Echinocandins for Pneumocystis jirovecii pneumonia in non‑HIV patients: A case report
- Authors:
- Published online on: August 7, 2018 https://doi.org/10.3892/etm.2018.6587
- Pages: 3227-3232
Abstract
Introduction
As an opportunistic infection, Pneumocystis jirovecii pneumonia (PJP) is a severe and life-threatening complication experienced by immunocompromised patients (1). With the advent of highly active antiretroviral therapy and prophylaxis strategies, the incidence of PJP has decreased markedly among patients with human immunodeficiency virus (HIV), with a mortality rate <10% (2). By contrast, non-HIV patients with PJP are characterized by advanced age, increased comorbidities, non-classical clinical symptoms, rapid deterioration and poor prognosis (3–7). Once acute respiratory failure (ARF) develops, non-HIV patients with PJP most likely require intensive care and ventilatory support and have a mortality rate of up to 75.6% (5). Despite the aforementioned differences, treatment regimens remain the same for HIV and non-HIV patients with PJP; for example, the administration of trimethoprim/sulfamethoxazole (TMP-SMZ) as the first-line drug, then an adjunctive steroid (standard dosage) for severe ARF, followed by the second-line drug (8–15). Therefore, other treatment options need to be investigated.
Due to the ability to inhibit the synthesis of β-1, 3-glucan, a major component of the cell wall of P. jirovecii, echinocandins could be used in the treatment of PJP (15–20). During the past two decades, the prophylactic and therapeutic efficacies of echinocandins have been investigated in animal models and clinical studies (21,22). A cohort study demonstrated a high success rate (8/10) with caspofungin salvage treatment in HIV-patients with PJP; however, data regarding the treatment of PJP with echinocandins in non-HIV patients remain limited and controversial (15,20).
The current report described two HIV-negative cases of PJP in which echinocandins were used for salvage treatment at the Medical Intensive Care Unit, Peking Union Medical College Hospital (Beijing, China). Both patients provided written informed consent. A review of previous reports involving the use of echinocandins for the treatment of PJP in non-HIV patients was also conducted.
Case report
Case 1
A 71-year-old male presented to the Emergency Department of the Peking Union Medical College Hospital (Beijing, China) in October 2017 with a 1-week history of fever, non-productive cough and progressive dyspnea. The patient had been diagnosed with IgG4-related disease 5 months prior to admission. Prednisone (Shandong Luoxin Pharmaceutical Group Stock Co., Ltd., Linyi, China) was administered and the dosage was gradually reduced to 20 mg/day after achieving remission. The patient also had chronic renal failure with regular dialysis treatment. Examination at the emergency room disclosed severe hypoxemia; chest computed tomography (CT) exhibited diffuse bilateral ground-glass opacities (GGO) of lung fields with pleural effusion (Fig. 1A). The patient was transferred to the medical intensive care unit (MICU) for noninvasive positive pressure ventilation and continuous renal replacement therapy. Based on the radiographic findings, the patient was empirically treated with TMP-SMZ (15 mg/kg/day TMP; Shandong Xinhua Pharmaceutical Co., Ltd., Zibo, China) along with methylprednisolone (40 mg, twice daily; Pfizer, Inc., New York, NY, USA) for PJP, and moxifloxacin (400 mg/day; Bayer AG, Leverkusen, Germany) for possible infections with atypical pathogens. The patient's symptoms did not improve and required increased respiratory support. Therefore, a regimen of clindamycin (600 mg/12 h; Hubei Shishun Biotechnology Co., Ltd., Hubei, China) and primaquine (30 mg/day; Shanghai Zhongxi Pharmaceutical Co., Ltd., Shanghai, China) was initiated as salvage therapy on day 4 of the ICU stay, the day PJP was confirmed by positive PJ DNA and Gomorimethenamine silver staining in the bronchoalveolar lavage (BAL) specimen. Despite this treatment, the patient's condition further deteriorated and a repeated chest high-resolution CT scan revealed aggravation of the bilateral diffuse GGO combined with consolidation. Caspofungin (Merck & Co., Inc., Whitehouse Station, NJ, USA) was administered at 70 mg on day 8 in the ICU, followed by 50 mg daily. Treatment with moxifloxacin was discontinued on the same day due to no evidence of atypical pathogens. The patient's respiratory condition improved markedly and respiratory support was gradually decreased following treatment with caspofungin. The patient was weaned off non-invasive positive pressure ventilation on day 19 in the ICU. A chest high-resolution CT demonstrated that the majority of the patches were absorbed and the pulmonary infiltrations were reduced after 14 days of treatment with caspofungin (Fig. 1B). The patient was transferred to the general ward on after 22 days in the ICU and eventually recovered, and was discharged on day 54.
Case 2
A 68-year-old female with systemic lupus erythematosus (SLE) was admitted to the Department of Rheumatology of the Peking Union Medical College Hospital due to lupus disease activity in August 2017. Prior to admission, the patient was treated with methylprednisolone for nearly 3 months due to hemolytic anemia associated SLE. During this hospitalization period, the patient received methylprednisolone 0 mg/12 h; Pfizer, Inc.) in addition to cyclophosphamide (4 mg/kg/day; Sinopharm Shantou Jinshi Pharmaceutical Co., Ltd., Shantou, China). On day 11 after admission, the patient developed a fever of 38.5°C and shortness of breath. A chest CT exhibited diffuse bilateral GGO (Fig. 1C). Polymerase chain reaction (PCR) revealed that P. jirovecii was detected within induced sputum. Treatment with TMP-SMZ was initiated (15 mg/kg/day TMP component, Shandong Xinhua Pharmaceutical Co., Ltd.). Administration of immunosuppressive agents to the patient was discontinued. Despite this treatment, the patient remained febrile and exhibited increasing dyspnea requiring a reservoir face mask. Given the severity of the condition, the patient was transferred to the MICU to start high-flow nasal cannula (HFNC) oxygen therapy (flow of 60 l/min and 60% FiO2) on day 16; caspofungin (Merck & Co., Inc.) was administered as salvage therapy at a loading dose of 70 mg, followed by a maintenance dose of 50 mg daily. After 4 days of treatment with caspofungin, fever alleviated, respiratory conditions improved and the HFNC was replaced by conventional nasal prongs. The patient was transferred to the ICU ward on day 7. A follow-up chest CT scan demonstrated a partially normal appearance of the lung fields (Fig. 1D).
Quantitative polymerase chain reaction (qPCR)
DNA was extracted using a commercial kit (QIAamp DNA Mini kit; Qiagen GmbH, Hilden, Germany) following the manufacturers protocol, but with elution using 30 µl Tris-EDTA buffer solution (Beijing Leagene Biotech Co., Ltd., Beijing, China). Purified DNA was then used as a template to amplify the part of the mitochondrial gene, which encodes the large subunit of rRNA. PCR was performed using the following primers: pAZ102-E forward, 5′-GATGGCTGTTTCCAAGCCCA-3′ and reverse, 5′-GTGTACGTTGCAAAGTACTC-3′. Albumin forward, 5′-TGGTGAAATGGCTGACTGCT-3′ and reverse, 5′-CTCTGGTCTCACCAATCGGG-3′. PCR was performed with a total reaction volume of 20 µl, comprising: Template DNA 2 µl (10–100 ng), 0.4 µM of forward primer 0.4 µl, 0.4 Μm of reverse primer 0.4 µl, ddH2O 6.8 µl and the SYBR Green Mix (2×) 10 µl (SYBRGreen qPCR Master Mix, MedChemExpress USA, Monmouth Junction, NJ, USA). The thermocycling conditions were as follows: Pre-amplification denaturation at 95°C for 5 min; 40 cycles of 95°C for 15 sec, 60°C for 30 sec The relative amount of gene expression was normalized using Albumin and was calculated using the 2−ΔΔCq formula as previously described (23). PCR mixtures were prepared in a laminar-flow cabinet and several controls were implemented. All amplifications were performed in parallel with a negative control (ultrapure distilled water) and a positive control (BAL samples of patients with definite Pneumocystis pneumonia).
Gomorimethenamine silver staining
Slides were prepared using cytocentrifugation (13,800 × g, 15 min, 4°C), cut to a thickness of 2–3 µm and microwaved in a 10% chromic acid (Hubei XinRunde Chemical Co., Ltd., Hubei, China) solution at 65°C for 40 sec. Samples were then washed with water and cleared using 1% sodium metabisulfite for 30 sec. After the slides were washed with distilled water, they were placed in a Coplin jar containing 50 ml of methenamine working solution and microwaved at 65°C for a further 65 sec. The slides were rinsed again with distilled water and treated with 1% gold chloride for 2–5 sec. Following further rinsing with distilled water, samples were exposed to 5% sodium thiosulfate for 1 min, counterstained with a light green working solution (Beijing Leagene Biotech Co., Ltd.) and cleared using xylene. Samples were then covered with cover slips and examined using routine light microscopy at a magnification of ×70.
Through a literature review, the present study identified 22 HIV-negative patients with PJP treated with echinocandins (8–20). The demographic and clinical characteristics of these cases, and the two patients included in the present study, are summarized in Table I. Among these patients, the mean age was 49.8 years. Underlying conditions varied between the included cases, with solid organ transplant most commonly reported (11/24; 45.8%). Only three patients were given primary prophylaxis. All enrolled cases exhibited concurrent bilateral pulmonary infiltrations and were clinically treated for pneumonia. P. jirovecii was the predominant pathogen that was confirmed by methenamine silver staining or PCR. Of all patients, 8 and 16 were treated with echinocandins as initial and salvage regimens, respectively, and the mean duration of treatment with echinocandins was 19 days. All included patients but one (11) were treated with caspofungin at 70 mg on the first day with a maintenance dose of 50 mg/day. Associations between the type of echinocandin treatment strategy, adjunctive corticosteroids and the underlying disease are described in Table II.
![]() | Table I.Clinical characteristics of the reported cases of echinocandins use for Pneumocystis jirovecii pneumonia in patients. |
Discussion
The present study described two successful cases of treatment with echinocandins for non-HIV patients with PJP. In addition to the two cases in the present study, 24 non-HIV PJP cases treated with echinocandins were identified in the literature (8–20). This revealed that, although a rationale exists for the use of echinocandins in the treatment of PJP, the current clinical use appears to be low. Potential reasons for this may include that fact that the use of echinocandins to treat PJP has only appeared in recent years, the lack of convincing efficacy data and that the use of echinocandins for PJP treatment is currently off-label (11,19,20).
The present study analyzed the application strategy of caspofungin in non-HIV patients with PJP. The results reported in previous studies suggested that echinocandins were most frequently considered as a salvage regimen (16/24), with a mortality rate of 31.5% (5/16 patients) (8–9,11,13–16,19,20). As of yet, no sufficient data for the outcome of echinocandins as a salvage regimen in non-HIV patients with PJP have been reported. In fact, for HIV patients who fail to respond to initial treatment, several traditional salvage regimens have shown high therapeutic effectiveness, including the combination of clindamycin and primaquine [42-44/48 (88–92%)] or atovaquone [4/5 (80%)] (24). However, regarding non-HIV patients with PJP, the data of these traditional salvage regimens is limited. In a previous study, clindamycin-primaquine or pentamidine were used as salvage regimens following treatment failure of the first-line regimen in 12 non-HIV patients with PJP and the mortality rate was 66.7% (8/12) (25). Therefore, the present results indicated that use of echinocandins(caspofungin starting with a loading dosage of 70 mg followed by 50 mg/day) as salvage therapy resulted in favorable and comparative rates of mortality in non-HIV patients compared with previous salvage regimens; however a statistical comparison was not possible. This suggests that an echinocandin-based salvage regimen maybe an option for the treatment of PJP in non-HIV patients.
There were 8 cases from previously published studies that used an echinocandin-based regimen for the initial treatment (10–12,16–18,20) and exhibited a good response with survival rates of 87.5%. When only the 6/8 cases that used the combination regimen of echinocandins and TMP-SMZ were considered, an excellent response was observed as all 6 patients had survived the infection. When the cases that used the combined regimen of echinocandins and TMP-SMZ in salvage therapy were also included, the mortality rate was 13.3% (2/15). These results appeared to favor the combination of echinocandins and TMP-SMZ.
The combined regimen of echinocandins and TMP-SMZ has been associated with high effectiveness in clearing the invading P. jirovecii (26). P. jirovecii is a fungus that exists in either trophic or cyst forms (trophic/cyst 9:1) (27). The primary component of the cyst cell wall is β-1, 3-glucan, which is poorly expressed in the trophic forms. Therefore, echinocandins mainly act on cyst forms by inhibiting the β-1, 3-glucan synthaseenzyme and disturbing the integrity of the cell wall (21,22). Previous experiments suggested that the use of caspofungin alone was associated with a 90% decrease in cyst forms after 4 days and a 66% reduction in trophic forms after 21 days of treatment. Furthermore, in an animal model of PJP, the administration of low doses of caspofungin with TMP-SMX may provide an improved clearance of Pneumocystis infection (28). On the other hand, echinocandins exhibit reduced activity against the trophic forms of P. jirovecii and the use of echinocandin alone may not completely eradicate the infection. Therefore, the co-administration of echinocandins and TMP/SMZ, which is primarily active against trophic forms, may exert synergistic activity against P. jirovecii by fully inhibiting the life cycle of the organism. However, clinical data regarding this combined therapy regimen were confined to case reports only (13,16,25).
In conclusion, positive clinical effects of echinocandins were observed in the present study, which suggested that the addition of echinocandins to TMP/SMZ was active against trophic forms and may demonstrate activity against P. jirovecii by inhibiting the organism's life cycle. However, the present analysis was based exclusively on case reports. It is possible that patients with favorable outcomes from the use of echinocandins may have been selectively reported in these case reports. Therefore, a large sample, well-designed randomized trials, particularly in the use of echinocandins combined with TMP-SMZ for the treatment of PJP are warranted to verify these results.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
HBH, JMP and BD contributed to the conception, design and data interpretation. All authors read and approved the manuscript.
Ethics approval and consent to participate
Patients provided written informed consent to participate.
Patient consent for publication
Consent for publication was obtained from the patients.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
ARF |
acute respiratory failure |
CT |
computed tomography |
GGO |
ground-glass opacity |
HFNC |
high flow nasal cannula |
HIV |
human immunodeficiency virus |
MICU |
medical intensive care unit |
PJP |
Pneumocystis jirovecii pneumonia |
SLE |
systemic lupus erythematosus |
TMP-SMZ |
trimethoprim/sulfamethoxazole |
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