Download Single or 2-Dose Micafungin Regimen for

SUPPLEMENT ARTICLE
Single or 2-Dose Micafungin Regimen for
Treatment of Invasive Candidiasis: Therapia
Sterilisans Magna!
Tawanda Gumbo
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
The time the earth takes to rotate its axis (the day) has dictated how often pharmaceutical compounds are
dosed. The scientific link between the 2 events is materia medica arcana. As an example, in the treatment of
invasive candidiasis, antifungal therapy with intravenous micafungin is dosed daily. A literature review revealed
population pharmacokinetic analyses, in vivo pharmacokinetics/pharmacodynamics studies, and maximumtolerated-dose studies of micafungin that examined optimal micafungin dosing strategies. The half-life of
micafungin in patient blood was 14 hours in several studies, but was even longer in different organs, so that
the concentration will persist above minimum inhibitory concentrations of Candida species for several days.
Studies in mice and rabbits with persistent neutropenia and disseminated candidiasis, otherwise fatal, demonstrated that a single large dose of micafungin could clear disseminated candidiasis, even though the micafungin
half-life in such animals is shorter than in humans. Human pharmacokinetics/pharmacodynamics studies confirmed this link between micafungin efficacy and the ratio of the area under the concentration-time curve, and
the optimal exposures initially identified in neutropenic animals. Maximum tolerated dose studies have demonstrated safety of 900 mg administered daily for several weeks, whereas case reports demonstrate efficacy and
safety of single 1400-mg doses. Thus, a single dose of micafungin, or 2 such doses within a few days of each
other, is not only logical, but might even lead to faster clearance of Candida.
Keywords. pharmacokinetics/pharmacodynamics; intermittent therapy; maximum tolerated dose; micafungin;
invasive candidiasis.
Therapeutic results with the mouse have been exceptionally favorable. It has been possible with the
help of this substance to cure mice which were on
their second day of infection and would have died
in a few hours. This is a result which a priori would
not have been considered possible. We have found
a series of these compounds which are able to
quickly and in high proportion effect a cure
which I have called ‘Therapia sterilisans magna.’
Correspondence: Tawanda Gumbo, MD, Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, 3434 Live Oak St, Dallas, TX 75204 (tawanda.gumbo@
baylorhealth.edu).
Clinical Infectious Diseases® 2015;61(S6):S635–42
© The Author 2015. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/civ715
That is to say, a complete sterilization of a highly
infected organism with one dose.
—Paul Ehrlic, 1908 [1]
Invasive candidiasis is one of the most common community-acquired conditions to afflict immunocompromised patients throughout the world. In hospitalized
patients, invasive candidiasis, especially from Candida
albicans and Candida glabrata, is a common nosocomial infection [2, 3]. In severely sick patients, such as those
in the intensive care unit, fungal infections (mainly candidiasis) are the third most common group of infections
after gram-negative and gram-positive bacteria [4]. Left
untreated, invasive candidiasis has mortality rates of
35%–60%; even when treated it is associated with longer
length of stay in hospitals and high hospitalization
costs. Treatment of invasive candidiasis is recommended with 1 of 3 classes of agents: polyenes, triazoles, or
Intermittent Micafungin for Candidiasis
•
CID 2015:61 (Suppl 6)
•
S635
echinocandins [5]. Factors associated with poor outcome include severity of illness, organ dysfunction, abdominal source,
inadequate source control, and inadequate antifungal therapy
[3, 6, 7]. Specifically, echinocandins may be superior to other
classes of antifungal agents for the treatment of candidemia
and other forms of deeply invasive candidiasis [8, 9].
The echinocandin micafungin is indicated for the treatment
of candidemia and other forms of deeply invasive candidiasis,
and has clinical cure rates of approximately 72%, similar to
that of other echinocandins. Although this is a good success
rate, it nevertheless means that there is room for improvement
if therapy is further optimized, perhaps to the upper 90% range.
All currently licensed echinocandins, including micafungin, are
not absorbed by the gastrointestinal tract, and as a result must
be administered intravenously [10]. Thus, for the treatment of
candidiasis, echinocandins are administered as daily intravenous therapy for at least 2 weeks of therapy [5]. To achieve
this, patients need long-dwelling intravenous catheters, and either stay hospitalized, or receive the intravenous therapy via an
outpatient infusion program.
ECHINOCANDIN INHIBITION OF (1→3)-β-DGLUCAN SYNTHASE IS CONCENTRATIONDEPENDENT
Echinocandins kill Candida species because they inhibit (1→3)β-D-glucan synthesis; as glucan constitutes 60% of the fungal
cell wall, this leads to cell lysis. The inhibition of (1→3)-β-Dglucan synthase by echinocandins is concentration-dependent
[11–13]. This means more and faster fungal cell lysis as drug
concentration increases. In addition, as the cell wall is not encountered in human cells, and echinocandins have a specific
target in the fungal cell wall component (1 → 3)-β-D-glucan,
echinocandins tend to have a wide safety profile. This is particularly true with micafungin, which does not need a special vehicle for solubility and is dissolved in normal saline, obviating
concerns of toxicity from vehicles used to solve solubility problems of some other intravenous antifungal agents. This makes
micafungin attractive for high-dose intermittent therapy.
PHARMACOKINETIC CONSIDERATIONS FOR
INTERMITTENT AND SINGLE DOSES OF
MICAFUNGIN
Micafungin is a 2-compartment-model drug, which means that
the time-course and elimination rates of the drug behave as if
there were 2 compartments in the body (systemic circulation
and peripheral compartment). Given this, micafungin’s baseline
population pharmacokinetic parameter estimates as a 2-compartment model were found to be remarkably similar between adult
patients in 4 independent studies [14–17]. A large proportion of
S636
•
CID 2015:61 (Suppl 6)
•
Gumbo
the between-patient variability is driven by patient weight, based
on fractal geometry power laws, so that the relationship between
total micafungin clearance and weight3/4 leads to predictable
pharmacokinetics, ranging from 2.5-kg infants to obese 250-kg
adults [15, 18–20]. The population pharmacokinetic parameter
estimates are shown in Table 1. The “average” terminal (β-)
half-life of micafungin in the central compartment or systemic
circulation is about 14.1 ± 1.1 hour; the half-life is even longer
in peripheral tissues and organs (compartment 2) [15, 16].
Thus if one gave doses 7- to 14-fold higher than currently administered, which achieve a peak concentration of up to 70 mg/L,
then the micafungin concentrations would remain higher than
the minimum inhibitory concentrations (MICs) of >99% of Candida species for more than a week [21].
PHARMACOKINETICS/PHARMACODYNAMICS
“TO CURE MICE WHICH WERE ON THEIR
SECOND DAY OF INFECTION AND WOULD
HAVE DIED IN A FEW HOURS”
Gumbo et al performed a 24-hour dose-response pharmacokinetics/pharmacodynamics (PK/PD) study in severely neutropenic mice with disseminated C. glabrata [22]. The study, which
examined 3 different organs, the spleen, lung, and kidney, found
that the dose mediating 50% of maximal kill (ED50) was similar
for all 3 organs (Figure 1A). Next, we examined the effect of a
single micafungin dose administered at the start of the week on
daily kidney fungal burden for an entire week. The concentration-time profile of micafungin in the mice is shown in Figure 1B, which demonstrates a half-life of 6.1 hours in mouse
serum, <50% than in humans. Despite that shorter half-life,
as doses increased, a single dose was reached at which there
was no fungal regrowth, despite the severe neutropenia (Figure 1C). The dose-effect curve at the end of 7 days after a single
dose is shown in Figure 1D. Thus, a single dose of micafungin
that is large enough will result in sustained antifungal effect,
even during severe neutropenia. As the drug is virtually gone
Table 1. Population Pharmacokinetic Parameter Estimates of
Micafungin
Pharmacokinetic Parameter
Estimate
Relative
Standard Error
Central compartment
volume, L
11.7
55.7%
Clearance from peripheral
compartment, L/h
Volume of peripheral
compartment, L
26.5
70.9%
18.3
42.4%
Systemic clearance, L/h
a
Relative standard error for slope.
1.04 × (weight/66)3/4
6.99%a
Figure 1. Pharmacokinetics/pharmacodynamics on micafungin in neutropenic mice with disseminated candidiasis. A, The 24-hour dose-response curve
showing the dose mediating 50% of maximal kill (ED50) for one Candida glabrata strain. In 3 other C. glabrata strains, the ED50 ranged from 0.49 to 0.58 mg/
kg. Error bars are standard deviation. B, Micafungin serum and tissues concentrations after a single dose of micafungin, demonstrating higher kidney
concentrations than serum in the mice. Walsh et al have also demonstrated higher concentrations in some lung tissues than serum in humans [16]. C,
Time-kill curves for different single doses of micafungin. There is fungal regrowth with lower doses; however a dose is eventually reached that “crosses the
rubicon,” after which there is no Candida regrowth in these severely neutropenic mice. This is achieved between the doses of 25 mg/kg and 50 mg/kg. D,
Day 7 kidney fungal burden after a single dose at the beginning of the week, demonstrating a dose-effect relationship. Abbreviations: AUC0–24, 0–24 hour
area under the concentration-time curve; CFU, colony-forming units.
from site of infection by that time, this is true in vivo post antifungal effect.
Daily doses mediating 34%, 50%, and 80% of maximal kill
(ED34, ED50, and ED80, respectively) were delivered as either
daily doses, or the cumulative 7-day dose was combined (ie,
7 × daily dose) and delivered as a single dose at the start of therapy, or split into 2 equal doses and delivered on days 0 and 3.5,
to neutropenic mice with disseminated candidiasis. Thus, all
mice within a dose group received the same cumulative dose
for the week, and therefore the same 0- to 168-hour area
under the concentration-time curve (AUC) to MIC, but with
proportionally higher peak concentrations for the intermittent
doses. Figure 2A shows the ED34 results, which demonstrate
fungal regrowth with the once-weekly dose, whereas the
twice-weekly and daily therapy regimens gave identical kill
rates. In contrast, the ED50 dose (Figure 2B) demonstrates
that the once-weekly schedule led to identical fungal burden
to the daily therapy by day 7. In fact, the single dose killed faster
than the daily therapy. Figure 2C shows that a single ED99 dose
at start of therapy killed without any regrowth in the kidneys.
This study illustrates that if an optimal single dose is administered, there is no fungal regrowth. Importantly, this illustrates a
fundamental principle with micafungin, which is that one can
add each of the daily doses for half a week, or even for the entire
week, to administer intermittently at the start of therapy and
would still get the same efficacy as the divided doses given
daily. This property is what makes micafungin an AUC/MICdriven drug. This means that combining the entire daily doses
for the 2 weeks and delivering as a single dose will lead to the
same final microbial kill as daily dose, but at a faster rate.
Intermittent Micafungin for Candidiasis
•
CID 2015:61 (Suppl 6)
•
S637
Andes et al wanted to identify the particular AUC/MIC
threshold value associated with maximal micafungin fungal
kill of 14 different Candida species strains with a wide MIC distribution of 0.008–0.25 mg/L [23]. Mice were infected with
Candida and then treated with a daily micafungin dose for
4 days. The AUC/MIC associated with optimal efficacy was
independent of Candida species. Moreover, micafungin exposure associated with stasis (holding the fungal burden constant)
was a total AUC/MIC ratio of approximately 3000 or a nonprotein-bound (free-drug) ratio of 7.5. The micafungin exposure associated with fungicidal effect was a total AUC/MIC of
approximately 6000 (free-drug ratio = 14). Given these target
exposures, a once-weekly dose for stasis would be a total
AUC/MIC of 21 000, whereas that of a single dose once every
2 weeks would be 42 000.
Petraitiene et al examined fungal burden dynamics in rabbits
using the dose-scheduling approach [24]. They also specifically
examined the impact of micafungin dosing schedule on liver
and kidney toxicity, as well as efficacy in the central nervous system and vascular tissues. The rabbits were made neutropenic
using antineoplastic chemotherapy, were started on antibacterial therapy as in patients with febrile neutropenia, infected with
C. albicans, and developed disseminated disease. On “the second day of infection,” the rabbits received micafungin therapy
as either 1 mg/kg every day, 2 mg/kg every other day, or 3 mg/
kg every 72 hours; rabbits were sacrificed on day 6. The mean
fungal burden was examined in 7 different organs. In every
organ the most intermittent dose sterilized the tissues, as compared to daily therapy, which sterilized in 4 of 7 organs; nevertheless, there was no statistically difference in fungal burden by
dosing schedule. There were no differences in liver function
tests, or renal function or electrolyte concentration. Thus, the
higher-dose intermittent approach was efficacious without increased toxicity.
BEYOND MICE AND SICK BUNNIES: PK/PD
EVIDENCE FROM CLINICAL TRIALS
Figure 2. Effect of micafungin dose-schedule on fungal burden in mice.
A, The dose mediating 34% of maximal kill (ED34) dose shows regrowth of
fungi with the once-weekly dose after day 3; however, the twice-weekly
and once-weekly doses showed fairly similar levels of microbial kill. Error
bars are standard deviation. B, In the dose mediating 50% of maximal kill
(ED50), there is faster microbial kill with the once-weekly dose than daily
(about 1.0 log10 colony-forming units [CFU]/g more kill). The ED50 dose was
just below the dose of 25 mg/kg associated with the rubicon phenomenon.
Even with the regrowth that started after day 5, however, the day 7 fungal
burden is similar in all 3 groups. This is defined as area under the concentration-time curve/minimum inhibitory concentration–driven efficacy. C,
The optimal dose shows no fungal regrowth over 7 days.
S638
•
CID 2015:61 (Suppl 6)
•
Gumbo
Andes and colleagues recently examined the factors associated
with optimal cure of candidemia and deeply invasive candidiasis in 493 patients enrolled in phase 3 trials who were treated
with micafungin for invasive candidiasis [17]. They employed
an agnostic method, classification and regression tree analysis,
which identifies predictors of microbial and clinical cure and
ranks them by order of importance [25, 26]. They identified
the following factors as predictive of cure: severity of illness, a
micafungin total AUC/MIC > 3000 for all Candida species, or
AUC/MIC > 5000 for non–Candida parapsilosis species, an
MIC < 0.5 mg/L, and a history of steroid use. If patients had micafungin AUC/MIC > 3000, they had a clinical and mycological
cure rate of 98%. In humans, micafungin protein binding is
about 99.75%, so that an AUC/MIC > 3000 translates to a free
drug ratio of 7.5, whereas the AUC/MIC > 5000 translates to a
free drug ratio of 12.5 [17, 27]. These values are virtually identical to those identified in neutropenic mice, discussed earlier
[22, 23]. Thus, micafungin doses and dosing schedules (AUC/
MIC values) identified in mice and bunnies directly translate to
humans with invasive candidiasis.
Patients with esophageal candidiasis were randomized to micafungin either 150 mg daily or 300 mg every other day in multicenter randomized controlled trials [28]. Mycological response
at end of therapy was 145 of 184 (79%) with daily doses vs 115
of 132 (87%) on every-other-day dosing (P = .056); relapse rates
were 22 of 181 (12%) vs 7 of 126 (6%), respectively (P = .051)
[28]. Thus, the more intermittent dose improved cure rates to
close to 90% and halved relapse rates. The AUCs were identical
between the dosing regimens; however, the 300 mg dose every
other day had a 2-times-higher peak than the 150-mg dose,
but a lower trough concentration, suggesting that the larger
peak concentration could have driven efficacy. The more
intermittent the cumulative dose, the higher the peak concentration, which means that based on this clinical study, it may
be more desirable to give intermittent dosing instead of daily
therapy. This is similar to PK/PD findings in rabbits and
mice, reinforcing that PK/PD-derived dosing schedules in
these animals translate well to the clinic.
. . . BUT CAN PATIENTS TOLERATE HIGH-DOSE
MICAFUNGIN?
A main concern has been that administering micafungin at high
doses could lead to increased rates of cardiovascular and hepatic
toxicity. These worries arose because of concerns with the dose
of 300 mg every other day, which at one point was viewed as
associated with more adverse events than the 150-mg daily
dose. However, in our study of adult volunteers, in whom approximately 60% had chronic comorbid conditions such as
the metabolic syndrome, who were carefully monitored in a
medical unit with before-and-after biochemistry tests and 4
hourly examinations, there was no higher toxicity after a single
300-mg infusion (maximum dose 7.0 mg/kg) compared to 100
mg (maximum dose 2.2 kg) [15]. Indeed, several other studies
in which micafungin 3–4 mg/kg was administered to children
intermittently revealed no toxicity [29, 30].
Two formal maximum tolerated dose (MTD) studies have
been performed, and give an indication of the total micafungin
doses that patients can tolerate. In the first study, Hiemenz at
al enrolled 74 patients undergoing bone marrow transplant
who were treated with daily micafungin doses of 12.5–200 mg
for up to 4 weeks [31]. The MTD was not reached. The rate of
adverse events did not increase with doses up to 200 mg each
day. Sirohi et al also performed a formal MTD study of 36
adult patients undergoing bone marrow transplant who received
3, 4, 6, or 8 mg/kg daily for 7 to 28 days [32]. Actual doses administered ranged from 170 mg to 900 mg each day, administered over 1 hour. Patients were carefully monitored prior to
therapy, during therapy, and at the end of therapy for serious adverse events. Adverse events assessed as at least possibly related to
micafungin were phlebitis, gastrointestinal symptoms, and injection site reactions. These were not dose dependent; no patients
had grade 3 or 4 adverse reaction. Rash and pruritus were observed in 2 patients, both of whom received 8 mg/kg/day, but
were considered mild. The relationships between dose categories,
dose, duration of therapy, changes in creatinine, and changes in
aspartate aminotransferase, are shown in Figure 3, which demonstrates no increased hepatotoxicity or renal failure, even in patients who received mean total cumulative doses of 12 000 mg
[32]. The MTD was not reached up to 900 mg each day, a cumulative dose multi-fold that of 2 doses of 1000 mg once each week
or 2000 mg as a single dose. Clearly, higher doses than currently
licensed can be tolerated by patients.
USE OF MICAFUNGIN ONCE EVERY 2 WEEKS
DUE TO DIFFICULT PATIENT CIRCUMSTANCES
High-dose intravenous micafungin has been used on a number
of occasions, mainly due to lack of alternatives in particular
challenging patient situations. In one such case, a 27-year-old
schoolteacher with a history of recurrent esophageal candidiasis
and candidemia was admitted with fever, rigors, and hypotension, consistent with prior multiple episodes of sepsis-like syndrome each year that had led to multiple hospitalizations. Blood
cultures grew C. albicans. While it was recognized that she had
an immunodeficiency, it was nevertheless still unclear if this was
a variant of common variable immunodeficiency, or another
immunodeficiency. Thus, she was not on immunoglobulin replacement therapy. To try and prevent the candidiasis, various
strategies had been tried in the past, including prophylactic oral
fluconazole of up to 400 mg a day, which always failed due to
poor fluconazole absorption, as was the case with the current
admission. During the admission, the patient was treated with
100 mg of micafungin each day, and was discharged home to
complete 2 weeks of intravenous micafungin. At the end of therapy, she was seen in the outpatient clinic accompanied by her
mother. She informed the physician that she wanted to try
high-dose intermittent micafungin therapy (based on her Google search of mouse studies), but did not want to come to a physician’s office several times a week or receive home care. The
patient was counseled that what she proposed was not the licensed dose for micafungin, but she was insistent. A test regimen of micafungin 700 mg was administered in the clinic in
week 1, followed by 1400 every other week, with follow-up of
liver function tests 3 days after each dose. She did well for 12
Intermittent Micafungin for Candidiasis
•
CID 2015:61 (Suppl 6)
•
S639
Figure 3. Maximum tolerated dose and changes in aspartate aminotransferase (AST) and creatinine. The figure summarizes data from tables by Sirohi
et al [32]; error bars are standard deviation. The gray bars are mean dose administered and clear bars are duration of therapy. Blue bars are mean creatinine
values before start of micafungin therapy; brown bars are creatinine values at end of treatment. There were no dose-dependent increases in creatinine.
Purple bars depict mean AST before start of micafungin therapy, and yellow bars are AST values at end of treatment. There were no dose-dependent
changes in AST.
weeks (a total of seven 1400-mg infusions once every 2 weeks),
with no recurrence of esophageal candidiasis or candidemia. A
week after the last infusion, she was readmitted with elevated
liver function tests indicative of hepatotoxicity, and was switched
to liposomal amphotericin B. However, toxicology results revealed
that she had taken advantage of her intravenous line to infuse a
high-dose mixture of recreational drugs that included acetaminophen, cocaine, and narcotics she had bought illegally on the street.
Her liver function tests resolved during the hospitalization. On
discharge, she resumed intermittent 1400 mg intravenous micafungin without elevation of liver function enzymes, until she
was started on intravenous immunoglobulin G after discharge.
WHY SHOULD THE TIME THE EARTH TAKES TO
ROTATE ITS AXIS DICTATE WHEN TO DOSE
MICAFUNGIN?
The pharmacokinetics of micafungin, the PK/PD properties in
animal models, and the PK/PD properties in clinical studies, suggest that high intermittent doses of micafungin could be useful.
An optimal enough dose, administered at least as 2 doses, or even
as a single dose, will not lead to fungal regrowth; indeed, there
could be faster fungal kill and sterilization with such doses.
S640
•
CID 2015:61 (Suppl 6)
•
Gumbo
The concern of increased toxicity on such high doses will continue, and should indeed be taken seriously. Available clinical data
of tolerance of large doses of approximately 1000 mg administered daily, and even 1400 mg administered every 2 weeks in
case reports, suggest that such doses are likely well tolerated. Nevertheless, a formal study that examines single doses between
1000 mg and 2000 mg is still warranted. However, it is safe to
say that there seems to be no obvious link between the Copernican revolutions, including the earth’s rotation around its axis,
and the efficacy of antibiotics such as micafungin.
Given that micafungin clearance increases with patient weight,
there is a decrease in drug concentrations at patient weights >66
kg. To compensate for this decrease in micafungin concentrations,
we derived the formula “dose (mg) = patient weight + 42” to be
used by clinicians at the bedside [19]. In such patients, the daily
dose would be derived first, and then just multiplied by 14 days
for a single dose, or 7 days for 2 doses. It should be noted that
this increased dose will not lead to concentration-related toxicity
as the dose increase is to counter low micafungin peak and AUC
concentrations. However, it may be safer to escalate the doses, starting with 700 mg, and then stepping up the dose if patient tolerates.
When, and under what circumstances, should highintermittent doses be investigated? First, the approach would
not be used as an excuse to delay therapy and wait for positive
Candida cultures. Delay in therapy, especially in neutropenic
patients, is well known to increase therapy failure and obviate
the benefits of micafungin therapy [34–36]. Moreover, new
technologies such as matrix-assisted laser desorption/ionization
time-of-flight and polymerase chain reaction–based methods
that can diagnose candidemia as well as drug resistance within
hours mean that definitive evidence of on infection can now be
obtained within hours [37–40]. Such diagnostics will obviate
delay of therapy and allow rapid escalation of intermittent
micafungin doses. The combined effect of rapid diagnosis and
a rapidly fungicidal dosing regimen could be synergistic in improving patient outcomes.
A single dose, or even 2 doses of micafungin, delivered for the
treatment of invasive candidiasis could be a win-win-win, for
patients, their physicians and nurses, and the hospital. For the
patient, advantages include decreased need for long-dwelling
venous catheters and their attendant complications; that they
do not need to stay in hospital for treatment or, if they go
home, do not need visits to and from infusion centers; and
that they may have faster recovery from invasive candidiasis
to close that gap between the 72% and 98% response rates
[33]. For doctors and hospital staff, the advantages include decreased time related to preparing drug each day and decreased
nursing time related to hanging and administering the intravenous infusions. The approach of a single dose or 2 doses of
micafungin would also make the lack of oral echinocandin formulation less relevant.
Notes
Financial support. This work resulted from a symposium sponsored by
Astellas Pharma USA.
Supplement sponsorship. This article appears as part of the supplement
“Advances and New Directions for Echinocandins,” supported by Astellas
Pharma Global Development, Inc.
Potential conflict of interest. T. G. has worked as consultant for Astellas
Pharma USA, is an advisor for LuminaCare Solutions, and founded Jacaranda Biomed Inc.
The author has submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
1. Ehrlich P. Ueber moderne chemotherapie. Beiträge zur experimentellen
Pathologie und Chemotherapie 1908: 165–202.
2. Pfaller M, Neofytos D, Diekema D, et al. Epidemiology and outcomes of
candidemia in 3648 patients: data from the Prospective Antifungal
Therapy (PATH Alliance(R)) registry, 2004–2008. Diagn Microbiol Infect Dis 2012; 74:323–31.
3. Gumbo T, Isada CM, Hall G, Karafa MT, Gordon SM. Candida glabrata
fungemia. Clinical features of 139 patients. Medicine (Baltimore) 1999;
78:220–7.
4. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;
302:2323–9.
5. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines
for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:503–35.
6. Puig-Asensio M, Peman J, Zaragoza R, et al. Impact of therapeutic strategies on the prognosis of candidemia in the ICU. Crit Care Med 2014;
42:1423–32.
7. Bassetti M, Righi E, Ansaldi F, et al. A multicenter study of septic shock
due to candidemia: outcomes and predictors of mortality. Intensive
Care Med 2014; 40:839–45.
8. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472–82.
9. Andes DR, Safdar N, Baddley JW, et al. Impact of treatment strategy on
outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin
Infect Dis 2012; 54:1110–22.
10. Gumbo T, Ikeda F, Louie A. Glucan synthase inhibitors. In: Nightangle
CH, Murakawa T, Ambrose P, Drusano G, eds. Antimicrobial pharmacodynamics in theory and clinical practice. 2nd ed. New York: Informa
Healthcare, 2007:355–77.
11. Onishi J, Meinz M, Thompson J, et al. Discovery of novel antifungal
(1,3)-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 2000; 44:368–77.
12. Douglas CM, D’Ippolito JA, Shei GJ, et al. Identification of the FKS1
gene of Candida albicans as the essential target of 1,3-beta-D-glucan
synthase inhibitors. Antimicrob Agents Chemother 1997; 41:2471–9.
13. Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol 1994; 48:471–97.
14. Gumbo T, Hiemenz J, Ma L, Keirns JJ, Buell DN, Drusano GL. Population pharmacokinetics of micafungin in adult patients. Diagn Microbiol Infect Dis 2008; 60:329–31.
15. Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people.
Antimicrob Agents Chemother 2011; 55:5107–12.
16. Walsh TJ, Goutelle S, Jelliffe RW, et al. Intrapulmonary pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant patients. Antimicrob Agents Chemother 2010; 54:3451–9.
17. Andes D, Ambrose PG, Hammel JP, et al. Use of pharmacokineticpharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. Antimicrob
Agents Chemother 2011; 55:2113–21.
18. Hope WW, Seibel NL, Schwartz CL, et al. Population pharmacokinetics
of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother 2007; 51:3714–9.
19. Pasipanodya JG, Hall RG, Gumbo T. In silico-derived bedside formula
for individualized micafungin dosing for obese patients in the age of
deterministic chaos. Clin Pharmacol Ther 2015; 97:292–7.
20. Mandelbrot BB. The fractal geometry of nature. New York: W.H.
Freeman and Company, 1982.
21. 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.
22. Gumbo T, Drusano GL, Liu W, et al. Once-weekly micafungin therapy
is as effective as daily therapy for disseminated candidiasis in mice
with persistent neutropenia. Antimicrob Agents Chemother 2007;
51:968–74.
23. 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.
24. Petraitiene R, Petraitis V, Hope WW, Walsh TJ. Intermittent dosing of
micafungin is effective for treatment of experimental disseminated
candidiasis in persistently neutropenic rabbits. Clin Infect Dis 2015;
61(suppl 6):S643–51.
25. Pasipanodya JG, McIlleron H, Burger A, Wash PA, Smith P, Gumbo T.
Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis 2013; 208:1464–73.
Intermittent Micafungin for Candidiasis
•
CID 2015:61 (Suppl 6)
•
S641
26. Breiman L, Friedman J, Stone CJ, Olshen RA. Classification and regression trees. Boca Raton, FL: Chapman and Hall/CRC, 1984.
27. Hebert MF, Smith HE, Marbury TC, et al. Pharmacokinetics of
micafungin in healthy volunteers, volunteers with moderate liver disease,
and volunteers with renal dysfunction. J Clin Pharmacol 2005; 45:
1145–52.
28. Andes DR, Reynolds DK, Van Wart SA, Lepak AJ, Kovanda LL,
Bhavnani SM. Clinical pharmacodynamic index identification for micafungin in esophageal candidiasis: dosing strategy optimization. Antimicrob Agents Chemother 2013; 57:5714–6.
29. Mehta PA, Vinks AA, Filipovich A, et al. Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic
stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow
Transplant 2010; 16:1458–62.
30. Bochennek K, Balan A, Muller-Scholden L, et al. Micafungin twice
weekly as antifungal prophylaxis in paediatric patients at high risk for
invasive fungal disease. J Antimicrob Chemother 2015; 70:1527–30.
31. Hiemenz J, Cagnoni P, Simpson D, et al. Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in
adult patients undergoing a bone marrow or peripheral stem cell transplant. Antimicrob Agents Chemother 2005; 49:1331–6.
32. Sirohi B, Powles RL, Chopra R, et al. A study to determine the safety
profile and maximum tolerated dose of micafungin (FK463) in patients
undergoing haematopoietic stem cell transplantation. Bone Marrow
Transplant 2006; 38:47–51.
S642
•
CID 2015:61 (Suppl 6)
•
Gumbo
33. Gumbo T. Impact of pharmacodynamics and pharmacokinetics on
echinocandin dosing strategies. Curr Opin Infect Dis 2007; 20:587–91.
34. Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional
study. Clin Infect Dis 2006; 43:25–31.
35. Hope WW, Drusano GL, Moore CB, et al. Effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis. Antimicrob Agents Chemother 2007; 51:285–95.
36. Garnacho-Montero J, Díaz-Martín A, García-Cabrera E, et al. Impact
on hospital mortality of catheter removal and adequate antifungal therapy in Candida spp. bloodstream infections. J Antimicrob Chemother
2013; 68:206–13.
37. Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight
combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 2013; 57:1237–45.
38. Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid
multiplex polymerase chain reaction-based blood culture identification
and susceptibility testing. Clin Infect Dis 2015; 61:1071–80.
39. MacFadden DR, Leis JA, Mubareka S, Daneman N. The opening and
closing of empiric windows: the impact of rapid microbiologic diagnostics. Clin Infect Dis 2014; 59:1199–200.
40. Saracli MA, Fothergill AW, Sutton DA, Wiederhold NP. Detection of
triazole resistance among Candida species by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF
MS). Med Mycol 2015; 53:736–42.