Adverse Drug Reactions

Adverse Drug Reactions in Patients The Journal of Clinical Pharmacology

2016, 0(0) 1–9
Receiving Systemic Antifungal Therapy 
C 2016, The American College of

Clinical Pharmacology
DOI: 10.1002/jcph.772
at a High-Complexity Hospital

Maria Clara Padovani de Souza, MSc1,2 , Andrezza Gouvêa dos Santos1,2 ,

and Adriano Max Moreira Reis, PhD1,2

Abstract
The aim of the present study was to determine the frequency of adverse drug reactions (ADRs) associated with the use of systemic antifungal drugs in
patients hospitalized at a high-complexity hospital. In addition, factors associated with ADRs were investigated. This cross-sectional retrospective study
involved the investigation of 183 medical records of patients receiving systemic antifungal therapy. Antifungal drugs were classified using the fourth
level of the Anatomical Therapeutic Chemical System. ADR causality was classified using the Naranjo algorithm. Drug interactions were assessed
using DRUG-REAX software. Data were analyzed with descriptive statistics and univariate and multivariate logistic regression. A total of 53 patients
(29.0%) had at least 1 ADR involving antifungals. Ninety-six ADRs were detected. The main ADRs observed were an infusion reaction in 24 patients
(25.0%), hypokalemia in 22 (22.9%), nephrotoxicity in 18 (18.7%), and hepatotoxicity in 15 (15.6%). Amphotericin B and voriconazole were associated
with ADRs of major clinical impact. Eleven of the ADRs (11.4%) were related to drug interactions. The following 3 factors were contributors to the
multivariate model for the occurrence of ADRs caused by antifungal drug use: neoplasm diagnosis (odds ratio [OR], 3.9; 1.9–7.9), length of hospital
stay (OR, 2.2; 1.1–4.5), and the use of ࣙ13 drugs (OR, 3.4; 1.6–7.2). Our study revealed positive associations between the occurrence of ADRs and
diagnosis of a neoplasm, the length of stay, and the use of multiple drugs concomitant with antifungals. These risk factors should be considered in
antifungal stewardship, among other actions, to promote the rational use of antifungal agents.

Keywords
antifungal therapy, antifungal agents, adverse drug reaction, drug interaction, drug utilization

Invasive fungal diseases are associated with high rates transplant units.2,5 Antifungal drugs are associated
of morbidity and mortality, particularly for hospi- with important drug interactions; however, there is little
talized patients.1–3 The incidence and prevalence of knowledge about the negative clinical consequences of
these diseases remain important nosocomial problems, these interactions. It is important to know more about
particularly affecting high-risk patients in intensive care the adverse drug reactions (ADRs) induced by new
and those with severe hematological and oncological systemic antifungal drugs, as well as about the safety
conditions.1,2 profiles of the different amphotericin B formulations in
The use of systemic antifungal drugs is essential for different clinical practice settings.6–8
the prevention and treatment of these invasive fungal The aim of this study was to determine the frequency
diseases. Over the last decade, new antifungal drugs of ADRs associated with the use of systemic antifun-
have been introduced in clinical practice.3 Different gal drugs in patients admitted to a high-complexity
antifungal drugs have different spectra of action, mech-
anisms of action, clinical efficacy, tolerability, routes
of administration, potential drug–drug interactions,
1 Hospital
safety profiles, and costs.2,3 Appropriate use of these das Clı́nicas, Universidade Federal de Minas Gerais, Belo
Horizonte, Minas Gerais, Brasil
novel agents has important implications for patient 2 Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo
care and for health care–associated infection control.3 Horizonte, Minas Gerais, Brasil
Inappropriate use of antifungal agents may result in
Submitted for publication 12 April 2016; accepted 14 May 2016.
adverse events, unnecessary exposure, higher costs, and
increased microbial resistance.1–4 Corresponding Author:
Adriano Max Moreira Reis, PhD, Faculdade de Farmácia, Universidade
Investigations of the safety of antifungal agent use
Federal de Minas Gerais, Av. Antônio Carlos 6627 Pampulha, Belo
in hospitals are rare and are restricted to oncology Horizonte, MG, Brasil 31270–901
and hematology settings and hematopoietic stem cell Email: amreis@outlook.com
2 The Journal of Clinical Pharmacology / Vol 0 No 0 2016

hospital. Factors associated with ADRs were also in- or hepatotoxic were identified by searches of the rele-
vestigated. vant specialized literature.9–12
To identify ADRs related to the use of antifun-
Methods gals that occurred during patient hospitalization, we
analyzed drug prescriptions, laboratory tests, nursing
Study Design and Setting
notes, and clinical evolution. The data collected from
This cross-sectional, retrospective study was developed
the medical records were complemented by information
at a public teaching hospital in southeastern Brazil.
accessed from the hospital’s computerized system of
This hospital has approximately 500 beds and pro-
pathology and laboratory medicine. Causality of ADRs
vides tertiary care, encompassing infectious diseases,
was verified by employing the Naranjo algorithm.13
hematology, oncology, pediatrics, neonatology, and
ADRs classified as doubtful by the Naranjo algorithm
hematopoietic stem cell and solid organ transplanta-
were not included in the study. ADR severity was
tion, among other specialties. This study was approved
classified as follows: (1) mild, with no need for any
by the university’s institutional review board. The sign-
therapy; (2) moderate, requiring a change of drug, with
ing of informed consent forms was waived, as the study
a need for specific treatment; (3) severe, involving a
was retrospective and did not involve subjecting the
potentially life-threatening event leading to prolonged
patients to any procedures.
hospitalization or a shift to a high level of care and
possible morbidity or death.14
Patients In ADR analysis, the following definitions were
Patients of all ages who were treated at the investigated adopted:
hospital during the period from January to December Nephrotoxicity—a serum creatinine level 1.5 to 2
2013 with a length of stay of more than 5 days and who times higher than that observed prior to the initiation
received systemic antifungal treatment for more than of treatment or an increase of 0.3 mg/dL in the absolute
24 hours were included in this study. For patients with serum creatinine level over the 48 hours of treatment.
multiple hospitalizations with antifungal use, only the These parameters were based on the classification of the
first treatment of the year was included in the study. Acute Kidney Injury Network to define acute kidney
Over a period of 12 months, 347 medical records for injury.15
patients using antifungals were identified in the com- Hepatotoxicity—increases in the levels of alanine
puterized physician order entry system of the hospital. aminotransferase, aspartate aminotransferase, and al-
This number was used for the sample size calculation. kaline phosphatase to 5 times those observed before
The prospective estimation of sample size based on treatment or to 3 times the upper limit of the reference
a confidence interval of 95%, a margin of error of examination performed before treatment.16
0.05, and an ADR prevalence of 50% was 183 patient Hypokalemia or hypomagnesemia—a plasma elec-
records. The sample size calculation was performed trolyte level below the lower limit of the laboratory test.
using the OpenEpi version 2.0 program. Infusion reaction—included when the ADR regis-
tered in the medical records or in the nursing notes or
Data Collection the description of symptoms was consistent with an
Data related to the clinical evolution and pharma- infusion-related reaction to an antifungal agent (fever,
cotherapy of the patients were collected using a data shaking, chills, nausea, vomiting, and uncontrolled
collection form developed specifically for this study. The blood pressure).9
patients’ medical records were the main information Potential drug interactions were detected using
sources. A retrospective review of the medical records DRUG-REAX software (Micromedex Truven Health
was performed to collect relevant data, including pa- Analytics).17 Only those drug interactions that were
tient characteristics, main diagnoses, length of hospi- contraindicated or serious or moderate in severity were
tal stay, fungal diseases, prescribed antifungal drugs, included in the study. Patients with ADRs that were
fungal agents and their sites of infection, laboratory related to drug interactions were identified.
findings, concomitant medications used, and clinical
changes before and after drug treatment. Statistical Analysis
Treatment episodes were defined as the continued The response variable in this study was the occurrence
use of a systemic antifungal agent during hospitaliza- of an ADR. The explanatory variables were as follows:
tion and the antifungal drug used; the dose and route the patients’ demographic characteristics (sex), clini-
of administration were also considered. We recorded cal conditions (diagnosis and comorbidities), pharma-
all episodes of antifungal treatment prescribed to the cotherapeutic characteristics (duration of use of the
patients. Drugs used concomitantly with antifungal antifungal agent, number of drugs used simultaneously
agents were recorded, and those that were nephrotoxic with the antifungal agent, and use of nephrotoxic or
Souza et al 3

hepatotoxic drugs), and length of hospital stay and Table 1. Frequencies of Adverse Drug Reactions Stratified by Antifungal
outcome of hospitalization (discharge or death). Drugs
Descriptive analysis was performed by determining Number Number Percentage
the absolute and percent frequencies for categorical of of (ADR to
variables, and measurements of central tendency (mean Antifungal Exposures ADR ADRsa Exposure)
and median) and dispersion (standard deviation and Amphotericin B 36 Infusion reaction 12 33.3
interquartile range) were calculated for quantitative deoxycholate
variables. Analysis of the normality of quantitative Hypokalemia 16 44.4
variables was performed using the Shapiro-Wilk and Nephrotoxicity 10 27.8
Hypomagnesemia 05 13.9
Kolmogorov-Smirnov tests. Univariate analyses for
Cutaneous 01 2.7
comparisons between the response variable and quan- reactions
titative explanatory variables were performed using the Amphotericin 19 Infusion reaction 07 36.8
Student t test when the usual model assumptions (nor- lipid complex
mality and homoscedasticity) were met. Categorical Hypokalemia 03 15.8
Nephrotoxicity 04 21.0
explanatory variables were compared with the variable
Hypomagnesemia 03 15.8
responses by performing Pearson’s chi-square test or Liposomal 19 Infusion reaction 03 15.8
Fisher’s exact test. A 95% confidence interval and sig- amphotericin B
nificance level of .05 were used. The length of hospital Hypokalemia 03 15.8
stay, concomitant medications used with the antifungal Nephrotoxicity 01 5.3
Hypomagnesemia 02 10.5
drugs, and length of antifungal use were categorized by
Hepatotoxicity 01 5.3
the median as qualitative variables, but these variables Fluconazole 170 Hepatotoxicity 08 4.7
were also analyzed by logistic regression as continuous Sleepiness 01 0.6
variables. Nephrotoxicity 02 1.2
We performed forward stepwise logistic regression Bleeding 01 0.6
Oversedation 01 0.6
analysis. The explanatory variables with a P ࣘ .25,
Voriconazole 43 Hepatotoxicity 05 11.6
as determined by univariate analyses, were included in Cardiotoxicity 01 2.3
the logistic regression model, along with the variables Blurred vision 01 2.3
considered clinically relevant. Only the variables that Cutaneous reaction 01 2.3
maintained a P < .05 were included in the final model. Nephrotoxicity 01 2.3
Caspofungin 09 Infusion reaction 01 11.1
The goodness of fit of the final model was assessed by
Hepatotoxicity 01 11.1
the Hosmer-Lemeshow test. Statistical analyses were Micafungin 14 Infusion reaction 01 7.1
performed using Statistical Package for Social Sciences Anidulafungin 04 No ADR – –
software (SPSS) version 21. Ketoconazole 03 No ADR – –
Itraconazole 03 No ADR – –

a
More than 1 ADR occurred per patient.
Results
A total of 183 patients who received systemic antifungal
therapy and met the established criteria were included antifungal is shown in Table 1. The profile of the 96
in the study. Of these patients, 105 (57.4%) were male, ADRs shows that amphotericin B deoxycholate was
13 were newborns or infants, and 33 were pediatric the most frequently involved antifungal, with 44 ADRs
patients (between 1 and 18 years of age). The median (45.8%); followed by amphotericin B lipid complex,
age was 43 years, with a minimum of 5 days and with 17 ADRs (17.7%); fluconazole, with 13 ADRs
maximum of 85 years. (13.6%): liposomal amphotericin B, with 10 ADRs
Among the 183 patients included in this study, the (10.4%); and voriconazole, with 9 ADRs (9.4%). The
most frequent diagnoses according to the ICD-10 were remaining antifungals were associated with 3 ADRs
as follows: neoplasms in 73 patients (39.9%); infectious (3.1%). Considering the number of exposures and the
and parasitic diseases in 30 (16.4%); diseases of the number of patients exposed to each antifungal agent,
blood and blood-forming organs and certain disorders the frequency of ADRs associated with fluconazole
involving the immune system in 11 (6.0%); and diseases use was low, but those associated with amphotericin
of the digestive system in 11 (6.0%). B deoxycholate and amphotericin B lipid complex use
A total of 53 patients (29.0%) experienced at least were high (Table 1).
1 ADR. In addition, 96 ADRs were related to an- With regard to the causality between the antifungal
tifungal use. Among the analyzed antifungals, only agent used and the ADR, as determined using the
anidulafungin, ketoconazole, and itraconazole did not Naranjo algorithm, causalities for 63 ADRs (65.6%)
cause an ADR. The number of exposures to each were classified as possible, those for 28 (29.2%) were
4 The Journal of Clinical Pharmacology / Vol 0 No 0 2016

Table 2. Profile of Adverse Drug Reactions Associated With Antifungal interact with ondansetron, prednisone, sulfamethoxa-
Use Identified in 183 Patients zole + trimethoprim, and tramadol.
Adverse Drug Reaction Antifungal Drug Involved na % Analysis of the patients’ clinical histories showed
that 11 of the 96 ADRs (11.4%) were related to drug
Amphotericin B deoxycholate
interactions. Nephrotoxicity and hypokalemia were the
Amphotericin B lipid complex
Infusion reaction Liposomal Amphotericin B 24 25.0 ADRs mostly frequently involved in drug interactions.
Caspofungin Table 3 shows the drug interactions and resulting
Micafungin ADRs.
Amphotericin B deoxycholate The variables with a P < .25 as determined by
Hypokalemia Amphotericin B lipid complex 22 22.9
univariate analyses were included in the logistic re-
Liposomal amphotericin B
Amphotericin B deoxycholate gression model, as shown in Table 4. Multivariate
Amphotericin B lipid complex analysis revealed that the diagnosis of a neoplasm was
Nephrotoxicity Liposomal amphotericin B 18 18.7 associated with ADR occurrence (OR, 3.9; 95%CI, 1.9–
Voriconazole 7.9), in addition to hospitalization for more than 41
Fluconazole
days (OR, 2.2; 95%CI, 1.1–4.5). Among the factors
Fluconazole
Hepatotoxicity Voriconazole 15 15.6 associated with pharmacotherapy, only the number of
Caspofungin drugs administered concomitantly with the antifungal
Liposomal amphotericin B agent remained in the final logistic regression model
Amphotericin B deoxycholate (OR, 3.4; 95% CI, 1.6–7.2). We chose the model with
Hypomagnesemia Amphotericin B lipid complex 10 10.4
concomitant drug use and length of antifungal use as
Liposomal amphotericin B
Sleepiness Fluconazole 01 1.0 categorical variables because it had a better Nagelk-
Cardiotoxicity Voriconazole 01 1.0 erke R-squared value than the model with continuous
Bleeding Fluconazole 01 1.0 variables.
Cutaneous reaction Amphotericin B deoxycholate 02 2.1
Voriconazole
Blurred vision Voriconazole 01 1.0
Oversedation Fluconazole 01 1.0
Total 96 100.0
Discussion
a
In this study, an ADR related to antifungal use occurred
More than 1 ADR occurred per patient.
in approximately 30.0% of the patients, and positive
associations between ADR occurrence and neoplasm
classified as probable, and those for 5 (5.2%) were diagnosis and prolonged hospital stay were detected.
classified as definite. Based on the classifications of The number of concomitant medications used with
severity, the observed ADRs were determined to be of the antifungal agents was also found to be positively
clinical importance, with 3 classified as serious (3.1%), associated with ADR occurrence.
87 as moderate (90.6%), and 6 as mild (6.3%). Among National and international studies addressing the
the 53 patients who experienced an ADR, 24 (45.3%) safe use of antifungals in hospitals are scarce in the
had more than 1 ADR. The maximum number of literature and are restricted to oncology and hematol-
ADRs experienced by 1 patient was 5. The patients with ogy settings and to hematopoietic stem cell transplant
multiple ADRs were distributed as follows: 13 with 2 units.2,5 Methodological differences in the investiga-
ADRs (24.5%), 5 with 3 ADRs (9.4%), 4 with 4 ADRs tions, the analyzed antifungals, and patient complexity
(7.5%), and 2 with 5 ADRs (3.8%). would complicate any comparison of these results with
The ADR most frequently detected was an infu- those of our study. These differences also explain the
sion reaction in 24 patients (25.0%), followed by hy- ADR prevalence that has been reported.
pokalemia in 22 patients (22.9%), nephrotoxicity in 18 The ADR profile detected in the present study re-
(18.7%), and hepatotoxicity in 15 (15.6%). Table 2 lists flects current knowledge about the safety of systemic
the ADRs and antifungals involved. antifungals and the prevalence of adverse reactions in-
A total of 155 of the 183 patients (84.7%) were duced by amphotericin B deoxycholate, amphotericin B
exposed to at least 1 interaction between an antifun- lipid complex, and voriconazole.2,5,7,18–20 Observational
gal and another drug. A total of 96 combinations studies investigating the use of antifungal agents in
of 1 antifungal agent and 1 other drug were iden- different care settings contribute to clarification of the
tified that resulted in drug interactions. The number risk–benefit balance for these antimicrobials.
of drug interactions was 601. The antifungal agent The main ADR detected was an infusion reaction
that was most frequently involved in drug interactions related to administration, mainly involving ampho-
was fluconazole, corresponding with 480 interactions tericin. Similar to previous clinical trials, which have
(79.9%). Fluconazole was found to most frequently reported frequency of infusion reactions ranging from
Souza et al 5

Table 3. Frequencies of Adverse Drug Reactions Related to Drug–Drug Interactions

Adverse Drug Reaction (ADR) Drug–Drug Interaction (DDI) Potential DDI, n DDI-Related ADR, n %

Amphotericin B deoxycholate + Cyclosporine 4 1

Nephrotoxicity Fluconazole + cyclosporine 10 1
Voriconazole + cyclosporine 5 1
Fluconazole + tacrolimus 17 1
Total 4 36.4
Hypokalemia Liposomal amphotericin B + dexamethasone 1 1
Liposomal amphotericin B + hydrocortisone 6 1
Total 2 18.2
Hepatotoxicity Fluconazole + cyclosporine 10 1 9.1
Bleeding Fluconazole + warfarin 4 1 9.1
Oversedation Fluconazole + fentanyl 18 1 9.1
Sleepiness Fluconazole + tramadol 32 1 9.1
Cardiotoxicity Voriconazole + ondansetron 16 1 9.1
Total 11 100.0

Table 4. Univariate and Multivariate Analyses of Factors Associated With Adverse Drug Reactions

Adverse Drug Reaction Univariate Analysis Multivariate Analysisa

Variable Yes, n No, n OR (95%CI) P OR (95%CI) P

Sex
Female 19 59 0.7 (0.3–1.3) .237
Male 34 71 1 — —
Length of hospital stay
ࣙ41 Days 34 57 2.3 (1.2– 4.4) .013 2.2 (1.1–4.5) .03
<41 Days 19 73 1 1
Hospitalization outcome
Death 16 20 2.4 (1.1–5.1) .022
Discharge 37 110 1 — —
Admission diagnosis neoplasms
Yes 32 42 3.2 (1.6–6.2) .000 3.9 (1.9–7.9) < .001
No 21 88 1 1
Comorbidity liver disease
Yes 3 21 0.3 (0.09–1.1) .056
No 50 109 1 — —
Drug therapy hepatotoxic drug
Yes 50 113 2.5 (0.7–8.9) .145
No 03 17 1 — —
Concomitant drugs used with antifungalb
ࣙ13 37 56 3.1 (1.5–6.1) .001 3.4 (1.6–7.2) .001
<13 16 74 1 1
Length of antifungal useb
ࣙ9 Days 36 60 2.5 (1.2–4.8) .007
<9 Days 17 70 1 — —

OR, odds ratio; CI, confidence interval.

a
Hosmer-Lemeshow test: χ2 = 3.48; degrees of freedom = 6; P = .75.
b
Stratified by median.

34.0 to 51.0%,18 infusion reactions were common in the infusion-related reactions.7,21–25 These facts explain the
patients investigated in this study. low incidence of infusion reactions associated with
The small sizes and negative charges of the lipo- liposomal amphotericin B observed in our study.
somes in the liposomal amphotericin B formulation Infusion reactions associated with echinocandin use
divert the normal macrophage response, with alteration among the patients in this study were uncommon and
from a proinflammatory to an anti-inflammatory cy- occurred at a lower frequency than those associated
tokine profile, resulting in a decrease in the upregulation with polyenic antibiotic use, which is also in accordance
of proinflammatory cytokines and the attenuation of with the findings of previous studies.18
6 The Journal of Clinical Pharmacology / Vol 0 No 0 2016

Nephrotoxicity is a factor limiting the use of ampho- inhibiting the metabolism of drugs such as omeprazole,
tericin B, which is associated with substantial morbid- ondansetron, and tramadol. Analysis of drug–drug in-
ity, mortality, and elevated health care costs.7,26 During teractions among systemic antifungal drugs conducted
the infusion of amphotericin B, vasoconstriction of the at a hospital in France revealed that the majority of the
afferent renal arterioles occurs, resulting in decreases in interactions involved fluconazole.38 A drug interaction
renal blood flow and the glomerular filtration rate. Kid- can cause the increased occurrence of ADRs or reduce
ney cells are highly exposed to amphotericin B, which the drug’s effectiveness.6,39
explains the high nephrotoxicity of this drug.7,27,28 Cyclosporine was one of the drugs that interacted
The high costs of lipid formulations limit access to with antifungal agents, resulting in greater numbers
these drugs, which are generally used as a treatment of ADRs, such as nephrotoxicity when used in com-
option for patients with nephrotoxicity resulting from bination with deoxycholate amphotericin B, flucona-
use of amphotericin B deoxycholate or from previous zole, or voriconazole and hepatotoxicity when used
renal dysfunction. The use of amphotericin B deoxy- in combination with fluconazole. Tacrolimus was also
cholate should be avoided in patients with impaired found to interact with fluconazole, causing ADRs. Cy-
renal function or in those with an increased risk of closporine and tacrolimus are associated with nephro-
developing renal dysfunction, such as elderly patients, toxicity, primarily because they alter intraglomerular
those using other nephrotoxic drugs, or those with hemodynamics.11 To minimize ADRs, doses of cy-
unstable hemodynamics.29–31 closporine and tacrolimus should be adjusted, and
Electrolytic potassium and magnesium disorders the serum levels of these drugs in patients should be
are also among the most frequent ADRs induced by monitored.5,9,17
amphotericin B deoxycholate. Thus, serum potassium Another interaction that resulted in clinically
level should be monitored periodically during treatment relevant adverse reactions (cardiotoxicity) was that
with amphotericin B, and potassium supplementation between voriconazole and ondansetron.
should be provided. These measures should be adopted Coadministration of voriconazole with drugs that
during the early treatment phase and are important to are metabolized by cytochrome P4503A and that may
prevent severe electrolyte abnormalities.32–34 prolong the QT interval, such as ondansetron, can lead
Hepatotoxicity was mainly induced by triazoles to serious consequences because of the additive effects
in this study, and voriconazole was associated with of both drugs on the QT interval. If concomitant
the highest number of cases. Hepatotoxicity was also therapy is truly necessary, then electrocardiographic
caused by fluconazole, caspofungin, and liposomal monitoring is recommended.6,9,17
amphotericin B. A systematic review has shown that Concomitant administration of fluconazole and
the use of fluconazole and echinocandin is associated warfarin may cause a serious reaction and should be
with a lower incidence of adverse hepatic events and a performed with caution, as it may result in an increased
decreased risk of treatment discontinuation. Notably, international normalized ratio and may thus expose
itraconazole and voriconazole have been associated patients to an increased risk of bleeding. When possible,
with an increased risk of liver damage.35 fluconazole should be replaced by another antifungal
Liposomal amphotericin B and fluconazole were agent.9 The clinical manifestation of the interaction
associated with an increased risk of hepatotoxicity in between fluconazole and warfarin was identified in our
patients undergoing hematopoietic stem cell transplan- study.
tation, regardless of the medical characteristics or the Length of hospital stay was associated with the oc-
other medications used. However, the magnitude of currence of ADRs. Length of stay has been investigated
the risk of injury was higher for patients receiving and described in the literature as a risk factor for the oc-
liposomal amphotericin B.20 A major risk factor for currence of these reactions.37 In the multivariate logistic
hepatotoxicity is the concomitant use of an antifungal model, the associated factors included a diagnosis of
agent with a cytochrome CYP3A4 inhibitor or another neoplasm, length of hospital stay, and use of multiple
hepatotoxic drug.36 drugs. Use of an increasing number of drugs has been
The complex pharmacotherapy associated with the well correlated with an increasing probability of ADRs,
concomitant use of multiple drugs increases the like- especially in patients with complex clinical conditions
lihood of drug interactions and ADRs in patients that affect antifungal agent administration. The clinical
with fungal infections.2,36–38 A number of drug interac- impact of ADRs contributes to prolonged hospital
tions involving antifungals have been identified and are stays, resulting in higher costs and compromising pa-
largely related to fluconazole. Azole antifungal agents tient safety.37,40,41
have the potential to cause interactions, most often by Neoplasms in patients are associated with various
inhibiting cytochrome P3A4.6,39 In this study, pharma- clinical factors that require an antifungal prescrip-
cokinetic interactions were detected, with fluconazole tion, and comorbidities requiring multiple medications
Souza et al 7

predispose patients to drug interactions and ADRs.1,2 Conclusion

Considering the widespread use of antifungal agents Amphotericin B and voriconazole were the antifun-
in clinical practice and that cancer patients are often gals most often associated with adverse reactions of
excluded from clinical trials, the importance of identify- substantial clinical impact. Infusion reactions during
ing antifungal agents that cause ADRs and drug inter- administration, hypokalemia, nephrotoxicity, and hep-
actions in these patients is clear.2 Thus, the association atotoxicity were the most common adverse reactions
identified here between neoplasm diagnosis and ADRs observed. The number of ADRs associated with drug
is important because it adds knowledge about antifun- interactions was small, suggesting that clinical manifes-
gal safety in this group of patients, demonstrating the tations of drug interactions that cause harm to patients
risk of ADRs and the need for preventive strategies and do not frequently occur during antifungal therapy.
monitoring. However, the reactions had a relevant clinical impact.
Strategies for ADR prevention in patients using an- The occurrence of ADRs associated with antifungal
tifungals include multidisciplinary actions to optimize use was positively associated with the diagnosis of a
their use and to reduce the risk factors associated neoplasm, a prolonged hospital stay and the number
with ADRs. Stewardship programs are important for of drugs used concomitantly with an antifungal. These
promoting the rational use of antifungals and patient risk factors should be considered in the development of
safety, in addition to reducing drug resistance and treatment guidelines, antifungal stewardship programs,
improving the control of health care–associated in- and other actions to promote the rational use of
fections. The definition of treatment protocols based antifungal agents. In current medical practice, the use
on scientific evidence is also an impact strategy that of systemic antifungal drugs in hospitals is increasing,
contributes to reduced costs.42–44 The therapeutic mon- and the findings of this study contribute important
itoring of antifungal drugs, especially voriconazole and information to promote the rational use and safety of
itraconazole, has been suggested as a means to monitor antifungal therapy.
toxicity and to ensure safe and effective plasma drug
levels. Evidence-based clinical guidelines are essential Acknowledgments
for the incorporation of therapeutic drug monitoring
into clinical practice.18,45,46 We thank Pró-Reitoria de Pesquisa da Universidade Federal
This investigation of ADRs caused by antifungal de Minas Gerais e Fundação de Apoio a Pesquisa de Minas
drugs covered all antifungal drug classes and included Gerais-FAPEMIG for providing a scientific initiation schol-
patients in different care units, and these are the arship.
strengths of this study. Given the complexities of the
ADR determinants and the methodology used, the Funding
results should be evaluated in the context of the study No funding was provided.
limitations. The cross-sectional design did not permit
causal relationships to be established between the as- Declaration of Conflicting Interests
sociated factors and ADR occurrence. The collection No conflicts of interest exist.
of retrospective data may generate bias in analysis of
ADRs because of the possibility of obtaining miss-
ing or incomplete medical records. The exclusion of References
ADRs classified by the Naranjo algorithm as having 1. Gross BN, Steib-Bauert M, Kern WV, et al. Hospital use of
dubious causality may have resulted in underestimation systemic antifungal drugs: a multi-center surveillance update
from Germany. Infection. 2015;43(4):423–429.
of the ADR frequency. Another limitation is that the
2. Metzke B, Neubauer WC, Hieke S, et al. Use of systemic
antifungal cumulative dose was not investigated as a antifungals in daily clinical pratice in the haematology and
parameter for ADRs. Further, the study was conducted oncology setting: results of a prospective observational analysis.
at a single hospital, which restricts the generalizability Pharmacoepidemiol Drug Saf. 2012;21:953–963.
of the results. 3. Nivoix Y, Launoy A, Lutun P, et al. Adherence to recommenda-
tions for the use of antifungal agents in a tertiary care hospital.
Despite these limitations, the findings of this study
J Antimicrob Chemother. 2012;67:2506–2513.
support the optimization of systemic antifungal drug 4. Doi AM, Pignatari AC, Edmond MB, et al. Epidemiology
therapy safety. Future investigations may be conducted and microbiologic characterization of nosocomial candidemia
at different hospitals. These findings also contribute to from a Brazilian National Surveillance Program. PLoS One.
the understanding of the factors associated with the 2016;11(1):e0146909.
5. Egger SS, Meier S, Leu C, et al. Drug interactions and ad-
occurrence of ADRs caused by antifungals and to the
verse events associated with antimycotic drugs used for invasive
promotion of safe and rational antifungal use, as well aspergillosis in hematopoietic SCT. Bone Marrow Transplant.
as the prevention of fungal resistance. 2010;45:1197–1203.
8 The Journal of Clinical Pharmacology / Vol 0 No 0 2016

6. Bruggemann RJM, Alffenaar JWC, Blijlevens NMA, et al. 26. Wade RL, Chaudhari P, Natoli JL, et al. Nephrotoxicity and
Clinical relevance of the pharmacokinetic interactions of azole other adverse events among inpatients receiving liposomal am-
antifungal drugs with other coadministered agents. Clin Infect photericin B or amphotericin B lipid complex. Diagn Microbiol
Dis. 2009; 48:1441–1458. Infect Dis. 2013;76:361–367.
7. Hamill RJ. Amphotericin B Formulations: A Comparative 27. Krieger M. The use of amphotericin B to detect inhibitors of
Review of Efficacy and Toxicity. Drugs. 2013;73:919– cellular cholesterol biosynthesis. Anal Biochem. 1983;135:383–
934. 391.
8. Ramı́rez E, Garcı́a-Rodrı́guez J, Borobia AM, et al. Use of 28. Wasan KM, Rosenblum MG, Cheung L, et al. Influence of
antifungal agents in a pediatric and adult high-risk areas. Eur lipoproteins on renal cytotoxicity and antifungal activity of
J Clin Microbiol Infect Dis. 2012;31:337–347 amphotericin B. Antimicrob Agents Chemother. 1994;38:223–
9. DRUG-DEX R
(2014) System (electronic version). Truven 227.
Health Analytics, Greenwood Village, Colorado, USA. http:// 29. Karimzadeh I, Khalili H, Farsaei S, et al. Role of diuretics and
www-micromedexsolutions-com.ez27.periodicos.capes.gov.br/. lipid formulations in the prevention of amphotericin B-induced
Accessed March 10, 2014. nephrotoxicity. Eur J Clin Pharmacol. 2013;69:1351–1368.
10. Schetz M, Dasta J, Goldstein S, et al. Drug-induced acute kidney 30. Álvarez-Lerma F, Soriano MC, Rodrı́guez M, et al. Impact
injury. Curr Opin Crit Care. 2005;11:555–565. of liposomal amphotericin B on renal function in critically ill
11. Bentley ML, Corwin HL, Dasta J. Drug Induced acute kidney patients with renal function impairment. Rev Esp Quimioter.
injury in the critically ill adult: Recognition and prevention 2012;25:206–215.
strategies. Crit Care Med. 2010;38(Suppl 3):S169–S174. 31. Lortholary O, Charlemagne A, Bastides F, et al. A multicentre
12. Smith E, Desmond P. Prescribing in patients with abnormal liver pharmacoepidemiological study of therapeutic practices in inva-
function tests. Aust Fam Physician. 2013;42:30–33. sive fungal infections in France during 1998-1999. J Antimicrob
13. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating Chemother. 2004;54:456–464.
the probabiliting of adverse drug reactions. Clin Pharmacol Ther. 32. Malani PN, Depestel DD, Riddell J, et al. Experience with
1981;30:239–245 community-based amphotericin B infusion therapy. Pharma-
14. Hartwig SC, Siegel J, Schneider PJ. Preventability and severity cotherapy. 2005;25:690–697.
assessment in reporting adverse drug reactions. Am J Hosp 33. Girois SBF, Chapuis E, Decullier BGP. Adverse effects of
Pharm. 1992;49:2229–2232 antifungal therapies in invasive fungal infections: review and
15. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury meta-analysis. Eur J Clin Microbiol Infect Dis. 2006;25:138–149.
Network: report of an iniciative to improve outcomes in acute 34. Usami E, Kimura M, Kanematsu T, et al. Evaluation of hy-
kidney injury. Crit Care. 2007;11:R31. pokalemia and potassium supplementation during administra-
16. Gorski E, Esterly JS, Postelnick M, et al. Evaluation of hepato- tion liposomal-amphotericin B. Exp Ther Med. 2014;7:941–946.
toxicity with off-label oral-treatment doses of voriconazole for 35. Wang JL, Chang CH, Young-Xu Y, et al. Systematic review
invasive fungal infections. Antimicrob Agents Chemother. 2011; and meta-analysis of the tolerability and hepatotoxicity of
55:184–189. antifungalsin empirical and definitive therapy for invasive fungal
17. DRUG-REAX R
2014. System (electronic version). Truven infection. Antimicrob Agents Chemother. 2010;54:2409–2419.
Health Analytics, Greenwood Village, Colorado, USA. http:// 36. Raschi E, Poluzzi E, Koci A, et al. Assessing liver injury
www-micromedexsolutions.com.ez27.periodicos.capes.gov.br. associated with antimycotics: Concise literature review and clues
Accessed March 10, 2014. from data mining of the FAERS database. World J Hepatol.
18. Chau MM, Kong DC, van Hal SJ, et al. Consensus guidelines 2014;6:601–612.
for optimising antifungal drug delivery and monitoring to avoid 37. Krähenbühl-Melcher A, Schlienger R, Lampert M, et al. Drug
toxicity and improve outcomes in patients with haematological related problems in hospitals: a review of the recent literature.
malignancy. Intern Med J. 2014;44:1364–1388. Drug Saf. 2007;30:379–407.
19. Cronin S, Chandrasekar PH. Safety of triazole antifungal drugs 38. Depont F, Vargas F, Dutronc H, et al. Drug-drug interactions
in patients with cancer. J Antimicrob Chemother. 2010;65:410– with systemic antifungals in clinical practice. Pharmacoepidemiol
416. Drug Saf. 2007;16:1227–1233.
20. Fischer MA, Wolfgang C, Winkelmayer WC, et al. The hepa- 39. Trevisan DD, Silva JB, Oliveira HC, et al. Prevalence and clinical
totoxicity of antifungal medications in bone marrow transplant significance of potential drug-drug interaction in hematopoi-
Recipients. Clin Infect Dis. 2005; 41:301-–307. etic stem cell transplantation. Cancer Chemother Pharmacol.
21. Ben-Ami R, Lewis RE, Kontoyiannis DP. Immunopharmacol- 2015;75:393–400.
ogy of modern antifungals. Clin Infect Dis. 2008;47:226–235 40. Atuah KN, Hughes D, Pirmohamed M. Clinical pharmacology:
22. Eriksson U, Seifert B, Schaffner A. Comparison of effects special safety considerations in drug development and pharma-
of amphotericin B deoxycholate infused over 4 or 24 hours: covigilance. Drug Saf. 2004;27:535–554.
randomised controlled trial. BMJ. 2001; 322:579–582. 41. Evans RS, Loyd JF, Stoddard GJ, et al. Risk factors for
23. Adler-Moore J, Proffitt RT. AmBisome: liposomal formulation, adverse drug events: a 10-year analysis. Ann Pharmacother.
structure, mechanism of action and pre-clinical experience. An- 2005;39:1161–1168.
timicrob Chemother. 2002;49(Suppl 1):21–30. 42. Ananda-Rajaha MR, Slavinb MA, Thursky KT. The case for
24. Bellocchio S, Gaziano R, Bozza S, et al. Liposomal ampho- antifungal stewardship. Curr Opin Infect Dis. 2012;25:107–115.
tericin B activates antifungal resistance with reduced toxicity by 43. Micallef C, Aliyu SH, Santos R, et al. Introduction of an
diverting toll-like receptor signalling from TLR-2 to TLR-4. J antifungal stewardship programme targeting high-cost antifun-
Antimicrob Chemother. 2005;55:214–222. gals at a tertiary hospital in Cambridge England. J Antimicrob
25. Simitsopoulou M, Roilides E, Dotis J, et al. Differential expres- Chemother dkv040. 2015;70:1908–1911.
sion of cytokines and chemokines in human monocytes induced 44. Mondain V, Lieutier F, Hasseine L, et al. A 6-year antifun-
by lipid formulations of amphotericin B. Antimicrob Agents gal stewardship programme in a teaching hospital. Infection.
Chemother. 2005;49:1397–1403. 2013;41:621–628.
Souza et al 9

45. Gautier-Veyret E, Fonrose X, Tonini J, et al. Variability of 46. Karthaus M, Lehrnbecher T, Lipp HP, et al. Therapeutic
voriconazole plasma concentrations after allogeneic hematopoi- drug monitoring in the treatment of invasive aspergillosis with
etic stem cell transplantation: impact of cytochrome p450 poly- voriconazole in cancer patients an evidence-based approach. Ann
morphisms and comedications on initial and subsequent trough Hematol. 2015;94:547–556.
levels. Antimicrob Agents Chemother. 2015;59:2305–2314.