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Antifungal pharmacodynamics: Latin America's perspective.


The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

[c] 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (


Invasive fungal infections are currently an important cause of morbidity and mortality, especially in immunosuppressed patients and those admitted in intensive care units. (1,2) Candida spp. are the most frequent etiological agent of fungal infections in humans, ranking fourth among the etiologic agents of bloodstream infections in the United States, with a mortality similar to septic shock. In Latin America, a higher incidence of candidemia has been reported compared to countries of the northern hemisphere. (3) Additionally, the diversity of climates and habitats in Latin America leads to a higher incidence of endemic mycoses, including histoplasmosis, paracoccidioidomycosis, and coccidioidomycosis. (4)

In the last years, the incidence of healthcare-associated fungal infections has been rising, mainly of invasive candidiasis and aspergillosis. (5) There has also been an increased report of non-albicans Candida infections, which display reduced susceptibility to antifungal drugs. (6) Finally, the number of patients with profound immunosuppression secondary to the treatment of hematologic malignancies and organ transplantation is growing, and it has been associated with the increase of invasive fungal infections due to several genera of molds that represent formidable diagnostic and therapeutic challenges. (7) Despite the availability of effective antifungal drugs, mortality due to fungal infections remains high, (8) a fact that has prompted the search for new products and a better understanding of the pharmacology of these agents to optimize therapy.

There are additional components in Latin America to the "host-fungi-drug" triad that may alter the pharmacodynamics (PD) with unknown impact on resistance. For economic and political reasons, generics are extensively used despite their unproven therapeutic equivalence and, in some cases, the treatment must be stopped due to shortage in supply. Moreover, the pharmacokinetics (PK)/PD knowledge has not been extensively introduced in the curriculum of medical schools and related clinical medical education activities are limited, mainly because PK and PD integrations may be seen as complex and not practical. In consequence, the advancements on the PD of antifungal have not been implemented as in other regions of the world.


A literature search was performed in the PubMed/MEDLINE database looking for clinical trials, journal articles or reviews available in full-text, written in Spanish or English languages, published from January 1962 to July 2015, including the keywords: pharmacodynamics (PD), pharmacokinetics (PK), antifungals, candidiasis, and aspergillosis. Papers about antifungal therapy co-authored by the expert in the field David R. Andes, were also searched. Out of 140 papers identified the authors selected the relevant papers about in vitro, in vivo, and clinical PD of antifungal agents, mainly emphasizing on the PK/PD concepts; to build a practical review for general physicians, especially in developing countries. The references of the selected papers were also used if the authors considered them relevant for the review.


General concepts of antimicrobial pharmacodynamics

The study of the PK and PD properties of any antimicrobial is based on the exposure-response relationship of the drug and the infecting pathogen. (9) This relationship can be modeled (Fig. 1) by integrating a PK parameter (e.g., maximal concentration or [C.sub.max], and area under the curve or AUC) and a PD parameter related with the response expected against the infecting microorganism (i.e., minimal inhibitory concentration or MIC). The knowledge derived from these integrations has facilitated the design of optimal drug regimens and potentially reduce toxicity and the development of resistance. (10)

Classically, PK studies are about assessing absorption, distribution, metabolism, and elimination of drugs. The aim of PK is to determine the time-concentration drug profile in different fluids and the degree of penetration to different organs, because the drug effect is expected to correlate with the concentration at the site of the infection. Once a drug is inside of the human body, its movement between compartments and fluids depends on factors such as the fraction of unbound drug. For this reason, in addition to the total drug concentration, for PK studies it is necessary to determine the degree of protein binding as only unbound drug exerts pharmacological activity (11)

PD studies, on the other hand, have to do with the relation between the drug concentration at site of action and the response or effect. In anti-infective pharmacology, PD studies integrate the susceptibility of the microorganisms (measured by the MICs) with the antimicrobial exposure (based on the PK data) and the observed effect or response. With this information it is possible to estimate PD indices (or PK/PD index) related to efficacy, as well as their level necessary for specific therapeutic goals. For antifungal drugs, three PD indices have been described: (i) the fraction of the dosing interval the free drug concentration is above the MIC ([fT.sub.>MIC]); (ii) the ratio of the area under the concentration-time curve and the MIC (fAUC/MIC); and (iii) the ratio of the maximum concentration or peak and the MIC (f[C.sub.max]/MIC). During the last 15 years, these indices have been used to design optimal antifungal dosing regimens with known probability of success along a wide range of MIC and also to establish susceptibility breakpoints. (12,13)

To elucidate the PK/PD index for each antifungal, in vitro and in vivo studies are necessary. The process begins with in vitro susceptibility testing to determine the MIC under reproducible conditions, (14) followed by a PK study to estimate the population parameters (clearance and volume of distribution). The final step is a dose-response experiment to relate exposure with antimicrobial effect using drug fractionation, that is, testing the same dose in multiple dosing schedules (e.g. q1h, q3h, q6h, q8h, q12h, and q24h). At the end, the three indices mentioned before ([fT.sub.>MIC], f[C.sub.max]/MIC and fAUC/MIC) are plotted against the effect to determine which index exhibits the best correlation with efficacy and to estimate the level required to achieve a particular endpoint (for instance, to obtain 50% of maximal efficacy or 90% survival). Thus, for drugs driven by thef[C.sub.max]/MIC index (concentration-dependent), the dosing strategy is to use large doses with infrequent intervals, whereas for [fT.sub.>MIC] drugs (time-dependent) the optimal regimen would be smaller but more frequent doses or even extended or continuous infusion. In the case of drugs driven by fAUC/MIC, the key factor is the total amount of drug administered in 24 h, independently of the dosing schedule used.

Another key factor to determine the PD indices is the persistent effect, i.e., the capacity of a drug to suppress the growth of the fungus after the compound is fully removed from the medium (the post-antifungal effect or PAFE), or after the concentration falls below the MIC (sub-MIC PAFE). (15) Drugs driven byf[C.sub.max]/MIC and fAUC/MIC exhibit prolonged PAFE whilst the fT>MIC driven ones usually display short or no PAFE. The duration of the PAFE depends on the type of action (fungicidal or fungistatic), the drug concentration and the pathogen being treated. For example, the echinocandins are fungicidal and exhibit long PAFE against Candida spp., while fungistatic and devoid of PAFE against Aspergillus fumigatus. (16)

The systemic antifungal classes currently available are polyenes, triazoles, echinocandins, and flucytosine. For all of them, the PK/PD indices have been determined both in vitro and in vivo, (17-21) and the results confirmed by clinical studies (Table 1), demonstrating that dose optimization to attain PD targets leads to higher clinical efficacy (22,23) Due to limited availability of flucytosine in developing countries, the present review will focus on the PD of polyenes, triazoles, and echinocandins.


This antifungal class includes amphotericin B deoxycholate ([AMB.sub.d]) and the lipid formulations: lipid complex ([]), colloidal dispersion ([]), and liposomal ([AMB.sub.l]).

The mechanism of action requires its binding to the ergosterol in the fungal membrane, altering the cellular permeability and leading to cell death. All formulations of AMB display a concentration-dependent effect with prolonged PAFE, and the driving PK/PD index is thef[C.sub.max]/MIC. (15,16,19,24)

Dose fractionation studies with the neutropenic mouse disseminated candidiasis (NMDC) model, confirmed that the fungicidal efficacy of AMBd correlated with large, infrequent doses; for instance, dosing [AMB.sub.d] every 72 h (q72h) achieved maximal efficacy with doses 5-7 times lower than q6h or q12h schedules. (19) For fungistatic and maximally fungicidal effects, the [C.sub.max]/MIC were 2-4 and 10, respectively. Similarly, but in the murine model of invasive pulmonary aspergillosis, q72h dosing schedules also led to a larger reduction in the fungal burden and longer survival of infected animals in comparison with q8h or q24h; in this model, the [C.sub.max]/MIC required for maximal efficacy was 2.4. (25)

In the NMDC model, [AMB.sub.d] was 4.3- to 5.9-fold more potent than [] and [AMB.sub.l] in a mg/kg basis. (26) Similarly, in the neutropenic-rabbit model of invasive pulmonary aspergillosis, near-maximal antifungal activity was evident with [AMB.sub.d] at 1 mg/kg/day and [] and [AMB.sub.l] at 5 mg/kg/day. (27) Thus, to achieve the needed [C.sub.max]/MIC with lipid formulations in clinical practice, the daily dose should be almost 5-times higher than the dose of [AMB.sub.d]. In opposition to the narrow therapeutic index of [AMB.sub.d], the lipid formulations are significantly less toxic in relation to the dose of [AMB.sub.d], specifically in terms of electrolytic imbalance, azotemia, renal tubular acidosis, anemia, and arrhythmias. (28)

Regarding the PK of polyenes, the concentration-time profile of amphotericin is nonlinear but there are important differences between [AMB.sub.d] and lipid formulations. (29) [AMB.sub.d] is extensively distributed to tissues such as liver, kidneys, spleen and, in small quantities (<1%), to heart and brain, but clearance (Cl) from these sites is so slow (38 [+ or -] 15 mL/h/kg) as it takes more than one week to clear a single dose. Additionally, it has a volume of distribution ([V.sub.d]) of 5 [+ or -] 3 L/kg and the protein binding is very high (>95%). (30,31) AMB levels in cerebrospinal fluid and vitreous are null to minimal, therefore intrathecal or intravitreal administration is needed in selected cases.

The lipid vehicle in the other formulations of amphotericin B alters the distribution and clearance of the drug. (30,32) For example, as [] is a complex of AMB with lipid molecules, it displays the highest [V.sub.d] (131 [+ or -] 8 L/kg) and fastest Cl (426 [+ or -] 189 mL/h/kg) of all formulations. In contrast, [AMB.sub.l] has the lowest [V.sub.d] (0.11 [+ or -] 0.08 L/kg) and Cl (11 [+ or -] 6 mL/h/kg) among amphotericin formulations, while [] has a similar [V.sub.d] but faster clearance (117 mL/h/kg) than [AMB.sub.d]. Additionally, as lipid forms accumulate more in the mononuclear phagocytic system and 10-times less in the kidneys, they are less frequently associated with nephrotoxicity than [AMB.sub.d]. (33)

Among the lipid formulations, [AMB.sub.l] is the smallest, unilamellar molecule (60-70 nm vs. 1600-11,000 nm for []), achieving the highest [C.sub.max] (83 [+ or -] 35 mg/L) after a single dose, (34) but also displaying the highest protein binding. However, the small size of AMBl facilitates slightly higher concentrations in central nervous system compared to other lipid formulations. In fact, in the central nervous system model of candidiasis, only AMBl and AMBd sterilized the brain tissue, whereas the other lipid formulations did not, (34) and only [AMB.sub.d] and [AMB.sub.l] reached detectable cerebrospinal fluid concentrations, with a transfer rate ranging from 0.02% to 0.92%. (35)

The clinical correlation of the potential PD differences among lipid formulations has been difficult to establish because there are limitations regarding the MIC determination and the differences in the models used to establish the PK/PD indices. Further, therapeutic monitoring is not generally advocated for AMB and there are no widely accepted drug exposure targets. However, the optimal target attainment has been defined for [AMB.sub.d] as well as [AMB.sub.l]. A PK/PD study in nine children with fungal infection treated with [AMB.sub.l] found that, while a [C.sub.max]/MIC = 40 [+ or -] 13 produced a partial response, full response needed it to be 67.9 [+ or -] 17 (p = 0.021). (36) Considering that AMBd is approximately 5x more potent than [AMB.sub.l], these results are consistent with the reported value of [C.sub.max]/MIC of 10 for maximal efficacy of [AMB.sub.d].

Cornelly et al. conducted a multicenter randomized double-blind study in patients with probable or demonstrated mold invasive infections. Their study aimed to optimize the [C.sub.max]/MIC with [AMB.sub.l] comparing a 3 mg/kg vs. a 10 mg/kg dose based on a previous work that showed that the latter reaches [C.sub.max] > 100 mg/L. No significant differences were found in the global clinical response (50% vs. 46%) or survival after 12 weeks (71% vs. 58%), but there was a higher incidence of renal toxicity (16% vs. 30%). (37) The absence of clinical benefit of the higher dose can be explained by the fact that at 3 mg/kg the goal of the PK/PD index required for maximal efficacy has already been reached, and higher doses only lead to increased toxicity. Finally, a 999-patient simulation based in the neutropenicrabbit model of invasive pulmonary aspergillosis showed that 3mg/kg/day of [AMB.sub.l] or 1 mg/kg/day of [AMB.sub.d] was predicted to result in near-maximal antifungal activity and suppression of biomarkers. (27) The optimal dose of [] and [] has not been as clearly established as the [AMB.sub.d] and [AMB.sub.l].


These fungistatic drugs act blocking the synthesis of ergosterol mainly by inhibiting the cytochrome [P.sub.450] dependent 14-[alpha] demethylase (CYP51A1), which converts lanosterol into ergosterol. (38,39) These drugs are actually time-dependent, but they also exhibit prolonged PAFE, therefore the PD index driving efficacy is the fAUC/MIC. (13,15,17,18,24,40)

Fluconazole absorption from the gastrointestinal tract is almost complete and unaffected by gastric acidity or food, is poorly metabolized, and bioavailability is near 100%. Its elimination half-life ranges from 25 to 30 h, it exhibits minimal protein binding (12%), and is excreted mainly by the kidneys. The [C.sub.max] obtained after a 100 mg oral dose was 2 mg/L. (41) As fluconazole is a small molecule (MW=309) actively distributed into body fluids ([V.sub.d] = 46[+ or -] 8L), the levels attained in cerebrospinal fluid (or even in brain parenchyma) at steady state are [greater than or equal to]50% of the concentration observed in plasma. Due to this PK property, fluconazole is a well-accepted alternative therapy for cryptococcal (at high doses of 1200-2000 mg/day) and Candida meningoencephalitis. Itraconazole, by contrast, is a large molecule (MW = 705) highly bound to proteins, exhibiting a cerebrospinal fluid/plasma concentration ratio of [less than or equal to]0.12 (42) that prevent its use in fungal CNS infections.

Regarding fluconazole, Louie et al. demonstrated in the murine model of systemic candidiasis that the effect of this drug on the fungal burden was the same when administering a single dose or dividing it in two or four injections. (40) However, it should be noted that prolonged periods of exposure below the MIC might favor resistance of C. albicans against fluconazole. (43,44) Multiple studies in vivo with fluconazole against several species of Candida along a wide MIC range have conclusively shown that the fAUC/MIC necessary to reach 50% of the maximal efficacy ([ED.sub.50]) is between 12.5 and 50 12,13,40 We determined in the NMDC model that two vastly different strains of C. albicans (MIC 0.25 and 4mg/L) required fAUC/MIC of 25-38 to attain the [ED.sub.50]. (45)

The relationship between fluconazole dose, the MIC of the infecting agent, and the outcome in patients with mucocutaneous candidiasis and candidemia has been addressed in several papers. (12,22,23) Rex et al. published two decades ago that the clinical efficacy of fluconazole began to diminish with MIC above 8 mg/L, but they did not run a PK/PD analysis. (22) Later, Rodriguez-Tudela et al. studied 126 patients with candidemia and 110 with pharyngeal candidiasis finding that dose/MIC ratios of at least 100 (corresponding to fAUC/MIC = 79) predicted cure for 93% of the subjects. (22) In the Latin America Invasive Mycosis Network, the MIC90 for blood-isolated C. albicans, C. parapsilosis, and C. tropicalis were [less than or equal to]1 mg/[L.sup.3]; as those three strains represent 82% of cases, no more than 400 mg/day of fluconazole should be necessary to treat most of patients.

With the other triazoles, similar fAUC/MIC ratios have been found against several Candida spp. (17,18,46) For example, voriconazole and posaconazole require respectively fAUC/MIC of 11-52 and 6-27 to reach the [ED.sub.50] in the NMDC model, while isavuconazole (protein binding > 95%) required fAUC/MIC of 34 to achieve 90% survival, quite similar to other triazoles. Pharmacokinetic studies of voriconazole in humans have shown 58% protein binding and nonlinear saturable kinetics, with the AUC increasing in a higher proportion than the dose. At doses of 200mgPO q12h or 3 mg/kg IV q12h, the fAUC is 20. (47) Considering that the target for [ED.sub.50] is fAUC/MIC around 20 (range 11-50), one could infer that clinical success would be attained with strains with MIC up to 1 mg/L. This agrees with the susceptibility breakpoint defined by CLSI, highlighting the relevance of the PK/PD approach. (48) All Candida species isolated in the Latin America Invasive Mycosis Network had a MIC [less than or equal to] 0.5 mg/L.

The pharmacodynamics of voriconazole has also been studied in the disseminated aspergillosis model (induced by intravenous inoculation). (49) The fAUC/MIC required for 50% survival ([ED.sub.50]) was around 12, while for 100% survival ([E.sub.max]) it went up to 80-100. Regarding posaconazole, Lepak et al. assessed its pharmacodynamics against Aspergillus spp. in the pulmonary invasive aspergillosis model (induced by nasal instillation), (50) finding that the fAUC/MIC necessary to achieve the ED50 was 1.8, but at least 10 was required to reach the [E.sub.max]. Howard et al. published similar results, (51) and Conte et al. found in a study of pulmonary transplant patients (52) that posaconazole concentration was 50 times higher in alveolar cells than in serum or epithelial lining fluid. These results suggest that the PK/PD profile of posaconazole is favorable for the treatment of pulmonary aspergillosis.

There are also pharmacodynamic data with voriconazole in patients with invasive aspergillosis, a frequent indication of this drug. The recommended trough levels of voriconazole for therapeutic drug monitoring (TDM) correlating with lower toxicity and better survival outcomes range from 1 to 2mg/[L.sup.53]; however, a large inter-individual variability in the kinetics of the drug was observed. In consequence, 25% of patients achieved trough levels < 1 mg/L and therapy failed, whilst 31% had levels >5.5 mg/L and caused toxicity. Based on these data, a randomized clinical study was carried out to assess the impact of TDM of voriconazole in 110 patients with invasive fungal infections. The trial showed that TDM was associated with higher efficacy (81% vs. 57%, p = 0.04) and lower drug discontinuation due to toxicity (4% vs. 17%, p = 0.02). (54) These results support the recent recommendations by the British Society for Medical Mycology indicating TDM for all patients receiving voriconazole. The goal is to reach trough levels ([C.sub.min]) between 1 and 4-6mg/L or, ideally, a [C.sub.min]/MIC ratio of 2-5. (55)

Posaconazole is characterized by a long half-life (approximately 30 h), saturable absorption at 800mg/day, high protein binding (98%), and a long time to reach steady state concentrations (10 days). (56) It is usually administered as a suspension twice a day, so the concentration-time curve is almost flat with very similar peaks and troughs. Among 67 patients with refractory invasive aspergillosis that received posaconazole and underwent TDM, it was found that those with peak ([C.sub.max]) and average concentrations ([C.sub.avg]) of 0.14 and 0.13 mg/L, respectively, only had 24% response. In contrast, in patients with [C.sub.max] and [C.sub.avg] of 1.48 and 1.25 mg/L, 75% had a favorable response. (57) These results support the recommendation of trough levels > 1 mg/L for patients with established infections and 0.7 mg/L for prophylaxis. (55) The PK of posaconazole also exhibits high between-subject variability in patients with hematologic malignancies, (58) another reason for TDM. To the best of our knowledge, there are no clinical studies correlating the fAUC/MIC of posaconazole with clinical outcome, but considering that 800 mg per day yields fAUC around 0.30-0.44, (52,59) a fAUC/MIC near 3 can be attained with MICs up to 0.125 mg/L, the EUCAST susceptibility breakpoint for A. fumigatus. (60) To improve bioavailability and reduce between-subject variability in patients, a delayed-release (DR) tablet formulation was developed. At a dose of 300 mg once a day (three 100 mg DR tablets), 90% of patients achieved posaconazole serum concentrations greater than 700 ng/mL, compared with 58% patients receiving the oral suspension. Acid suppression did not affect posaconazole levels in the DR tablet cohort. (61)


These are large lipoproteins with negligible oral bioavailability, extensive protein binding (>95%), lack of renal clearance, and no penetration to cerebrospinal fluid. Their unique mechanism of action (inhibition of 1,3-[beta]-glucan synthase), high in vivo efficacy, and safety profile, has increased its use as treatment for invasive candidiasis and aspergillosis. The three approved agents are caspofungin, anidulafungin, and micafungin.

Being the newer group of antifungals, echinocandins have been studied thoroughly from a PK/PD perspective. (62) They are fungicidal against Candida spp. and fungistatic against Aspergillus spp. The PD index that best drive their action is the f[C.sub.max]/MIC, displaying prolonged PAFE. (21,63-65) However, in the NMDC model, the fAUC/MIC ratio is also a strong predictor of efficacy, presumably due to the prolonged tissue distribution of these compounds including the kidneys, where the antifungal effect is measured in this model. Dose fractionation studies have shown that the dose required to reduce the fungal burden by 1 [log.sub.10] is 4-fold lower when the drugs are administered once daily (21,62) Of note, a paradoxical effect consisting in a reduced fungicidal efficacy against Candida spp. has been observed in vitro at concentrations above the MIC. (66) Such effect results of compensatory responses to 1,3-[beta]-glucan synthesis and disappears when human serum is added, indicating that it is not likely to impact the treatment of patients with candidemia. (67)

The magnitude of PD indices bound to maximal efficacy in animal models of invasive candidiasis is a f[C.sub.max]/MIC of 1 or a fAUC/MIC between 10 and 20 for anidulafungin, micafungin, (62) and caspofungin. Considering that the usual dose of anidulafungin (200 mg loading dose followed by 100 mg q24h) is associated with f[C.sub.max] = 1.15 mg/L and fAUC = 1.12 [mghL.sup.-1], (68) the PD target will be attained against strains with MIC [less than or equal to] 0.125 mg/L. Recent epidemiological studies indicate that the M[IC.sub.90] of anidulafungin is <0.125 mg/L for many Candida species excepting C. parapsilosis, C. guilliermondii, C. lusitaniae and C. famata. (69) An in vivo PD study found that the fAUC/MIC to be fungistatic against C. parapsilosis and C. glabrata was 7, in contrast to 20 against C. albicans. (70) These data support the CLSI susceptibility breakpoint of 0.25 mg/L for C. albicans, C. tropicalis, and C. krusei, and 2 mg/L for C. parapsilosis. (71)

The majority of clinical trials with echinocandins have focused on the evaluation of clinical efficacy (72,73) and its relation to the MIC. (74) Regarding micafungin, a PK/PD analysis of data from 493 patients found that a fAUC/MIC between 7.5 and 30 was associated with 98% microbiological success, compared to 85% when the index was <7.5. (75) Finally, in patients with C. parapsilosis infection, a fAUC/MIC > 0.71 was related to 100% microbiological success compared with 82% in patients with values < 0.71. This is a further demonstration that C. parapsilosis requires a 10-fold lesser fAUC/MIC, in line with its higher susceptibility breakpoint.

Finally, in pediatric patients, dosing adjustment is necessary for most antifungal drugs to obtain the same exposure achieved in adults. Also, differences are known in drug metabolism and clearance, and the magnitude of the PK/PD indices requires more studies in that specific population. Fungal infections in children compared to adults may affect organs and systems differently (e.g. CNS infection during candidemia is frequent in children). A recent review on pediatric pharmacology of antifungal agents is available. (76)

Conclusion and future perspectives

Fungal diseases are a growing public health problem. Although epidemiological data are scant, a prospective survey shows an incidence of 0.98 per 1000 hospital admissions in Latin America, approximately four-times the incidence reported in Europe and North America. (77) Medical comorbidities and political, economic, and climatic factors are contributing to increase and to perpetuate the problem. In addition, antifungal pharmacology knowledge has been progressively increasing, mainly, by the determination of drug exposure-response relationships. The integration of PK/PD has facilitated the design of optimal drug regimens that help maximize efficacy while simultaneously reducing toxicity, ameliorating the development of resistance and cutting costs, as corroborated by clinical trials. (78) This knowledge can be applied to each patient in any clinical setting (Table 1), although TDM is necessary to assure that the magnitude of the PK/PD indices required for maximal efficacy are effectively achieved. This process would introduce an additional expenditure related to the quantification of drugs in specialized laboratories, which could be offset by the much greater economic and social benefits of optimized therapy (79)

Author's contribution

JMG made the search of literature, reviewed the papers included, and wrote the first draft of the manuscript. CAR, MA and AZ reviewed the literature, made criticism to the article and approved the final version. OV reviewed and edited the final text.

Conflicts of interest

Gonzalez, Agudelo and Vesga have no conflicts of interest to declare. Rodriguez has received honorary for unrelated lectures from Roche and Amgen. Zuluaga has received honorary for unrelated lectures from Allergan, Amgen, Lilly, Mundipharma, Novo Nordisk, Pfizer, Roche and Sanofi. None of these companies or any other pharmaceutical company was involved in the design, execution, or publication of this study.


Funding for this project came from the Universidad de Antioquia (UdeA) and Sistema General Regalias of Colombia (BPIN: 2013000100183). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


(1.) Azie N, Neofytos D, Pfaller M, Meier-Kriesche HU, Quan SP, Horn D. The PATH (Prospective Antifungal Therapy) Alliance(R) registry and invasive fungal infections: update 2012. Diagn Microbiol Infect Dis. 2012;73:293-300.

(2.) Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP, National Nosocomial Infections Surveillance System H. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis. 2002;35:627-30.

(3.) Nucci M, Queiroz-Telles F, Alvarado-Matute T, et al. Epidemiology of candidemia in Latin America: a laboratory-based survey. PLOS ONE. 2013;8:e59373.

(4.) Colombo AL, Tobon A, Restrepo A, Queiroz-Telles F, Nucci M. Epidemiology of endemic systemic fungal infections in Latin America. Med Mycol. 2011;49:785-98.

(5.) Alangaden GJ. Nosocomial fungal infections: epidemiology, infection control, and prevention. Infect Dis Clin N Am. 2011;25:201-25.

(6.) Pfaller MA, Andes DR, Diekema DJ, et al. Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008. PLOS ONE. 2014;9:e101510.

(7.) Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50:1101-11.

(8.) Kriengkauykiat J, Ito JI, Dadwal SS. Epidemiology and treatment approaches in management of invasive fungal infections. Clin Epidemiol. 2011;3:175-91.

(9.) Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-10, quiz 1-2.

(10.) Drusano GL. Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis. 2007;45 Suppl. 1:S89-95.

(11.) Craig WA, Kunin CM. Significance of serum protein and tissue binding of antimicrobial agents. Annu Rev Med. 1976;27:287-300.

(12.) 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.

(13.) 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.

(14.) CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts. M27-A3. Wayne, PA: Clinical and Laboratory Standard Institute; 2008.

(15.) Turnidge JD, Gudmundsson S, Vogelman B, Craig WA. The postantibiotic effect of antifungal agents against common pathogenic yeasts. J Antimicrob Chemother. 1994;34: 83-92.

(16.) Manavathu EK, Ramesh MS, Baskaran I, Ganesan LT, Chandrasekar PH. A comparative study of the post-antifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans. J Antimicrob Chemother. 2004;53:386-9.

(17.) 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.

(18.) Andes D, Marchillo K, Stamstad T, Conklin R. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother. 2003;47:3165-9.

(19.) Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother. 2001;45:922-6.

(20.) Louie A, Deziel M, Liu W, Drusano MF, Gumbo T, Drusano GL. 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.

(21.) 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.

(22.) 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.

(23.) Baddley JW, Patel M, Bhavnani SM, Moser SA, Andes DR. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother. 2008;52:3022-8.

(24.) Ernst EJ, Klepser ME, Pfaller MA. Postantifungal effects of echinocandin, azole, and polyene antifungal agents against Candida albicans and Cryptococcus neoformans. Antimicrob Agents Chemother. 2000;44:1108-11.

(25.) Wiederhold NP, Tam VH, Chi J, Prince RA, Kontoyiannis DP, Lewis RE. Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2006;50: 469-73.

(26.) Andes D, Safdar N, Marchillo K, Conklin R. 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.

(27.) Al-Nakeeb Z, Petraitis V, Goodwin J, Petraitiene R, Walsh TJ, Hope WW. Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus. Antimicrob Agents Chemother. 2015;59:2735-45.

(28.) Gallis HA. Amphotericin B: a commentary on its role as an antifungal agent and as a comparative agent in clinical trials. Clin Infect Dis. 1996;22 Suppl. 2:S145-7.

(29.) Atkinson AJ Jr, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother. 1978;13:271-6.

(30.) Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother. 2002;46:834-40.

(31.) Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother. 2002;46:828-33.

(32.) Adedoyin A, Bernardo JF, Swenson CE, et al. Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies. Antimicrob Agents Chemother. 1997;41:2201-8.

(33.) Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis. 1998;27:603-18.

(34.) 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.

(35.) Strenger V, Meinitzer A, Donnerer J, et al. Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B. J Antimicrob Chemother. 2014;69:2522-6.

(36.) 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.

(37.) Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289-97.

(38.) Sanati H, Belanger P, Fratti R, Ghannoum M. A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrob Agents Chemother. 1997;41:2492-6.

(39.) Hof H. A new, broad-spectrum azole antifungal: posaconazole - mechanisms of action and resistance, spectrum of activity. Mycoses. 2006;49 Suppl. 1:2-6.

(40.) 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.

(41.) Debruyne D. Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. Clin Pharmacokinet. 1997;33:52-77.

(42.) Kethireddy S, Andes D. CNS pharmacokinetics of antifungal agents. Expert Opin Drug Metab Toxicol. 2007;3:573-81.

(43.) Andes D, Forrest A, Lepak A, Nett J, Marchillo K, Lincoln L. Impact of antimicrobial dosing regimen on evolution of drug resistance in vivo: fluconazole and Candida albicans. Antimicrob Agents Chemother. 2006;50:2374-83.

(44.) Andes D, Lepak A, Nett J, Lincoln L, Marchillo K. 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.

(45.) Gonzalez JM, Agudelo M, Leiva LM, Rodriguez CA, Vesga O, editors. Standardization of a murine model of Candida albicans infection to study therapeutic equivalence (TE) of fluconazole (FCZ) generics. Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology; 2012.

(46.) Warn PA, Sharp A, Parmar A, Majithiya J, Denning DW, Hope WW. Pharmacokinetics and pharmacodynamics of a novel triazole, isavuconazole: mathematical modeling, importance of tissue concentrations, and impact of immune status on antifungal effect. Antimicrob Agents Chemother. 2009;53:3453-61.

(47.) Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother. 2002;46:2546-53.

(48.) CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts. M27-S4. Wayne, PA: Clinical and Laboratory Standard Institute; 2012.

(49.) Mavridou E, Bruggemann RJ, Melchers WJ, Verweij PE, Mouton JW. Impact of cyp51A mutations on the pharmacokinetic and pharmacodynamic properties of voriconazole in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother. 2010;54:4758-64.

(50.) Lepak AJ, Marchillo K, Vanhecker J, Andes DR. Posaconazole pharmacodynamic target determination against wild-type and Cyp51 mutant isolates of Aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2013;57:579-85.

(51.) Howard SJ, Lestner JM, Sharp A, et al. Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy. J Infect Dis. 2011;203:1324-32.

(52.) Conte JE Jr, DeVoe C, Little E, Golden JA. Steady-state intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole in lung transplant recipients. Antimicrob Agents Chemother. 2010;54:3609-13.

(53.) Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46:201-11.

(54.) Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012;55:1080-7.

(55.) Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother. 2014;69:1162-76.

(56.) Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother. 2003;47:2788-95.

(57.) Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44: 2-12.

(58.) Dolton MJ, Bruggemann RJ, Burger DM, McLachlan AJ. Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis. Antimicrob Agents Chemother. 2014;58:6879-85.

(59.) Ullmann AJ, Cornely OA, Burchardt A, et al. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother. 2006;50: 658-66.

(60.) Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope WW, European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility T EUCAST technical note on Aspergillus and amphotericin B, itraconazole, and posaconazole. Clin Microbiol Infect. 2012;18:E248-50.

(61.) Durani U, Tosh PK, Barreto JN, Estes LL, Jannetto PJ, Tande AJ. Retrospective comparison of posaconazole levels in patients taking the delayed-release tablet versus the oral suspension. Antimicrob Agents Chemother. 2015;59:4914-8.

(62.) Andes DR, Diekema DJ, Pfaller MA, Marchillo K, Bohrmueller J. 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.

(63.) Wiederhold NP, Kontoyiannis DP, Chi J, Prince RA, Tam VH, Lewis RE. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis. 2004;190:1464-71.

(64.) Lewis RE, Albert ND, Kontoyiannis DP. Comparison of the dose-dependent activity and paradoxical effect of caspofungin and micafungin in a neutropenic murine model of invasive pulmonary aspergillosis. J Antimicrob Chemother. 2008;61:1140-4.

(65.) 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.

(66.) Stevens DA, Espiritu M, Parmar R. Paradoxical effect of caspofungin: reduced activity against Candida albicans at high drug concentrations. Antimicrob Agents Chemother. 2004;48:3407-11.

(67.) Shields RK, Nguyen MH, Du C, Press E, Cheng S, Clancy CJ. Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum. Antimicrob Agents Chemother. 2011;55:2641-7.

(68.) Leitner JM, Meyer B, Fuhrmann V, et al. Multiple-dose pharmacokinetics of anidulafungin during continuous venovenous haemofiltration. J Antimicrob Chemother. 2011;66:880-4.

(69.) Pfaller MA, Boyken L, Hollis RJ, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol. 2008;46:150-6.

(70.) Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010;54:2497-506.

(71.) CLSI. Clinical breakpoints for Candida and the echinocandins. Subcommittee on antifungal susceptibility tests. Wayne, PA: Clinical and Laboratory Standard Institute; 2010.

(72.) Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:2472-82.

(73.) Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007;369:1519-27.

(74.) 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.

(75.) 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.

(76.) Autmizguine J, Guptill JT, Cohen-Wolkowiez M, Benjamin DK Jr, Capparelli EV. Pharmacokinetics and pharmacodynamics of antifungals in children: clinical implications. Drugs. 2014;74:891-909.

(77.) Nucci M, Thompson-Moya L, Guzman-Blanco M, et al. Recommendations for the management of candidemia in adults in Latin America. Latin America Invasive Mycosis Network. Rev Iberoam Micol. 2013;30:179-88.

(78.) Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39:650-5.

(79.) van Lent-Evers NA, Mathot RA, Geus WP, van Hout BA, Vinks AA. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Therap Drug Monit. 1999;21:63-73.

Javier M. Gonzalez (a,b), Carlos A. Rodriguezb, Maria Agudelo (b,c), Andres F. Zuluaga (b), Omar Vesga (b,c,*)

(a) Clinica CARDIO VID, Medellin, Colombia (b) Universidad de Antioquia, Facultad de Medicina, Grupo Investigador de Problemas en Enfermedades Infecciosas (GRIPE), Medellin, Colombia (c) Hospital Universitario San Vicente Fundacion, Unidad de Enfermedades Infecciosas, Medellin, Colombia

(*) Corresponding author.

E-mail address: (O. Vesga).


Article history:

Received 6 May 2016

Accepted 19 September 2016

Available online 5 November 2016


Antifungal agents






Table 1--Summary of the PK/PD indices and their required magnitude for
efficacy with antifungal drugs and recommended goals for therapeutic
drug monitoring (TDM).

Antifungal class        Drug           PK/PD index
                                       driving the

                  AMB lipid          f[C.sub.max]/MIC
                  AMB liposomal

                  AMB colloidal

Triazoles                            fAUC/MIC




                  sulfate (prodrug)

                  Anidulafungin      f[C.sub.max]/MIC
Echinocandins                        (or

Antifungal class        Target to attain           Preferred

                  [greater than or equal to]10  0.4-1 mg/kg IV
                  [greater than or equal to]50  5 mg/kg IV q24h

                  [greater than or equal to]50  3-5 mg/kg IV
                  [greater than or equal to]50  4 mg/kg IV q24h

                  Not determined                200 mg PO q24h


                  13-50                         400-800 mg/day
                                                PO/IV for
                                                1200-2000 mg/day
                                                PO/IV for
                                                Dosing can be
                                                scheduled q12h
                                                or q24h
                  11-52 (candidiasis)           200 mg PO q12h
                  80-100 (aspergillosis)

                   6-27 (candidiasis)           200-600 mg PO
                  20 (aspergillosis)            q24h

                  34                            Loading dose
                                                372 mg q8h x 6
                                                doses, then
                                                372 mg IV q24h
                  1 (or 10-20)                  Loading dose
Echinocandins                                   200 mg IV, then
                                                100 mg IV q24h
                  1 (or 7.5-30)                 150 mg IV q24h
                  1 (or 10-20)                  Loading dose
                                                70 mg IV, then
                                                50 mg IV q24h

Antifungal class      TDM goal        References
                    (trough con-
                   centrations in
                     mg/L) [79]

                  Not               18, 27
                  Not               25
                  Not               25
                  Not               25
                  0.5-1 (measured   54
                  during the first
Triazoles         5 days of
                  therapy and
                  regularly after)
                  Not used.         12, 13, 39, 44

                  1-5 (measured     17
                  during the first
                  5 days of
                  therapy and
                  regularly after)
                  >0.7              16, 60
                  >1 (established
                  Unknown           45

                  Not used          20

                  Not used          74
                  Not used          69
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Author:Gonzalez, Javier M.; Rodriguezb, Carlos A.; Agudelo, Maria; Zuluaga, Andres F.; Vesga, Omar
Publication:The Brazilian Journal of Infectious Diseases
Article Type:Report
Geographic Code:0LATI
Date:Jan 1, 2017
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