbour acquired resistance mechanisms.34 Now, standard dosages of fluconazole (400 mg/day) are considered to have a higher probability of treatment failure when the 24 h fluconazole MIC is ≥4 mg/L.34 Echinocandins Caspofungin, the first echinocandin approved for clinical use, entered clinical trials in 1995 when there was still a dire need for new therapies active against fluconazole-resistant oral–oesophageal candidiasis.35 Early pharmacokinetic studies suggested that a 70 mg loading dose of caspofungin followed by 50 mg daily would result in levels >1 mg/L on the first day of therapy, a target that exceeded the MIC of 90% of the most clinically relevant Candida species.35,36 Subsequent animal studies provided a clearer description of the PK/PD behaviour of echinocandins during the treatment of invasive candidiasis. Andes and colleagues examined the effects of altered dosing intervals and escalating doses for a novel glucan synthesis inhibitor, HMR 3270, in a neutropenic murine model of disseminated candidiasis.37 The investigators found that treatment outcome was strongly correlated with drug dose and organism MIC, with a total drug Cmax/MIC 3.72 or AUC/MIC >300 suppressing Candida growth in the model. Maximal fungicidal effects were observed as the Cmax/MIC approached 10. Subsequent studies with caspofungin, micafungin and anidulafungin confirmed that 5- to 8-fold less drug was required to achieve similar reductions in Candida tissue fungal burden if echinocandins were administered as single dose.38–45 In a direct comparison of caspofungin, micafungin and anidulafungin against different Candida species., Andes et al.38 later reported that fAUC/MIC was highly predictive of treatment response for all three echinocandins, but fAUCs were lower for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) compared with C. albicans (mean, 20). These species-specific PD targets later served as the basis (along with population MIC data) for unique CLSI and EUCAST Candida species-specific susceptibility breakpoints for the echinocandins.46,47 The clinical validity of echinocandin PK/PD targets was subsequently analysed in 493 patients with invasive candidiasis who received micafungin as part of the Phase 3 clinical trial.48 A population PK model was used to estimate micafungin exposures and was validated in a subset of patients with available PK data. The investigators identified the following independent risk factors affecting cure: severity of illness, a micafungin total AUC/MIC >3000 for all Candida species, or a total drug AUC/MIC >5000 for non-C. parapsilosis species, an MIC <0.5 mg/L, and a history of steroid use (Table 1). Patients with a micafungin total drug AUC/MIC >3000 achieved clinical and mycological cure rates of 98%. Considering protein binding in humans, an AUC/MIC target >3000 translates to a free drug ratio of 7.5, whereas the AUC/MIC >5000 translates to a free drug ratio of 12.5.49 When corrected for protein binding, the micafungin AUC/MIC targets identified in the clinical trials (7.5 and 12.5, respectively) were almost identical to free-drug micafungin AUC/MIC targets previously identified in neutropenic mice.38,45,50 Collectively, these data suggested that higher intermittent dosing would optimize the PD of echinocandin therapy.51 This concept was tested in a randomized study of micafungin for oral oesophageal candidiasis that compared micafungin administered 150 mg daily with 300 mg dosed every other day.52 The mycological response rate at the end of therapy was higher in patients who received the higher-dose, intermittent micafungin regimen (85% versus 79%, respectively, P = 0.056) with significantly lower relapse rates (6% versus 12%, respectively, P = 0.05). More recently, Gumbo50 described a patient with underlying immunodeficiency of unclear aetiology and a history of recurrent oesophageal candidiasis who was initially treated with a standard micafungin dose of 100 mg daily for 2 weeks. The patient was subsequently administered a single 700 mg dose in the following week, followed by 1400 mg doses every other week with liver function test monitoring 3 days after each dose. The patient tolerated the regimen for 12 weeks until she developed evidence of liver function test abnormalities that was later attributed to injection of illicit drugs with acetaminophen. She later resumed the 1400 mg dosing every 2 weeks without elevation of liver enzymes. Several studies have explored the potential efficacy and safety of higher-dose daily echinocandin regimens. The largest of these studies was performed by Betts and colleagues,53 who performed a double-blind randomized trial in 204 patients with invasive candidiasis, with 104 patients receiving a standard 70 mg loading dose of caspofungin followed by 50 mg daily and 95 patients receiving 150 mg daily. A non-significant trend towards improved clinical and microbiological response was observed in patients receiving the higher-dose regimen, with overall response at day 10 of therapy of 94.5% versus 84% in the high- versus low-dose groups, respectively (Δ10.5%, 95% CI 0.7%–20.9%). Mortality was similar in both groups at 8 weeks and no safety concerns were found for caspofungin at a dose of 150 mg/day. Notably, most patients in the trials (>70%) had lower APACHE II scores and had uncomplicated candidaemia (84%). This study was also performed prior to wider dissemination of echinocandin-resistant C. glabrata; therefore it is possible that differences between the two dosing groups may have been greater in more critically ill patients with a higher prevalence of resistant organisms. Additional evaluations of dosing for current and novel echinocandins in development [e.g. rezafungin (CD101)] have been completed recently and are reviewed separately.54 Amphotericin B lipid formulations Lipid formulations of amphotericin B are recommended over conventional amphotericin B-deoxycholate (DAmB) for the treatment of invasive candidiasis except in resource-limited areas.55 Each of the three lipid formulations [amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD) and liposomal amphotericin B (LAmB)] is complexed to a different lipid carrier system, exhibits different PK properties, and is 5- to 7-fold less potent than DAmB on a mg/kg basis depending on the tissue site analysed.56 Studies comparing escalating doses and altering treatment intervals in invasive candidiasis have found that the Cmax/MIC is the PD parameter that best correlates with DAmB treatment outcome in experimental invasive candidiasis,57 with the AUC/MIC ratio and time above MIC less predictive of fungicidal activity. In disseminated candidiasis models, differences in the rates of Candida liver, spleen and lung fungal burden mirrored differences in tissue kinetics of amphotericin B measured by bioassay for each of the lipid amphotericin B formulations.56 Limited clinical data are available linking amphotericin B PK/PD to clinical endpoints. Restricted dosing and the limited MIC range for amphotericin against Candida species are factors that complicate clinical PK/PD studies.58 Toxicity of higher DAmB doses may also obscure the benefit of higher drug exposures.59 One paediatric study reported that a Cmax/MIC >40 was associated with maximal response during liposomal amphotericin B treatment,60 which, after correcting for potency differences, is similar to the DAmB Cmax/MIC of 10 reported in preclinical models of disseminated candidaemia.59 Flucytosine Flucytosine is occasionally used in combination with amphotericin B-based regimens for the treatment of CNS candidiasis, native valve endocarditis or fluconazole-resistant urinary candidiasis.55 Studies examining flucytosine PD in animal models of invasive candidiasis and cryptococcosis have shown that the percentage of time flucytosine concentrations surpass the MIC best predicts antifungal efficacy, with a %T>MIC of at least 40 required for fungistatic effect.61,62 Therefore, lower doses but more frequent administration of the drug (e.g. 25 mg/kg every 6 h) optimizes PK/PD target attainment and reduces the risk of bone marrow toxicity, which is linked to peak concentrations >100 mg/L.63 Patient-level considerations for dosing Triazoles Fluconazole is still considered the preferred triazole for the step-down treatment of candidaemia in non-neutropenic critically ill patients by several guidelines, with voriconazole being a valuable alternative.64 Although moderately lipophilic in nature, fluconazole is the only triazole significantly eliminated by the renal route. Considerable interindividual PK variability of fluconazole was documented in a small cohort of critically ill patients (n = 21) who were treated with a median dose of 400 mg/day. In 33% of these, drug exposure was insufficient to attain the PK/PD target of AUC/MIC >100, in spite of a relatively low median creatinine clearance (CLCR) (45 mL/min).2 Accordingly, it may be hypothesized that the risk of fluconazole underexposure with the fixed 400 mg/day dose may be even higher among patients with augmented renal clearance (CLCR >130 mL/min).65 The PK of voriconazole was also assessed in critically ill patients after standard intravenous (iv) dosing (6 mg/kg loading dose and 3–4 mg/kg twice daily thereafter) in a prospective observational study involving 18 patients with different degrees of renal function (12 with normal renal function, CLCR ≥60 mL/min, and 6 with moderate renal impairment, CLCR 40–55 mL/min).66 Large interindividual variability in Cmin was observed. Cmin was outside the desired therapeutic range (1–5.5 mg/L)67 in more than half of cases (56%), with 37% of patients having suboptimal exposure (≤1 mg/L) and 19% having potentially toxic levels (>5.5 mg/L). The wide interindividual variability was unrelated to differences in renal function, in agreement with the fact that voriconazole is a non-renally cleared drug. Voriconazole is a highly lipophilic drug that is almost completely metabolized by three CYP450 isoenzymes, namely CYP3A4, CYP2C9 and CYP2C19.68 Voriconazole shows wide interindividual PK variability among several different types of patient populations. This is mainly due to the genetic polymorphism of CYP2C19, the primary enzyme involved in the elimination pathway of voriconazole. Importantly, the distribution of the genetic polymorphisms of CYP2C19 may vary greatly among the various racial/ethnic groups. It has been shown that up to one-third of Caucasians may be ultra-rapid metabolizers of CYP2C19, and may experience drug underexposure with therapeutic failure; conversely, up to 20% of Asians may be poor metabolizers and may experience drug overexposure with toxicity.68 The wide interindividual variability of voriconazole was confirmed in a very large study of real-life therapeutic drug monitoring (TDM). Among 14 923 voriconazole Cmin values, almost half were outside the desired range (39.2% <1 mg/L and 10.4% >5.5 mg/L).69 The interindividual PK variability of voriconazole may become even wider during polytherapy owing to drug–drug interactions. It has been shown that co-medication with CYP450 inhibitors (i.e. proton pump inhibitors) and/or with CYP450 inducers (i.e. corticosteroids, phenobarbital, carbamazepine and rifampicin) may significantly influence voriconazole clearance.70,71 TDM of voriconazole is recommended by several guidelines.67,72 Therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype have also been developed.73 Both fluconazole (at doses >200 mg/day) and voriconazole are potent inhibitors of CYP2C9, CYP2C19 and CYP3A4. This may cause overexposure during co-administration with drugs that are substrates of these CYP450 isoenzymes.74 A recent study aimed at evaluating the prevalence of triazole drug–drug interactions among hospitalized adults who were identified within a database containing data from over 150 hospitals.75 The study showed that 82% of hospitalizations with voriconazole use included the use of at least one drug that resulted in a severe drug–drug interaction. Management of these interactions should involve appropriate dosage adjustments when necessary, and TDM when available (e.g. immunosuppressive drugs). The relatively high lipophilicity of the triazoles may ensure high penetration rates of these antifungals into deep tissues with a valid diffusion even through the anatomical barriers. These properties are clinically relevant in deep-seated Candida infections. Triazoles may achieve therapeutically relevant concentrations in several tissues, with tissue-to-plasma ratios of ≥0.7 in most cases, even in CSF and/or in cerebrum.76 Both fluconazole and voriconazole were shown to concentrate in the aqueous humour,77,78 and are therefore considered valuable agents in the treatment of Candida endophthalmitis. Likewise, it was recently shown the valuable intra-abdominal penetration of fluconazole into the bile and the ascites of three liver transplant patients ensured optimal PD exposure with successful clinical treatment of deep-seated candidiasis.79 Echinocandins The echinocandins are considered the first-line choice of treatment for candidaemia in non-neutropenic critically patients by several guidelines.64 Anidulafungin, caspofungin and micafungin are highly protein-bound hydrophilic compounds, which are ultimately eliminated mainly through ubiquitous spontaneous degradation. The echinocandins are administered at fixed dosages (anidulafungin, 200 mg loading dose followed by 100 mg/day; caspofungin, 70 mg loading dose followed by 50 mg/day; micafungin, 100 mg/day) and are traditionally considered as drugs that are easy to manage in critically ill patients, thanks to the low potential for drug–drug interaction and to the non-renal and less extensive hepatic clearance.80 However, recent studies have raised questions concerning the appropriateness of fixed standard dosages of these antifungal agents in attaining optimal PK/PD targets against Candida infections in the critically ill patients. Caspofungin PK was assessed in 21 critically ill patients. All of the patients had moderate hepatic dysfunction (Child–Pugh class B) and most were severely hypoalbuminaemic (<25 g/L in 81% of cases). Caspofungin showed limited intra-individual and moderate inter-individual PK variability, with drug exposures comparable to those observed in other non-critically ill patients. Although the authors concluded that ICU patients do not need higher dosages compared with other reference groups, it should not be overlooked that all of the study patients were affected by moderate hepatic dysfunction, namely a pathophysiological condition that was shown to increase caspofungin exposure. However, in critically ill patients with low albumin, the volume of distribution and clearance of echinocandins is likely increased. The PK of anidulafungin in critically ill patients was assessed in 20 subjects, most of whom were elderly, underwent abdominal surgery and had Candida peritonitis.81 No relationship between anidulafungin exposure, in terms of AUC, and disease severity scores [e.g. APACHE 2, simplified acute physiology score (SAPS), SOFA 2] or albuminaemia levels was found. However, anidulafungin exposure in this patient population was lower than that observed in the general patient population. This led the authors to conclude that, although no problem would be expected in the treatment of infections due to very susceptible strains of C. albicans or C. glabrata, conversely dosage adjustment based on TDM could be needed when dealing with Candida strains having higher MICs near to the clinical breakpoint. The presence of lower anidulafungin exposure compared with that in healthy volunteers or other patient populations was subsequently confirmed in another cohort of critically ill patients.82 The PK of micafungin was also found to be altered among 20 critically ill patients, most of whom were elderly and had moderate (Child–Pugh class B) or severe (Child–Pugh class C) hepatic dysfunction.83 Micafungin PK was assessed twice, on day 3 (n = 20) and on day 7 (n = 12). The PK behaviour was similar on the two assessment days and overall micafungin exposure in these critically ill patients was lower than that in healthy volunteers, even if not significantly different from that of other reference populations. The authors suggested that higher than standard dosages could be considered in this setting, and that TDM might represent a helpful tool for optimizing patient care. Their hydrophilic nature coupled with their high molecular weight prevent the echinocandins from achieving therapeutically effective concentrations in infection sites protected by anatomical barriers. Therefore, when dealing with Candida endophthalmitis or with CNS infections, echinocandin monotherapy should be avoided.84,85 Amphotericin B lipid formulations The PK of amphotericin B lipid formulations has never been investigated in critically ill patients with candidaemia and/or invasive candidiasis. However, according to the peculiar characteristics of these moieties, which are cleared from the bloodstream mainly by the reticulo-endothelial system, it is unlikely that the PK behaviour of these formulations would be affected by critical illness. Standard dosages up to 5 mg/kg/day should be appropriate even in this setting. When in presence of deep-seated complications, such as Candida endophthalmitis and/or of CNS infections, liposomal amphotericin B should be the preferred formulation. This is based on clinical experience and on evidence from preclinical animal models showing that the liposomal formulation achieved the highest concentrations in the aqueous humour, CSF and brain parenchymal tissue.86,87 Flucytosine Flucytosine PK have not been investigated in critically ill patients.88 This antifungal agent has limited protein binding and is eliminated by glomerular filtration. Accordingly, it would be expected that dose intensification could be a valuable approach for avoiding subinhibitory concentrations in critically ill patients with augmented renal clearance. Flucytosine may achieve therapeutically relevant concentrations in the vitreous humour and in the CSF, and may therefore represent an option in combination therapy for the treatment of fungal infections located in the eye or in the CSF.88,89 Special populations Renal impairment Renal impairment may represent an important concern for adjusting maintenance dosages for those antifungals that normally are eliminated by the renal route. Fluconazole is the only triazole that needs adjustments of the maintenance dose in relation to renal impairment. Since fluconazole undergoes glomerular filtration with partial tubular reabsorption, it has been recently documented that estimation of the glomerular filtration rate might not accurately predict fluconazole clearance, and this may interfere with correct dosage adjustments.90 TDM was suggested as a helpful tool for optimizing fluconazole exposure in the setting of critically ill patients, especially when renal replacement therapies (RRTs) are applied.67 An early study assessed the PK of fluconazole among 16 critically ill patients who underwent continuous veno-venous haemofiltration (CVVH).91 The ultrafiltration flow rate was of 1000–2000 mL/h in predilution mode. The authors showed that fluconazole is very efficiently eliminated during CVVH and that a dosage of 800 mg/day would be needed to ensure appropriate drug exposure in this setting. The PK behaviour of fluconazole was recently assessed also in critically ill patients receiving prolonged intermittent RRT.92 Monte Carlo simulations were performed in order to estimate the PTA of achieving an AUC/MIC ratio of 100 during the initial 48 h of antifungal therapy. It was shown that a fluconazole dosing regimen of 800 mg loading dose plus 400 mg twice daily (every 12 h or pre- and post-prolonged intermittent RRT) would be appropriate. Likewise, fluconazole PK was assessed during sustained low-efficiency diafiltration (SLED-f), which is a technique increasingly being utilized in critically ill patients because of its practical advantages over continuous RRT.93,94 It was shown that during a single SLED-f session of 6 h, 72% of fluconazole was cleared compared with the much lower clearance (33%–38%) reported during a 4 h intermittent haemodialysis session. The authors concluded that doses >200 mg/day should be required for attaining optimal PK/PD in patients undergoing SLED-f. Voriconazole is a non-renally cleared triazole whose iv use is contraindicated in critically ill patients with CLCR <50 mL/min. This recommendation is provided to prevent the accumulation of the sulphobutylether-β-cyclodextrin (SBECD) vehicle, which is present in the iv formulation and which is predominately excreted by glomerular filtration. A prospective, open-label PK study was carried out among 10 critically ill patients receiving iv voriconazole while undergoing continuous RRT (CRRT). The aim was to verify whether CVVH (median total ultrafiltration rate of 38 mL/kg/h) may sufficiently remove SBECD to allow for the use of iv voriconazole without significant risk of SBECD accumulation.95 Voriconazole clearance was only minimal during CVVH, which conversely removed SBECD efficiently at a rate similar to the ultrafiltration rate. The findings allowed the authors to conclude that standard dosages of iv voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation. The echinocandins are non-renally cleared drugs, and do not require dosage adjustments in the presence of renal impairment.96 Recent studies assessed the PK behaviour of anidulafungin and of caspofungin in critically ill patients undergoing CRRT and confirmed that no dosage adjustment for these echinocandins is needed under these circumstances.97–99 Amphotericin B lipid formulations are not renally cleared and do not need any dosage adjustments, either in the presence of renal impairment or in the presence of CRRT.100 Flucytosine is eliminated by glomerular filtration, and proportional dosage adjustments are required in patients with renal impairment.88 A recent case report provided evidence that dosing may be an issue for flucytosine in patients undergoing CRRT.101 Hepatic impairment Liver disease encompasses a wide range of both acute and chronic pathological changes that can alter the PK and tissue penetration of antifungal agents. Chronic cirrhosis is associated with changes in protein binding, altered volume of distribution, metabolism and altered renal clearance of many antibiotics and antifungals.102 Recommendations for antifungal dosing adjustment in patients with hepatic dysfunction, however, are not straightforward. Reduction of antifungal doses by one-third to one-half is recommended in the summary of manufacturers’ product characteristics (SmPC) in patients with moderate to severe hepatic insufficiency (i.e. Child–Pugh class B or greater) receiving treatment with itraconazole, voriconazole, caspofungin and possibly posaconazole.103 No dose adjustment is recommended for micafungin in patients with mild or moderate hepatic impairment.103 No dose adjustment is needed for Child–Pugh scores of 7–9. For severe hepatic dysfunction (Child–Pugh scores of 10–12), increased micafungin clearance results in 7%–39% lower serum concentrations, but the clinical significance of this finding is unknown. Fluconazole is cleared primarily through glomerular filtration and does not require adjustment for liver dysfunction. Similarly, anidulafungin is degraded through a non-hepatic enzymatic process and does not have a dosage adjustment recommendation in patients with severe hepatic dysfunction. No specific recommendations are available for amphotericin B products, but given their limited metabolism, dosage adjustment in hepatic dysfunction is unlikely to be necessary. A problem with these recommendations is that the Child–Pugh classification system was not developed to predict drug elimination capacity. The classification system is based on the two clinical features (encephalopathy and ascites) and three laboratory-based parameters (albumin, bilirubin and prothrombin time). Hepatic dysfunction is categorized into groups called A, B and C or ‘mild’, ‘moderate’ and ‘severe’, corresponding to 5–6, 7–9 and 10–15 scores, respectively. As a result, even subjects with a normal hepatic function are given a total score of 5 points (since each variable gives a score of 1 point even within the normal range) and would consequently be classified as having mild hepatic impairment.104 Moreover, laboratory-based parameters used in calculation of the Child–Pugh classification lack specificity for liver disease. For example, albumin levels may be influenced by inflammation and nutritional status and are often low in critically ill patients with sepsis. Bilirubin may be increased due to cholestasis, hepatocellular failure or haemolysis.104 Hence, PK data used to define the dosing recommendation in patients with Child–Pugh B or C chronic alcoholic or viral liver cirrhosis may not be applicable to critically ill patients with organ dysfunction. Several recent studies have suggested that hypoalbuminaemia, which could lead to a classification of ‘moderately severe’ Child–Pugh B, may be a risk factor for inadequate echinocandin exposure.6,105,106 Caspofungin labelling includes a recommendation for reduction of maintenance doses from 50 mg daily to 35 mg daily in patients with Child–Pugh class B or greater liver dysfunction. However, Martial and colleagues106 reported that dosage reduction following these guidelines in non-cirrhotic ICU patients resulted in inadequate caspofungin exposures, especially for isolates near the current susceptibility breakpoints (MIC 0.125 mg/L). The authors recommended that a higher maintenance dose of caspofungin, 70 mg/day, should be administered in ICU patients with Child–Pugh B liver dysfunction if the classification is driven primarily by hypoalbuminaemia. Extracorporeal membrane oxygenation Extracorporeal membrane oxygenation (ECMO) is a type of cardiopulmonary bypass, which is used to sustain temporarily cardiac and/or respiratory function in critically ill patients. It was shown that ECMO may significantly affect the PK behaviour of drugs by various mechanisms (sequestration in the circuit, increased volume of distribution and decreased drug elimination), even if a lack of predictability is of concern.107 Voriconazole, being highly lipophilic, was shown to be significantly sequestered in the circuit,108,109 so that TDM is recommended for optimal antifungal treatment under these circumstances.109 Fluconazole, which is hydrophilic and renally cleared, may be significantly affected by haemodilution. Higher volume of distribution but similar clearance were observed in infants and children during ECMO when compared with historical controls not on ECMO.110,111 Caspofungin was found to be affected by ECMO to a lesser extent.109 Obesity Specific dosing guidance for antifungals in obese patients remains limited. A general dosing recommendation for all triazole antifungals is not possible given the marked physicochemical and PK differences between agents in the same class. Population PK models devised in patient populations with BMI classifications of obese (30–40 kg/m2) and morbidly obese (>40 kg/m2) suggest that fluconazole should be dosed based on total body weight (12 mg/kg loading dose, followed by 6 mg/kg/day maintenance) adjusted for renal function,112 whereas voriconazole should be dosed based on adjusted body weight.113,114 Although fewer data are available for itraconazole, posaconazole and isavuconazole, their greater physicochemical similarity to voriconazole suggests that they should be similarly dosed based on lean body weight.115 Liposomal amphotericin B has limited distribution into adipose tissue and, given potential toxicity concerns with doses based on total body weight in obese patients, doses should be calculated based on a patient’s lean body weight.116 Body weight is an important variable influencing the volume of distribution and clearance of all three echinocandins.115 Higher total body clearance of caspofungin has been reported among surgical ICU patients with a total body weight >75 kg.117 An increase in the daily caspofungin maintenance dose of 25%–50% has been proposed for patients weighing >75 kg with severe infection.118 In a PK study in patients with BMI <25, 25–40 and >40 kg/m2, micafungin clearance increased in proportion to weight in subjects weighing between 65 and 150 kg.119 The investigators proposed a bedside formula for individualized micafungin dosing in obese patients up to 200 kg: dose (mg) = patient weight (kg) + 42.120 Anidulafungin PK are also affected by weight. Lempers and colleagues reported that anidulafungin exposure was on average 32.5% lower in obese patients (BMI >40 kg/m2) compared with the general patient population.121 Although more data are needed, these studies collectively suggest that daily echinocandin doses should be increased by 25%–50% in patients weighing >75 kg, especially in critically ill patients with invasive candidiasis. Summary The overarching message of this review is that PK variability is a significant problem for antifungal therapy in the treatment of invasive candidiasis in adult patients. While its impact on treatment outcome in the past may have been minimized by lower MICs, increasing resistance among the echinocandins and triazoles is now pushing the limits of conventional dosing (Table 2). Therefore, new dosing paradigms rooted in PK/PD principles, analogous to once-daily (infrequent) dosing of aminoglycosides or continuous infusions of β-lactams with possible TDM, should be explored for current and future antifungal agents to maximize their effectiveness and preserve their utility for future generations of patients who will be at risk of invasive candidiasis. Table 2. Overview of antifungal dosing in invasive candidiasis Drug  Standard dose  Hepatic impairment  Renal impairment  CRRT  Obesity  Fluconazole  LD 800 mg 12 mg/kg day 1→MD 400 mg (6 mg/kg/day) q24h.124  Limited data, no specific recommendations.103  100–200 mg q24h if CLCR <50 mL/min; supplemental dose of 50–100 mg after IHD.  300–400 mg q12h.92  No dosage adjustment; dose on total body weight.118  Voriconazole  LD 6 mg/kg q12h day 1→MD 4 mg/kg 12 h.124  Mild to moderate hepatic insufficiency (Child–Pugh Class A and B): 6 mg/kg q12h × 2 doses (load), then 2 mg/kg iv q12h. Monitor serum concentrations.103  No dosage adjustment.  No dosage adjustment.95  Dose based on adjusted body weight.116  Anidulafungin  LD 200 mg day 1→100 mg q24h.124  For Child–Pugh class A, B, or C: usual dose.103  No dosage adjustment.  No dosage adjustment.97  Increase the daily echinocandin dose by at least 25%–50% of the usual dose in patients weighing >75 kg.118  Caspofungin  LD 70 mg day 1→50 mg q24h.124  For Child–Pugh score of 7–9, after initial 70 mg load on day 1, decrease daily dose to 35 mg q24h.103 Recent studies have suggested dosages should not be reduced in ICU patients if Child–Pugh score driven by hypoalbuminaemia.106  No dosage adjustment.  No dosage adjustment.98  Increase the daily echinocandin dose by at least 25% to 50% of the usual dose in patients weighing >75 kg.118  Micafungin  100 mg q24h.124  No dose adjustment needed For Child–Pugh score of 7–9. For severe hepatic dysfunction (Child–Pugh score of 10–12): increased micafungin clearance resulting in 7%–39% lower serum concentrations, but the clinical significance is unknown.103  No dosage adjustment.  No data. Usual dose likely.  Increase the daily echinocandin dose by least 25%–50% of the usual dose in patients weighing >75 kg.118–120Alternative dosing formula proposed for patients up to 200 kg. Dose (mg) = patient weight + 42.119  Lipid formulation of amphotericin B  3–5 mg/kg q24h.124  No data. Usual dose likely.103  No dosage adjustment.  No dosage adjustment.  Dose based on lean body weight.118  Flucytosine  25 mg/kg q6h.124  No data. Usual dose likely.103  25 mg/kg q 24–48 h; supplementary dose of 20–50 mg/kg after IHD.  NA  Dose based on ideal body weight.118  Drug  Standard dose  Hepatic impairment  Renal impairment  CRRT  Obesity  Fluconazole  LD 800 mg 12 mg/kg day 1→MD 400 mg (6 mg/kg/day) q24h.124  Limited data, no specific recommendations.103  100–200 mg q24h if CLCR <50 mL/min; supplemental dose of 50–100 mg after IHD.  300–400 mg q12h.92  No dosage adjustment; dose on total body weight.118  Voriconazole  LD 6 mg/kg q12h day 1→MD 4 mg/kg 12 h.124  Mild to moderate hepatic insufficiency (Child–Pugh Class A and B): 6 mg/kg q12h × 2 doses (load), then 2 mg/kg iv q12h. Monitor serum concentrations.103  No dosage adjustment.  No dosage adjustment.95  Dose based on adjusted body weight.116  Anidulafungin  LD 200 mg day 1→100 mg q24h.124  For Child–Pugh class A, B, or C: usual dose.103  No dosage adjustment.  No dosage adjustment.97  Increase the daily echinocandin dose by at least 25%–50% of the usual dose in patients weighing >75 kg.118  Caspofungin  LD 70 mg day 1→50 mg q24h.124  For Child–Pugh score of 7–9, after initial 70 mg load on day 1, decrease daily dose to 35 mg q24h.103 Recent studies have suggested dosages should not be reduced in ICU patients if Child–Pugh score driven by hypoalbuminaemia.106  No dosage adjustment.  No dosage adjustment.98  Increase the daily echinocandin dose by at least 25% to 50% of the usual dose in patients weighing >75 kg.118  Micafungin  100 mg q24h.124  No dose adjustment needed For Child–Pugh score of 7–9. For severe hepatic dysfunction (Child–Pugh score of 10–12): increased micafungin clearance resulting in 7%–39% lower serum concentrations, but the clinical significance is unknown.103  No dosage adjustment.  No data. Usual dose likely.  Increase the daily echinocandin dose by least 25%–50% of the usual dose in patients weighing >75 kg.118–120Alternative dosing formula proposed for patients up to 200 kg. Dose (mg) = patient weight + 42.119  Lipid formulation of amphotericin B  3–5 mg/kg q24h.124  No data. Usual dose likely.103  No dosage adjustment.  No dosage adjustment.  Dose based on lean body weight.118  Flucytosine  25 mg/kg q6h.124  No data. Usual dose likely.103  25 mg/kg q 24–48 h; supplementary dose of 20–50 mg/kg after IHD.  NA  Dose based on ideal body weight.118  LD, loading dose; MD, maintenance dose; IHD, intermittent haemodialysis; NA, not available. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara. Transparency declarations F. P. has received speaker honoraria from and attended advisory boards for Basilea Pharmaceutics, Gilead, MSD and Pfizer. R. E. L. has received speaker honoraria from Basilea Pharmaceutica, Gilead and MSD, and received research grants from Gilead and Pfizer.  The authors received no compensation for their contribution to the Supplement. This article was co-developed and published based on all authors’ approval. References 1 Sinnollareddy M, Peake SL, Roberts MS et al.   Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review. Int J Antimicrob Agents  2012; 39: 1– 10. http://dx.doi.org/10.1016/j.ijantimicag.2011.07.013 Google Scholar CrossRef Search ADS PubMed  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. http://dx.doi.org/10.1186/s13054-015-0758-3 Google Scholar CrossRef Search ADS PubMed  3 Baddley JW, Patel M, Bhavnani SM et al.   Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother  2008; 52: 3022– 8. http://dx.doi.org/10.1128/AAC.00116-08 Google Scholar CrossRef Search ADS PubMed  4 Labelle AJ, Micek ST, Roubinian N et al.   Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med  2008; 36: 2967– 72. http://dx.doi.org/10.1097/CCM.0b013e31818b3477 Google Scholar CrossRef Search ADS PubMed  5 Pai MP, Turpin RS, Garey KW. Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother  2007; 51: 35– 9. http://dx.doi.org/10.1128/AAC.00474-06 Google Scholar CrossRef Search ADS PubMed  6 Jullien V, Azoulay E, Schwebel C et al.   Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation. J Antimicrob Chemother  2017; 72: 181– 9. http://dx.doi.org/10.1093/jac/dkw352 Google Scholar CrossRef Search ADS PubMed  7 Timsit JF, Azoulay E, Schwebel C et al.   Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA  2016; 316: 1555– 64. http://dx.doi.org/10.1001/jama.2016.14655 Google Scholar CrossRef Search ADS PubMed  8 Kullberg BJ, Arendrup MC. Invasive candidiasis. N Engl J Med  2015; 373: 1445– 56. http://dx.doi.org/10.1056/NEJMra1315399 Google Scholar CrossRef Search ADS PubMed  9 Shah DN, Yau R, Lasco TM et al.   Impact of prior inappropriate fluconazole dosing on isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia. Antimicrob Agents Chemother  2012; 56: 3239– 43. http://dx.doi.org/10.1128/AAC.00019-12 Google Scholar CrossRef Search ADS PubMed  10 Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis  2014; 27: 484– 92. Google Scholar CrossRef Search ADS PubMed  11 Jensen RH, Johansen HK, Soes LM et al.   Posttreatment antifungal resistance among colonizing Candida isolates in candidemia patients: results from a systematic multicenter study. Antimicrob Agents Chemother  2015; 60: 1500– 8. Google Scholar CrossRef Search ADS PubMed  12 Prigent G, Ait-Ammar N, Levesque E et al.   Echinocandin resistance in Candida species isolates from liver transplant recipients. Antimicrob Agents Chemother  2017; 61: pii= e01229– 16. Google Scholar PubMed  13 Clancy CJ, Nguyen MH. Emergence of Candida auris: an international call to arms. Clin Infect Dis  2017; 64: 141– 3. http://dx.doi.org/10.1093/cid/ciw696 Google Scholar CrossRef Search ADS PubMed  14 Ostrosky-Zeichner L. Candida glabrata and FKS mutations: witnessing the emergence of the true multidrug-resistant Candida. Clin Infect Dis  2013; 56: 1733– 4. http://dx.doi.org/10.1093/cid/cit140 Google Scholar CrossRef Search ADS PubMed  15 Rex JH, Bennett JE, Sugar AM et al.   A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med  1994; 331: 1325– 30. Google Scholar CrossRef Search ADS PubMed  16 White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev  1998; 11: 382– 402. Google Scholar PubMed  17 Pfaller MA, Rex JH, Rinaldi MG. Antifungal susceptibility testing: technical advances and potential clinical applications. Clin Infect Dis  1997; 24: 776– 84. http://dx.doi.org/10.1093/clinids/24.5.776 Google Scholar CrossRef Search ADS PubMed  18 Clinical Laboratory and Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Approved Standard M27-A . CLSI, Wayne, PA, USA, 1997. 19 Rex JH, Pfaller MA, Galgiani JN et al.   Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis  1997; 24: 235– 47. Google Scholar CrossRef Search ADS PubMed  20 Andes D, van Ogtrop M. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother  1999; 43: 2116– 20. Google Scholar PubMed  21 Louie A, Drusano GL, Banerjee P et al.   Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother  1998; 42: 1105– 9. Google Scholar PubMed  22 Lepak AJ, Marchillo K, VanHecker J et al.   Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model. Antimicrob Agents Chemother  2013; 57: 5642– 8. http://dx.doi.org/10.1128/AAC.01354-13 Google Scholar CrossRef Search ADS PubMed  23 Andes D, Marchillo K, Stamstad T et al.   In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother  2003; 47: 3165– 9. http://dx.doi.org/10.1128/AAC.47.10.3165-3169.2003 Google Scholar CrossRef Search ADS PubMed  24 Andes D, Marchillo K, Conklin R et al.   Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Antimicrob Agents Chemother  2004; 48: 137– 42. http://dx.doi.org/10.1128/AAC.48.1.137-142.2004 Google Scholar CrossRef Search ADS PubMed  25 Andes D, Lepak A, Nett J et al.   In vivo fluconazole pharmacodynamics and resistance development in a previously susceptible Candida albicans population examined by microbiologic and transcriptional profiling. Antimicrob Agents Chemother  2006; 50: 2384– 94. http://dx.doi.org/10.1128/AAC.01305-05 Google Scholar CrossRef Search ADS PubMed  26 Rex JH, Pfaller MA, Walsh TJ et al.   Antifungal susceptibility testing: practical aspects and current challenges. Clin Microbiol Rev  2001; 14: 643– 58. Google Scholar CrossRef Search ADS PubMed  27 Arendrup MC, Cuenca-Estrella M, Donnelly JP et al.   Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother  2009; 53: 2704– 5, author reply 5–6. Google Scholar CrossRef Search ADS PubMed  28 Lee SC, Fung CP, Huang JS et al.   Clinical correlates of antifungal macrodilution susceptibility test results for non-AIDS patients with severe Candida infections treated with fluconazole. Antimicrob Agents Chemother  2000; 44: 2715– 8. http://dx.doi.org/10.1128/AAC.44.10.2715-2718.2000 Google Scholar CrossRef Search ADS PubMed  29 Rodriguez-Tudela JL, Almirante B, Rodriguez-Pardo D et al.   Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob Agents Chemother  2007; 51: 3599– 604. Google Scholar CrossRef Search ADS PubMed  30 Takakura S, Fujihara N, Saito T et al.   Clinical factors associated with fluconazole resistance and short-term survival in patients with Candida bloodstream infection. Eur J Clin Microbiol Infect Dis  2004; 23: 380– 8. http://dx.doi.org/10.1007/s10096-004-1128-2 Google Scholar CrossRef Search ADS PubMed  31 Clancy CJ, Yu VL, Morris AJ et al.   Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia. Antimicrob Agents Chemother  2005; 49: 3171– 7. http://dx.doi.org/10.1128/AAC.49.8.3171-3177.2005 Google Scholar CrossRef Search ADS PubMed  32 Goa KL, Barradell LB. Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs  1995; 50: 658– 90. Google Scholar CrossRef Search ADS PubMed  33 Cuesta I, Bielza C, Larranaga P et al.   Data mining validation of fluconazole breakpoints established by the European Committee on Antimicrobial Susceptibility Testing. Antimicrob Agents Chemother  2009; 53: 2949– 54. http://dx.doi.org/10.1128/AAC.00081-09 Google Scholar CrossRef Search ADS PubMed  34 Pfaller MA, Andes D, Diekema DJ et al.   Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug Resist Updat  2010; 13: 180– 95. http://dx.doi.org/10.1016/j.drup.2010.09.002 Google Scholar CrossRef Search ADS PubMed  35 Balkovec JM, Hughes DL, Masurekar PS et al.   Discovery and development of first in class antifungal caspofungin (CANCIDAS(R)) – a case study. Nat Prod Rep  2014; 31: 15– 34. http://dx.doi.org/10.1039/C3NP70070D Google Scholar CrossRef Search ADS PubMed  36 Stone JA, Holland SD, Wickersham PJ et al.   Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother  2002; 46: 739– 45. http://dx.doi.org/10.1128/AAC.46.3.739-745.2002 Google Scholar CrossRef Search ADS PubMed  37 Andes D, Marchillo K, Lowther J et al.   In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model. Antimicrob Agents Chemother  2003; 47: 1187– 92. http://dx.doi.org/10.1128/AAC.47.4.1187-1192.2003 Google Scholar CrossRef Search ADS PubMed  38 Andes D, Diekema DJ, Pfaller MA et al.   In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother  2010; 54: 2497– 506. http://dx.doi.org/10.1128/AAC.01584-09 Google Scholar CrossRef Search ADS PubMed  39 Andes D, Diekema DJ, Pfaller MA et al.   In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model. Antimicrob Agents Chemother  2008; 52: 539– 50. http://dx.doi.org/10.1128/AAC.01061-07 Google Scholar CrossRef Search ADS PubMed  40 Andes DR, Diekema DJ, Pfaller MA et al.   In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother  2008; 52: 3497– 503. Google Scholar CrossRef Search ADS PubMed  41 Gumbo T, Drusano GL, Liu W et al.   Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis. Antimicrob Agents Chemother  2006; 50: 3695– 700. http://dx.doi.org/10.1128/AAC.00507-06 Google Scholar CrossRef Search ADS PubMed  42 Louie A, Deziel M, Liu W et al.   Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother  2005; 49: 5058– 68. http://dx.doi.org/10.1128/AAC.49.12.5058-5068.2005 Google Scholar CrossRef Search ADS PubMed  43 Petraitiene R, Petraitis V, Hope WW et al.   Intermittent dosing of micafungin is effective for treatment of experimental disseminated candidiasis in persistently neutropenic rabbits. Clin Infect Dis  2015; 61 Suppl 6: S643– 51. Google Scholar CrossRef Search ADS PubMed  44 Pfaller MA, Diekema DJ, Ostrosky-Zeichner L et al.   Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol  2008; 46: 2620– 9. Google Scholar CrossRef Search ADS PubMed  45 Gumbo T, Drusano GL, Liu W et al.   Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia. Antimicrob Agents Chemother  2007; 51: 968– 74. http://dx.doi.org/10.1128/AAC.01337-06 Google Scholar CrossRef Search ADS PubMed  46 Pfaller MA, Diekema DJ, Andes D et al.   Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat  2011; 14: 164– 76. http://dx.doi.org/10.1016/j.drup.2011.01.004 Google Scholar CrossRef Search ADS PubMed  47 Lepak A, Castanheira M, Diekema D et al.   Optimizing echinocandin dosing and susceptibility breakpoint determination via in vivo pharmacodynamic evaluation against Candida glabrata with and without fks mutations. Antimicrob Agents Chemother  2012; 56: 5875– 82. http://dx.doi.org/10.1128/AAC.01102-12 Google Scholar CrossRef Search ADS PubMed  48 Andes D, Ambrose PG, Hammel JP et al.   Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. Antimicrob Agents Chemother  2011; 55: 2113– 21. http://dx.doi.org/10.1128/AAC.01430-10 Google Scholar CrossRef Search ADS PubMed  49 Hebert MF, Smith HE, Marbury TC et al.   Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol  2005; 45: 1145– 52. http://dx.doi.org/10.1177/0091270005279580 Google Scholar CrossRef Search ADS PubMed  50 Gumbo T. Single or 2-dose micafungin regimen for treatment of invasive candidiasis: therapia sterilisans magna! Clin Infect Dis  2015; 61 Suppl 6: S635– 42. Google Scholar CrossRef Search ADS PubMed  51 Lepak A, Marchillo K, VanHecker J et al.   Efficacy of extended-interval dosing of micafungin evaluated using a pharmacokinetic/pharmacodynamic study with humanized doses in mice. Antimicrob Agents Chemother  2015; 60: 674– 7. Google Scholar CrossRef Search ADS PubMed  52 Andes DR, Reynolds DK, Van Wart SA et al.   Clinical pharmacodynamic index identification for micafungin in esophageal candidiasis: dosing strategy optimization. Antimicrob Agents Chemother  2013; 57: 5714– 6. http://dx.doi.org/10.1128/AAC.01057-13 Google Scholar CrossRef Search ADS PubMed  53 Betts RF, Nucci M, Talwar D et al.   A multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis  2009; 48: 1676– 84. http://dx.doi.org/10.1086/598933 Google Scholar CrossRef Search ADS PubMed  54 Bader JC, Bhavnani SM, Andes DR et al.   We can do better: a fresh look at echinocandin dosing. J Antimicrob Chemother  2018; 73 Suppl 1: i44– i50. 55 Pappas PG, Kauffman CA, Andes DR et al.   Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis  2016; 62: e1– 50. Google Scholar CrossRef Search ADS PubMed  56 Andes D, Safdar N, Marchillo K et al.   Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models. Antimicrob Agents Chemother  2006; 50: 674– 84. http://dx.doi.org/10.1128/AAC.50.2.674-684.2006 Google Scholar CrossRef Search ADS PubMed  57 Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother  2001; 45: 922– 6. http://dx.doi.org/10.1128/AAC.45.3.922-926.2001 Google Scholar CrossRef Search ADS PubMed  58 Park BJ, Arthington-Skaggs BA, Hajjeh RA et al.   Evaluation of amphotericin B interpretive breakpoints for Candida bloodstream isolates by correlation with therapeutic outcome. Antimicrob Agents Chemother  2006; 50: 1287– 92. http://dx.doi.org/10.1128/AAC.50.4.1287-1292.2006 Google Scholar CrossRef Search ADS PubMed  59 Lepak AJ, Andes DR. Antifungal pharmacokinetics and pharmacodynamics. Cold Spring Harb Perspect Med  2014; 5: a019653. Google Scholar CrossRef Search ADS PubMed  60 Hong Y, Shaw PJ, Nath CE et al.   Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother  2006; 50: 935– 42. http://dx.doi.org/10.1128/AAC.50.3.935-942.2006 Google Scholar CrossRef Search ADS PubMed  61 Andes D, van Ogtrop M. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob Agents Chemother  2000; 44: 938– 42. http://dx.doi.org/10.1128/AAC.44.4.938-942.2000 Google Scholar CrossRef Search ADS PubMed  62 Hope WW, Warn PA, Sharp A et al.   Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing. Antimicrob Agents Chemother  2007; 51: 3760– 2. http://dx.doi.org/10.1128/AAC.00488-07 Google Scholar CrossRef Search ADS PubMed  63 Pasqualotto AC, Howard SJ, Moore CB et al.   Flucytosine therapeutic monitoring: 15 years experience from the UK. J Antimicrob Chemother  2007; 59: 791– 3. http://dx.doi.org/10.1093/jac/dkl550 Google Scholar CrossRef Search ADS PubMed  64 Deshpande A, Gaur S, Bal AM. Candidaemia in the non-neutropenic patient: a critique of the guidelines. Int J Antimicrob Agents  2013; 42: 294– 300. http://dx.doi.org/10.1016/j.ijantimicag.2013.06.005 Google Scholar CrossRef Search ADS PubMed  65 Baptista JP, Udy AA. Augmented renal clearance in critical illness: “the elephant in the ICU”? Minerva Anestesiol  2015; 81: 1050– 2. Google Scholar PubMed  66 Myrianthefs P, Markantonis SL, Evaggelopoulou P et al.   Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study. Int J Antimicrob Agents  2010; 35: 468– 72. Google Scholar CrossRef Search ADS PubMed  67 Ashbee HR, Barnes RA, Johnson EM et al.   Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother  2014; 69: 1162– 76. http://dx.doi.org/10.1093/jac/dkt508 Google Scholar CrossRef Search ADS PubMed  68 Owusu Obeng A, Egelund EF, Alsultan A et al.   CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy  2014; 34: 703– 18. Google Scholar CrossRef Search ADS PubMed  69 Wiederhold NP, Pennick GJ, Dorsey SA et al.   A reference laboratory experience of clinically achievable voriconazole, posaconazole, and itraconazole concentrations within the bloodstream and cerebral spinal fluid. Antimicrob Agents Chemother  2014; 58: 424– 31. http://dx.doi.org/10.1128/AAC.01558-13 Google Scholar CrossRef Search ADS PubMed  70 Cojutti P, Candoni A, Forghieri F et al.   Variability of voriconazole trough levels in haematological patients: influence of comedications with cytochrome P450(CYP) inhibitors and/or with CYP inhibitors plus CYP inducers. Basic Clin Pharmacol Toxicol  2016; 118: 474– 9. http://dx.doi.org/10.1111/bcpt.12530 Google Scholar CrossRef Search ADS PubMed  71 Dolton MJ, McLachlan AJ. Voriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity. Int J Antimicrob Agents  2014; 44: 183– 93. http://dx.doi.org/10.1016/j.ijantimicag.2014.05.019 Google Scholar CrossRef Search ADS PubMed  72 Tissot F, Agrawal S, Pagano L et al.   ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica  2017; 102: 433– 44. http://dx.doi.org/10.3324/haematol.2016.152900 Google Scholar CrossRef Search ADS PubMed  73 Moriyama B, Obeng AO, Barbarino J et al.   Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther  2016; doi: 10.1002/cpt.583. 74 Andes D, Azie N, Yang H et al.   Drug-drug interaction associated with mold-active triazoles among hospitalized patients. Antimicrob Agents Chemother  2016; 60: 3398– 406. http://dx.doi.org/10.1128/AAC.00054-16 Google Scholar CrossRef Search ADS PubMed  75 Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy  2010; 30: 842– 54. http://dx.doi.org/10.1592/phco.30.8.842 Google Scholar CrossRef Search ADS PubMed  76 Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev  2014; 27: 68– 88. http://dx.doi.org/10.1128/CMR.00046-13 Google Scholar CrossRef Search ADS PubMed  77 Mian UK, Mayers M, Garg Y et al.   Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state. J Ocul Pharmacol Ther  1998; 14: 459– 71. http://dx.doi.org/10.1089/jop.1998.14.459 Google Scholar CrossRef Search ADS PubMed  78 Spriet I, Delaere L, Lagrou K et al.   Intraocular penetration of voriconazole and caspofungin in a patient with fungal endophthalmitis. J Antimicrob Chemother  2009; 64: 877– 8. http://dx.doi.org/10.1093/jac/dkp306 Google Scholar CrossRef Search ADS PubMed  79 Pea F, Righi E, Cojutti P et al.   Intra-abdominal penetration and pharmacodynamic exposure to fluconazole in three liver transplant patients with deep-seated candidiasis. J Antimicrob Chemother  2014; 69: 2585– 6. http://dx.doi.org/10.1093/jac/dku169 Google Scholar CrossRef Search ADS PubMed  80 Muilwijk EW, Schouten JA, van Leeuwen HJ et al.   Pharmacokinetics of caspofungin in ICU patients. J Antimicrob Chemother  2014; 69: 3294– 9. http://dx.doi.org/10.1093/jac/dku313 Google Scholar CrossRef Search ADS PubMed  81 van Wanrooy MJ, Rodgers MG, Uges DR et al.   Low but sufficient anidulafungin exposure in critically ill patients. Antimicrob Agents Chemother  2014; 58: 304– 8. http://dx.doi.org/10.1128/AAC.01607-13 Google Scholar CrossRef Search ADS PubMed  82 Bruggemann RJ, Middel-Baars V, de Lange DW et al.   Pharmacokinetics of anidulafungin in critically ill intensive care unit patients with suspected or proven invasive fungal infections. Antimicrob Agents Chemother  2017; 61: pii= e01894– 16. Google Scholar PubMed  83 Lempers VJ, Schouten JA, Hunfeld NG et al.   Altered micafungin pharmacokinetics in intensive care unit patients. Antimicrob Agents Chemother  2015; 59: 4403– 9. http://dx.doi.org/10.1128/AAC.00623-15 Google Scholar CrossRef Search ADS PubMed  84 Gauthier GM, Nork TM, Prince R et al.   Subtherapeutic ocular penetration of caspofungin and associated treatment failure in Candida albicans endophthalmitis. Clin Infect Dis  2005; 41: e27– 8. Google Scholar CrossRef Search ADS PubMed  85 Strenger V, Farowski F, Muller C et al.   Low penetration of caspofungin into cerebrospinal fluid following intravenous administration of standard doses. Int J Antimicrob Agents  2017; 50: 272– 5. http://dx.doi.org/10.1016/j.ijantimicag.2017.02.024 Google Scholar CrossRef Search ADS PubMed  86 Goldblum D, Rohrer K, Frueh BE et al.   Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model. Antimicrob Agents Chemother  2002; 46: 3719– 23. http://dx.doi.org/10.1128/AAC.46.12.3719-3723.2002 Google Scholar CrossRef Search ADS PubMed  87 Groll AH, Giri N, Petraitis V et al.   Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis  2000; 182: 274– 82. http://dx.doi.org/10.1086/315643 Google Scholar CrossRef Search ADS PubMed  88 Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother  2000; 46: 171– 9. http://dx.doi.org/10.1093/jac/46.2.171 Google Scholar CrossRef Search ADS PubMed  89 Stockmann C, Constance JE, Roberts JK et al.   Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications. Clin Pharmacokinet  2014; 53: 429– 54. http://dx.doi.org/10.1007/s40262-014-0139-0 Google Scholar CrossRef Search ADS PubMed  90 Putt TL, Duffull SB, Schollum JB et al.   GFR may not accurately predict aspects of proximal tubule drug handling. Eur J Clin Pharmacol  2014; 70: 1221– 6. http://dx.doi.org/10.1007/s00228-014-1733-7 Google Scholar CrossRef Search ADS PubMed  91 Bergner R, Hoffmann M, Riedel KD et al.   Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg. Nephrol Dial Transplant  2006; 21: 1019– 23. http://dx.doi.org/10.1093/ndt/gfi284 Google Scholar CrossRef Search ADS PubMed  92 Gharibian KN, Mueller BA. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach. Clin Nephrol  2016; 86: 43– 50. http://dx.doi.org/10.5414/CN108824 Google Scholar CrossRef Search ADS PubMed  93 Sinnollareddy MG, Roberts MS, Lipman J et al.   Influence of sustained low-efficiency diafiltration (SLED–f) on interstitial fluid concentrations of fluconazole in a critically ill patient: use of microdialysis. Int J Antimicrob Agents  2015; 46: 121– 4. http://dx.doi.org/10.1016/j.ijantimicag.2015.02.017 Google Scholar CrossRef Search ADS PubMed  94 Sinnollareddy MG, Roberts MS, Lipman J et al.   Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents  2015; 45: 192– 5. http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013 Google Scholar CrossRef Search ADS PubMed  95 Kiser TH, Fish DN, Aquilante CL et al.   Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy. Crit Care  2015; 19: 32. Google Scholar CrossRef Search ADS PubMed  96 Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag  2007; 3: 71– 97. http://dx.doi.org/10.2147/tcrm.2007.3.1.71 Google Scholar CrossRef Search ADS PubMed  97 Aguilar G, Azanza JR, Carbonell JA et al.   Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration. J Antimicrob Chemother  2014; 69: 1620– 3. http://dx.doi.org/10.1093/jac/dkt542 Google Scholar CrossRef Search ADS PubMed  98 Roger C, Wallis SC, Muller L et al.   Caspofungin population pharmacokinetics in critically ill patients undergoing continuous veno-venous haemofiltration or haemodiafiltration. Clin Pharmacokinet  2016; doi:10.1007/s40262-016-0495-z. 99 Weiler S, Seger C, Pfisterer H et al.   Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. Antimicrob Agents Chemother  2013; 57: 4053– 7. http://dx.doi.org/10.1128/AAC.00335-13 Google Scholar CrossRef Search ADS PubMed  100 Trotman RL, Williamson JC, Shoemaker DM et al.   Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis  2005; 41: 1159– 66. http://dx.doi.org/10.1086/444500 Google Scholar CrossRef Search ADS PubMed  101 Kunka ME, Cady EA, Woo HC et al.   Flucytosine pharmacokinetics in a critically ill patient receiving continuous renal replacement therapy. Case Rep Crit Care  2015; 2015: 927496. Google Scholar PubMed  102 Westphal JF, Jehl F, Vetter D. Pharmacological, toxicologic, and microbiological considerations in the choice of initial antibiotic therapy for serious infections in patients with cirrhosis of the liver. Clin Infect Dis  1994; 18: 324– 35. http://dx.doi.org/10.1093/clinids/18.3.324 Google Scholar CrossRef Search ADS PubMed  103 Cota JM, Burgess DS. Antifungal dose adjustment in renal and hepatic dysfunction: pharmacokinetic and pharmacodynamic considerations. Curr Fungal Infect Reports  2010; 4: 120– 8. http://dx.doi.org/10.1007/s12281-010-0015-9 Google Scholar CrossRef Search ADS   104 European Medicines Agency. Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf. 105 Grau S, Luque S, Campillo N et al.   Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis. J Antimicrob Chemother  2015; 70: 2854– 61. http://dx.doi.org/10.1093/jac/dkv173 Google Scholar CrossRef Search ADS PubMed  106 Martial LC, Bruggemann RJ, Schouten JA et al.   Dose reduction of caspofungin in intensive care unit patients with Child Pugh B will result in suboptimal exposure. Clin Pharmacokinet  2016; 55: 723– 33. http://dx.doi.org/10.1007/s40262-015-0347-2 Google Scholar CrossRef Search ADS PubMed  107 Shekar K, Fraser JF, Smith MT et al.   Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care  2012; 27: 741 e9– 18. Google Scholar CrossRef Search ADS   108 Mehta NM, Halwick DR, Dodson BL et al.   Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment. Intensive Care Med  2007; 33: 1018– 24. http://dx.doi.org/10.1007/s00134-007-0606-2 Google Scholar CrossRef Search ADS PubMed  109 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. http://dx.doi.org/10.1093/jac/dkp026 Google Scholar CrossRef Search ADS PubMed  110 Watt KM, Benjamin DKJr, Cheifetz IM et al.   Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J  2012; 31: 1042– 7. Google Scholar PubMed  111 Watt KM, Gonzalez D, Benjamin DKJr et al.   Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive candidiasis in children supported with extracorporeal membrane oxygenation. Antimicrob Agents Chemother  2015; 59: 3935– 43. http://dx.doi.org/10.1128/AAC.00102-15 Google Scholar CrossRef Search ADS PubMed  112 Alobaid AS, Wallis SC, Jarrett P et al.   Effect of obesity on the population pharmacokinetics of fluconazole in critically ill patients. Antimicrob Agents Chemother  2016; 60: 6550– 7. http://dx.doi.org/10.1128/AAC.01088-16 Google Scholar CrossRef Search ADS PubMed  113 Davies-Vorbrodt S, Ito JI, Tegtmeier BR et al.   Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review. Pharmacotherapy  2013; 33: 22– 30. http://dx.doi.org/10.1002/phar.1156 Google Scholar CrossRef Search ADS PubMed  114 Moriyama B, Jarosinski PF, Figg WD et al.   Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype. Pharmacotherapy  2013; 33: e19– 22. Google Scholar CrossRef Search ADS PubMed  115 Payne KD, Hall RG. Dosing of antifungal agents in obese people. Expert Rev Anti Infect Ther  2016; 14: 257– 67. http://dx.doi.org/10.1586/14787210.2016.1128822 Google Scholar CrossRef Search ADS PubMed  116 Stone NR, Bicanic T, Salim R et al.   Liposomal amphotericin B (AmBisome®): a review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions. Drugs  2016; 76: 485– 500. Google Scholar CrossRef Search ADS PubMed  117 Nguyen TH, Hoppe-Tichy T, Geiss HK et al.   Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother  2007; 60: 100– 6. http://dx.doi.org/10.1093/jac/dkm125 Google Scholar CrossRef Search ADS PubMed  118 Amsden J, Slain D. Antifungal dosing in obesity: a review of the literature. Curr Fungal Infect Rep  2011; 5: 83. http://dx.doi.org/10.1007/s12281-011-0049-7 Google Scholar CrossRef Search ADS   119 Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother  2011; 55: 5107– 12. http://dx.doi.org/10.1128/AAC.05193-11 Google Scholar CrossRef Search ADS PubMed  120 Pasipanodya JP, Hall RG2nd, Gumbo T. In silico-derived bedside formula for individualized micafungin dosing for obese patients in the age of deterministic chaos. Clin Pharmacol Ther  2015; 97: 292– 7. http://dx.doi.org/10.1002/cpt.38 Google Scholar CrossRef Search ADS PubMed  121 Lempers VJ, van Rongen A, van Dongen EP et al.   Does weight impact anidulafungin pharmacokinetics? Clin Pharmacokinet  2016; 55: 1289– 94. Google Scholar CrossRef Search ADS PubMed  122 Louie A, Liu QF, Drusano GL et al.   Pharmacokinetic studies of fluconazole in rabbits characterizing doses which achieve peak levels in serum and area under the concentration-time curve values which mimic those of high-dose fluconazole in humans. Antimicrob Agents Chemother  1998; 42: 1512– 4. Google Scholar PubMed  123 Hope WW, Seibel NL, Schwartz CL et al.   Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother  2007; 51: 3714– 9. http://dx.doi.org/10.1128/AAC.00398-07 Google Scholar CrossRef Search ADS PubMed  124 Cornely OA, Bassetti M, Calandra T et al.   ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect  2012; 18 Suppl 7: 19– 37. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Overview of antifungal dosing in invasive candidiasis

Loading next page...
 
/lp/ou_press/overview-of-antifungal-dosing-in-invasive-candidiasis-CqoaS3SlCD
Publisher
Oxford University Press
Copyright
© The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0305-7453
eISSN
1460-2091
D.O.I.
10.1093/jac/dkx447
Publisher site
See Article on Publisher Site

Abstract

Abstract In the past, most antifungal therapy dosing recommendations for invasive candidiasis followed a ‘one-size fits all’ approach with recommendations for lowering maintenance dosages for some antifungals in the setting of renal or hepatic impairment. A growing body of pharmacokinetic/pharmacodynamic research, however now points to a widespread ‘silent epidemic’ of antifungal underdosing for invasive candidiasis, especially among critically ill patients or special populations who have altered volume of distribution, protein binding and drug clearance. In this review, we explore how current adult dosing recommendations for antifungal therapy in invasive candidiasis have evolved, and special populations where new approaches to dose optimization or therapeutic drug monitoring may be needed, especially in light of increasing antifungal resistance among Candida spp. Introduction A growing body of evidence suggests that antifungal therapy is frequently underdosed in treatment of invasive candidiasis, especially in critically ill patients.1 In a pharmacokinetic point prevalence study from 68 European ICUs, Sinnollareddy et al.2 found that one-third of fluconazole-treated patients failed to achieve minimum recommended pharmacokinetic/pharmacodynamic (PK/PD) target exposures, a factor previously identified in several retrospective studies as an independent risk factor for death.3–5 Drug exposures of anidulafungin and caspofungin were also variable or lower, on average, compared with exposures previously reported for healthy subjects. Recently, Jullien et al. reported that drug exposures among patients enrolled in a placebo-controlled trial of micafungin empirical therapy for invasive candidiasis were 50% lower than the values reported for healthy subjects, and 25% lower compared with hospitalized non-ICU patients.6,7 A possible silent epidemic of antifungal underdosing in hospitals among patients with invasive candidiasis is troubling for several reasons. First, the most commonly used agents, echinocandins and fluconazole, are well tolerated by patients even at much higher doses. Therefore, the risks versus benefits of using higher doses clearly favour more aggressive dosing for invasive candidiasis, where crude mortality rates still approach 40% even with effective therapy.8 Second, insufficient dosing of triazoles has been linked to the emergence of resistance,9 and Candida isolates with acquired multidrug resistance to fluconazole and echinocandins are increasing in frequency, with reported rates as high as 25%–30% when isolates are tested from deep tissue sites or mucosa after azole or echinocandin treatment.8,10–12 Finally, antifungal underdosing could theoretically favour the emergence and spread of MDR Candida glabrata and Candida auris in the critically ill and severely immunocompromised populations.13,14 In this article, we will review our current scientific rationale of antifungal dosing for invasive candidiasis, and summarize recent data concerning subpopulations of adult patients at risk for invasive candidiasis where dosing must be altered. We will also summarize adult patient-specific considerations that must be addressed when individualizing therapy and antifungal dosing for invasive candidiasis. Pharmacodynamic basis for antifungal dosing Triazoles Fluconazole was developed during the 1980s and first approved for clinical use in 1990. The drug quickly became the preferred agent for preventing and treating oral oesophageal candidiasis in patients with AIDS at a time before the availability of HAART. Fluconazole was the only available antifungal with predictable oral absorption and limited adverse effects. Intravenous fluconazole was also proved to be as effective as and less toxic than amphotericin B deoxycholate for the treatment of invasive candidiasis.15 However, long-term treatment with fluconazole, which was necessary in patients with advanced AIDS and persistently low CD4+ counts, inevitably led to relapsing oesophageal candidiasis that failed to respond to conventional fluconazole doses (100–400 mg/day).16 In some cases, fluconazole failures were linked to breakthrough infection caused by isolates with elevated MICs. However, many patients with relapsed oropharyngeal candidiasis would often still respond to higher doses of fluconazole.17 By 1997, the National Committee for Clinical Laboratory Standards (now Clinical Laboratory Standards Institute, CLSI) had developed susceptibility breakpoints for interpretation of fluconazole MICs performed using a proposed standardized broth microdilution method.18 Breakpoints for fluconazole included a novel ‘susceptible-dose dependent’ (SDD) category based on the clinical experience described above, where higher doses of fluconazole (12 mg/kg or 800 mg per day) were recommended for isolates with MICs ranging from 8 to 32 mg/L.19 The concept of a ‘pharmacodynamic’ SDD breakpoint was later supported by studies in animal models of invasive candidiasis that explored how changes in the dosing interval affected fluconazole efficacy over a wide range of doses. Andes and van Ogtrop20 and Louie et al.21 independently demonstrated that a fluconazole free-drug 24 h AUC to MIC ratio (fAUC/MIC) of 25–50 was associated with a 50% reduction in fungal tissue burden in neutropenic mice with disseminated candidiasis. This PK/PD target was roughly equivalent to maintaining fluconazole concentrations above the MIC throughout the entire dosing interval (i.e. 1 × MIC × 24 h = AUC/MIC 24) (Table 1). Subsequent studies confirmed that an fAUC/MIC target of 25–50 was predictive of efficacy for other triazoles (voriconazole, posaconazole, isavuconazole) if free (non-protein-bound) concentrations were considered.22–24 An fAUC/MIC target of 25–50 was also confirmed to produce 50% reduction in tissue fungal burden among other Candida species with different resistance profiles and/or resistance mechanisms.25 Table 1. PK/PD properties of antifungal agents for invasive candidiasis Antifungal  Activity against Candida spp.  PK/PD parameter associated with treatment efficacy  PK/PD references  Polyenes  fungicidal       DAmB    Cmax/MIC >10  Andes et al., 200157      AUC/MIC >100  Andes et al., 200656      (varies depending on tissue infection site)     LAmB    Cmax/MIC >40  Hong et al., 200660  Triazoles  fungistatic  fAUC/MIC 25–100  Andes and van Ogtrop, 199920   fluconazole      Louie et al., 199821,122   itraconazole      Andes et al., 200424   voriconazole      Andes et al., 200323   posaconazole      Lepak et al., 201322   isavuconazole      Lepak et al., 201551  Echinocandins  fungicidal  fAUC/MIC >20  Andes et al., 200337   anidulafungin    (C. albicans)  Andes et al., 200840 and 201148   caspofungin      Andes et al., 201038   micafungin            fAUC/MIC >7  Gumbo et al., 200745      (C. glabrata, C. parapsilosis)  Andes et al., 200839        Hope et al., 2007123        Petraitiene et al., 201543  Pyrimidine analogues  fungistatic  T>MIC 40%  Andes and van Ogtrop, 200061   flucytosine      Hope et al., 200762  Antifungal  Activity against Candida spp.  PK/PD parameter associated with treatment efficacy  PK/PD references  Polyenes  fungicidal       DAmB    Cmax/MIC >10  Andes et al., 200157      AUC/MIC >100  Andes et al., 200656      (varies depending on tissue infection site)     LAmB    Cmax/MIC >40  Hong et al., 200660  Triazoles  fungistatic  fAUC/MIC 25–100  Andes and van Ogtrop, 199920   fluconazole      Louie et al., 199821,122   itraconazole      Andes et al., 200424   voriconazole      Andes et al., 200323   posaconazole      Lepak et al., 201322   isavuconazole      Lepak et al., 201551  Echinocandins  fungicidal  fAUC/MIC >20  Andes et al., 200337   anidulafungin    (C. albicans)  Andes et al., 200840 and 201148   caspofungin      Andes et al., 201038   micafungin            fAUC/MIC >7  Gumbo et al., 200745      (C. glabrata, C. parapsilosis)  Andes et al., 200839        Hope et al., 2007123        Petraitiene et al., 201543  Pyrimidine analogues  fungistatic  T>MIC 40%  Andes and van Ogtrop, 200061   flucytosine      Hope et al., 200762  When the outcomes of oesophageal candidiasis treatment were analysed according to the MIC of the infecting isolate, fluconazole treatment was successful in 91%–100% of treated patients when the estimated fAUC/MIC surpassed 25, but was only 27%–35% successful in patients with a fAUC/MIC <25.26 Most patients with normal body habitus and renal function could achieve fAUC/MIC >25 up to a fluconazole MIC of 8 mg/L, but doses of 12 mg/kg/day (800 mg) were confirmed to be important for achieving this PK/PD target for SDD isolates (MIC 8–32 mg/L).19 Multiple observational studies have since documented a link between fluconazole fAUC/MIC and the outcomes of invasive candidiasis.3,5,26–31 Given the nearly 1:1 linear relationship between fluconazole dose and AUC,32 investigators have also reported that fluconazole dose/MIC >100 was an independent predictor of treatment success when MICs were determined using the EUCAST methodology.27,29,31 A fluconazole dose/MIC target of 100 was subsequently used as the basis for proposal of a EUCAST susceptibility breakpoint for fluconazole of ≤2 mg/L.33 The CLSI later adopted this same MIC susceptibility cut-off when it was shown that the lower breakpoint had improved sensitivity for detecting C. albicans that harbour acquired resistance mechanisms.34 Now, standard dosages of fluconazole (400 mg/day) are considered to have a higher probability of treatment failure when the 24 h fluconazole MIC is ≥4 mg/L.34 Echinocandins Caspofungin, the first echinocandin approved for clinical use, entered clinical trials in 1995 when there was still a dire need for new therapies active against fluconazole-resistant oral–oesophageal candidiasis.35 Early pharmacokinetic studies suggested that a 70 mg loading dose of caspofungin followed by 50 mg daily would result in levels >1 mg/L on the first day of therapy, a target that exceeded the MIC of 90% of the most clinically relevant Candida species.35,36 Subsequent animal studies provided a clearer description of the PK/PD behaviour of echinocandins during the treatment of invasive candidiasis. Andes and colleagues examined the effects of altered dosing intervals and escalating doses for a novel glucan synthesis inhibitor, HMR 3270, in a neutropenic murine model of disseminated candidiasis.37 The investigators found that treatment outcome was strongly correlated with drug dose and organism MIC, with a total drug Cmax/MIC 3.72 or AUC/MIC >300 suppressing Candida growth in the model. Maximal fungicidal effects were observed as the Cmax/MIC approached 10. Subsequent studies with caspofungin, micafungin and anidulafungin confirmed that 5- to 8-fold less drug was required to achieve similar reductions in Candida tissue fungal burden if echinocandins were administered as single dose.38–45 In a direct comparison of caspofungin, micafungin and anidulafungin against different Candida species., Andes et al.38 later reported that fAUC/MIC was highly predictive of treatment response for all three echinocandins, but fAUCs were lower for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) compared with C. albicans (mean, 20). These species-specific PD targets later served as the basis (along with population MIC data) for unique CLSI and EUCAST Candida species-specific susceptibility breakpoints for the echinocandins.46,47 The clinical validity of echinocandin PK/PD targets was subsequently analysed in 493 patients with invasive candidiasis who received micafungin as part of the Phase 3 clinical trial.48 A population PK model was used to estimate micafungin exposures and was validated in a subset of patients with available PK data. The investigators identified the following independent risk factors affecting cure: severity of illness, a micafungin total AUC/MIC >3000 for all Candida species, or a total drug AUC/MIC >5000 for non-C. parapsilosis species, an MIC <0.5 mg/L, and a history of steroid use (Table 1). Patients with a micafungin total drug AUC/MIC >3000 achieved clinical and mycological cure rates of 98%. Considering protein binding in humans, an AUC/MIC target >3000 translates to a free drug ratio of 7.5, whereas the AUC/MIC >5000 translates to a free drug ratio of 12.5.49 When corrected for protein binding, the micafungin AUC/MIC targets identified in the clinical trials (7.5 and 12.5, respectively) were almost identical to free-drug micafungin AUC/MIC targets previously identified in neutropenic mice.38,45,50 Collectively, these data suggested that higher intermittent dosing would optimize the PD of echinocandin therapy.51 This concept was tested in a randomized study of micafungin for oral oesophageal candidiasis that compared micafungin administered 150 mg daily with 300 mg dosed every other day.52 The mycological response rate at the end of therapy was higher in patients who received the higher-dose, intermittent micafungin regimen (85% versus 79%, respectively, P = 0.056) with significantly lower relapse rates (6% versus 12%, respectively, P = 0.05). More recently, Gumbo50 described a patient with underlying immunodeficiency of unclear aetiology and a history of recurrent oesophageal candidiasis who was initially treated with a standard micafungin dose of 100 mg daily for 2 weeks. The patient was subsequently administered a single 700 mg dose in the following week, followed by 1400 mg doses every other week with liver function test monitoring 3 days after each dose. The patient tolerated the regimen for 12 weeks until she developed evidence of liver function test abnormalities that was later attributed to injection of illicit drugs with acetaminophen. She later resumed the 1400 mg dosing every 2 weeks without elevation of liver enzymes. Several studies have explored the potential efficacy and safety of higher-dose daily echinocandin regimens. The largest of these studies was performed by Betts and colleagues,53 who performed a double-blind randomized trial in 204 patients with invasive candidiasis, with 104 patients receiving a standard 70 mg loading dose of caspofungin followed by 50 mg daily and 95 patients receiving 150 mg daily. A non-significant trend towards improved clinical and microbiological response was observed in patients receiving the higher-dose regimen, with overall response at day 10 of therapy of 94.5% versus 84% in the high- versus low-dose groups, respectively (Δ10.5%, 95% CI 0.7%–20.9%). Mortality was similar in both groups at 8 weeks and no safety concerns were found for caspofungin at a dose of 150 mg/day. Notably, most patients in the trials (>70%) had lower APACHE II scores and had uncomplicated candidaemia (84%). This study was also performed prior to wider dissemination of echinocandin-resistant C. glabrata; therefore it is possible that differences between the two dosing groups may have been greater in more critically ill patients with a higher prevalence of resistant organisms. Additional evaluations of dosing for current and novel echinocandins in development [e.g. rezafungin (CD101)] have been completed recently and are reviewed separately.54 Amphotericin B lipid formulations Lipid formulations of amphotericin B are recommended over conventional amphotericin B-deoxycholate (DAmB) for the treatment of invasive candidiasis except in resource-limited areas.55 Each of the three lipid formulations [amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD) and liposomal amphotericin B (LAmB)] is complexed to a different lipid carrier system, exhibits different PK properties, and is 5- to 7-fold less potent than DAmB on a mg/kg basis depending on the tissue site analysed.56 Studies comparing escalating doses and altering treatment intervals in invasive candidiasis have found that the Cmax/MIC is the PD parameter that best correlates with DAmB treatment outcome in experimental invasive candidiasis,57 with the AUC/MIC ratio and time above MIC less predictive of fungicidal activity. In disseminated candidiasis models, differences in the rates of Candida liver, spleen and lung fungal burden mirrored differences in tissue kinetics of amphotericin B measured by bioassay for each of the lipid amphotericin B formulations.56 Limited clinical data are available linking amphotericin B PK/PD to clinical endpoints. Restricted dosing and the limited MIC range for amphotericin against Candida species are factors that complicate clinical PK/PD studies.58 Toxicity of higher DAmB doses may also obscure the benefit of higher drug exposures.59 One paediatric study reported that a Cmax/MIC >40 was associated with maximal response during liposomal amphotericin B treatment,60 which, after correcting for potency differences, is similar to the DAmB Cmax/MIC of 10 reported in preclinical models of disseminated candidaemia.59 Flucytosine Flucytosine is occasionally used in combination with amphotericin B-based regimens for the treatment of CNS candidiasis, native valve endocarditis or fluconazole-resistant urinary candidiasis.55 Studies examining flucytosine PD in animal models of invasive candidiasis and cryptococcosis have shown that the percentage of time flucytosine concentrations surpass the MIC best predicts antifungal efficacy, with a %T>MIC of at least 40 required for fungistatic effect.61,62 Therefore, lower doses but more frequent administration of the drug (e.g. 25 mg/kg every 6 h) optimizes PK/PD target attainment and reduces the risk of bone marrow toxicity, which is linked to peak concentrations >100 mg/L.63 Patient-level considerations for dosing Triazoles Fluconazole is still considered the preferred triazole for the step-down treatment of candidaemia in non-neutropenic critically ill patients by several guidelines, with voriconazole being a valuable alternative.64 Although moderately lipophilic in nature, fluconazole is the only triazole significantly eliminated by the renal route. Considerable interindividual PK variability of fluconazole was documented in a small cohort of critically ill patients (n = 21) who were treated with a median dose of 400 mg/day. In 33% of these, drug exposure was insufficient to attain the PK/PD target of AUC/MIC >100, in spite of a relatively low median creatinine clearance (CLCR) (45 mL/min).2 Accordingly, it may be hypothesized that the risk of fluconazole underexposure with the fixed 400 mg/day dose may be even higher among patients with augmented renal clearance (CLCR >130 mL/min).65 The PK of voriconazole was also assessed in critically ill patients after standard intravenous (iv) dosing (6 mg/kg loading dose and 3–4 mg/kg twice daily thereafter) in a prospective observational study involving 18 patients with different degrees of renal function (12 with normal renal function, CLCR ≥60 mL/min, and 6 with moderate renal impairment, CLCR 40–55 mL/min).66 Large interindividual variability in Cmin was observed. Cmin was outside the desired therapeutic range (1–5.5 mg/L)67 in more than half of cases (56%), with 37% of patients having suboptimal exposure (≤1 mg/L) and 19% having potentially toxic levels (>5.5 mg/L). The wide interindividual variability was unrelated to differences in renal function, in agreement with the fact that voriconazole is a non-renally cleared drug. Voriconazole is a highly lipophilic drug that is almost completely metabolized by three CYP450 isoenzymes, namely CYP3A4, CYP2C9 and CYP2C19.68 Voriconazole shows wide interindividual PK variability among several different types of patient populations. This is mainly due to the genetic polymorphism of CYP2C19, the primary enzyme involved in the elimination pathway of voriconazole. Importantly, the distribution of the genetic polymorphisms of CYP2C19 may vary greatly among the various racial/ethnic groups. It has been shown that up to one-third of Caucasians may be ultra-rapid metabolizers of CYP2C19, and may experience drug underexposure with therapeutic failure; conversely, up to 20% of Asians may be poor metabolizers and may experience drug overexposure with toxicity.68 The wide interindividual variability of voriconazole was confirmed in a very large study of real-life therapeutic drug monitoring (TDM). Among 14 923 voriconazole Cmin values, almost half were outside the desired range (39.2% <1 mg/L and 10.4% >5.5 mg/L).69 The interindividual PK variability of voriconazole may become even wider during polytherapy owing to drug–drug interactions. It has been shown that co-medication with CYP450 inhibitors (i.e. proton pump inhibitors) and/or with CYP450 inducers (i.e. corticosteroids, phenobarbital, carbamazepine and rifampicin) may significantly influence voriconazole clearance.70,71 TDM of voriconazole is recommended by several guidelines.67,72 Therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype have also been developed.73 Both fluconazole (at doses >200 mg/day) and voriconazole are potent inhibitors of CYP2C9, CYP2C19 and CYP3A4. This may cause overexposure during co-administration with drugs that are substrates of these CYP450 isoenzymes.74 A recent study aimed at evaluating the prevalence of triazole drug–drug interactions among hospitalized adults who were identified within a database containing data from over 150 hospitals.75 The study showed that 82% of hospitalizations with voriconazole use included the use of at least one drug that resulted in a severe drug–drug interaction. Management of these interactions should involve appropriate dosage adjustments when necessary, and TDM when available (e.g. immunosuppressive drugs). The relatively high lipophilicity of the triazoles may ensure high penetration rates of these antifungals into deep tissues with a valid diffusion even through the anatomical barriers. These properties are clinically relevant in deep-seated Candida infections. Triazoles may achieve therapeutically relevant concentrations in several tissues, with tissue-to-plasma ratios of ≥0.7 in most cases, even in CSF and/or in cerebrum.76 Both fluconazole and voriconazole were shown to concentrate in the aqueous humour,77,78 and are therefore considered valuable agents in the treatment of Candida endophthalmitis. Likewise, it was recently shown the valuable intra-abdominal penetration of fluconazole into the bile and the ascites of three liver transplant patients ensured optimal PD exposure with successful clinical treatment of deep-seated candidiasis.79 Echinocandins The echinocandins are considered the first-line choice of treatment for candidaemia in non-neutropenic critically patients by several guidelines.64 Anidulafungin, caspofungin and micafungin are highly protein-bound hydrophilic compounds, which are ultimately eliminated mainly through ubiquitous spontaneous degradation. The echinocandins are administered at fixed dosages (anidulafungin, 200 mg loading dose followed by 100 mg/day; caspofungin, 70 mg loading dose followed by 50 mg/day; micafungin, 100 mg/day) and are traditionally considered as drugs that are easy to manage in critically ill patients, thanks to the low potential for drug–drug interaction and to the non-renal and less extensive hepatic clearance.80 However, recent studies have raised questions concerning the appropriateness of fixed standard dosages of these antifungal agents in attaining optimal PK/PD targets against Candida infections in the critically ill patients. Caspofungin PK was assessed in 21 critically ill patients. All of the patients had moderate hepatic dysfunction (Child–Pugh class B) and most were severely hypoalbuminaemic (<25 g/L in 81% of cases). Caspofungin showed limited intra-individual and moderate inter-individual PK variability, with drug exposures comparable to those observed in other non-critically ill patients. Although the authors concluded that ICU patients do not need higher dosages compared with other reference groups, it should not be overlooked that all of the study patients were affected by moderate hepatic dysfunction, namely a pathophysiological condition that was shown to increase caspofungin exposure. However, in critically ill patients with low albumin, the volume of distribution and clearance of echinocandins is likely increased. The PK of anidulafungin in critically ill patients was assessed in 20 subjects, most of whom were elderly, underwent abdominal surgery and had Candida peritonitis.81 No relationship between anidulafungin exposure, in terms of AUC, and disease severity scores [e.g. APACHE 2, simplified acute physiology score (SAPS), SOFA 2] or albuminaemia levels was found. However, anidulafungin exposure in this patient population was lower than that observed in the general patient population. This led the authors to conclude that, although no problem would be expected in the treatment of infections due to very susceptible strains of C. albicans or C. glabrata, conversely dosage adjustment based on TDM could be needed when dealing with Candida strains having higher MICs near to the clinical breakpoint. The presence of lower anidulafungin exposure compared with that in healthy volunteers or other patient populations was subsequently confirmed in another cohort of critically ill patients.82 The PK of micafungin was also found to be altered among 20 critically ill patients, most of whom were elderly and had moderate (Child–Pugh class B) or severe (Child–Pugh class C) hepatic dysfunction.83 Micafungin PK was assessed twice, on day 3 (n = 20) and on day 7 (n = 12). The PK behaviour was similar on the two assessment days and overall micafungin exposure in these critically ill patients was lower than that in healthy volunteers, even if not significantly different from that of other reference populations. The authors suggested that higher than standard dosages could be considered in this setting, and that TDM might represent a helpful tool for optimizing patient care. Their hydrophilic nature coupled with their high molecular weight prevent the echinocandins from achieving therapeutically effective concentrations in infection sites protected by anatomical barriers. Therefore, when dealing with Candida endophthalmitis or with CNS infections, echinocandin monotherapy should be avoided.84,85 Amphotericin B lipid formulations The PK of amphotericin B lipid formulations has never been investigated in critically ill patients with candidaemia and/or invasive candidiasis. However, according to the peculiar characteristics of these moieties, which are cleared from the bloodstream mainly by the reticulo-endothelial system, it is unlikely that the PK behaviour of these formulations would be affected by critical illness. Standard dosages up to 5 mg/kg/day should be appropriate even in this setting. When in presence of deep-seated complications, such as Candida endophthalmitis and/or of CNS infections, liposomal amphotericin B should be the preferred formulation. This is based on clinical experience and on evidence from preclinical animal models showing that the liposomal formulation achieved the highest concentrations in the aqueous humour, CSF and brain parenchymal tissue.86,87 Flucytosine Flucytosine PK have not been investigated in critically ill patients.88 This antifungal agent has limited protein binding and is eliminated by glomerular filtration. Accordingly, it would be expected that dose intensification could be a valuable approach for avoiding subinhibitory concentrations in critically ill patients with augmented renal clearance. Flucytosine may achieve therapeutically relevant concentrations in the vitreous humour and in the CSF, and may therefore represent an option in combination therapy for the treatment of fungal infections located in the eye or in the CSF.88,89 Special populations Renal impairment Renal impairment may represent an important concern for adjusting maintenance dosages for those antifungals that normally are eliminated by the renal route. Fluconazole is the only triazole that needs adjustments of the maintenance dose in relation to renal impairment. Since fluconazole undergoes glomerular filtration with partial tubular reabsorption, it has been recently documented that estimation of the glomerular filtration rate might not accurately predict fluconazole clearance, and this may interfere with correct dosage adjustments.90 TDM was suggested as a helpful tool for optimizing fluconazole exposure in the setting of critically ill patients, especially when renal replacement therapies (RRTs) are applied.67 An early study assessed the PK of fluconazole among 16 critically ill patients who underwent continuous veno-venous haemofiltration (CVVH).91 The ultrafiltration flow rate was of 1000–2000 mL/h in predilution mode. The authors showed that fluconazole is very efficiently eliminated during CVVH and that a dosage of 800 mg/day would be needed to ensure appropriate drug exposure in this setting. The PK behaviour of fluconazole was recently assessed also in critically ill patients receiving prolonged intermittent RRT.92 Monte Carlo simulations were performed in order to estimate the PTA of achieving an AUC/MIC ratio of 100 during the initial 48 h of antifungal therapy. It was shown that a fluconazole dosing regimen of 800 mg loading dose plus 400 mg twice daily (every 12 h or pre- and post-prolonged intermittent RRT) would be appropriate. Likewise, fluconazole PK was assessed during sustained low-efficiency diafiltration (SLED-f), which is a technique increasingly being utilized in critically ill patients because of its practical advantages over continuous RRT.93,94 It was shown that during a single SLED-f session of 6 h, 72% of fluconazole was cleared compared with the much lower clearance (33%–38%) reported during a 4 h intermittent haemodialysis session. The authors concluded that doses >200 mg/day should be required for attaining optimal PK/PD in patients undergoing SLED-f. Voriconazole is a non-renally cleared triazole whose iv use is contraindicated in critically ill patients with CLCR <50 mL/min. This recommendation is provided to prevent the accumulation of the sulphobutylether-β-cyclodextrin (SBECD) vehicle, which is present in the iv formulation and which is predominately excreted by glomerular filtration. A prospective, open-label PK study was carried out among 10 critically ill patients receiving iv voriconazole while undergoing continuous RRT (CRRT). The aim was to verify whether CVVH (median total ultrafiltration rate of 38 mL/kg/h) may sufficiently remove SBECD to allow for the use of iv voriconazole without significant risk of SBECD accumulation.95 Voriconazole clearance was only minimal during CVVH, which conversely removed SBECD efficiently at a rate similar to the ultrafiltration rate. The findings allowed the authors to conclude that standard dosages of iv voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation. The echinocandins are non-renally cleared drugs, and do not require dosage adjustments in the presence of renal impairment.96 Recent studies assessed the PK behaviour of anidulafungin and of caspofungin in critically ill patients undergoing CRRT and confirmed that no dosage adjustment for these echinocandins is needed under these circumstances.97–99 Amphotericin B lipid formulations are not renally cleared and do not need any dosage adjustments, either in the presence of renal impairment or in the presence of CRRT.100 Flucytosine is eliminated by glomerular filtration, and proportional dosage adjustments are required in patients with renal impairment.88 A recent case report provided evidence that dosing may be an issue for flucytosine in patients undergoing CRRT.101 Hepatic impairment Liver disease encompasses a wide range of both acute and chronic pathological changes that can alter the PK and tissue penetration of antifungal agents. Chronic cirrhosis is associated with changes in protein binding, altered volume of distribution, metabolism and altered renal clearance of many antibiotics and antifungals.102 Recommendations for antifungal dosing adjustment in patients with hepatic dysfunction, however, are not straightforward. Reduction of antifungal doses by one-third to one-half is recommended in the summary of manufacturers’ product characteristics (SmPC) in patients with moderate to severe hepatic insufficiency (i.e. Child–Pugh class B or greater) receiving treatment with itraconazole, voriconazole, caspofungin and possibly posaconazole.103 No dose adjustment is recommended for micafungin in patients with mild or moderate hepatic impairment.103 No dose adjustment is needed for Child–Pugh scores of 7–9. For severe hepatic dysfunction (Child–Pugh scores of 10–12), increased micafungin clearance results in 7%–39% lower serum concentrations, but the clinical significance of this finding is unknown. Fluconazole is cleared primarily through glomerular filtration and does not require adjustment for liver dysfunction. Similarly, anidulafungin is degraded through a non-hepatic enzymatic process and does not have a dosage adjustment recommendation in patients with severe hepatic dysfunction. No specific recommendations are available for amphotericin B products, but given their limited metabolism, dosage adjustment in hepatic dysfunction is unlikely to be necessary. A problem with these recommendations is that the Child–Pugh classification system was not developed to predict drug elimination capacity. The classification system is based on the two clinical features (encephalopathy and ascites) and three laboratory-based parameters (albumin, bilirubin and prothrombin time). Hepatic dysfunction is categorized into groups called A, B and C or ‘mild’, ‘moderate’ and ‘severe’, corresponding to 5–6, 7–9 and 10–15 scores, respectively. As a result, even subjects with a normal hepatic function are given a total score of 5 points (since each variable gives a score of 1 point even within the normal range) and would consequently be classified as having mild hepatic impairment.104 Moreover, laboratory-based parameters used in calculation of the Child–Pugh classification lack specificity for liver disease. For example, albumin levels may be influenced by inflammation and nutritional status and are often low in critically ill patients with sepsis. Bilirubin may be increased due to cholestasis, hepatocellular failure or haemolysis.104 Hence, PK data used to define the dosing recommendation in patients with Child–Pugh B or C chronic alcoholic or viral liver cirrhosis may not be applicable to critically ill patients with organ dysfunction. Several recent studies have suggested that hypoalbuminaemia, which could lead to a classification of ‘moderately severe’ Child–Pugh B, may be a risk factor for inadequate echinocandin exposure.6,105,106 Caspofungin labelling includes a recommendation for reduction of maintenance doses from 50 mg daily to 35 mg daily in patients with Child–Pugh class B or greater liver dysfunction. However, Martial and colleagues106 reported that dosage reduction following these guidelines in non-cirrhotic ICU patients resulted in inadequate caspofungin exposures, especially for isolates near the current susceptibility breakpoints (MIC 0.125 mg/L). The authors recommended that a higher maintenance dose of caspofungin, 70 mg/day, should be administered in ICU patients with Child–Pugh B liver dysfunction if the classification is driven primarily by hypoalbuminaemia. Extracorporeal membrane oxygenation Extracorporeal membrane oxygenation (ECMO) is a type of cardiopulmonary bypass, which is used to sustain temporarily cardiac and/or respiratory function in critically ill patients. It was shown that ECMO may significantly affect the PK behaviour of drugs by various mechanisms (sequestration in the circuit, increased volume of distribution and decreased drug elimination), even if a lack of predictability is of concern.107 Voriconazole, being highly lipophilic, was shown to be significantly sequestered in the circuit,108,109 so that TDM is recommended for optimal antifungal treatment under these circumstances.109 Fluconazole, which is hydrophilic and renally cleared, may be significantly affected by haemodilution. Higher volume of distribution but similar clearance were observed in infants and children during ECMO when compared with historical controls not on ECMO.110,111 Caspofungin was found to be affected by ECMO to a lesser extent.109 Obesity Specific dosing guidance for antifungals in obese patients remains limited. A general dosing recommendation for all triazole antifungals is not possible given the marked physicochemical and PK differences between agents in the same class. Population PK models devised in patient populations with BMI classifications of obese (30–40 kg/m2) and morbidly obese (>40 kg/m2) suggest that fluconazole should be dosed based on total body weight (12 mg/kg loading dose, followed by 6 mg/kg/day maintenance) adjusted for renal function,112 whereas voriconazole should be dosed based on adjusted body weight.113,114 Although fewer data are available for itraconazole, posaconazole and isavuconazole, their greater physicochemical similarity to voriconazole suggests that they should be similarly dosed based on lean body weight.115 Liposomal amphotericin B has limited distribution into adipose tissue and, given potential toxicity concerns with doses based on total body weight in obese patients, doses should be calculated based on a patient’s lean body weight.116 Body weight is an important variable influencing the volume of distribution and clearance of all three echinocandins.115 Higher total body clearance of caspofungin has been reported among surgical ICU patients with a total body weight >75 kg.117 An increase in the daily caspofungin maintenance dose of 25%–50% has been proposed for patients weighing >75 kg with severe infection.118 In a PK study in patients with BMI <25, 25–40 and >40 kg/m2, micafungin clearance increased in proportion to weight in subjects weighing between 65 and 150 kg.119 The investigators proposed a bedside formula for individualized micafungin dosing in obese patients up to 200 kg: dose (mg) = patient weight (kg) + 42.120 Anidulafungin PK are also affected by weight. Lempers and colleagues reported that anidulafungin exposure was on average 32.5% lower in obese patients (BMI >40 kg/m2) compared with the general patient population.121 Although more data are needed, these studies collectively suggest that daily echinocandin doses should be increased by 25%–50% in patients weighing >75 kg, especially in critically ill patients with invasive candidiasis. Summary The overarching message of this review is that PK variability is a significant problem for antifungal therapy in the treatment of invasive candidiasis in adult patients. While its impact on treatment outcome in the past may have been minimized by lower MICs, increasing resistance among the echinocandins and triazoles is now pushing the limits of conventional dosing (Table 2). Therefore, new dosing paradigms rooted in PK/PD principles, analogous to once-daily (infrequent) dosing of aminoglycosides or continuous infusions of β-lactams with possible TDM, should be explored for current and future antifungal agents to maximize their effectiveness and preserve their utility for future generations of patients who will be at risk of invasive candidiasis. Table 2. Overview of antifungal dosing in invasive candidiasis Drug  Standard dose  Hepatic impairment  Renal impairment  CRRT  Obesity  Fluconazole  LD 800 mg 12 mg/kg day 1→MD 400 mg (6 mg/kg/day) q24h.124  Limited data, no specific recommendations.103  100–200 mg q24h if CLCR <50 mL/min; supplemental dose of 50–100 mg after IHD.  300–400 mg q12h.92  No dosage adjustment; dose on total body weight.118  Voriconazole  LD 6 mg/kg q12h day 1→MD 4 mg/kg 12 h.124  Mild to moderate hepatic insufficiency (Child–Pugh Class A and B): 6 mg/kg q12h × 2 doses (load), then 2 mg/kg iv q12h. Monitor serum concentrations.103  No dosage adjustment.  No dosage adjustment.95  Dose based on adjusted body weight.116  Anidulafungin  LD 200 mg day 1→100 mg q24h.124  For Child–Pugh class A, B, or C: usual dose.103  No dosage adjustment.  No dosage adjustment.97  Increase the daily echinocandin dose by at least 25%–50% of the usual dose in patients weighing >75 kg.118  Caspofungin  LD 70 mg day 1→50 mg q24h.124  For Child–Pugh score of 7–9, after initial 70 mg load on day 1, decrease daily dose to 35 mg q24h.103 Recent studies have suggested dosages should not be reduced in ICU patients if Child–Pugh score driven by hypoalbuminaemia.106  No dosage adjustment.  No dosage adjustment.98  Increase the daily echinocandin dose by at least 25% to 50% of the usual dose in patients weighing >75 kg.118  Micafungin  100 mg q24h.124  No dose adjustment needed For Child–Pugh score of 7–9. For severe hepatic dysfunction (Child–Pugh score of 10–12): increased micafungin clearance resulting in 7%–39% lower serum concentrations, but the clinical significance is unknown.103  No dosage adjustment.  No data. Usual dose likely.  Increase the daily echinocandin dose by least 25%–50% of the usual dose in patients weighing >75 kg.118–120Alternative dosing formula proposed for patients up to 200 kg. Dose (mg) = patient weight + 42.119  Lipid formulation of amphotericin B  3–5 mg/kg q24h.124  No data. Usual dose likely.103  No dosage adjustment.  No dosage adjustment.  Dose based on lean body weight.118  Flucytosine  25 mg/kg q6h.124  No data. Usual dose likely.103  25 mg/kg q 24–48 h; supplementary dose of 20–50 mg/kg after IHD.  NA  Dose based on ideal body weight.118  Drug  Standard dose  Hepatic impairment  Renal impairment  CRRT  Obesity  Fluconazole  LD 800 mg 12 mg/kg day 1→MD 400 mg (6 mg/kg/day) q24h.124  Limited data, no specific recommendations.103  100–200 mg q24h if CLCR <50 mL/min; supplemental dose of 50–100 mg after IHD.  300–400 mg q12h.92  No dosage adjustment; dose on total body weight.118  Voriconazole  LD 6 mg/kg q12h day 1→MD 4 mg/kg 12 h.124  Mild to moderate hepatic insufficiency (Child–Pugh Class A and B): 6 mg/kg q12h × 2 doses (load), then 2 mg/kg iv q12h. Monitor serum concentrations.103  No dosage adjustment.  No dosage adjustment.95  Dose based on adjusted body weight.116  Anidulafungin  LD 200 mg day 1→100 mg q24h.124  For Child–Pugh class A, B, or C: usual dose.103  No dosage adjustment.  No dosage adjustment.97  Increase the daily echinocandin dose by at least 25%–50% of the usual dose in patients weighing >75 kg.118  Caspofungin  LD 70 mg day 1→50 mg q24h.124  For Child–Pugh score of 7–9, after initial 70 mg load on day 1, decrease daily dose to 35 mg q24h.103 Recent studies have suggested dosages should not be reduced in ICU patients if Child–Pugh score driven by hypoalbuminaemia.106  No dosage adjustment.  No dosage adjustment.98  Increase the daily echinocandin dose by at least 25% to 50% of the usual dose in patients weighing >75 kg.118  Micafungin  100 mg q24h.124  No dose adjustment needed For Child–Pugh score of 7–9. For severe hepatic dysfunction (Child–Pugh score of 10–12): increased micafungin clearance resulting in 7%–39% lower serum concentrations, but the clinical significance is unknown.103  No dosage adjustment.  No data. Usual dose likely.  Increase the daily echinocandin dose by least 25%–50% of the usual dose in patients weighing >75 kg.118–120Alternative dosing formula proposed for patients up to 200 kg. Dose (mg) = patient weight + 42.119  Lipid formulation of amphotericin B  3–5 mg/kg q24h.124  No data. Usual dose likely.103  No dosage adjustment.  No dosage adjustment.  Dose based on lean body weight.118  Flucytosine  25 mg/kg q6h.124  No data. Usual dose likely.103  25 mg/kg q 24–48 h; supplementary dose of 20–50 mg/kg after IHD.  NA  Dose based on ideal body weight.118  LD, loading dose; MD, maintenance dose; IHD, intermittent haemodialysis; NA, not available. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara. Transparency declarations F. P. has received speaker honoraria from and attended advisory boards for Basilea Pharmaceutics, Gilead, MSD and Pfizer. R. E. L. has received speaker honoraria from Basilea Pharmaceutica, Gilead and MSD, and received research grants from Gilead and Pfizer.  The authors received no compensation for their contribution to the Supplement. This article was co-developed and published based on all authors’ approval. References 1 Sinnollareddy M, Peake SL, Roberts MS et al.   Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review. Int J Antimicrob Agents  2012; 39: 1– 10. http://dx.doi.org/10.1016/j.ijantimicag.2011.07.013 Google Scholar CrossRef Search ADS PubMed  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. http://dx.doi.org/10.1186/s13054-015-0758-3 Google Scholar CrossRef Search ADS PubMed  3 Baddley JW, Patel M, Bhavnani SM et al.   Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother  2008; 52: 3022– 8. http://dx.doi.org/10.1128/AAC.00116-08 Google Scholar CrossRef Search ADS PubMed  4 Labelle AJ, Micek ST, Roubinian N et al.   Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med  2008; 36: 2967– 72. http://dx.doi.org/10.1097/CCM.0b013e31818b3477 Google Scholar CrossRef Search ADS PubMed  5 Pai MP, Turpin RS, Garey KW. Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother  2007; 51: 35– 9. http://dx.doi.org/10.1128/AAC.00474-06 Google Scholar CrossRef Search ADS PubMed  6 Jullien V, Azoulay E, Schwebel C et al.   Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation. J Antimicrob Chemother  2017; 72: 181– 9. http://dx.doi.org/10.1093/jac/dkw352 Google Scholar CrossRef Search ADS PubMed  7 Timsit JF, Azoulay E, Schwebel C et al.   Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA  2016; 316: 1555– 64. http://dx.doi.org/10.1001/jama.2016.14655 Google Scholar CrossRef Search ADS PubMed  8 Kullberg BJ, Arendrup MC. Invasive candidiasis. N Engl J Med  2015; 373: 1445– 56. http://dx.doi.org/10.1056/NEJMra1315399 Google Scholar CrossRef Search ADS PubMed  9 Shah DN, Yau R, Lasco TM et al.   Impact of prior inappropriate fluconazole dosing on isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia. Antimicrob Agents Chemother  2012; 56: 3239– 43. http://dx.doi.org/10.1128/AAC.00019-12 Google Scholar CrossRef Search ADS PubMed  10 Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis  2014; 27: 484– 92. Google Scholar CrossRef Search ADS PubMed  11 Jensen RH, Johansen HK, Soes LM et al.   Posttreatment antifungal resistance among colonizing Candida isolates in candidemia patients: results from a systematic multicenter study. Antimicrob Agents Chemother  2015; 60: 1500– 8. Google Scholar CrossRef Search ADS PubMed  12 Prigent G, Ait-Ammar N, Levesque E et al.   Echinocandin resistance in Candida species isolates from liver transplant recipients. Antimicrob Agents Chemother  2017; 61: pii= e01229– 16. Google Scholar PubMed  13 Clancy CJ, Nguyen MH. Emergence of Candida auris: an international call to arms. Clin Infect Dis  2017; 64: 141– 3. http://dx.doi.org/10.1093/cid/ciw696 Google Scholar CrossRef Search ADS PubMed  14 Ostrosky-Zeichner L. Candida glabrata and FKS mutations: witnessing the emergence of the true multidrug-resistant Candida. Clin Infect Dis  2013; 56: 1733– 4. http://dx.doi.org/10.1093/cid/cit140 Google Scholar CrossRef Search ADS PubMed  15 Rex JH, Bennett JE, Sugar AM et al.   A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med  1994; 331: 1325– 30. Google Scholar CrossRef Search ADS PubMed  16 White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev  1998; 11: 382– 402. Google Scholar PubMed  17 Pfaller MA, Rex JH, Rinaldi MG. Antifungal susceptibility testing: technical advances and potential clinical applications. Clin Infect Dis  1997; 24: 776– 84. http://dx.doi.org/10.1093/clinids/24.5.776 Google Scholar CrossRef Search ADS PubMed  18 Clinical Laboratory and Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Approved Standard M27-A . CLSI, Wayne, PA, USA, 1997. 19 Rex JH, Pfaller MA, Galgiani JN et al.   Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis  1997; 24: 235– 47. Google Scholar CrossRef Search ADS PubMed  20 Andes D, van Ogtrop M. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother  1999; 43: 2116– 20. Google Scholar PubMed  21 Louie A, Drusano GL, Banerjee P et al.   Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother  1998; 42: 1105– 9. Google Scholar PubMed  22 Lepak AJ, Marchillo K, VanHecker J et al.   Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model. Antimicrob Agents Chemother  2013; 57: 5642– 8. http://dx.doi.org/10.1128/AAC.01354-13 Google Scholar CrossRef Search ADS PubMed  23 Andes D, Marchillo K, Stamstad T et al.   In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother  2003; 47: 3165– 9. http://dx.doi.org/10.1128/AAC.47.10.3165-3169.2003 Google Scholar CrossRef Search ADS PubMed  24 Andes D, Marchillo K, Conklin R et al.   Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Antimicrob Agents Chemother  2004; 48: 137– 42. http://dx.doi.org/10.1128/AAC.48.1.137-142.2004 Google Scholar CrossRef Search ADS PubMed  25 Andes D, Lepak A, Nett J et al.   In vivo fluconazole pharmacodynamics and resistance development in a previously susceptible Candida albicans population examined by microbiologic and transcriptional profiling. Antimicrob Agents Chemother  2006; 50: 2384– 94. http://dx.doi.org/10.1128/AAC.01305-05 Google Scholar CrossRef Search ADS PubMed  26 Rex JH, Pfaller MA, Walsh TJ et al.   Antifungal susceptibility testing: practical aspects and current challenges. Clin Microbiol Rev  2001; 14: 643– 58. Google Scholar CrossRef Search ADS PubMed  27 Arendrup MC, Cuenca-Estrella M, Donnelly JP et al.   Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother  2009; 53: 2704– 5, author reply 5–6. Google Scholar CrossRef Search ADS PubMed  28 Lee SC, Fung CP, Huang JS et al.   Clinical correlates of antifungal macrodilution susceptibility test results for non-AIDS patients with severe Candida infections treated with fluconazole. Antimicrob Agents Chemother  2000; 44: 2715– 8. http://dx.doi.org/10.1128/AAC.44.10.2715-2718.2000 Google Scholar CrossRef Search ADS PubMed  29 Rodriguez-Tudela JL, Almirante B, Rodriguez-Pardo D et al.   Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob Agents Chemother  2007; 51: 3599– 604. Google Scholar CrossRef Search ADS PubMed  30 Takakura S, Fujihara N, Saito T et al.   Clinical factors associated with fluconazole resistance and short-term survival in patients with Candida bloodstream infection. Eur J Clin Microbiol Infect Dis  2004; 23: 380– 8. http://dx.doi.org/10.1007/s10096-004-1128-2 Google Scholar CrossRef Search ADS PubMed  31 Clancy CJ, Yu VL, Morris AJ et al.   Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia. Antimicrob Agents Chemother  2005; 49: 3171– 7. http://dx.doi.org/10.1128/AAC.49.8.3171-3177.2005 Google Scholar CrossRef Search ADS PubMed  32 Goa KL, Barradell LB. Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs  1995; 50: 658– 90. Google Scholar CrossRef Search ADS PubMed  33 Cuesta I, Bielza C, Larranaga P et al.   Data mining validation of fluconazole breakpoints established by the European Committee on Antimicrobial Susceptibility Testing. Antimicrob Agents Chemother  2009; 53: 2949– 54. http://dx.doi.org/10.1128/AAC.00081-09 Google Scholar CrossRef Search ADS PubMed  34 Pfaller MA, Andes D, Diekema DJ et al.   Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug Resist Updat  2010; 13: 180– 95. http://dx.doi.org/10.1016/j.drup.2010.09.002 Google Scholar CrossRef Search ADS PubMed  35 Balkovec JM, Hughes DL, Masurekar PS et al.   Discovery and development of first in class antifungal caspofungin (CANCIDAS(R)) – a case study. Nat Prod Rep  2014; 31: 15– 34. http://dx.doi.org/10.1039/C3NP70070D Google Scholar CrossRef Search ADS PubMed  36 Stone JA, Holland SD, Wickersham PJ et al.   Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother  2002; 46: 739– 45. http://dx.doi.org/10.1128/AAC.46.3.739-745.2002 Google Scholar CrossRef Search ADS PubMed  37 Andes D, Marchillo K, Lowther J et al.   In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model. Antimicrob Agents Chemother  2003; 47: 1187– 92. http://dx.doi.org/10.1128/AAC.47.4.1187-1192.2003 Google Scholar CrossRef Search ADS PubMed  38 Andes D, Diekema DJ, Pfaller MA et al.   In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother  2010; 54: 2497– 506. http://dx.doi.org/10.1128/AAC.01584-09 Google Scholar CrossRef Search ADS PubMed  39 Andes D, Diekema DJ, Pfaller MA et al.   In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model. Antimicrob Agents Chemother  2008; 52: 539– 50. http://dx.doi.org/10.1128/AAC.01061-07 Google Scholar CrossRef Search ADS PubMed  40 Andes DR, Diekema DJ, Pfaller MA et al.   In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother  2008; 52: 3497– 503. Google Scholar CrossRef Search ADS PubMed  41 Gumbo T, Drusano GL, Liu W et al.   Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis. Antimicrob Agents Chemother  2006; 50: 3695– 700. http://dx.doi.org/10.1128/AAC.00507-06 Google Scholar CrossRef Search ADS PubMed  42 Louie A, Deziel M, Liu W et al.   Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother  2005; 49: 5058– 68. http://dx.doi.org/10.1128/AAC.49.12.5058-5068.2005 Google Scholar CrossRef Search ADS PubMed  43 Petraitiene R, Petraitis V, Hope WW et al.   Intermittent dosing of micafungin is effective for treatment of experimental disseminated candidiasis in persistently neutropenic rabbits. Clin Infect Dis  2015; 61 Suppl 6: S643– 51. Google Scholar CrossRef Search ADS PubMed  44 Pfaller MA, Diekema DJ, Ostrosky-Zeichner L et al.   Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol  2008; 46: 2620– 9. Google Scholar CrossRef Search ADS PubMed  45 Gumbo T, Drusano GL, Liu W et al.   Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia. Antimicrob Agents Chemother  2007; 51: 968– 74. http://dx.doi.org/10.1128/AAC.01337-06 Google Scholar CrossRef Search ADS PubMed  46 Pfaller MA, Diekema DJ, Andes D et al.   Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat  2011; 14: 164– 76. http://dx.doi.org/10.1016/j.drup.2011.01.004 Google Scholar CrossRef Search ADS PubMed  47 Lepak A, Castanheira M, Diekema D et al.   Optimizing echinocandin dosing and susceptibility breakpoint determination via in vivo pharmacodynamic evaluation against Candida glabrata with and without fks mutations. Antimicrob Agents Chemother  2012; 56: 5875– 82. http://dx.doi.org/10.1128/AAC.01102-12 Google Scholar CrossRef Search ADS PubMed  48 Andes D, Ambrose PG, Hammel JP et al.   Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. Antimicrob Agents Chemother  2011; 55: 2113– 21. http://dx.doi.org/10.1128/AAC.01430-10 Google Scholar CrossRef Search ADS PubMed  49 Hebert MF, Smith HE, Marbury TC et al.   Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol  2005; 45: 1145– 52. http://dx.doi.org/10.1177/0091270005279580 Google Scholar CrossRef Search ADS PubMed  50 Gumbo T. Single or 2-dose micafungin regimen for treatment of invasive candidiasis: therapia sterilisans magna! Clin Infect Dis  2015; 61 Suppl 6: S635– 42. Google Scholar CrossRef Search ADS PubMed  51 Lepak A, Marchillo K, VanHecker J et al.   Efficacy of extended-interval dosing of micafungin evaluated using a pharmacokinetic/pharmacodynamic study with humanized doses in mice. Antimicrob Agents Chemother  2015; 60: 674– 7. Google Scholar CrossRef Search ADS PubMed  52 Andes DR, Reynolds DK, Van Wart SA et al.   Clinical pharmacodynamic index identification for micafungin in esophageal candidiasis: dosing strategy optimization. Antimicrob Agents Chemother  2013; 57: 5714– 6. http://dx.doi.org/10.1128/AAC.01057-13 Google Scholar CrossRef Search ADS PubMed  53 Betts RF, Nucci M, Talwar D et al.   A multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis  2009; 48: 1676– 84. http://dx.doi.org/10.1086/598933 Google Scholar CrossRef Search ADS PubMed  54 Bader JC, Bhavnani SM, Andes DR et al.   We can do better: a fresh look at echinocandin dosing. J Antimicrob Chemother  2018; 73 Suppl 1: i44– i50. 55 Pappas PG, Kauffman CA, Andes DR et al.   Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis  2016; 62: e1– 50. Google Scholar CrossRef Search ADS PubMed  56 Andes D, Safdar N, Marchillo K et al.   Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models. Antimicrob Agents Chemother  2006; 50: 674– 84. http://dx.doi.org/10.1128/AAC.50.2.674-684.2006 Google Scholar CrossRef Search ADS PubMed  57 Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother  2001; 45: 922– 6. http://dx.doi.org/10.1128/AAC.45.3.922-926.2001 Google Scholar CrossRef Search ADS PubMed  58 Park BJ, Arthington-Skaggs BA, Hajjeh RA et al.   Evaluation of amphotericin B interpretive breakpoints for Candida bloodstream isolates by correlation with therapeutic outcome. Antimicrob Agents Chemother  2006; 50: 1287– 92. http://dx.doi.org/10.1128/AAC.50.4.1287-1292.2006 Google Scholar CrossRef Search ADS PubMed  59 Lepak AJ, Andes DR. Antifungal pharmacokinetics and pharmacodynamics. Cold Spring Harb Perspect Med  2014; 5: a019653. Google Scholar CrossRef Search ADS PubMed  60 Hong Y, Shaw PJ, Nath CE et al.   Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother  2006; 50: 935– 42. http://dx.doi.org/10.1128/AAC.50.3.935-942.2006 Google Scholar CrossRef Search ADS PubMed  61 Andes D, van Ogtrop M. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob Agents Chemother  2000; 44: 938– 42. http://dx.doi.org/10.1128/AAC.44.4.938-942.2000 Google Scholar CrossRef Search ADS PubMed  62 Hope WW, Warn PA, Sharp A et al.   Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing. Antimicrob Agents Chemother  2007; 51: 3760– 2. http://dx.doi.org/10.1128/AAC.00488-07 Google Scholar CrossRef Search ADS PubMed  63 Pasqualotto AC, Howard SJ, Moore CB et al.   Flucytosine therapeutic monitoring: 15 years experience from the UK. J Antimicrob Chemother  2007; 59: 791– 3. http://dx.doi.org/10.1093/jac/dkl550 Google Scholar CrossRef Search ADS PubMed  64 Deshpande A, Gaur S, Bal AM. Candidaemia in the non-neutropenic patient: a critique of the guidelines. Int J Antimicrob Agents  2013; 42: 294– 300. http://dx.doi.org/10.1016/j.ijantimicag.2013.06.005 Google Scholar CrossRef Search ADS PubMed  65 Baptista JP, Udy AA. Augmented renal clearance in critical illness: “the elephant in the ICU”? Minerva Anestesiol  2015; 81: 1050– 2. Google Scholar PubMed  66 Myrianthefs P, Markantonis SL, Evaggelopoulou P et al.   Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study. Int J Antimicrob Agents  2010; 35: 468– 72. Google Scholar CrossRef Search ADS PubMed  67 Ashbee HR, Barnes RA, Johnson EM et al.   Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother  2014; 69: 1162– 76. http://dx.doi.org/10.1093/jac/dkt508 Google Scholar CrossRef Search ADS PubMed  68 Owusu Obeng A, Egelund EF, Alsultan A et al.   CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy  2014; 34: 703– 18. Google Scholar CrossRef Search ADS PubMed  69 Wiederhold NP, Pennick GJ, Dorsey SA et al.   A reference laboratory experience of clinically achievable voriconazole, posaconazole, and itraconazole concentrations within the bloodstream and cerebral spinal fluid. Antimicrob Agents Chemother  2014; 58: 424– 31. http://dx.doi.org/10.1128/AAC.01558-13 Google Scholar CrossRef Search ADS PubMed  70 Cojutti P, Candoni A, Forghieri F et al.   Variability of voriconazole trough levels in haematological patients: influence of comedications with cytochrome P450(CYP) inhibitors and/or with CYP inhibitors plus CYP inducers. Basic Clin Pharmacol Toxicol  2016; 118: 474– 9. http://dx.doi.org/10.1111/bcpt.12530 Google Scholar CrossRef Search ADS PubMed  71 Dolton MJ, McLachlan AJ. Voriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity. Int J Antimicrob Agents  2014; 44: 183– 93. http://dx.doi.org/10.1016/j.ijantimicag.2014.05.019 Google Scholar CrossRef Search ADS PubMed  72 Tissot F, Agrawal S, Pagano L et al.   ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica  2017; 102: 433– 44. http://dx.doi.org/10.3324/haematol.2016.152900 Google Scholar CrossRef Search ADS PubMed  73 Moriyama B, Obeng AO, Barbarino J et al.   Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther  2016; doi: 10.1002/cpt.583. 74 Andes D, Azie N, Yang H et al.   Drug-drug interaction associated with mold-active triazoles among hospitalized patients. Antimicrob Agents Chemother  2016; 60: 3398– 406. http://dx.doi.org/10.1128/AAC.00054-16 Google Scholar CrossRef Search ADS PubMed  75 Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy  2010; 30: 842– 54. http://dx.doi.org/10.1592/phco.30.8.842 Google Scholar CrossRef Search ADS PubMed  76 Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev  2014; 27: 68– 88. http://dx.doi.org/10.1128/CMR.00046-13 Google Scholar CrossRef Search ADS PubMed  77 Mian UK, Mayers M, Garg Y et al.   Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state. J Ocul Pharmacol Ther  1998; 14: 459– 71. http://dx.doi.org/10.1089/jop.1998.14.459 Google Scholar CrossRef Search ADS PubMed  78 Spriet I, Delaere L, Lagrou K et al.   Intraocular penetration of voriconazole and caspofungin in a patient with fungal endophthalmitis. J Antimicrob Chemother  2009; 64: 877– 8. http://dx.doi.org/10.1093/jac/dkp306 Google Scholar CrossRef Search ADS PubMed  79 Pea F, Righi E, Cojutti P et al.   Intra-abdominal penetration and pharmacodynamic exposure to fluconazole in three liver transplant patients with deep-seated candidiasis. J Antimicrob Chemother  2014; 69: 2585– 6. http://dx.doi.org/10.1093/jac/dku169 Google Scholar CrossRef Search ADS PubMed  80 Muilwijk EW, Schouten JA, van Leeuwen HJ et al.   Pharmacokinetics of caspofungin in ICU patients. J Antimicrob Chemother  2014; 69: 3294– 9. http://dx.doi.org/10.1093/jac/dku313 Google Scholar CrossRef Search ADS PubMed  81 van Wanrooy MJ, Rodgers MG, Uges DR et al.   Low but sufficient anidulafungin exposure in critically ill patients. Antimicrob Agents Chemother  2014; 58: 304– 8. http://dx.doi.org/10.1128/AAC.01607-13 Google Scholar CrossRef Search ADS PubMed  82 Bruggemann RJ, Middel-Baars V, de Lange DW et al.   Pharmacokinetics of anidulafungin in critically ill intensive care unit patients with suspected or proven invasive fungal infections. Antimicrob Agents Chemother  2017; 61: pii= e01894– 16. Google Scholar PubMed  83 Lempers VJ, Schouten JA, Hunfeld NG et al.   Altered micafungin pharmacokinetics in intensive care unit patients. Antimicrob Agents Chemother  2015; 59: 4403– 9. http://dx.doi.org/10.1128/AAC.00623-15 Google Scholar CrossRef Search ADS PubMed  84 Gauthier GM, Nork TM, Prince R et al.   Subtherapeutic ocular penetration of caspofungin and associated treatment failure in Candida albicans endophthalmitis. Clin Infect Dis  2005; 41: e27– 8. Google Scholar CrossRef Search ADS PubMed  85 Strenger V, Farowski F, Muller C et al.   Low penetration of caspofungin into cerebrospinal fluid following intravenous administration of standard doses. Int J Antimicrob Agents  2017; 50: 272– 5. http://dx.doi.org/10.1016/j.ijantimicag.2017.02.024 Google Scholar CrossRef Search ADS PubMed  86 Goldblum D, Rohrer K, Frueh BE et al.   Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model. Antimicrob Agents Chemother  2002; 46: 3719– 23. http://dx.doi.org/10.1128/AAC.46.12.3719-3723.2002 Google Scholar CrossRef Search ADS PubMed  87 Groll AH, Giri N, Petraitis V et al.   Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis  2000; 182: 274– 82. http://dx.doi.org/10.1086/315643 Google Scholar CrossRef Search ADS PubMed  88 Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother  2000; 46: 171– 9. http://dx.doi.org/10.1093/jac/46.2.171 Google Scholar CrossRef Search ADS PubMed  89 Stockmann C, Constance JE, Roberts JK et al.   Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications. Clin Pharmacokinet  2014; 53: 429– 54. http://dx.doi.org/10.1007/s40262-014-0139-0 Google Scholar CrossRef Search ADS PubMed  90 Putt TL, Duffull SB, Schollum JB et al.   GFR may not accurately predict aspects of proximal tubule drug handling. Eur J Clin Pharmacol  2014; 70: 1221– 6. http://dx.doi.org/10.1007/s00228-014-1733-7 Google Scholar CrossRef Search ADS PubMed  91 Bergner R, Hoffmann M, Riedel KD et al.   Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg. Nephrol Dial Transplant  2006; 21: 1019– 23. http://dx.doi.org/10.1093/ndt/gfi284 Google Scholar CrossRef Search ADS PubMed  92 Gharibian KN, Mueller BA. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach. Clin Nephrol  2016; 86: 43– 50. http://dx.doi.org/10.5414/CN108824 Google Scholar CrossRef Search ADS PubMed  93 Sinnollareddy MG, Roberts MS, Lipman J et al.   Influence of sustained low-efficiency diafiltration (SLED–f) on interstitial fluid concentrations of fluconazole in a critically ill patient: use of microdialysis. Int J Antimicrob Agents  2015; 46: 121– 4. http://dx.doi.org/10.1016/j.ijantimicag.2015.02.017 Google Scholar CrossRef Search ADS PubMed  94 Sinnollareddy MG, Roberts MS, Lipman J et al.   Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. Int J Antimicrob Agents  2015; 45: 192– 5. http://dx.doi.org/10.1016/j.ijantimicag.2014.08.013 Google Scholar CrossRef Search ADS PubMed  95 Kiser TH, Fish DN, Aquilante CL et al.   Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy. Crit Care  2015; 19: 32. Google Scholar CrossRef Search ADS PubMed  96 Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag  2007; 3: 71– 97. http://dx.doi.org/10.2147/tcrm.2007.3.1.71 Google Scholar CrossRef Search ADS PubMed  97 Aguilar G, Azanza JR, Carbonell JA et al.   Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration. J Antimicrob Chemother  2014; 69: 1620– 3. http://dx.doi.org/10.1093/jac/dkt542 Google Scholar CrossRef Search ADS PubMed  98 Roger C, Wallis SC, Muller L et al.   Caspofungin population pharmacokinetics in critically ill patients undergoing continuous veno-venous haemofiltration or haemodiafiltration. Clin Pharmacokinet  2016; doi:10.1007/s40262-016-0495-z. 99 Weiler S, Seger C, Pfisterer H et al.   Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. Antimicrob Agents Chemother  2013; 57: 4053– 7. http://dx.doi.org/10.1128/AAC.00335-13 Google Scholar CrossRef Search ADS PubMed  100 Trotman RL, Williamson JC, Shoemaker DM et al.   Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis  2005; 41: 1159– 66. http://dx.doi.org/10.1086/444500 Google Scholar CrossRef Search ADS PubMed  101 Kunka ME, Cady EA, Woo HC et al.   Flucytosine pharmacokinetics in a critically ill patient receiving continuous renal replacement therapy. Case Rep Crit Care  2015; 2015: 927496. Google Scholar PubMed  102 Westphal JF, Jehl F, Vetter D. Pharmacological, toxicologic, and microbiological considerations in the choice of initial antibiotic therapy for serious infections in patients with cirrhosis of the liver. Clin Infect Dis  1994; 18: 324– 35. http://dx.doi.org/10.1093/clinids/18.3.324 Google Scholar CrossRef Search ADS PubMed  103 Cota JM, Burgess DS. Antifungal dose adjustment in renal and hepatic dysfunction: pharmacokinetic and pharmacodynamic considerations. Curr Fungal Infect Reports  2010; 4: 120– 8. http://dx.doi.org/10.1007/s12281-010-0015-9 Google Scholar CrossRef Search ADS   104 European Medicines Agency. Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf. 105 Grau S, Luque S, Campillo N et al.   Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis. J Antimicrob Chemother  2015; 70: 2854– 61. http://dx.doi.org/10.1093/jac/dkv173 Google Scholar CrossRef Search ADS PubMed  106 Martial LC, Bruggemann RJ, Schouten JA et al.   Dose reduction of caspofungin in intensive care unit patients with Child Pugh B will result in suboptimal exposure. Clin Pharmacokinet  2016; 55: 723– 33. http://dx.doi.org/10.1007/s40262-015-0347-2 Google Scholar CrossRef Search ADS PubMed  107 Shekar K, Fraser JF, Smith MT et al.   Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care  2012; 27: 741 e9– 18. Google Scholar CrossRef Search ADS   108 Mehta NM, Halwick DR, Dodson BL et al.   Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment. Intensive Care Med  2007; 33: 1018– 24. http://dx.doi.org/10.1007/s00134-007-0606-2 Google Scholar CrossRef Search ADS PubMed  109 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. http://dx.doi.org/10.1093/jac/dkp026 Google Scholar CrossRef Search ADS PubMed  110 Watt KM, Benjamin DKJr, Cheifetz IM et al.   Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J  2012; 31: 1042– 7. Google Scholar PubMed  111 Watt KM, Gonzalez D, Benjamin DKJr et al.   Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive candidiasis in children supported with extracorporeal membrane oxygenation. Antimicrob Agents Chemother  2015; 59: 3935– 43. http://dx.doi.org/10.1128/AAC.00102-15 Google Scholar CrossRef Search ADS PubMed  112 Alobaid AS, Wallis SC, Jarrett P et al.   Effect of obesity on the population pharmacokinetics of fluconazole in critically ill patients. Antimicrob Agents Chemother  2016; 60: 6550– 7. http://dx.doi.org/10.1128/AAC.01088-16 Google Scholar CrossRef Search ADS PubMed  113 Davies-Vorbrodt S, Ito JI, Tegtmeier BR et al.   Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review. Pharmacotherapy  2013; 33: 22– 30. http://dx.doi.org/10.1002/phar.1156 Google Scholar CrossRef Search ADS PubMed  114 Moriyama B, Jarosinski PF, Figg WD et al.   Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype. Pharmacotherapy  2013; 33: e19– 22. Google Scholar CrossRef Search ADS PubMed  115 Payne KD, Hall RG. Dosing of antifungal agents in obese people. Expert Rev Anti Infect Ther  2016; 14: 257– 67. http://dx.doi.org/10.1586/14787210.2016.1128822 Google Scholar CrossRef Search ADS PubMed  116 Stone NR, Bicanic T, Salim R et al.   Liposomal amphotericin B (AmBisome®): a review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions. Drugs  2016; 76: 485– 500. Google Scholar CrossRef Search ADS PubMed  117 Nguyen TH, Hoppe-Tichy T, Geiss HK et al.   Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother  2007; 60: 100– 6. http://dx.doi.org/10.1093/jac/dkm125 Google Scholar CrossRef Search ADS PubMed  118 Amsden J, Slain D. Antifungal dosing in obesity: a review of the literature. Curr Fungal Infect Rep  2011; 5: 83. http://dx.doi.org/10.1007/s12281-011-0049-7 Google Scholar CrossRef Search ADS   119 Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother  2011; 55: 5107– 12. http://dx.doi.org/10.1128/AAC.05193-11 Google Scholar CrossRef Search ADS PubMed  120 Pasipanodya JP, Hall RG2nd, Gumbo T. In silico-derived bedside formula for individualized micafungin dosing for obese patients in the age of deterministic chaos. Clin Pharmacol Ther  2015; 97: 292– 7. http://dx.doi.org/10.1002/cpt.38 Google Scholar CrossRef Search ADS PubMed  121 Lempers VJ, van Rongen A, van Dongen EP et al.   Does weight impact anidulafungin pharmacokinetics? Clin Pharmacokinet  2016; 55: 1289– 94. Google Scholar CrossRef Search ADS PubMed  122 Louie A, Liu QF, Drusano GL et al.   Pharmacokinetic studies of fluconazole in rabbits characterizing doses which achieve peak levels in serum and area under the concentration-time curve values which mimic those of high-dose fluconazole in humans. Antimicrob Agents Chemother  1998; 42: 1512– 4. Google Scholar PubMed  123 Hope WW, Seibel NL, Schwartz CL et al.   Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother  2007; 51: 3714– 9. http://dx.doi.org/10.1128/AAC.00398-07 Google Scholar CrossRef Search ADS PubMed  124 Cornely OA, Bassetti M, Calandra T et al.   ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect  2012; 18 Suppl 7: 19– 37. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Jan 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off