Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study

M. Winkler, J. Pratschke, U. Schulz, S. Zheng, M. Zhang, W. Li, M. Lu, D. Sgarabotto, G. Sganga, P. Kaskel, S. Chandwani, L. Ma, J. Petrovic, M. Shivaprakash. Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study. Transpl Infect Dis 2010: 12: 230–237. All rights reserved Objective This study was designed to determine clinical outcomes with caspofungin in patients with proven or probable invasive fungal infection (IFI) after a solid organ transplant (SOT) procedure. Methods In this retrospective observational study, data were collected for a single episode of IFI in patients with an SOT between January 2004 and June 2007. Response was determined by the investigator as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT). The primary effectiveness population was the proportion of patients who received ≥5 doses of caspofungin (modified all-patients-treated population). Safety was assessed for patients who received ≥1 dose of caspofungin. Results A total 81 of patients from 13 sites in China, Germany, Italy, and the United Kingdom were enrolled, including 49 (60%) liver, 22 (27%) heart, 5 (6%) lung, 2 (2%) kidney, 2 (2%) liver and kidney, and 1 (1%) pancreas and kidney recipients. Candidiasis was diagnosed in 64/81 patients (79%) and aspergillosis in 22/81 patients (27%). Most patients received caspofungin monotherapy (75%). Caspofungin was given as first-line therapy to 59 (73%) patients. The overall favorable response at EOCT was 87% (58/67; 95% confidence interval [CI]: 76%, 94%), with favorable responses in 88% (43/49; 95% CI: 75%, 95%) of patients receiving caspofungin monotherapy and 83% (15/18; 95% CI: 59%, 96%) of patients receiving combination therapy with caspofungin (modified all-patients-treated population). Response by type of SOT was as follows: liver 87% (39/45), heart 93% (14/15), kidney 100% (5/5), and lung 50% (2/4). An overall survival rate (all-patients-treated) of 69% (56/81; 95% CI: 59%, 79%) was observed at 7 days post EOCT. No serious drug-related adverse events were reported. Conclusion In this study, caspofungin was effective and well tolerated in the treatment of IFIs involving SOT recipients.

Fungal infections are a common cause of morbidity and mortality in solid organ transplant (SOT) recipients. The reported incidence of fungal infections ranges from 4^42% in liver transplant recipients (1) and from 15^35% in lung transplant recipients (2). Candida species are the most common pathogens, accounting for approximately 43^80% of fungal infections following liver (1,3), heart (4), and lung transplantation (5). Aspergillus species have been isolated from approximately 9^34% of patients with invasive fungal infection (IFI) after liver transplantation (6) and 20^50% after lung transplantation (5^7 ). Increased mortality rates (20^90%) have been reported among SOT recipients su¡ering from IFIs compared with SOT patients with no IFI (6,8,9).
Risk factors for Candida infection include a high intraoperative transfusion requirement as well as post-transplant bacterial infection (1). Renal failure and the need for dialysis have been described as risk factors for early-onset Aspergillus infection; risk factors in patients with late-onset infections (43 months after transplantation) included age, intensi¢ed immunosuppression due to factors such as chronic transplant rejection, and post-transplant renal failure (10).While optimizing treatment of IFI in SOT patients may decrease attributable mortality (6,11), limited data are available from randomized clinical trials regarding which treatments are most e¡ective for SOT patients with IFI (12). Current therapeutic options for invasive fungal disease include echinocandins, polyenes, and azoles (13^16).
Caspofungin is an echinocandin approved for treating adult and pediatric patients with invasive candidiasis, as empirical therapy in presumed fungal infections including Candida or Aspergillus in febrile, neutropenic adult patients, and for treatment of invasive aspergillosis in adults who are refractory or intolerant to other antifungal agents. It is metabolized independently of cytochrome 450 and may therefore have fewer interactions with calcineurin inhibitors (CNIs) such as cyclosporine or tacrolimus (17^19). This retrospective observational study evaluated the e¡ectiveness and safety of caspofungin as treatment for invasive fungal disease in patients who had received an SOT.

Patients and methods
This retrospective, multicenter observational study was designed to evaluate clinical and safety outcomes in patients with proven or probable invasive fungal disease treated with caspofungin following a SOT. The study was performed at 13 transplant centers in China (n 5 3), Germany (n 5 5), Italy (n 5 4), and the United Kingdom (n 5 1). Central and local regulatory and Independent Ethics Committee approvals were obtained as required by each site or country.
Patients who received an SOT between January 2004 and January 2007 and had received caspofungin following SOT for treatment of a proven or probable IFI were eligible for inclusion. EORTC-MSG criteria were used as a guide to assess whether IFI cases were proven or probable (20). Charts were reviewed between July 2007 and December 2007. If multiple transplant procedures took place, the procedure closest in time to the onset of post-transplant IFI was considered. Patients who participated in Merck-sponsored clinical studies for IFI during the hospitalization were excluded. As this was a retrospective observational study, no medication was provided to sites. Caspofungin was admin-istered according to clinician's judgment and local diagnostic and treatment pathways.

E¡ectiveness and safety assessments
Data for consecutive patient cases meeting the eligibility criteria were entered at each site into this observational study. Internet-based electronic case report forms were used to collect patient data. Demographic characteristics, medical history, caspofungin dosing regimen, other antifungal drugs received, co-administered immunosuppressive agents, and dose and duration of therapy were recorded. Information was collected on co-morbidities and predisposing risk factors, i.e., active malignancy, renal failure requiring dialysis, primary graft non-function, retransplantation, exposure to 43 antibiotics, recent use of central venous catheter, current steroid dose (i.e., during this hospitalization), current monoclonal antibody use for immunosuppression (i.e., during this hospitalization), hyperglycemia, neutropenia (absolute neutrophil count o500 cells/mL), recent parenteral nutrition (hyperalimentation), United Network for Organ Sharing (UNOS) Class 1 (i.e., patients with a life expectancy of o7 days without a liver transplant and with fulminant [sudden] liver failure, or with newly transplanted liver not functioning, respectively [21]) clinical urgency of transplantation, pretransplantation fungal colonization, cytomegalovirus (CMV) infection, long duration of transplant procedure (45 h), biliary construction using Roux loop, re-operation (laparatomy) within 5 days after transplantation, need for substantial ( 40 U) intraoperative transfusions, hepatic iron overload, thrombocytopenia, fulminant hepatic failure, recent intensive care unit (ICU) stay (i.e., during this hospitalization), and ambient/community-acquired exposure (i.e., before hospitalization). Data on type of SOT, site of IFI following transplantation, mycology, and severity of illness measures were also collected.
According to the pre-speci¢ed analysis plan, the primary e¡ectiveness population was based on a modi¢ed all-patients-treated population, which included all patients who received 5 doses of caspofungin for treatment of IFI. Mycological information, if available, was collected via chart review and included site of fungal infection, type of fungal infection, diagnostic tests used to identify fungal species, and diagnosis of the infection. As part of the chart review, no post hoc veri¢cation of mycological tests and no resistance tests were performed. The chart review involved taking data as available in the charts.
Safety was assessed for the all-patients-treated population, which was de¢ned as any patient who received at least 1 dose of caspofungin. A summary of the number and percentage of patients who had at least 1 drug-related adverse event leading to early discontinuation of caspofungin or death was produced by collecting drug-related clinical and laboratory adverse events, drug^drug interactions, and discontinuations or deaths associated with drug-related adverse events. Drug-related events referred to those events considered by the investigator as possibly, probably, or de¢nitely related to caspofungin therapy. All outcomes were determined based on the judgment of the investigator.

De¢nitions of response
The primary endpoint was the proportion of patients who received 5 doses of caspofungin and had a favorable response to treatment. Treatment response was determined by the investigator as favorable (complete or partial) at the end of caspofungin therapy (EOCT), or unfavorable (stable disease or disease progression) at EOCT. In addition, survival was assessed at hospital discharge.
Complete response was de¢ned as resolution of all attributable clinical and radiological signs and symptoms of invasive mycosis at EOCT; partial response was de¢ned as a substantial reduction of attributable clinical and radiological pre-treatment signs and symptoms of invasive mycosis at EOCT; stable disease was de¢ned as minimal or no reduction of attributable clinical and radiological signs and symptoms of invasive mycosis at EOCT; and failure was de¢ned as worsening of signs and symptoms of invasive mycosis at EOCT. Response was determined based on the treating physician's clinical judgment. Minimal observation period was 7 days after EOCT.

Statistical analysis
Patient characteristics, patient risk factors for invasive fungal disease, indication for caspofungin therapy, immunosuppressive therapy at onset of caspofungin therapy, and proportion of favorable response by pathogen were assessed overall, and by type of therapy (caspofungin monotherapy and caspofungin combination therapy, respectively) using descriptive statistics.

Risk factors and immunosuppression
Patients had a median of 8 risk factors for IFI at initiation of caspofungin therapy (

Prior or adjuvant antifungal therapy
All patients were treated with caspofungin either as ¢rstline (n 5 59) or second-line (n 5 22) therapy. At the discretion of the treating physician, and based on local diagnostic and treatment pathways only, caspofungin was given as monotherapy to 61 patients; the remaining 20 patients received concomitant therapy with other antifungal agents.
Before initiation of caspofungin, 30 patients had been treated with other antifungals. Of these, 10 had received  Table 4).

Safety
In the all-patients-treated population, 25/81 (30.9%) patients had died at the end of observation, i.e., hospital dis-Immunosuppressive therapy at onset of caspofungin therapy

Discussion
Invasive fungal disease has become an important cause of death in SOT recipients, particularly following lung or liver transplantation. Amphotericin B was the only drug available for these patients for years, thus amphotericin B and its lipid formulations were often used to treat these patients despite the risk of hepatic failure (22) and renal impairment (23), which can be exacerbated when combined with CNIs (6). SOT recipients may in fact be excluded from large trials because of the potential confounding complications of mandatory immunosuppressive therapy. Drug interactions with CNIs are a major issue in transplant patients. The advent of newer agents such as the echinocandins may represent a therapeutic opportunity. Caspofungin is not associated with major drug-to-drug interactions involving the cyto-chrome 450 metabolism of CNIs (18). This factor was important in the present study, where 9 patients were switched to caspofungin from another antifungal agent owing to drug interactions with immunosuppressive therapy. Most patients who were e¡ectively managed with caspofungin received concomitant immunosuppressive agents. These results are particularly relevant because current published data on caspofungin in SOT patients have been mostly in the form of anecdotal case reports (24^26), reports on small patient groups (27 ), and salvage studies (19). In our study, Candida was the most common cause of fungal infection. Sites of infection were comparable to those reported in other studies (1,9).We found a relatively higher number of Candida and Aspergillus mixed infections compared with the literature (6), although Fujishita et al. (28) reported 3 hematooncological cases of pulmonary mycosis due to mixed Candida and Aspergillus infection in 32 patients (9.4%). One possible explanation for the higher number of mixed infections is that many studies focus on either Aspergillus or Candida species while our study evaluated all eligible SOT recipients.
Caspofungin was e¡ective as ¢rst-and second-line therapy in this group of patients with a favorable response rate of 87% in SOT recipients with proven or probable IFI. It was noteworthy that 89% of patients with proven or probable invasive Candida infection and 74% of patients with proven or probable Aspergillus infection responded to caspofungin treatment, similar to results reporting that caspofungin was an e¡ective treatment in invasive aspergillosis after SOT (29). Prophylaxis for spontaneous bacterial peritonitis, fulminant hepatitis, retransplantation, dialysis, and CMV viremia have been identi¢ed as risk factors for invasive Candida infection in liver transplant recipients (30). Favorable response rates in our patients presenting these 5 risk factors were between 62.5% (retransplantation) and 85.7% (exposure to 43 antibiotics).
The overall mortality observed (31% at 7 days post EOCT) was relatively high. This is most likely because the patients included in this study were severely ill. The 24 patients with APACHE II score data had a median score of 23, where a score of 420 is often used to indicate high severity  of illness. Also, a large majority of patients received immunosuppressive therapy. The mean duration of transplant operation of 7 h indicates more di⁄cult operative procedures. This study had several inherent limitations. As a retrospective observational study, there was no comparator arm. Also, because of potential confounding due to imbalances of prognostic factors, no conclusions should be drawn regarding the outcome of caspofungin monotherapy relative to the outcome of caspofungin combination therapy. Results may have been a¡ected by the relatively low number of patients in some categories, and there was a relatively brief follow-up period after the EOCT.
Nevertheless, in this retrospective observational study, the clinical response rate of patients treated with caspofungin for IFI after SOTwas comparable to rates shown in randomized trials in non-SOT patients.