Download Pre-medication practices and incidence of

Journal of Antimicrobial Chemotherapy (2008) 62, 1392– 1400
doi:10.1093/jac/dkn394
Advance Access publication 23 September 2008
Pre-medication practices and incidence of infusion-related reactions
in patients receiving AMPHOTECw: data from the Patient
Registry of Amphotericin B Cholesteryl Sulfate Complex
for Injection Clinical Tolerability (PRoACT) registry
David L. Paterson1,2, Kristin David3*, Mirando Mrsic4, Petr Cetkovsky5, Xin-Hua Weng6,
Jaroslav Sterba7, Gregerly Krivan8, Darinka Boskovic9, Minqiang Lu10 and Li-Ping Zhu6
on behalf of the PRoACT Investigators
1
University of Pittsburgh, Pittsburgh, PA, USA; 2Centre for Clinical Research, University of Queensland,
Brisbane, Australia; 3ProSanos Corporation, Harrisburg, PA, USA; 4University Hospital Centre, Zagreb, Croatia;
5
Institute of Haematology and Blood Transfusion, Prague, Czech Republic; 6Huashan Hospital, Shanghai, China;
7
Department of Paediatric Oncology, Brno, Czech Republic; 8Szent Laszlo Hospital, BMT Unit, Budapest,
Hungary; 9Clinical Centre of Serbia, Belgrade, Serbia; 10The Third Affiliated Hospital of Sun Yat-sen University,
Guangzhou, China
Received 8 July 2008; returned 8 August 2008; revised 15 August 2008; accepted 23 August 2008
Background: Clinical studies have suggested that rates of infusion-related reactions (IRRs) may be
higher with amphotericin B colloidal dispersion (ABCD) versus other forms of amphotericin
B. However, these studies did not permit the use of pre-medications upfront, which are now commonly
used.
Objectives: To describe the use of pre-medications and determine the rate of IRRs in the real-world
setting.
Methods: PRoACT, a multicentre, worldwide observational registry, captured real-world data about
pre-medication practices and IRRs in patients receiving ABCD. Eligible patients were those beginning
treatment with ABCD; treatment was according to the site’s standard treatment practice. Incidence of
IRRs was collected during the first 10 days of ABCD therapy. Clinical response data were collected
12 weeks after treatment start.
Results: One hundred and seventy patients from 21 worldwide sites were included (median age
37 years; 52% male). There were a total of 1230 ABCD infusions (mean dose 2.8 mg/kg/day); 90% of the
infusions (1105/1230) had pre-medication. Common pre-medications included corticosteroids, antihistamines, paracetamol (acetaminophen) and metamizole. The overall IRR rate was 12% (147/1230)
and was lower in infusions with pre-medication (11%) versus no pre-medication (22%), P < 0.001.
Corticosteroids were associated with a decreased incidence of IRRs (P < 0.05), while paracetamol and
antihistamines were not. The most common IRRs were chills (7%), fever (7%) and rigors (5%).
Clearance of the fungal infection occurred in 52% of the participants.
Conclusions: These data suggest a lower rate of IRRs with ABCD than previously reported. Pre-medication
is associated with decreased IRR incidence. Corticosteroids in particular appear to decrease IRRs
while paracetamol and antihistamines, though commonly used, do not.
Keywords: liposomal, tolerability, fungal infections
.....................................................................................................................................................................................................................................................................................................................................................................................................................................
*Corresponding author. Tel: þ1-717-635-2140; Fax: þ1-717-635-2575; E-mail: [email protected]
.....................................................................................................................................................................................................................................................................................................................................................................................................................................
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# The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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ABCD, pre-medications and IRRs
Introduction
Invasive fungal infections are a significant medical concern as
they are difficult to treat and are associated with high mortality.
Early antifungal treatment is essential to successful outcomes.
Conventional amphotericin B deoxycholate (c-AmB) has been
widely used for treatment as it offers the broadest spectrum of
activity of all available antifungals, including both yeast and
moulds.1 – 4 While c-AmB is effective in treating fungal infections,
it has adverse side effects, in particular, nephrotoxicity, that limit
its use.5 – 8 Lipid-based amphotericin B formulations reduce nephrotoxicity while remaining efficacious against various fungi. The
lipid formulations currently on the market include: amphotericin B
colloidal dispersion (ABCD) (AMPHOCILw or AMPHOTECw),9
amphotericin B lipid complex (ABLC) (Abelcetw)10 and liposomal
amphotericin B (L-AMB) (AmBisomew).11 These lipid-based
formulations display similar efficacy to each other as well as to
c-AmB, with a decreased risk of nephrotoxicity and mortality
compared with c-AmB.12,13
While clinical studies have demonstrated ABCD to be effective and safe,14 – 17 infusion-related reactions (IRRs), i.e. periinfusional events such as chills, rigors, sweats and fever, are perceived to be more common with the use of ABCD compared
with other lipid-based formulations of amphotericin B.18,19
However, the incidence of IRRs may be reduced when ABCD is
administered with pre-medications. Previous studies did not
employ a standard pre-medication regimen,18 or used premedications not found to be effective in preventing IRRS
(e.g. paracetamol and diphenhydramine).19,20
The PRoACT (Patient Registry of AMPHOTECw/
AMPHOCILw Clinical Tolerability) registry was designed to
examine the IRR rate in ABCD-treated patients who also received
pre-medications. This global, prospective registry represents the
first post-marketing study employed to specifically capture IRR
rates in a lipid-based formulation of amphotericin B. The specific
goals of PRoACT were to understand the current pre-treatment
practices associated with ABCD use and the corresponding rate of
IRRs in ‘real-world clinical practice’ (i.e. outside of clinical trials).
Methods
Study design and conduct
The PRoACT registry was a 12 week, observational patient registry.
Global investigators and sites which already utilized ABCD in their
routine antifungal treatment process were identified and invited to
participate in the study. This study was conducted in accordance
with the Declaration of Helsinki and good clinical practices.21
Participants
Eligible patients were defined as adult or paediatric patients who
received at least one dose of ABCD, patients who did not have any
contraindications to ABCD and patients who were not lactating.
Investigators were explicitly instructed to enrol patients only after
the treatment decision had been made and ABCD use had already
been selected based on the clinician’s best clinical judgement.
Data collected and evaluation schedule
The following information was collected: basic demographics,
co-morbidities, concomitant medications, history of prior antifungal
use, laboratory values [i.e. haemoglobin, haematocrit, platelets,
absolute neutrophil count, serum creatinine, alanine aminotransferase, aspartate aminotransferase, serum bilirubin, alkaline phosphatase, serum potassium, and serum magnesium], type of fungal
infection, daily collection of treatment information [ pre-medication
type, dose, date and time pre-medication dose was administered,
date and time of ABCD infusion start, total daily dose (mg), and
duration of study drug infusion in minutes] and response to treatment and mortality. Vital signs (temperature, systolic and diastolic
blood pressure, respiration rate) and data on whether IRR-type clinical symptoms (i.e. rigors, fever, chills, nausea, pain, hypertension,
hypotension, tachycardia, chest pain, vasodilation, hypoxaemia)
were present within 24 h prior to the first ABCD infusion were also
recorded pre- and post-infusion.
Information on each patient enrolled into the PRoACT registry
was collected each day for the first 10 days of antifungal therapy
with ABCD. Information regarding the patient’s antifungal response
to treatment and mortality status was collected 12 weeks (+2
weeks) after the date of the first treatment with ABCD.
Primary outcomes
The primary outcomes were the rate of pre-medication use and the
incidence of IRRs. Pre-medication use was considered for each infusion. IRRs were considered overall (i.e. treatment days 1 –10) and
following the first infusion; IRR rates were compared between
ABCD infusions that had pre-medication and ABCD infusions that
did not have pre-medication. Rates of IRRs were also compared
between specific pre-medications and classes of drugs.
Secondary outcomes
The secondary outcomes were response rates, mortality rates
(overall and between participants with and without corticosteroid
pre-medication), adverse event rates and rates of nephrotoxicity and
hepatotoxicity. Response rates (i.e. proportion of participants with
clearance of the fungal infection) and mortality rates (i.e. proportion
of patients deceased) were assessed at 12 weeks (+2 weeks) after
start of ABCD. A responder was defined according to the Mycoses
Study Group (MSG) criteria.22 A non-responder was defined as participants who still had their fungal infection (as defined by the MSG
criteria) or patients who were switched to another antifungal treatment. Adverse events were assessed as the overall proportion of participants with a treatment-emergent adverse event, as the proportion
of participants with an adverse event related to ABCD and as the
proportion of participants who discontinued ABCD due to an
adverse event. Nephrotoxicity was defined as an increase in serum
creatinine of more than two times the value obtained prior to ABCD
initiation. Hepatotoxicity was defined as an increase in alanine transaminase levels to more than five times that at baseline (i.e. prior to
ABCD treatment), if baseline values were less than twice the upper
limit of normal (ULN). For patients in whom baseline values were
more than five times ULN, hepatotoxicity was defined as an increase
in transaminase levels to more than twice that at baseline.
Statistical analysis
Descriptive statistics (means, standard deviations for continuous
data; frequencies and percents for categorical data) were used to
describe the registry population. x2 tests were used to compare proportional differences between groups. For most analyses, the unit of
analysis was infusions rather than participants. A P value of 0.05
was considered statistically significant.
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Paterson et al.
Results
Participants
A total of 170 participants were enrolled in the PRoACT registry
from 21 sites worldwide from 1 November 2006 to 31
December 2007 (n ¼ 50 participants from the Czech Republic;
n ¼ 40 from Croatia; n ¼ 33 from China; n ¼ 13 from Hungary;
n ¼ 13 from Serbia; n ¼ 10 from Puerto Rico; n ¼ 7 from
Poland; n ¼ 4 from Thailand). Table 1 displays the demographic
characteristics of the sample.
The most common underlying condition was haematological
malignancy (67% of the participants). The most common site of
infection was the lungs (41% of the participants) [Table S1,
available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].
Slightly less than half of the enrolled patients (80/170,
47.1%) had received antifungal therapy prior to their initiation
of ABCD. Inadequate response to a prior antifungal(s) was the
most common reason reported for changing from a prior antifungal to ABCD [reported for 53.8% (43/80) of the participants
who had prior antifungal therapy]. Nephrotoxicity accounted for
the reason in 21.3% (17/80) of the participants who had
switched from a prior antifungal to ABCD. Other reasons were:
identification of the fungal organism 8.8% (7/80); hepatotoxicity: 7.5% (6/80); ‘other’ toxicity 2.5% (2/80); infusion tolerability 1.2% (1/80); and ‘other’ 18.8% (15/80) or unknown
3.8% (3/80). In the 80 participants with prior antifungal treatment, prior antifungals included: azoles [55.0%, 44/80 (fluconazole: n ¼ 22; itraconazole: n ¼ 14; posaconazole: n ¼ 2;
Table 1. Summary of demographics and baseline characteristics of
participants in the PRoACT registry
n ¼ 170
Age (years), n (%)
,18
18– 49
50– 64
65
Age (years), mean (SD)
Gender, n (%)
male
female
32 (18.8)
84 (49.4)
44 (25.9)
10 (5.9)
37.0 (18.7)
88 (51.8)
82 (48.2)
Race, n (%)
Asian
White
37 (21.8)
133 (78.2)
Ethnicity, n (%)
Hispanic/Latino
non-Hispanic/non-Latino
unknown
26 (15.3)
142 (83.5)
2 (1.2)
Weight (kg), mean (SD)
62.5 (22.6)
Height (m), mean (SD)
1.6 (0.2)
Body mass index, mean (SD)
22.4 (4.9)
voriconazole: n ¼ 6)]; c-AmB: (46.3%, 37/80); other lipid-based
formulations of amphotericin B [7.5%, 6/80 (ABLC n ¼ 5;
L-AmB: n ¼ 1)]; echinocandin (caspofungin) (13.8%, 11/80);
and flucytosine (3.8%, 3/80).
The majority of participants enrolled in the PRoACT registry
(78.8%) were receiving one or more concomitant medications at
the initiation of ABCD therapy. The most common types of concomitant medications reported were corticosteroids (42.4%),
immunotherapy drugs (25.3%), non-steroidal anti-inflammatory
drugs (NSAIDS) (5.3%) and other drugs associated with nephrotoxicity (64.1%) (i.e. aciclovir, amikacin).
ABCD therapy
There were a total of 1230 infusions in the 170 participants. The
average length of ABCD infusion received by participants was
5.9 h with a range of 10 min to 18 h. The average total daily
dose of ABCD was 165 mg with a range of 15 – 580 mg; the
mean daily dose overall (for the 1230 infusions) was 2.8 mg/kg,
while the mean daily dose per participant was 2.9 mg/kg.
A total of 13.7% (169/1230 infusions) of the ABCD infusion
episodes also had a concomitant antifungal therapy at the
time of the ABCD treatment [concomitant antifungals included:
caspofungin 38 (3.1%); flucytosine 58 (4.7%); fluconazole 54
(4.4%); voriconazole 23 (1.9%); itraconazole 21 (1.7%)].
Nearly half of the participants (82/170, 48.2%) completed 10
days of ABCD therapy. Participants could have had more than
one reason recorded for discontinuing ABCD prior to 10 days of
treatment. The most prevalent reason for discontinuing treatment
prior to 10 days was improvement in their symptoms or clearance of the fungal infection (30/88, 34%). A full list of reasons
for discontinuation can be found in Table S2 [available as
Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].
Seventeen participants discontinued prior to 10 days of treatment
due to infusion intolerability; of these participants, one had
not received any pre-medication and one received no premedications prior to the first two infusions and then received
20 mg methylprednisolone and 500 mg paracetamol prior to the
third infusion. The remaining 15 patients received one or more
of the following pre-medications: paracetamol (n ¼ 7), diphenhydramine (n ¼ 3), methylprednisone/methylprednisolone (n ¼
5), metamizole (n ¼ 5), hydrocortisone (n ¼ 5), chloropyramine
(n ¼ 4), prednisolone (n ¼ 1), chlorphenamine maleate (n ¼ 1),
calcium gluconate (n ¼ 1), loratadine (n ¼ 1), pethidine (n ¼ 1)
and/or dexamethasone (n ¼ 1).
Primary outcomes
Pre-medication use. Pre-medications were used in 89.8% of all
infusions (1105/1230). Overall, 10.2% of the infusions had no
pre-medication, 36.7% had one pre-medication, 38.7% had two
pre-medications, 14.2% had three pre-medications and two infusions had four pre-medications. Corticosteroids were the most
common class of drugs used for pre-medication (67% of the
infusions), antihistamines were used in 41.4% of the infusions,
paracetamol and metamizole were used in 24.3% and 20.7% of
the ABCD infusions, respectively (Table 2).
IRRs. Overall, IRRs occurred in 12% (147/1230) of the ABCD
infusions. The rate of IRRs following the first infusion only was
32.9% (56/170). The most common IRR was fever (86/1230,
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147 (12%)
65 (5%)
86 (7%)
85 (7%)
6 (0.5%)
3 (0.2%)
2 (0.2%)
8 (1%)
5 (0.4%)
14 (1%)
2 (0.2%)
6 (0.5%)
7 (1%)
3 (4%)
0 (0%)
3 (4%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
8 (9%)
2 (2%)
5 (6%)
2 (2%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (1%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
5 (5%)
1 (1%)
3 (3%)
2 (2%)
0 (0%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
6 (6%)
4 (4%)
3 (3%)
2 (2%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
11 (10%)
5 (4%)
5 (4%)
5 (4%)
0 (0%)
0 (0%)
0 (0%)
2 (2%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
8 (6%)
3 (2%)
7 (6%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
13 (9%)
7 (5%)
8 (6%)
9 (6%)
2 (1%)
0 (0%)
0 (0%)
1 (1%)
2 (1%)
1 (1%)
0 (0%)
0 (0%)
1 (1%)
56 (33%)
29 (17%)
29 (17%)
42 (25%)
1 (1%)
1 (1%)
1 (1%)
5 (3%)
2 (1%)
8 (5%)
1 (1%)
5 (3%)
5 (3%)
7.0%), followed by chills (85/1230, 6.9%) and rigors (65/1230,
5.3%); other IRRs occurred in 1.2% of the infusions or less
(Table 3). Pre-medication was associated with an overall 51.9%
decreased incidence of IRRs; not receiving pre-medication was
associated with a significant increased risk of an IRR (OR: 2.4,
95% CI 1.51 – 3.80, P ¼ 0.0001). The IRR rate in pre-medicated
ABCD infusions was 10.8% while the IRR rate associated with
ABCD infusions that did not have pre-medication was 22.4%,
P , 0.001. Following the first infusion only, the IRR rate in premedicated ABCD infusions was 31.5% while the IRR rate
associated with ABCD infusions that did not have premedication was 42.9% (P ¼ 0.30).
The incidence of IRRs following pre-medicated infusions
decreased by 50% from day 1 to day 2 (31.5% to 15.6%) of
ABCD therapy and by 58% from day 2 to day 3 (15.6% to
6.5%) of therapy. After the third day of ABCD therapy, the IRR
rate remained relatively constant and did not exceed 9.1%
(Figure 1). The incidence of IRRs following infusions that were
not pre-medicated decreased from day 1 to day 2 (from 42.9%
to 26.7%; 38% decrease) and from day 2 to day 3 (26.7% to
20.0%, 25% decrease); however, from day 3 to day 10 the rate
of IRRs was erratic and generally well above the rate of the premedicated infusions (Figure 1).
The incidence of IRRs differed based on specific premedications given. The IRR rate associated with receipt of
specific pre-medications is shown in Figure 2, and the IRR rate
associated with receipt of specific pre-medications following the
first infusion of ABCD therapy only is shown in Figure 3.
Table 3. Overall incidence of specific IRRs by day of ABCD infusion
a
Infusions could have had more than one pre-medication; therefore, total is
.1230 and total percentage is .100.
Any
Rigors
Fever
Chills
Nausea
Vomiting
Pain
Hypertension
Hypotension
Tachycardia
Vasodilation
Hypoxaemia
Other
0.1%
1 (0.1%)
9, n ¼ 90
Mineral supplement
calcium gluconate
8, n ¼ 96
5.4%
67 (5.4%)
7, n ¼ 108
Narcotic analgesic
pethidine
6, n ¼ 115
20.6%
254 (20.7%)
5, n ¼ 124
NSAIDs
metamizole
4, n ¼ 141
24.3%
299 (24.3%)
3, n ¼ 148
Antipyretics
paracetamol
2, n ¼ 156
41.4%
198 (16.1%)
84 (6.8%)
55 (4.5%)
53 (4.3%)
51 (4.1%)
44 (3.6%)
25 (2.0%)
1, n ¼ 170
Antihistamines
chloropyramine
promethazine
diphenhydramine
dithiaden
loratadine
clemastine
chlorphenamine
IRR
67.3%
295 (24.0%)
289 (23.5%)
220 (17.9%)
23 (1.9%)
1 (0.1%)
Treatment day
Corticosteroids
hydrocortisone
methylprednisolone
dexamethasone
prednisolone/prednisone
dexamethasone and methylprednisolone
10, n ¼ 82
n ¼ 1230a
11 (7%)
3 (2%)
6 (4%)
7 (5%)
1 (1%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
1 (1%)
0 (0%)
0 (0%)
0 (0%)
Table 2. Pre-medications used in the PRoACT registry
26 (17%)
11 (7%)
17 (11%)
15 (10%)
2 (1%)
0 (0%)
1 (1%)
0 (0%)
0 (0%)
1 (1%)
1 (1%)
1 (1%)
1 (1%)
Total, n ¼ 1230
ABCD, pre-medications and IRRs
Paterson et al.
50%
No pre-medication
Pre-medication
45%
43%
40%
35%
32%
30%
27%
25%
23%
20%
20%
16%
15%
22%
22%
20%
15%
10%
9%
9%
7%
5%
7%
5%
5%
7%
3%
0%
Day 1
Day 2
Day 3
Day 4
Day 6
Day 5
Day 7
Day 8
Day 9
1%
Day 10
Figure 1. Incidence of IRRs by day of ABCD therapy for infusions with and without pre-medication.
With pre-medication
Without pre-medication
P = 0.14
P < 0.001
16%
P = 0.001
P = 0.031
P = 0.079
14.4%
13.7%
13.5%
12.9%
12%
12.9%
11.2%
9.0%
7.7%
8%
6.4%
5.9%
4%
0%
Acetaminophen
Hydrocortisone
Methylprednisolone
Metamizole
Dexamethasone
Figure 2. Overall IRR rates by specific pre-medications (n ¼ 1230 ABCD infusions).
When considering the IRR rate by drug class, there was a significantly lower incidence of IRRs following infusions where
pre-medication with corticosteroids was given (8.1%) compared
with infusions where corticosteroids were not given (19.9%),
P , 0.001. In particular, dexamethasone appeared to have strong
effect; following the first infusion of ABCD, 12.0% of the
infusions where dexamethasone was given had an IRR versus
36.6% of the infusions where dexamethasone was not given
(P ¼ 0.016), and for overall infusions, 7.7% of the infusions
where dexamethasone was given had an IRR versus 12.9% of
the infusions where dexamethasone was not given (P ¼ 0.03).
Conversely, pre-medication with an antihistamine or paracetamol
was associated with an increased IRR rate.
Secondary outcomes
Response rates. Information on clinical outcome at 12 weeks
after initiation of ABCD was available on 143 participants.
Fifty-two percent (75/143) of the participants positively
responded to ABCD, 8% (12/143) of the participants failed to
respond to treatment and 39.2% (56/143) of the participants had
indeterminate information on status at 12 weeks post-treatment
start.
Mortality rates. Twenty-five percent of the participants (43/170)
were deceased by 12 weeks after the onset of ABCD therapy.
Participants could have had more than one reason recorded as to
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ABCD, pre-medications and IRRs
With pre-medication
60%
P = 0.006
Without pre-medication
51.3%
50%
P = 0.247
P = 0.168
P = 0.016
P = 0.350
40%
35.5%
30%
27.5%
26.1%
36.6%
35.6%
34.5%
25.8%
23.7%
20%
12.0%
10%
0%
Acetaminophen
Hydrocortisone
Methylprednisolone
Metamizole
Dexamethasone
Figure 3. Overall IRR rates by specific pre-medications following first ABCD infusion (n ¼ 170).
the cause of death. Almost half of the deaths were due to the
patient’s underlying health condition (19/43, 44%); 30% (13/43)
were due to an infection other than the fungal infection being
primarily treated in the study, 12% (5/43) were reported as
being due to a combination of the patient’s underlying health
condition and the primary fungal infection, 9.3% (4/43) deaths
were reported as being due to the primary fungal infection
alone, 7.0% (3/43) deaths were reported as due to graft versus
host disease, 7.0% (3/43) due to multi-organ failure, 4.7% (2/43)
due to respiratory failure, 4.7% (2/43) due to septic shock
without identification of the causal agent and one death each
due to multidrug-resistant Pseudomonas, CMV pneumonitis and
renal insufficiency.
There was a trend towards lower mortality rates between participants who received pre-medication with a corticosteroid (28/
128, 21.9%) versus no pre-medication with a corticosteroid (15/
42, 35.7%), but this was not statistically significant (P ¼ 0.07).
Adverse events. Fifteen percent (n ¼ 25) of the participants had
a treatment emergent adverse event (hepatotoxicity n ¼ 3;
nephrotoxicity n ¼ 2; other n ¼ 20); eight of these were serious
adverse events. Table S3 lists the details of the adverse events.
Discussion
These data demonstrate a significant relationship between the
use of pre-medications and a reduced rate of IRRs in the treatment of invasive fungal infections, as well as significant
decreases in IRRs attributable to specific pre-medications.
Previous studies suggested an increased rate of IRRs with
ABCD compared with c-AmB and other lipid-based formulations of c-AmB. A lack of pre-medications may account for
the increased rate of IRRs previously observed for ABCD. In
this study, pre-medications were given in 90% of the infusions,
and the overall rate of IRRs was quite low at 12%. Considering
the first infusion only, pre-medications were given in 88% of the
infusions and the overall IRR rate was 31.5%. Data are lacking
on the global rates of pre-medication use in amphotericindriven antifungal treatment. However, the frequent use of
pre-medication in the PRoACT registry suggest that current era
pre-medication use is greater than that reported from previous
clinical studies of amphotericin. A meta-analysis of outcomes
associated with c-AmB, ABLC, L-AmB and ABCD that
included published data through August 200113 found that only
half of the eight studies included in the analyses allowed premedications before the first dose of amphotericin [ABCD versus
c-AmB19, L-AmB versus c-AmB23, c-AmB versus L-AmB
(none for L-AmB)24,25], two included pre-medications after the
first dose of amphotericin (c-AmB versus L-AmB26, c-AmB
versus ABLC27) and two did not report whether pre-medications
were used (c-AmB versus ABLC28,29). A study published in
2002, which reported a greater incidence of IRRs in patients
treated with ABCD versus c-AmB, only allowed pre-medications
after the first dose.30 These previous studies consisted of overwhelmingly US, European, Australian and Canadian sites. The
PRoACT registry primarily included sites from China and
former Eastern bloc countries; it is unknown whether the current
use of pre-medications is similarly high in countries that did not
participate in the PRoACT registry.
The intent of the PRoACT registry was to collect data on
rates of IRRs associated with ABCD given pre-medication
versus ABCD given no pre-medication; therefore, a comparison
group of patients treated with different lipid-based formulations
of amphotericin was not included. Thus, we are limited in contrasting ABCD-associated IRR rates observed in this study to
historical reports of IRR rates. Notwithstanding this limitation,
the 12% IRR rate is lower than rates observed in the initial
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Paterson et al.
clinical studies of L-AmB11 (47.5% experienced chills) and
ABLC10 (18% experienced chills). The frequent use of premedications in the PRoACT registry likely contributed to the
low rate of IRRs. However, IRRs occurred at a relatively low
rate even in the participants who did not receive premedications. In fact, the rate of IRRs following ABCD infusions
with no pre-medication (22.4%) was similar to the IRR rate
associated with L-AmB in the largest amphotericin trial to date,
the National Institute of Allergy and Infectious Diseases
Mycoses Study Group.26 In that randomized double-blind trial
between c-AmB and L-AmB, pre-medication was not allowed
prior to the first dose of the drug, and IRRs without fever
occurred after 20.6% (746/3622) of the L-AmB infusions.
The lower mean dose of ABCD used in the PRoACT registry
(2.9 mg/kg/day) compared with prior clinical studies of ABCD
(median dose 4 mg/kg/day)9 may have contributed to the low
IRR rate observed in PRoACT. The moderately long mean duration of infusion could also have impacted the incidence of
IRRs. In addition, there is the possibility that concomitant medications may have contributed to the low rate of IRRs. Forty-two
percent of the patients enrolled in the PRoACT registry were
reported as receiving corticosteroids during their antifungal treatment and 5% were reported as receiving NSAIDs. However,
most patients with invasive fungal infections have an underlying
condition associated with corticosteroid therapy (e.g. bone
marrow transplantation, solid organ transplantation and treatment
of haematological malignancies), as well as other immunemodulating drugs, and it is therefore likely that other clinical
studies of ABCD in particular, and amphotericin in general, also
had a large proportion of patients who received corticosteroids
(and NSAIDs) in addition to their antifungal treatment.
Consistent with data from 526 ABCD-treated patients from five
open-label studies of patients with systemic fungal infections,9
IRRs occurred most frequently in association with the first infusion
of ABCD. This observation is also consistent with a decline in
IRRs over time observed with c-AmB.20,31 A potential bias in
these results is that patients in whom ABCD was not initially tolerated may have discontinued ABCD prior to days 4–10 of treatment, and therefore, patients with the greatest likelihood for IRRs
may not have been included in the latter treatment days. However,
the rates of IRRs were generally lower following pre-medicated
infusions versus infusions without pre-medication regardless of the
therapy day. Between days 4 and 10 of treatment, the IRR rate following infusions that had pre-medication stayed below 10%. In
contrast, the IRR rate following infusions that did not have premedication was inconsistent, ranging from 7% to 23%.
Fifty-two percent of the patients discontinued ABCD prior to
10 full days of therapy. This discontinuation rate is comparable to
other antifungal therapies.32 In the treatment of invasive fungal
infections, patients are frequently switched on and off of a variety
of antifungals during the course of treatment. Moreover, one-third
of patients were discontinued due to improvement in their fungal
infection rather than due to ABCD tolerance issues.
Corticosteroids were the most commonly used class of drugs
in the PRoACT registry, and overall corticosteroid use was associated with a decreased incidence of IRRs. Hydrocortisone is frequently recommended for pre-medication33,34 and was the most
frequently used corticosteroid in the PRoACT registry and the
second most commonly used pre-medication overall. While
hydrocortisone was not associated with a decrease in IRRs following the initial dose of ABCD, it was associated with a significant
decrease in the incidence of IRRs when all infusions over the 10
days of therapy were considered together. A potentially clinically
significant lower rate of IRRs was also associated with the second
most frequently used corticosteroid in the PRoACT registry,
methylprednisolone, although the difference in IRRs between
infusions with and without methylprednisolone was not statistically significant. Dexamethasone, the third most frequently used
corticosteroid and the fifth most frequently used pre-medication
overall in the PRoACT registry was associated with a significant
decrease in the incidence of IRRs following both the initial
ABCD infusion as well as overall. In contrast to these data on corticosteroids and ABCD, in the surveillance study by Goodwin
et al.,20 pre-treatment with corticosteroids was not associated with
a decrease in IRRs. In fact, a trend towards a greater incidence of
IRRs with corticosteroids was observed. However, information on
specific corticosteroids was not collected and c-AmB, rather than
ABCD, was the focus in that study. There is some controversy as
to whether steroids should be used in the treatment of invasive
fungal infections.35 Corticosteroids are a risk factor for both incidence of invasive fungal infections and mortality in patients with
invasive fungal infections.36 However, it is high doses and long
duration of corticosteroids that confer these risks.35,37 In the
PRoACT registry, the average daily doses of hydrocortisone, dexamethasone and methylprednisone were 1.22, 0.6 and 0.73 mg/kg,
respectively. One study of HSCT patients with aspergillosis found
that prolonged administration of corticosteroids within the previous 2 months or receipt of a dose 2 mg/kg at the time of diagnosis were predictive of death.38 While it is unlikely that the use
of corticosteroids as pre-medication would cross a duration or
dose threshold associated with mortality risk, one should be alert
to the potential for harm, particularly in septic patients.39 It is
noteworthy, however, that in this study corticosteroids were not
associated with increased mortality: mortality rates between participants who received pre-medication with a corticosteroid
(21.9%) were lower than in those with no pre-medication with a
corticosteroid (35.7%).
Following corticosteroids, antihistamines were the second
most commonly used pre-medications in the PRoACT registry.
There was a wide range of antihistamines used and small
numbers of patients limit meaningful analyses of IRR rates
associated with the use of specific antihistamines. However, the
use of any antihistamine as pre-medication was associated with
an increased IRR rate. Based on this class analysis, antihistamines do not appear to be effective in preventing IRRs.
Paracetamol (acetaminophen, Tylenolw) is frequently recommended and commonly used as a response to, or for avoidance of, amphotericin B-related IRRs.31,40 – 43 In the PRoACT
registry, paracetamol was the most commonly reported drug
used as pre-medication and represented the third most common
class of drug used. However, there was no evidence that paracetamol was effective in preventing IRRs. In fact, pre-medication
with paracetamol was associated with a greater incidence of
IRRs than no pre-medication with paracetamol. Goodwin et al.20
reported a similar lack of effect of pre-treatment with paracetamol over a decade ago. The continued promotion of paracetamol
as a drug of choice in pre-medication, and the wide use of paracetamol as pre-medication, may be ineffective in preventing
IRRs and its continued use may perpetuate the idea that ABCD
is associated with IRRs despite pre-medication.
Following corticosteroids, antihistamines and paracetamol,
metamizole represented the fourth most common class of drug
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ABCD, pre-medications and IRRs
used in the PRoACT registry. Metamizole was also the fourth
most common drug used overall and was associated with a significant decreased risk of IRRs. While metamizole is banned in
Sweden, USA, Japan, Australia, Iran and part of the European
Union due to risk of agranulocytosis, it is still freely available in
some countries and remains one of the most popular analgesics
used in the majority of sites included in the PRoACT registry.
Taken as a whole, the use of any pre-medication was associated with an IRR rate that was half (10.8%) of that observed
without pre-medications (22.4%); pre-medication following the
first infusion was associated with a 27% decrease in the IRR rate.
These rates of IRRs following pre-medication are confounded by
the fact that they include pre-medications that were not observed
to effectively lower IRRs (e.g. paracetamol and antihistamines).
Although certain drugs were associated with a significantly
lower rate of IRRs (e.g. dexamethasone, hydrocortisone and
metamizole), we are limited in making definitive conclusions
about the effects of specific pre-medications on IRRs since
PRoACT participants may have taken more than one premedication per each ABCD infusion. In fact, there was more
than one pre-medication recorded in 53.1% of the infusions.
Despite this limitation, the strong effect size (i.e. a 40% decrease
for dexamethasone and a 53% decrease in the IRR rate for
hydrocortisone) observed for infusions where dexamethasone or
hydrocortisone was given, and the fact that they are from the
same class, strengthens the premise that these drugs effectively
prevent IRRs. Of the 254 ABCD infusions in which metamizole
was used, 90.2% (229/254) of these also included a corticosteroid as additional pre-medication. Thus, the decrease observed
for metamizole may have been confounded by corticosteroids.
There may be other specific pre-medications in addition to
the ones highlighted here that significantly reduce the risk of
IRRs (conversely, there may be drugs used as pre-medication
that are not effective), but due to their low frequency of use in
PRoACT, we were unable to detect significant differences.
These results may not be relevant to the treatment of all
patients with invasive fungal infections. The PRoACT registry
was largely made up of younger patients with fungal infections
complicating haematological conditions; thus, these results may
not be directly applicable to older patients or patients with different underlying conditions. Likewise, the majority of patients who
participated in PRoACT were from the Czech Republic, Croatia
and China; country-specific factors may limit the generalizability
of these results. Finally, the cost of lipid-based formulations of
amphotericin is considerably higher than that of c-AmB. Given
the already high cost of treatment, an additional cost of premedications may be thought to be prohibitive. However, since all
of the pre-medications included in this study are generic, the cost
associated with pre-medications should be minimal.
In conclusion, current data from PRoACT registry demonstrate that ABCD is associated with a low rate of IRRs when
used with proper pre-medications. Pre-medications, including
corticosteroids and metamizole, were associated with the lowest
rates of IRRs following ABCD infusion while paracetamol and
antihistamines were not associated with lower IRR rates.
Acknowledgements
PRoACT Investigators: Nadira Durakovic MD, University
Hospital Centre, Zagreb, Croatia; Humberto Guiot MD,
Universidad Medical Centre, San Juan, Puerto Rico; Maria
Stefaniak MD, Paediatric Clinical Hospital, Lublin, Poland;
Visanu Thamlikitku MD, Siriraj Hospital, Bangkok, Thailand;
Nenad Govedarovic MD, Klinicki Centar, Nis, Serbia; Carlos
Sanchez MD, Universidad Medical Centre, San Juan, Puerto
Rico; Michael Matysiak MD, Clinical Children’s Hospital,
Warsaw, Poland; Ruth Soto-Malave MD, Universidad Medical
Centre, San Juan, Puerto Rico; Jorge Santana-Bagur MD,
Universidad Medical Centre District Hospital, San Juan, Puerto
Rico; Tigran Torosjan MD, Medical University of Warsaw,
Warsaw, Poland; Sutep Jaruratanasirikul MD, Songkhlanagarind Hospital, Hat Yai, Thailand; Slobodon Marjanovic MD,
Military Medical Academy, Beograd, Serbia; Sinari Salleh MD,
Ampang Hospital, Kuala Lumpur, Malaysia; Ivanka Savic
MD, Klinicki Centar Novi Sad, Serbia.
Funding
Funding for the PRoACT registry was provided by Three Rivers
Pharmaceuticals.
Transparency declarations
K. D. is an employee of ProSanos Corporation. ProSanos
received research funding to support work on the PRoACT registry. The remaining authors have declared they have no relevant
conflicts of interest.
Author contributions: D. L. P.: (i) substantial contributions to
acquisition of data and interpretation of data; (ii) revising the
article critically for important intellectual content; and (iii) final
approval of the version to be published. K. D.: (i) substantial
contributions to analysis and interpretation of data; (ii) drafting
the article and revising it critically for important intellectual
content; and (iii) final approval of the version to be
published. K. D. had full access to all data and takes responsibility for the data. M. M., P. C., X.-H. W., J. S., G. K., D. B.,
M. L. and L.-P. Z. all had the following roles: (i) substantial
contributions to acquisition of data; (ii) revising the article critically for important intellectual content; and (iii) final approval
of the version to be published.
Supplementary data
Tables S1 –S3 are available as Supplementary data at JAC
Online (http://jac.oxfordjournals.org/).
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