Caspofungin treatment of Pneumocystis pneumonia during ...

Eur J Clin Microbiol Infect Dis (2006) 25: 52–54
DOI 10.1007/s10096-005-0065-z
BRIEF REPORT
C. Annaloro . A. Della Volpe . P. Usardi .
G. Lambertenghi Deliliers
Caspofungin treatment of Pneumocystis pneumonia
during conditioning for bone marrow transplantation
Published online: 20 December 2005
# Springer-Verlag 2005
Pneumocystis pneumonia (PCP) is a well-known complication
in AIDS patients, but it is also frequently diagnosed
in hemato-oncological patients [1]. High-dose cotrimoxazole
is the first-line treatment for PCP, but some patients
show contraindications and drug resistance may appear
[2]. Since Pneumocystis jirovecii cannot be cultivated in
vitro, mutations in the genes involved in folate metabolism
have been investigated as a possible expression of
cotrimoxazole resistance [3], but the search for a clinical
correlate has so far led to equivocal results [4]. There is
some doubt as to what may be the best alternative to
cotrimoxazole in the treatment of PCP [5]. The present
report refers to the use of caspofungin to treat a patient
with PCP undergoing bone marrow transplantation (BMT)
in whom cotrimoxazole had to be discontinued because of
its myelotoxicity.
A 45-year-old male patient with T-lymphoblastic leukemia
in second complete remission was scheduled to receive
an allogeneic BMT from an unrelated HLA-matched
donor in October 2004. In September, he was admitted to
hospital because of acute respiratory failure. Subsequent
examination of bronchoalveolar lavage (BAL) led to the
diagnosis of PCP, and a computed tomography (CT) scan
showed diffuse, bilateral, interstitial disease with “ground
glass” parenchyma and thickening of the interlobular septa.
Molecular, cultural and cytological investigations of the
BAL failed to identify any other pathogen. Transbronchial
biopsy was not performed. High-dose cotrimoxazole was
started in combination with methylprednisolone. A bone
marrow aspirate revealed signs of an initial leukemic relapse
that was treated with weekly vincristine and daily
C. Annaloro (*) . A. Della Volpe . P. Usardi .
G. Lambertenghi Deliliers
Ematologia I e Centro Trapianti di Midollo, Fondazione
Ospedale Maggiore and Università degli Studi di Milano,
Via Francesco Sforza 35,
20122 Milan, Italy
e-mail: c.annaloro@policlinico.mi.it
Tel.: +39-02-55033335
Fax: +39-02-55033341
oral 6-mercaptopurine, which led to a stable bone marrow
blast count and the maintenance of normal peripheral
hematometry.
During cotrimoxazole treatment, the CT findings improved
significantly but did not normalize, and the drug
was discontinued after 2 weeks because of patient refusal.
On 7 October, the patient was discharged for personal
reasons, and he continued taking oral cotrimoxazole at a
daily dose of 3,840 mg. Two weeks later, a further CT scan
showed persistence of significant lung infiltrates.
On 11 November, when the patient was admitted to
undergo BMT, a positron emission tomography (PET) scan
revealed the presence of diffuse, active, alveolar disease
(Fig. 1) and high-dose intravenous cotrimoxazole was
resumed. On 22 November, standard-dose caspofungin
(70 mg on the first day, followed by 50 mg/day) was added,
and a conditioning regimen was started including thiotepa
(15 mg/kg divided into three equal doses on days −8
and −7), and cyclophosphamide (50 mg/kg/day on days −4,
−3 and −2). A bone marrow aspirate showed a raised but
stable blast count. On 29 November, the CT findings were
unchanged, and cotrimoxazole was discontinued. On 30
November, BMT was performed, with standard-dose cyclosporine-A
and methotrexate being administered as graftversus-host
disease prophylaxis. During pancytopenia,
mixed Enterobacter/coagulase-negative Staphylococcus
bacteremia was observed. Polymorphonuclear recovery
was achieved on post-BMT day 25, and platelet recovery on
day 34, after being delayed by mild microangiopathic
hemolytic anemia responsive to defibrotide therapy. On
22 December, a CT scan showed complete resolution of
the lung infiltrates. On 5 January, caspofungin was discontinued
and a bone marrow aspirate showed complete
remission and full donor chimerism. On 12 January the
patient was discharged. One month later, the leukemia
relapsed; a CT scan did not show any lung infiltrates.
A diagnosis of PCP is frequently established in BMT
recipients, in whom immunodepression may play a primary
role, and also in hematological patients receiving chemotherapy
alone [1]. In such cases, cotrimoxazole may
interfere with the possibility of delivering the subsequent

53
Fig. 1 Positron emission tomography
scan showing persistence
of active lung disease
scheduled chemotherapeutic regimens or, as in this case,
with a planned BMT. Moreover, the widespread use of
cotrimoxazole as PCP prophylaxis, and the growing recognition
of further categories of patients in whom prophylaxis
may be indicated, are expected to increase the
incidence of cotrimoxazole resistance, even though this is
far from clear [2–4, 6].
It cannot be concluded that our patient had cotrimoxazole-resistant
PCP because the initial full-dose treatment
had only been delivered for 2 weeks before being tapered,
rather than the usually recommended 3 weeks [7]. Nevertheless,
high-dose cotrimoxazole was resumed for 2 further
weeks without achieving complete CT resolution. The
negative results of the BAL investigations rule out the
possibility that a second undiagnosed baseline infection
may have influenced the clinical and imaging evolution
of the disease; however, transbronchial biopsy was not
performed because of the risks involved with leukemic
patients. It could be argued that the drug actually cured the
PCP, and that the ensuing course was complicated by a
radiographically indistinguishable, undiagnosed fungal infection
responsive to caspofungin; however, this conflicts
with the clinical course and the continuity of the CT imaging
findings. It is also unlikely that the CT scans simply
showed the slow radiographic resolution of PCP in an
already cured patient because the relationship between CT
abnormalities and active disease was confirmed by PET.
Moreover, the patient had to be considered at high risk of a
PCP relapse since he was undergoing the severe combined
myelo- and immunosuppression required in cases of BMT
from an unrelated donor. Under these conditions, some
form of anti-PCP treatment was unavoidable and cotrimoxazole
was contraindicated because of its myelotoxicity
and possible ineffectiveness.
In addition to occasional cases of cotrimoxazole hypersensitivity,
the above considerations underline the need for
a reliable alternative to cotrimoxazole. Conventional second-line
treatments such as pentamidine or clindamycin/
primaquine are well established in clinical practice, but
their toxicities make them poorly suitable for patients
undergoing high-dose chemotherapy; atovaquone is a
promising alternative drug, but it has not yet been widely
used in PCP treatment, at least in hematological patients
[5, 8].
Caspofungin, the first available agent of the new antifungal
class of echinocandins, has been widely used to
treat systemic fungal infections and, in this setting, is
characterized by a favorable toxicity profile [9]. It is also
effective in animal PCP models [10, 11]. On the basis of
our experience, caspofungin deserves consideration as a
potential alternative in PCP patients who cannot be administered
cotrimoxazole; patients awaiting further, aggressive
cytotoxic treatment seem to represent a subset for
whom caspofungin may be particularly suited.
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