Successful treatment of severe Pneumocystis pneumonia in an immunosuppressed patient using caspofungin combined with clindamycin: a case report and literature review
Li et al. BMC Pulmonary Medicine
Successful treatment of severe Pneumocystis pneumonia in an immunosuppressed patient using caspofungin combined with clindamycin: a case report and literature review
Hongjuan Li 1
Haoming Huang 2
Hangyong He 0
0 Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University , Beijing 100020 , China
1 Department of Emergency, Guangdong Hospital of Traditional Chinese Medicine , Guangzhou, Guangdong 510105 , China
2 Department of Emergency, Guangzhou University of Traditional Chinese Medicine First Affiliated Hospital , Guangzhou, Guangdong 510405 , China
Background: Pneumocystis jirovecii is responsible for Pneumocystis pneumonia (PCP), which occurs almost exclusively in immunocompromised individuals. Trimethoprim-sulfamethoxazole (TMP-SMZ) is regarded as the first-line treatment and prophylaxis for P. jirovecii infection, but the frequency of adverse reactions and newly emerged antibiotic resistance limit its use. Case presentation: Ulcerations and hemorrhages involving the tongue were noted secondary to TMP-SMZ desensitization against PCP in a 46-year-old male who had previously been diagnosed with IgA nephropathy and sustained prolonged corticosteroid therapy. There was an urgent need for an alternative regimen due to the severe response to TMP-SMZ. The patient was successfully treated with a combination therapy of caspofungin and clindamycin. Conclusion: Caspofungin combined with clindamycin is an optional treatment for PCP when treatment with TMP-SMZ fails or in patients who cannot tolerate TMP-SMZ.
Pneumocystis pneumonia; Caspofungin; Clindamycin
Pneumocystis pneumonia (PCP) is an opportunistic
infection caused by Pneumocystis jirovecii, which mainly
occurs when cellular immunity is depressed because of
AIDS, malignancies, prolonged corticosteroid therapy, or
organ transplantation. Recent research has indicated that
underlying renal dysfunction and chronic renal pathology
are risk factors for PCP in patients with IgA nephropathy
. The PCP mortality rate is high among patients with
delayed diagnosis and treatment, and death is due to
severe respiratory failure [2, 3].
The first-line medication of treatment and prophylaxis
for P. jirovecii infection is trimethoprim-sulfamethoxazole
(TMP-SMZ) ; however, use of TMP-SMZ could be
problematic in patients with adverse reactions and drug
resistance. Caspofungin-based therapy has been shown to
be effective against Pneumocystis in animal models of PCP
[5–7]; however, the clinical experience with caspofungin
in human PCP are limited and controversial. Herein, we
report a case involving salvage therapy with caspofungin
and clindamycin in the successful management of an
immunosuppressed PCP patient who was allergic to
A 46-year-old male had been diagnosed with IgA
nephropathy based on renal biopsy 3 months before admission. A
concurrent diagnosis of chronic kidney dysfunction was
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established. He was treated with cyclophosphamide and
high-dose methylprednisolone, followed by
methylprednisolone (40 mg orally per day) for maintenance. He also had
hypertension, diabetes mellitus, gout, and leukoderma. He
was shown to be allergic to TMP-SMZ when treated for a
respiratory infection some years before. The allergic
reaction manifested as ulcerations involving the tongue and
genitalia, which resolved gradually with discontinuation of
The patient had a fever of 38 °C and sought medical
care at a local clinic with complaints of fever, chills,
wheezing, and a productive cough. No significant findings
were noted on chest X-ray (Fig. 1), and the patient was
offered symptomatic treatment and discharged. He returned
to the local clinic one week later because of worsening
symptoms. Arterial blood gas analysis showed type I
respiratory failure. A thoracic computed tomography (CT)
scan reported bilateral lung infiltrates with ground-glass
attenuation (Fig. 2a). The temperature climbed to 40 °C
and the patient was then transferred to the respiratory
intensive care unit (RICU).
After transfer to the RICU (day 1), the patient received
non-invasive positive pressure ventilation (NIPPV) for
respiratory support with continuous positive airway
pressure at 4 cmH2O (FiO2 50 %), and high-flow nasal
cannula oxygen supplement (FiO2 50 %) between gaps.
Chest auscultation demonstrated bibasilar crepitation.
Fig. 1 Posteroanterior chest X-ray image one week before the
patient’s transfer to the respiratory intensive care unit (RICU). No
significant finding was observed on the X-ray image at this date
An arterial blood sample was acquired under NIPPV
support (FiO2 50 %), and blood gas analysis showed the
following: pH, 7.39; PaCO2, 36 mmHg; PaO2, 88 mmHg;
and A-a O2 gradient, 68 mmHg. The leukocyte count
was 12.2 × 109/L. The procalcitonin level was 22.09 ng/
ml. Other laboratory findings included the following:
serum urea nitrogen, 30.83 mmol/L; serum creatinine,
478.50 umol/L; potassium, 5.3 mmol/L; and lactic acid
dehydrogenase, 729 U/L. The serum 1,3-β-D-glucan
level was > 1000 pg/ml (beyond the testing range). The
CD4+ T-cell count was 46 cells/mm3. HIV was excluded
by real-time polymerase chain reaction (PCR) analysis.
Pneumocystis jirovecii was visualized under light
microscopy in both induced sputum and bronchoalveolar
lavage fluid (BALF) with Gomori methenamine silver
staining. Cytomegalovirus (CMV)-pp65 antigen and
CMV-DNA were positive in blood samples. Induced
sputum and BALF were collected for real-time PCR
analysis, yielding positive P. jirovecii DNA and
CMVDNA. A high-resolution CT (HRCT) scan on day 14
demonstrated aggravation of the bilateral lower lobe
consolidation (Fig. 2b).
Because of the low oxygen index (PaO2/FiO2 =
166 mmHg) and infiltrates, the patient was thought to
have developed moderate acute respiratory distress
syndrome (ARDS), and a 21-day adjunctive
corticosteroid therapy was initiated on day 1. Methylprednisolone
(80 mg IVggt qd) was administered for the first 5 days,
then tapered to 40 mg IVggt qd for another 5 days, and
20 mg po qd for 11 days more. Because the patient was
allergic to TMP-SMZ which is a first-line choice for
PCP, a TMP-SMZ desensitization protocol (0.12 g po
q6h for 2 days, 0.48 g q6h for 2 days, and 0.96 g q6h for
2 days) was instituted on day 2. Ulcers and hemorrhages
were observed on the left side of the tongue on day 7,
which was believed to be an adverse reaction to
TMPSMZ. Therefore, TMP-SMZ therapy was abandoned on
day 7, and was subsequently replaced by a 21-day
combination therapy of caspofungin (50 mg IVggt qd) and
clindamycin (0.3 g IVggt q6h) from days 8 to 28.
Ganciclovir was added to cover CMV infection. Other
pathogens, such as bacteria, could not be excluded in this
case, thus cefoperazone-sulbactam and moxifloxacin
were added empirically.
The patient’s condition gradually remitted and the
oxygen index improved. The patient was transferred
back to the general ward on day 33. The
1,3-β-D-glucan levels and absolute cell counts of T-cell subsets
were carefully monitored. The CD4+ T-cell count
decreased when TMP-SMZ was discontinued, but
gradually normalized, which was accompanied by a
decreasing 1,3-β-D-glucan level (Fig. 3). Pneumocystis
jirovecii was undetectable microscopically in induced
sputum on day 9. The PCR became negative for
Fig. 2 High resolution CT scans of the chest at the levels of aortic arch, root of ascending aorta and pulmonary arteries from left to
right, performed from top to down on days 1 (a: December 2015), 14 (b: December 2015), 20 (c: January 2016) and 90 (d: February
2016). Bilateral lung infiltrates with ground-glass attenuation (a). Bilateral infiltrates and dense consolidations aggravated (b). Minimal
absorption compared to day 14 (c). Dense consolidations were significantly absorbed (d)
sputum P. jirovecii and CMV-DNA on days 13 and 29,
respectively. On day 20, HRCT revealed that the upper
lobe infiltrates and dense consolidations in the lower
lobes were absorbed compared to the last scan
(Fig. 2c). A follow-up HRCT was arranged on day 90,
which showed significant absorption of the dense
consolidations (Fig. 2d). The symptoms were nearly
relieved by the time he was discharged, with the
exception of occasional coughing. Because the patient
restored his normal CD4+ T-cell count, secondary
prophylaxis for PCP was not needed.
Pneumocystis jirovecii (formerly Pneumocystis carinii)
was initially classified as a protozoan parasite, and
molecular and genetic evidence categorized P. jirovecii among the
fungi. Although Pneumocystis cannot be cultivated on
standard artificial media and the lifecycle of the organism is
unclear, Pneumocystis does share some biological
characteristics with protozoa. Indeed, two apparently distinctive
forms can be observed under microscope (trophic and
cystic forms) . Although trophic forms are predominant in
infected tissues, glucans are only found in cystic forms .
Fig. 3 Serial monitoring of 1,3-β-D-glucan levels and absolute cell counts of T-cell subsets. The CD4+ T-cell count decreased when TMP-SMZ was
discontinued, but gradually became normal (b), which was accompanied by a decreasing 1,3-β-D-glucan level (a). TMP-SMZ was stopped on day 7.
Green arrows indicate the initiation of caspofungin and clindamycin on day 8. Red arrows indicate the cessation of the antifungal treatment on day 28
Clinical manifestations, and laboratory and imaging
studies are not pathognomonic in PCP, thus a
heightened clinical suspicion should be maintained in patients
known to be HIV-infected and immunosuppressed.
HRCT may be valuable in assessing lung injury and the
severity of PCP [10, 11]. A definitive diagnosis of PCP
requires the detection of trophic and/or cystic forms of
P. jirovecii at direct microscopic examination of lower
respiratory tract samples, such as induced sputum, BALF
and lung biopsy specimens . With the development of
PCR technology, especially real-time PCR assays, the
detection of P. jirovecii DNA in respiratory samples has
become an essential part of the laboratory diagnosis of
PCP [4, 12]. Nevertheless, due to its high sensitivity,
PCR may allow detection of P. jirovecii in latent
infections without PCP, which decreases its specificity .
All polysaccharides of the fungal cell wall are different
from those produced by mammalian cells. Among them,
1,3-β-D-glucan is a reliable adjunctive diagnostic marker
for PCP, but not a prognosis predictor ; negative
results are useful to rule out PCP in HIV patients .
Nevertheless, Kamada et al.  reported an
HIVinfected patient with PCP and normal 1,3-β-D-glucan
levels throughout the course of infection, which might
reflect an early phase infection with limited lung injury.
Interpreting 1,3-β-D-glucan results among non-HIV
individuals should be done with care and in parallel with
other clinical findings . Furthermore, 1,3-β-D-glucan
could be elevated in other invasive fungal diseases and
may obscure the diagnosis.
In HIV-infected patients, PCP rarely occurs when the
CD4+ T-cell count is > 200 cells/mm3 . Moreover,
CD4+ T-cell counts are of concern when initiating and
discontinuing PCP prophylaxis in HIV-infected
individuals . Yet, consensus about CD4+ T-cell counts has
not been well-established towards PCP unrelated to
HIV. Nevertheless, non-HIV patients with CD4+ T-cell
counts < 200 cells/mm3 appear to be at increased risk for
developing PCP , thus it is reasonable to monitor
CD4+ T-cell counts in such patients.
TMP-SMZ, an antibiotic used to treat a variety of
infections, is the first-line drug for PCP prophylaxis and
treatment, but treatment failure may occur because of
dihydropteroate synthase and dihydrofolate reductase
mutations during the course of the treatment [19, 20].
Adverse effects of TMP-SMZ are also common, such as
fever, rash, nausea, vomiting, transaminase elevation,
and more serious toxicities, including neutropenia,
thrombocytopenia, Stevens-Johnson syndrome, and toxic
epidermal necrolysis . With mild adverse reactions,
TMP-SMZ should be continued with a gradual dose
increment (desensitization) or at a reduced dose or
frequency. TMP-SMZ therapy should be aborted in
patients with possible or definite life-threatening
Echinocandins are antifungal agents that
noncompetitively inhibit 1,3-β-D-glucan synthase . Thus,
echinocandins are toxic to fungi in which the glucans
play an important role in maintaining the integrity of
the fungal cell wall  and partly contribute to the host
inflammatory response in the lung . Caspofungin
used alone or with low-dose TMP-SMZ has been shown
to be efficient in treating PCP on experimental animal
PCP models [5, 6]. Unlike TMP-SMZ, which primarily
eliminates trophic forms of Pneumocystis, caspofungin
clears cystic forms which might play a key role in
transmission . Nevertheless, the clinical use of
echinocandins, such as caspofungin, against P. jirovecii infection is
still controversial. Utili et al.  reported 4 cases of solid
organ transplant recipients infected by PCP who were
treated by caspofungin and TMP-SMZ with favorable
outcomes. While Utili et al.  summarized 8 reported cases
involving echinocandin-containing regimens for PCP
before 2007, two lymphoblastic leukemia patients died in
spite of prolonged echinocandin treatment in addition to
other anti-Pneumocystis therapies. In a retrospective
analysis among 80 HIV-PCP patients, 10 of whom had
confirmed PCP microbiologically, received caspofungin-based
salvage therapies, and showed satisfactory outcomes, one
patient died with bilateral pneumothoraces .
Clindamycin combined with primaquine has activity
against P. jirovecii, although the mechanism is still
unclear. In protozoa, clindamycin targets protein
synthesis in a parasite-specific organelle (the apicoplast) ,
which is related to mitochondrial function and the
lifecycle of the organism. In addition, reduction of protein
and nucleic acid synthesis has been observed in
Plasmodium falciparum when exposed to clindamycin .
Primaquine could interfere with the microbial electron
transport system by generating quinone metabolites and
superoxides in vivo , which may prevent the
proliferation of P. jirovecii. A previous study by Queener et al.
 demonstrated a higher efficacy of clindamycin
combined with primaquine compared to the use of each
drug alone for treatment and prophylaxis of PCP in rat
models. Clindamycin/primaquine regimens, the clinical
efficacy of which have been proven by clinical trial ,
appear to have the highest efficacy among alternative
therapies for PCP  and are now used as second-line
therapy in PCP management .
A moderate-to-severe PCP infection is defined as a PaO2
< 70 mmHg at room air or an A-a O2 gradient ≥ 35 mmHg
. Because our patient’s blood gas analysis was tested
under NIPPV, the severity of PCP had to be evaluated with
all of the clinical findings. In the current case, this
middleaged man, who had undergone prolonged corticosteroid
therapy for an underlying IgA nephropathy, was diagnosed
with PCP and developed ARDS. The adjunctive
corticosteroid dose needed to be individualized to balance
antiinflammatory against immunosuppressed effects. Thus, we
began high-dose methylprednisolone tapering. The patient
failed desensitization to TMP-SMZ. Given that primaquine
is not routinely available in our hospital, alternative therapy
with caspofungin plus clindamycin was initiated. The only
report of concomitant use of caspofungin with clindamycin
for PCP involves a patient who did not respond to
combination therapy and the infection was eventually controlled
following TMP-SMZ desensitization . Our patient
showed an impressive response to the treatment and
Because the microscopic images of respiratory tract
specimens were not attached to the patient’s documents, we
have no way to determine how the trophic and cystic forms
changed during the course of treatment, but elevated
1,3-βD-glucan levels implied that cysts had been producing
glucans on which caspofungin might have an effect. The
efficacy of clindamycin could not be determined clearly in our
case. Given that clindamycin improves the outcome
together with primaquine, the efficacy with caspofungin may
warrant further investigation. Our patient showed a
concomitant CMV infection and received ganciclovir for the
treatment, while clinical study suggested that concomitant
CMV infection in non-HIV related PCP did not affect
prognosis and antiviral drugs might be unnecessary .
In summary, this new combination therapy of caspofungin
plus clindamycin in managing PCP may be considered in
patients who fail standard treatment. Monitoring
1,3-β-Dglucan is of more convenience than other forms of testing,
such as BALF, and may provide early diagnostic clues.
Based on our case and a review of the literature, we
suggest that highly elevated 1,3-β-D-glucan levels may be
a predictor of a satisfactory caspofungin response to PCP.
ARDS: Acute respiratory distress syndrome; BALF: Bronchoalveolar lavage fluid;
CMV: Cytomegalovirus; CT: Computed tomography; HRCT: High-resolution
computed tomography; NIPPV: Non-invasive positive pressure ventilation;
PCP: Pneumocystis pneumonia; PCR: Polymerase chain reaction; RICU: Respiratory
intensive care unit; TMP-SMZ: Trimethoprim-sulfamethoxazole
We are grateful to Prof. Junling Zuo from Guangzhou University of
Traditional Chinese Medicine for his instructions and inspiring guidance.
Availability of data and materials
All data supporting our findings is contained within the manuscript.
HL and HYH were the physicians involved in the follow-up of the patient.
HMH and HL were responsible for the initial manuscript writing. HYH revised
the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval to report this case was not required.
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