Original Research

RESPIRATORY INFECTIONS

Posaconazole Therapy for Chronic

Refractory Coccidioidomycosis*

David A. Stevens, MD; Adrian Rendon, MD; Veronica Gaona-Flores, MD;

Antonino Catanzaro, MD, FCCP; Gregory M. Anstead, MD; Lisa Pedicone, PhD;
and J. Richard Graybill, MD

Background: Coccidioides infections often result in chronic relapsing disease that presents a
challenge to the currently available therapy. Posaconazole, an oral extended-spectrum triazole
agent, has been shown in vitro and in vivo to have potent activity against this fungus.
Methods: An open-label multinational study of posaconazole, 800 mg/d, administered in divided
doses for the treatment of invasive fungal infection that has been refractory to previous therapy
was conducted. The data were reviewed by an independent data review committee (DRC).
Fifteen patients met the criteria for proven coccidioidal infection and disease refractory to
previous therapy. Success was a complete or partial response; nonsuccess was stable disease, lack
of response to therapy, or undetermined response.
Results: The sites of coccidioidal infection were pulmonary (seven patients) and disseminated
(eight patients). Patients were refractory to previous therapy (including amphotericin B with or
without an azole) for a median duration of 306 days. At the end of treatment (posaconazole
treatment duration, 34 to 365 days), therapy for 11 of 15 patients (73%) was considered to be
successful by the DRC. Four responses were complete and seven were partial; these included five
patients with pulmonary sites and six patients with disseminated sites. In responders, improve­
ment was seen within months of the initiation of therapy. Five patients received therapy for > 12
months. The side effects were minimal.
Conclusions: Therapy for coccidioidomycosis remains a clinical challenge, especially when
patients have not responded to therapy with drugs that were recommended in treatment
guidelines. The success rate (73%) achieved in this case series suggests that oral posaconazole
should be considered as an important agent for the treatment of refractory coccidioidomycosis.
(CHEST 2007; 132:952–958)

Key words: antifungal; azole; coccidioidomycosis; posaconazole

Abbreviations: DRC � data review committee; ULN � upper limit of normal

� 200-fold and � 10-fold to 20-fold, respectively,

C mycoses
occidioidomycosis is one of the most difficult
to treat, related to the exponential
method of replication and the tendency to form
suppuration and granulomas, which may hamper
tissue resolution and drug penetration.1 Oral azole
therapy has been an important contribution to dis­
ease management, but the currently available drugs
require long-term therapy for responses, and relapse
after apparently successful therapy is common.1–3
Posaconazole4 is fungicidal against Coccidioides in
vitro5,6 and is the most curative drug in animal
models,5,6 where it has been demonstrated to be
more potent than fluconazole and itraconazole.5 A
preliminary report of a dose-finding clinical study4,7
has suggested that there was responsiveness of coc­
cidioidomycosis to the initial therapy for chronic
disease at lower doses than are currently being
studied for the treatment of deep mycoses. The
present multicenter international collaboration in­
vestigated therapy with posaconazole for coccidioid­
omycosis that was refractory to the currently avail­
able therapy and utilized doses greater than those
studied previously.7

952 Original Research

 Materials and Methods
Entry
Patients were eligible to participate if they were � 13 years old.
Coccidioidomycosis, for study entry, was defined to be proven or
probable by standardized criteria.8 A patient with refractory
coccidioidomycosis was defined as having received an adequate
duration of prior licensed antifungal therapy to evaluate re­
sponse, as alsoP verified after the study by an external Data
Review Committee (DRC), which was formed for the review of
several posaconazole open trials in invasive mycoses. The DRC
consisted of 15 experienced investigators and clinicians who were
familiar with the treatment of mycoses and 2 experts in the
radiography of invasive fungal infections. Three members of the
DRC reviewed a given case, and determined eligibility and
outcomes using protocol-defined criteria after 1, 3, and 6 months
of therapy and at the end of treatment on the protocol. The DRC
was not informed of the patient’s institution, which prior therapy
had been given, or the outcome of the case as scored by the
investigator independently. In addition, the same number of
comparable coccidioidomycosis cases not treated with posacon­
azole were admixed with the posaconazole-treated pool for DRC
assessment, so the DRC was not aware whether a patient had
been treated with posaconazole or not. These control cases also
had not responded to prior therapy and were given salvage
therapy with other agents.
With respect to the duration of prior therapy, all patients
included in the study had received at least 40 days of prior
appropriate antifungal therapy at conventional doses or higher
doses. The definition of “refractory” also required the DRC to
have determined that the patient had failed to improve or that
progression of disease while receiving prior therapy had oc­
curred. “Failure to improve” required one or more of the
*From the Santa Clara Valley Medical Center/Stanford Univer­
sity (Dr. Stevens), San Jose, CA; Hospital Universitario Dr. J. E.
Gonzalez (Dr. Rendon), Nuevo Leon, Mexico; Hospital de
Infectologia CMN La Raza (Dr. Gaona-Flores), La Raza PB,
Mexico; University of California at San Diego Medical Center
(Dr. Catanzaro), San Diego, CA; University of Texas Health
Sciences Center (Drs. Anstead and Graybill), San Antonio, TX;
Schering-Plough Research Institute (Dr. Pedicone), Kenilworth, NJ.
This study was supported by Schering-Plough Research Institute.
Dr. Stevens has participated on consultancy/advisory boards for
Schering-Plough, and has received research funding from Scher­
ing-Plough. Dr. Rendon has received research funding/grants
from a commercial entity for this or related studies. Dr. Catan­
zato has participated in advisory boards and has received research
funding/grants for University of California at San Diego clinical
research and consulting. Dr. Anstead has received payment for
participation in advisory boards and speakers’ bureau for Scher­
ing-Plough and has received grants/funding from Schering-
Plough. Dr. Pedicone is an employee of and shareholder in
Schering-Plough. Dr. Graybill has participated in speakers’ pan­
els and consultancy/advisory boards for Schering-Plough, and has
received research funding from Schering-Plough. Dr. Gaona-
Flores has no conflicts of interest to declare.
Manuscript received January 12, 2007; revision accepted May 8,
2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: David A. Stevens, MD, Division of Infectious
Diseases, Department of Medicine, Santa Clara Valley Medical
Center, 751 South Bascom Ave, San Jose, CA 95128-2699; e-mail:
stevens@stanford.edu.
DOI: 10.1378/chest.07-0114
www.chestjournal.org
following: lack of improvement in signs, symptoms, or imaging
findings; continued isolation of Coccidioides or histopathologic
demonstration of spherules and/or endospores while receiving
therapy; rising titers of coccidioidal complement-fixing antibody
or other surrogate marker of disease progression while receiving
therapy; or combination of microscopic examination per criteria8
with persistence of clinical symptoms referable to the original site
of disease for which therapy had been initiated. “Progression of
disease” required either the worsening of attributable signs,
symptoms, or imaging; or documentation of a new site of
disseminated infection while receiving therapy. “Intolerance of
prior therapy” (not required for study entry) was defined as organ
toxicity grade 3; adverse events were recorded and categorized
using a standardized system,9 nephrotoxicity, or idiosyncratic
reactions related to prior conventional antifungal therapy. Neph­
rotoxicity was defined as two serum creatinine determinations, at
least 1 day apart, that were more than twice the upper limit of
normal (ULN), recurrent elevation of creatinine to more than
twice the ULN on resumption of prior antifungal therapy, or the
elevation of serum creatinine level to more than twice the
baseline value.
Exclusion criteria included the following: pregnancy or lacta­
tion; use of inadequate contraception in women with child­
bearing potential; concurrent progressive neurologic disease; a
need for artificial ventilation with little likelihood of extubation
within 24 h after study entry; a history of serious or severe
hypersensitivity to azoles; or the use of medications known to
interact with azoles, with the potential then of toxicity resulting
from the use of those medications, within 10 days of study entry
or of the use of drugs that lower azole serum concentrations10
within 7 days of study entry. Additional exclusion criteria were as
follows: ECG results showing a prolonged QTc interval (ie,
� 20% above normal) within 7 days of study entry; a need for
concomitant systemic antifungal agents during the study period;
the presence of abnormal hepatic function test results (alanine
aminotransferase or aspartate aminotransferase levels � 10 times
the ULN); or anticipated survival for � 72 h.
The study protocol was reviewed and approved by an institu­
tional review board or independent ethics committee at each site.
Before receiving the first dose, each patient (or a legal represen­
tative) provided written informed consent in accordance with the
Declaration of Helsinki.
Whenever possible, doses were to be administered with food or
liquid nutritional supplement. Patients were to receive posacon­
azole for � 28 days and for � 7 days after the complete
resolution of all symptoms. All patients were prescribed 400 mg
twice daily orally as a 40 mg/mL suspension; ostensibly, all but
one patient took this dose for their entire study course (patient 3
took this dose for most of her course, but at times less).
Compliance issues caused the interruption of therapy in some
patients. Some patients received 200 mg four times daily for a
portion of the study, usually while hospitalized or per physician
order. Although the maximum protocol-defined duration of
treatment was 12 months, patients deemed by the investigator to
require ongoing further therapy could then be enrolled in other
nonrandomized treatment protocols.
Three of the patients’ courses have been published in part,
including in a group of six patients with refractory coccidioid­
omycosis, by the investigators.11 The prior study did not utilize
the protocol criteria, evaluations, or methodology of the present
study.
Evaluation of Outcome
The following modified intention-to-treat analysis for study
inclusion was used: patient receipt of at least one dose of
posaconazole, plus satisfying the definitions just enumerated.
CHEST / 132 / 3 / SEPTEMBER, 2007 953
Outcome was defined by the DRC as a complete response (ie, the
absence of any findings compatible with continued disease
activity) or a partial response (ie, the partial resolution of
coccidioidal disease and the absence of worsening at any site).
The primary efficacy end point was a response to pretherapy
abnormalities at the end of treatment. A nonsuccessful outcome
was defined as the absence of improvement in attributable
symptoms, signs, and radiographic abnormalities (stable disease)
or deterioration in attributable clinical or radiographic abnormal­
ities that necessitated alternative antifungal therapy or resulted in
death (failure). Stable disease was grouped with the latter
subcategory as “failure.” The term unevaluable was utilized by
the DRC if the information supplied was insufficient to make an
outcome determination. Investigators ascribed the relationship of
each adverse event to posaconazole (possible, probable, or
definite) and whether the event necessitated the premature
discontinuation of therapy or hospitalization.
Blood samples were collected for routine hematologic and
chemistry evaluations at 1, 3, and 6 months during treatment and
at the final posttherapy visit. A standard 12-lead ECG was
obtained at baseline and week 4.
Results
Demographics and Prior Therapy
Fifteen patients were studied. Five patients were
determined by the DRC to meet the definition of
intolerant, as well as refractory. Four patients were
� 60 years old (Table 1). Six patients were men. Five
patients were white; the others belonged to races or
ethnic groups that, epidemiologic studies indicate,
have a propensity for the development of severe
coccidioidal infection.1 Eight patients had serious
underlying diseases, several of which were associated
with immunosuppression. Eleven patients (73%) had
coccidioidal disease present for � 1 year prior to
receiving posaconazole therapy, and 5 patients had
coccidioidal disease � 4 years. Thus, this cohort was
largely composed of patients with chronic coccidioid­
omycosis. Ten patients had pulmonary coccidioidal
disease, with a variety of manifestations, as follows: 5
patients had bone and/or joint disease (3 with mul­
tiple sites of skeletal disease); 5 patients had soft-
tissue disease (4 had paravertebral abscesses); 4
patients had skin disease; 3 patients had extrapulmo­
nary lymph node disease; 1 patient had CNS disease;
1 patient had choroidal ocular disease12; and 1
patient possibly had the rare entity of coccidioidal
endocarditis (the total adds up to � 15, as patients
may have had more than one system involved with
coccidioidal disease). Thus, the cohort may be char­
acterized as having severe coccidioidal disease.1
Prior therapy had been given for up to 5 years, and
11 patients had received therapy for � 400 days
prior to receiving posaconazole (Table 1). Fourteen
patients had received other azoles, 8 patients had
received an amphotericin preparation, 7 patients had
received both, and 2 patients had undergone pulmo­
nary surgery as well as antifungal chemotherapy
954
prior to receiving posaconazole (Table 1) [the total
adds to up � 15, as patients may have had more than
one prior therapy]. Of those patients who had been
treated with azoles, 5 of 14 patients received � 400
mg daily, greater than conventional doses,1–3 which
was a presumed dose escalation because of a lack of
response to conventional doses. Thus, overall, these
patients had received intensive prior therapy.
Duration of Posaconazole Therapy
The patients received a range of 34 days to 1 year
of continuous therapy on the protocol (Table 2).
Some patients interrupted therapy, became noncom­
pliant, or both, or continued therapy while not
receiving this protocol (ie, the drug became available
through compassionate clearance or another proto­
col); thus, two patients received 13 and 24 months of
total posaconazole therapy. Twelve of 15 patients
received � 6 months of treatment while in the study.
Three of the patients had adjunctive surgery as part
of their treatment for coccidioidomycosis (Table 2).
Response to Posaconazole
The courses of treatment in 11 of 15 patients
(73%) were judged as responses by the DRC (Table
2). One patient was deemed to be unevaluable; this
patient had been deemed to be a responder by the
patient’s physician-investigator on the basis of data
available to the physician and that physician’s assess­
ment of it. Of the 14 patients whose courses of
treatment were deemed to be evaluable by the DRC,
11 were termed responses (79%), 4 were termed
complete responses, 7 were termed partial responses,
and 3 were termed failures. Of the latter three
courses, one patient was judged to have stable
disease (but not improved), and another died of
aspergillosis. (The investigators had judged that 80%
of the patients [12 of 15 patients] were responders.)
When the evaluable sites of disease were analyzed
separately, there appeared to be generally uniform
responsiveness by the sites. There were nine patients
with pulmonary disease; eight patients were judged
to have responded at the site (two with complete
responses). Of the patients with bone and joint
disease, four of five patients were assessed as having
responded at the site (one with complete response),
as were four of five patients with soft-tissue disease,
three of four patients with skin disease (one com­
plete response), three of three patients with (ex­
trapulmonary) lymph node disease (one complete
response), as well as the one patient with meningitis.
(The number of complete responses at sites could
exceed the total number of complete responses, as
each site was evaluated independently in this tally.)
Six patients’ outcomes were assessable by serial
Original Research
 Table 1—Patient Demographics*
Duration of
Patient No./ Coccidioidal Intolerant of Prior
Age, yr/Sex/Race Underlying Disease Disease† Duration of Prior Therapy Therapy‡ Site of Coccidioidal Disease

www.chestjournal.org
1/17/F/B None 42 d Left lower lobectomy, then AmBi, 5 No Bone (frontal, sternum, and vertebral),
mg/kg for 40 d skin, soft (paraspinous abscess); nodes
pulm (miliary, infiltrate, nodes,
pleural, and pleural effusion)
2/64/M/W HD, allo BMT, GVHD? 174 d 125 d of ABLC � IZ, 400 mg/d Yes Pulm (nodule, pneumonia, and pleural
effusion)
3/20/M/B None 422 d FZ, 800 mg/d for 29 d and 400 mg/d for Yes Soft, skin, pulm (nodule, mediastinal
293 d; AmBd, 0.7 mg/kg for 27 d; IZ, nodes); bone (sternum, clavicle, rib,
400 mg/d for 40 d; ABLC, 5 mg/kg ischium, MCP, femur, knee, foot, and
for 58 d; IZ, 200 mg/d for 23 d; ulna); possible endocarditis
AmBi, 5 mg/kg for 12 d (total, 422 d)
4/21/F/H Aspergillus pulm node (old TB) 1,055 d 417 d, including 241 d of IZ, 400 mg/d, No Pulm cavity

and pulm resection

5/37/F/H None 5.6 yr 1,611 d total, including 841 d of KTZ, No Skin

FZ, IZ at � 400 mg/d

6/42/M/H DM 5.5 mo 160 d total; FZ, 400 mg/d for 153 d; Yes Pulm infiltrate

AmBd, 39–50 mg/d for 9 d

7/31/M/H Glucocorticoid metabolic defect 15.5 mo 409 d, including IZ, 400 mg/d for 305d No Pulm (infiltrate, nodule, and cavity)

8/23/F/H None 503 d 503 d total (363 d IZ, 400 mg/d) No Pulm cavity

9/59/F/A None 791 d 785 d, including 731 d with FZ, 400 No Node, skin

mg/d
10/50/M/H Asthma 4 yr 4 yr, including 4 g of AmBd, and KTZ, Yes Node, bone (thoracic spine T8–T10);
400 mg/d; in the 71 d immediately soft, including paravertebral abscess
prior to study entry, IZ, 400 mg/d for with cord compression, pulm (pleural
10 d, and 600 mg/d for 55 d; FZ, 800 effusion)
mg/d for 6 d; AmBi for 22 d
11/43/M/B Sarcoid, prednisone 1,614 d 1,614 d of FZ, 400 mg/d, IZ, 400 mg/d, Yes Soft (paraspinal abscess); bone (SI, iliac)
then 600 mg/d, ABLC
12/64/F/H DM 17 mo 500 d of IZ, 400 mg/d No Pulm (cavity, nodule)
13/43/F/W None 7 yr 2,825 d of FZ, 800 or 400 mg/d No CNS (meningitis, hydrocephalus); blood
(culture positive)
14/65/F/W None 10 mo 271 d of FZ up to 800 mg/d, AmBd No Joint (hip)
15/63/F/W Pulm atypical mycobacterial infection? 2,110 d 2,110 d AmBd, FZ, 400 mg/d, or IZ, No Pulm (nodes, cavity, nodules); soft
prior gynecologic cancer 400 mg/d
*M � male; F � female; B � black; H � Hispanic; W � white; A � Asian; ABLC � amphotericin B lipid complex; Allo � allogeneic; AmBd � amphotericin B deoxycholate; AmBi � liposomal
amphotericin B; BMT � bone marrow transplant; DM � diabetes mellitus; FZ � fluconazole; GVHD � graft-vs-host disease; HD � Hodgkin disease; IZ � itraconazole; KTZ � ketoconazole;
MCP � metacarpal phalangeal joint; Node � lymph node; pulm � pulmonary; SI � sacroiliac; Soft � soft tissue; TB � tuberculosis.
†At protocol entry.

CHEST / 132 / 3 / SEPTEMBER, 2007

‡In addition to being refractory to treatment.

955
 Table 2—Patient Outcomes*
Outcomes
Patient Duration of Posaconazole Assessed by Assessment at
No. Therapy† DRC Month 1/3/6 Adverse Effects‡ Comments

1 365 d PR I§/I/I None Pos interrupted, recrudesced 13 mo

later; then soft debridement and Pos
therapy resumed, 1,200 mg/d; colonic
coccy developed and therapy switched
(after 730 d of total Pos therapy) to
VZ � IFN-�, then condition
worsened; switched to FZ, 1,600 mg/
d; died of peritonitis after bowel
perforation with active pulm coccy 25
mo after exit from Pos study
2 34 d F I�/NC/NC None Death ascribed to aspergillosis 39 d after
study
3 61 d, then noncompliant PR I/I�/NA None
4 42 d, interrupted; resumed U NC�/NC/I Diarrhea and nausea, probable Investigator on second Pos protocol
for 13 mo, then assessed as responder
noncompliant
5 365 d F I/I/I¶ Menstrual irregularities, alopecia,
hyperreflexia possible
6 10 mo CR NC/NC/NC¶ Abd pain probable; increased Sputum culture cleared
triglycerides, vesicular rash,
headache, paresthesia, and
hyperreflexia; memory loss
possible
7 7.5 mo PR I§/I/I None Bronchoscopy culture cleared
8 12 mo PR I/NC/I§ Nausea probable; alopecia, abd Pulm surgery on d 78
pain, headache, anorexia
possible
9 6 mo CR I§/I/I None
10 12 mo, then noncompliant PR NC/NC/I§ Adrenal hypofunction, decreased Adjunctive surgical drainage
gonadatropins possible
11 7 mo F (stable) None/none/ Dry skin, dry mouth, including
none alkaline phosphatase and
SGPT, possible
12 9 mo CR I§/I/I Abd pain, tremors, leg edema Bronchoscopy culture cleared
possible
13 12 mo PR I/none/I§ None CSF culture cleared
14 7 mo (then continued CR I§/I/I Gastroesophageal reflux, inc. Synovial fluid culture cleared;
while not with protocol) anxiety, dyspepsia, possible coccidioidal complement-fixing
antibody titer decline; adjunct surgery
15 12 mo PR I/none/none¶ None Sputum remained culture positive
*Abd � abdominal; coccy � coccidioidomycosis; CR � complete response; F � failure; IFN � interferon; inc � increased; Pos � posaconazole;
PR � partial response; SGPT � alanine aminotransferase; U � unevaluable; VZ � voriconazole; I � improved; NC � no change (comparisons
to baseline); NA � not applicable. See Table 1 for abbreviations not used in the text.
†This study protocol.

‡“Probable” and “possible” refer to investigator’s assessment as to whether adverse effect is related to posaconazole.

§Evaluation in which a durable response started.

�Denotes last evaluation of study.

¶Denotes final assessment was made on the basis of end of treatment and after the 6-month evaluation.

(ie, two or more) culture status determinations while
receiving therapy; follow-up cultures were not avail-
able in several patients because of clinical resolution
at the disease site and the absence of a specimen to
culture. Five patients had a positive culture finding
pretherapy and a negative culture posttherapy (two
from bronchoscopy specimens, one from sputum
cultures, one from cerebrospinal fluid, and one from
synovial fluid). The other patient remained culture-
positive from a sputum sample.
Time to Response
After 1 month of therapy, the conditions of 11 of
15 patients (73%) were deemed to have improved
compared to baseline; after 3 months of therapy, 7 of

956 Original Research

14 patients (50%) [1 other patient had not responded
to therapy and died before the 3-month evaluation);
and after 6 months of therapy, 10 of 13 patients
(77%). Two of the three nonresponders at 6 months
were later declared to be responders. One of the
responders, at 6 months, later was ultimately
deemed a failure. Another patient had exited the
study earlier as a failure, resumed therapy, and
responded at the 6-month evaluation. (One patient
had exited the study before the 6-month evaluation.)
Thus responses were generally prompt. The vari­
ability in response rates between months 1 and 3
reflects the sometimes variable course of coccidioid­
omycosis while receiving therapy. Therefore, the
time to a durable response (ie, a response that, once
attained, then remained) was studied. Five patients
had a response beginning at 1 month that was
sustained for � 6 months and to the end of the study
(another such patient was also deemed to be a
responder at 3-month evaluation and then was lost to
follow-up). Three other patients had responses be­
ginning at the 6-month evaluation that persisted to
the end of their study course (this applied to an
additional patient until scored, finally, as unevaluable
because of inadequate data). Two other patients had
responses that began after the 6-month evaluation
and persisted to the end of their study period. (Three
patients did not respond to therapy.)
Possible Adverse Effects
Seven patients had no possible side effects accord­
ing to the investigators. No patients had possible side
effects causing the interruption or discontinuation of
therapy, and none had adverse effects that were
definitely attributed to the drug. There were five
patients with side effects that were deemed to be
probably due to the drug (abdominal pain, two
patients; nausea, two patients; diarrhea, one patient).
Of the adverse effects deemed to be possibly related
to the drug, two patients each had headache, hyper­
reflexia, and alopecia; a variety of possible effects
were reported once each. Thus, the drug appears to
be well-tolerated in long-term therapy in patients
with chronic disease.
Follow-up After This Posaconazole Protocol
A problem with the evaluation of some prior
publications on therapy for patients with an often
relapsing and remitting disease such as coccidioid­
omycosis is the absence of postprotocol information.
Follow-up information was not available in most of
our patients after their study and evaluation period
concluded. However, the data indicate that one
complete responder is continuing posaconazole ther­
apy while not continuing with the protocol. Two
www.chestjournal.org
partial responders exited the study owing to noncom­
pliance. One patient, who had been deemed to be
unevaluable, interrupted therapy on treatment day
42, was treated on another posaconazole protocol for
13 months, and then became noncompliant; the
patient was deemed to have had a successful out­
come by the investigator on that protocol. One
partial responder interrupted therapy after 1 year,
then resumed under another posaconazole protocol
and recrudesced on therapy 1.4 years later. The
patient then underwent a therapeutic surgical pro­
cedure, and the dose was increased to 1,200 mg/d.
The patient then received another year of posacon­
azole therapy at that dose, but colonic coccidioid­
omycosis that was unresponsive to therapy with
voriconazole, interferon-�, and fluconazole, 1,600
mg/d, developed. The patient died with a perforated
bowel and active pulmonary coccidioidomycosis 25
months after exiting our study. The other study
death occurred in a patient who interrupted
posaconazole therapy at 34 days, in whom the clinical
findings then met the definition of failure; 39 days
later, the patient died of aspergillosis.
Discussion
The study documents the responsiveness to
posaconazole used for salvage therapy of chronic
coccidioidomycosis that was refractory to prior ther­
apy. It is consistent with recent suggestions13 for the
organization of salvage therapy trials. This study
cohort had, in addition, important comorbidities.
Posaconazole was well tolerated. The response to
posaconazole did not appear to be related to patients’
demographic characteristics, including race, under­
lying conditions, the site of infection, or type or
length of prior antifungal therapy, although a larger
population of treated patients would be needed to
assess these variables adequately. Our outcome con­
clusion is congruent with assessments of posacon­
azole from animal model studies5; an initial, short
dose-finding study7; and a prior, smaller, single-site
experience.11 This conclusion applies to multiple
sites of coccidioidal disease, except, at this time, to
coccidioidal meningitis. Culture reversion was doc­
umented in most instances where this could be
assessed. The response rate in this study compares
favorably with that in initial open studies of micon­
azole,14 ketoconazole,15,16 itraconazole,17,18, or flu­
conazole19,20 as therapy for disseminated nonmenin­
geal coccidioidomycosis. Those studies included
some patients who did not respond to therapy
(failures) or who had experienced relapses with prior
therapy. Most publications on therapy for coccidioid­
omycosis have reported on open trials because of the
CHEST / 132 / 3 / SEPTEMBER, 2007 957
difficulty in accruing sufficient numbers of patients
in a timely fashion, with one exception. In that trial,2
for the primary efficacy measure, response at 8
months, response rates were 50% with fluconazole
and 63% with itraconazole; response rates at 12
months were 57% and 72%, respectively. In that
trial, the exclusion of patients with extensive prior
exposure to antifungal agents during that episode of
infection disqualified at least some patients with
infections that were refractory to standard therapy.
Questions remain for further studies. A random­
ized trial for initial therapy (or for initial therapy plus
therapy for relapsed disease) of disseminated coccid­
ioidomycosis (populations that would be less ill than
that studied here) would allow a direct comparison
with therapy using other azoles.2 Whether longer
periods of posaconazole therapy than that studied
here could produce superior results is of interest.
Meningitis is the most devastating form of coccidioi­
dal disease and is the most difficult to treat21;
posaconazole results in that entity would be of great
interest; posaconazole has demonstrated activity
against other CNS mycoses in experimental animals
and man.22,23 Recent publications24 have docu­
mented posaconazole efficacy in salvage therapy for
other mycoses.
ACKNOWLEDGMENT: We thank Gavin Corcoran and Cathy
Bruno for assistance.
References
1 Chiller TM, Galgiani JN, Stevens DA. Coccidioidomycosis.
Infect Dis Clin North Am 2003; 17:41–57
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