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

952 Original Research

 Materials and Methods following: lack of improvement in signs, symptoms, or imaging
findings; continued isolation of Coccidioides or histopathologic
Entry demonstration of spherules and/or endospores while receiving
therapy; rising titers of coccidioidal complement-fixing antibody
Patients were eligible to participate if they were � 13 years old. or other surrogate marker of disease progression while receiving
Coccidioidomycosis, for study entry, was defined to be proven or therapy; or combination of microscopic examination per criteria8
probable by standardized criteria.8 A patient with refractory with persistence of clinical symptoms referable to the original site
coccidioidomycosis was defined as having received an adequate of disease for which therapy had been initiated. “Progression of
duration of prior licensed antifungal therapy to evaluate re­ disease” required either the worsening of attributable signs,
sponse, as alsoP verified after the study by an external Data symptoms, or imaging; or documentation of a new site of
Review Committee (DRC), which was formed for the review of disseminated infection while receiving therapy. “Intolerance of
several posaconazole open trials in invasive mycoses. The DRC prior therapy” (not required for study entry) was defined as organ
consisted of 15 experienced investigators and clinicians who were toxicity grade 3; adverse events were recorded and categorized
familiar with the treatment of mycoses and 2 experts in the using a standardized system,9 nephrotoxicity, or idiosyncratic
radiography of invasive fungal infections. Three members of the reactions related to prior conventional antifungal therapy. Neph­
DRC reviewed a given case, and determined eligibility and rotoxicity was defined as two serum creatinine determinations, at
outcomes using protocol-defined criteria after 1, 3, and 6 months least 1 day apart, that were more than twice the upper limit of
of therapy and at the end of treatment on the protocol. The DRC normal (ULN), recurrent elevation of creatinine to more than
was not informed of the patient’s institution, which prior therapy twice the ULN on resumption of prior antifungal therapy, or the
elevation of serum creatinine level to more than twice the
had been given, or the outcome of the case as scored by the
baseline value.
investigator independently. In addition, the same number of
Exclusion criteria included the following: pregnancy or lacta­
comparable coccidioidomycosis cases not treated with posacon­
tion; use of inadequate contraception in women with child­
azole were admixed with the posaconazole-treated pool for DRC bearing potential; concurrent progressive neurologic disease; a
assessment, so the DRC was not aware whether a patient had need for artificial ventilation with little likelihood of extubation
been treated with posaconazole or not. These control cases also within 24 h after study entry; a history of serious or severe
had not responded to prior therapy and were given salvage hypersensitivity to azoles; or the use of medications known to
therapy with other agents. interact with azoles, with the potential then of toxicity resulting
With respect to the duration of prior therapy, all patients from the use of those medications, within 10 days of study entry
included in the study had received at least 40 days of prior or of the use of drugs that lower azole serum concentrations10
appropriate antifungal therapy at conventional doses or higher within 7 days of study entry. Additional exclusion criteria were as
doses. The definition of “refractory” also required the DRC to follows: ECG results showing a prolonged QTc interval (ie,
have determined that the patient had failed to improve or that � 20% above normal) within 7 days of study entry; a need for
progression of disease while receiving prior therapy had oc­ concomitant systemic antifungal agents during the study period;
curred. “Failure to improve” required one or more of the the presence of abnormal hepatic function test results (alanine
aminotransferase or aspartate aminotransferase levels � 10 times
the ULN); or anticipated survival for � 72 h.
*From the Santa Clara Valley Medical Center/Stanford Univer­ The study protocol was reviewed and approved by an institu­
sity (Dr. Stevens), San Jose, CA; Hospital Universitario Dr. J. E. tional review board or independent ethics committee at each site.
Gonzalez (Dr. Rendon), Nuevo Leon, Mexico; Hospital de Before receiving the first dose, each patient (or a legal represen­
Infectologia CMN La Raza (Dr. Gaona-Flores), La Raza PB, tative) provided written informed consent in accordance with the
Mexico; University of California at San Diego Medical Center Declaration of Helsinki.
(Dr. Catanzaro), San Diego, CA; University of Texas Health Whenever possible, doses were to be administered with food or
Sciences Center (Drs. Anstead and Graybill), San Antonio, TX; liquid nutritional supplement. Patients were to receive posacon­
Schering-Plough Research Institute (Dr. Pedicone), Kenilworth, NJ. azole for � 28 days and for � 7 days after the complete
This study was supported by Schering-Plough Research Institute.
resolution of all symptoms. All patients were prescribed 400 mg
Dr. Stevens has participated on consultancy/advisory boards for
Schering-Plough, and has received research funding from Scher­ twice daily orally as a 40 mg/mL suspension; ostensibly, all but
ing-Plough. Dr. Rendon has received research funding/grants one patient took this dose for their entire study course (patient 3
from a commercial entity for this or related studies. Dr. Catan­ took this dose for most of her course, but at times less).
zato has participated in advisory boards and has received research Compliance issues caused the interruption of therapy in some
funding/grants for University of California at San Diego clinical patients. Some patients received 200 mg four times daily for a
research and consulting. Dr. Anstead has received payment for portion of the study, usually while hospitalized or per physician
participation in advisory boards and speakers’ bureau for Scher­ order. Although the maximum protocol-defined duration of
ing-Plough and has received grants/funding from Schering- treatment was 12 months, patients deemed by the investigator to
Plough. Dr. Pedicone is an employee of and shareholder in
require ongoing further therapy could then be enrolled in other
Schering-Plough. Dr. Graybill has participated in speakers’ pan­
els and consultancy/advisory boards for Schering-Plough, and has nonrandomized treatment protocols.
received research funding from Schering-Plough. Dr. Gaona- Three of the patients’ courses have been published in part,
Flores has no conflicts of interest to declare. including in a group of six patients with refractory coccidioid­
Manuscript received January 12, 2007; revision accepted May 8, omycosis, by the investigators.11 The prior study did not utilize
2007. the protocol criteria, evaluations, or methodology of the present
Reproduction of this article is prohibited without written permission study.
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: David A. Stevens, MD, Division of Infectious Evaluation of Outcome
Diseases, Department of Medicine, Santa Clara Valley Medical
Center, 751 South Bascom Ave, San Jose, CA 95128-2699; e-mail: The following modified intention-to-treat analysis for study
[email protected]. inclusion was used: patient receipt of at least one dose of
DOI: 10.1378/chest.07-0114 posaconazole, plus satisfying the definitions just enumerated.

www.chestjournal.org CHEST / 132 / 3 / SEPTEMBER, 2007 953

Outcome was defined by the DRC as a complete response (ie, the prior to receiving posaconazole (Table 1) [the total
absence of any findings compatible with continued disease adds to up � 15, as patients may have had more than
activity) or a partial response (ie, the partial resolution of
coccidioidal disease and the absence of worsening at any site).
one prior therapy]. Of those patients who had been
The primary efficacy end point was a response to pretherapy treated with azoles, 5 of 14 patients received � 400
abnormalities at the end of treatment. A nonsuccessful outcome mg daily, greater than conventional doses,1–3 which
was defined as the absence of improvement in attributable was a presumed dose escalation because of a lack of
symptoms, signs, and radiographic abnormalities (stable disease) response to conventional doses. Thus, overall, these
or deterioration in attributable clinical or radiographic abnormal­
ities that necessitated alternative antifungal therapy or resulted in
patients had received intensive prior therapy.
death (failure). Stable disease was grouped with the latter
subcategory as “failure.” The term unevaluable was utilized by Duration of Posaconazole Therapy
the DRC if the information supplied was insufficient to make an
outcome determination. Investigators ascribed the relationship of The patients received a range of 34 days to 1 year
each adverse event to posaconazole (possible, probable, or of continuous therapy on the protocol (Table 2).
definite) and whether the event necessitated the premature Some patients interrupted therapy, became noncom­
discontinuation of therapy or hospitalization. pliant, or both, or continued therapy while not
Blood samples were collected for routine hematologic and
chemistry evaluations at 1, 3, and 6 months during treatment and
receiving this protocol (ie, the drug became available
at the final posttherapy visit. A standard 12-lead ECG was through compassionate clearance or another proto­
obtained at baseline and week 4. 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.
Results Three of the patients had adjunctive surgery as part
Demographics and Prior Therapy of their treatment for coccidioidomycosis (Table 2).
Fifteen patients were studied. Five patients were
Response to Posaconazole
determined by the DRC to meet the definition of
intolerant, as well as refractory. Four patients were The courses of treatment in 11 of 15 patients
� 60 years old (Table 1). Six patients were men. Five (73%) were judged as responses by the DRC (Table
patients were white; the others belonged to races or 2). One patient was deemed to be unevaluable; this
ethnic groups that, epidemiologic studies indicate, patient had been deemed to be a responder by the
have a propensity for the development of severe patient’s physician-investigator on the basis of data
coccidioidal infection.1 Eight patients had serious available to the physician and that physician’s assess­
underlying diseases, several of which were associated ment of it. Of the 14 patients whose courses of
with immunosuppression. Eleven patients (73%) had treatment were deemed to be evaluable by the DRC,
coccidioidal disease present for � 1 year prior to 11 were termed responses (79%), 4 were termed
receiving posaconazole therapy, and 5 patients had complete responses, 7 were termed partial responses,
coccidioidal disease � 4 years. Thus, this cohort was and 3 were termed failures. Of the latter three
largely composed of patients with chronic coccidioid­ courses, one patient was judged to have stable
omycosis. Ten patients had pulmonary coccidioidal disease (but not improved), and another died of
disease, with a variety of manifestations, as follows: 5 aspergillosis. (The investigators had judged that 80%
patients had bone and/or joint disease (3 with mul­ of the patients [12 of 15 patients] were responders.)
tiple sites of skeletal disease); 5 patients had soft- When the evaluable sites of disease were analyzed
tissue disease (4 had paravertebral abscesses); 4 separately, there appeared to be generally uniform
patients had skin disease; 3 patients had extrapulmo­ responsiveness by the sites. There were nine patients
nary lymph node disease; 1 patient had CNS disease; with pulmonary disease; eight patients were judged
1 patient had choroidal ocular disease12; and 1 to have responded at the site (two with complete
patient possibly had the rare entity of coccidioidal responses). Of the patients with bone and joint
endocarditis (the total adds up to � 15, as patients disease, four of five patients were assessed as having
may have had more than one system involved with responded at the site (one with complete response),
coccidioidal disease). Thus, the cohort may be char­ as were four of five patients with soft-tissue disease,
acterized as having severe coccidioidal disease.1 three of four patients with skin disease (one com­
Prior therapy had been given for up to 5 years, and plete response), three of three patients with (ex­
11 patients had received therapy for � 400 days trapulmonary) lymph node disease (one complete
prior to receiving posaconazole (Table 1). Fourteen response), as well as the one patient with meningitis.
patients had received other azoles, 8 patients had (The number of complete responses at sites could
received an amphotericin preparation, 7 patients had exceed the total number of complete responses, as
received both, and 2 patients had undergone pulmo­ each site was evaluated independently in this tally.)
nary surgery as well as antifungal chemotherapy Six patients’ outcomes were assessable by serial

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

956 Original Research

14 patients (50%) [1 other patient had not responded partial responders exited the study owing to noncom­
to therapy and died before the 3-month evaluation); pliance. One patient, who had been deemed to be
and after 6 months of therapy, 10 of 13 patients unevaluable, interrupted therapy on treatment day
(77%). Two of the three nonresponders at 6 months 42, was treated on another posaconazole protocol for
were later declared to be responders. One of the 13 months, and then became noncompliant; the
responders, at 6 months, later was ultimately patient was deemed to have had a successful out­
deemed a failure. Another patient had exited the come by the investigator on that protocol. One
study earlier as a failure, resumed therapy, and partial responder interrupted therapy after 1 year,
responded at the 6-month evaluation. (One patient then resumed under another posaconazole protocol
had exited the study before the 6-month evaluation.) and recrudesced on therapy 1.4 years later. The
Thus responses were generally prompt. The vari­ patient then underwent a therapeutic surgical pro­
ability in response rates between months 1 and 3 cedure, and the dose was increased to 1,200 mg/d.
reflects the sometimes variable course of coccidioid­ The patient then received another year of posacon­
omycosis while receiving therapy. Therefore, the azole therapy at that dose, but colonic coccidioid­
time to a durable response (ie, a response that, once omycosis that was unresponsive to therapy with
attained, then remained) was studied. Five patients voriconazole, interferon-�, and fluconazole, 1,600
had a response beginning at 1 month that was mg/d, developed. The patient died with a perforated
sustained for � 6 months and to the end of the study bowel and active pulmonary coccidioidomycosis 25
(another such patient was also deemed to be a months after exiting our study. The other study
responder at 3-month evaluation and then was lost to death occurred in a patient who interrupted
follow-up). Three other patients had responses be­ posaconazole therapy at 34 days, in whom the clinical
ginning at the 6-month evaluation that persisted to findings then met the definition of failure; 39 days
the end of their study course (this applied to an later, the patient died of aspergillosis.
additional patient until scored, finally, as unevaluable
because of inadequate data). Two other patients had
responses that began after the 6-month evaluation Discussion
and persisted to the end of their study period. (Three
patients did not respond to therapy.) The study documents the responsiveness to
posaconazole used for salvage therapy of chronic
Possible Adverse Effects coccidioidomycosis that was refractory to prior ther­
apy. It is consistent with recent suggestions13 for the
Seven patients had no possible side effects accord­
organization of salvage therapy trials. This study
ing to the investigators. No patients had possible side
cohort had, in addition, important comorbidities.
effects causing the interruption or discontinuation of
Posaconazole was well tolerated. The response to
therapy, and none had adverse effects that were
posaconazole did not appear to be related to patients’
definitely attributed to the drug. There were five
demographic characteristics, including race, under­
patients with side effects that were deemed to be
lying conditions, the site of infection, or type or
probably due to the drug (abdominal pain, two
length of prior antifungal therapy, although a larger
patients; nausea, two patients; diarrhea, one patient).
population of treated patients would be needed to
Of the adverse effects deemed to be possibly related
assess these variables adequately. Our outcome con­
to the drug, two patients each had headache, hyper­
clusion is congruent with assessments of posacon­
reflexia, and alopecia; a variety of possible effects
azole from animal model studies5; an initial, short
were reported once each. Thus, the drug appears to
dose-finding study7; and a prior, smaller, single-site
be well-tolerated in long-term therapy in patients
experience.11 This conclusion applies to multiple
with chronic disease.
sites of coccidioidal disease, except, at this time, to
coccidioidal meningitis. Culture reversion was doc­
Follow-up After This Posaconazole Protocol
umented in most instances where this could be
A problem with the evaluation of some prior assessed. The response rate in this study compares
publications on therapy for patients with an often favorably with that in initial open studies of micon­
relapsing and remitting disease such as coccidioid­ azole,14 ketoconazole,15,16 itraconazole,17,18, or flu­
omycosis is the absence of postprotocol information. conazole19,20 as therapy for disseminated nonmenin­
Follow-up information was not available in most of geal coccidioidomycosis. Those studies included
our patients after their study and evaluation period some patients who did not respond to therapy
concluded. However, the data indicate that one (failures) or who had experienced relapses with prior
complete responder is continuing posaconazole ther­ therapy. Most publications on therapy for coccidioid­
apy while not continuing with the protocol. Two omycosis have reported on open trials because of the

www.chestjournal.org CHEST / 132 / 3 / SEPTEMBER, 2007 957

difficulty in accruing sufficient numbers of patients of posaconazole (SCH 56592) in patients with nonmeningeal
in a timely fashion, with one exception. In that trial,2 disseminated coccidioidomycosis [abstract]. In: Program and
abstracts of the 40th Interscience Conference on Antimicro­
for the primary efficacy measure, response at 8
bial Agents and Chemotherapy; September 17–20, 2000;
months, response rates were 50% with fluconazole Toronto, ON, Canada; abstract 1417
and 63% with itraconazole; response rates at 12 8 Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic
months were 57% and 72%, respectively. In that invasive fungal infections in immunocompromised patients
trial, the exclusion of patients with extensive prior with cancer and hematopoietic stem cell transplantation: an
exposure to antifungal agents during that episode of international consensus. Clin Infect Dis 2002; 34:7–14
infection disqualified at least some patients with 9 AIDS Clinical Trials Group. Table of grading severity of adult
adverse experiences. Rockville, MD: Division of AIDS, Na­
infections that were refractory to standard therapy.
tional Institute of Allergy and Infectious Diseases, 1996
Questions remain for further studies. A random­ 10 Tucker RM, Denning DW, Hanson LH, et al. Interaction of
ized trial for initial therapy (or for initial therapy plus azoles with rifampin, phenytoin, and carbamazepine: in vitro
therapy for relapsed disease) of disseminated coccid­ and clinical observations. Clin Infect Dis 1992; 14:165–174
ioidomycosis (populations that would be less ill than 11 Anstead GM, Corcoran G, Lewis J, et al. Refractory coccid­
that studied here) would allow a direct comparison ioidomycosis treated with posaconazole. Clin Infect Dis 2005;
with therapy using other azoles.2 Whether longer 40:1770 –1776
12 Blumenkranz MS, Stevens DA. Endogenous coccidioidal
periods of posaconazole therapy than that studied
endophthalmitis. Ophthalmology 1980; 87:974 –984
here could produce superior results is of interest. 13 Almyroudis NG, Kontoyiannis DP, Sepkowitz KA, et al.
Meningitis is the most devastating form of coccidioi­ Issues related to the design and interpretation of clinical trials
dal disease and is the most difficult to treat21; of salvage therapy for invasive mold infection. Cin Infect Dis
posaconazole results in that entity would be of great 2006; 43:1449 –1455
interest; posaconazole has demonstrated activity 14 Stevens DA. Miconazole in the treatment of coccidioidomy­
against other CNS mycoses in experimental animals cosis. Drugs 1983; 26:347–354
15 Stevens DA, Stiller RL, Williams PL, et al. Experience with
and man.22,23 Recent publications24 have docu­
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