Second-line therapy with caspofungin for mucosal or invasive candidiasis: results from the caspofungin compassionate-use study

Nicholas A. Kartsonis*, Alfred Saah, C. Joy Lipka, Arlene Taylor and Carole A. Sable

Merck Research Laboratories, West Point, PA, USA

Received 28 August 2003; returned 21 January 2004; revised 30 January 2004; accepted 10 February 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: To prospectively assess the efficacy and safety of caspofungin as second-line therapy for mucosal or invasive candidiasis in patients enrolled in the caspofungin compassionate-use study.

Materials and methods: Thirty-seven patients with mucosal or invasive candida infections (17 oesophageal, four oropharyngeal and 16 invasive candidiasis) were enrolled in the caspofungin compassionate-use study. All patients were refractory to or intolerant of intravenous amphotericin B or lipid amphotericin formulation(s). Efficacy was assessed at the end of intravenous caspofungin therapy based on clinical (and, where appropriate, microbiological) response.

Results: HIV was the most common (91%) risk factor in patients with mucosal candidiasis; patients with invasive candidiasis commonly had acute leukaemia/lymphoma (50%) or diabetes mellitus (31%). Most patients with mucosal candidiasis (91%) and invasive candidiasis (94%) were refractory to >=1 antifungal agent(s). A favourable response was noted in 82% (14/17) with oesophageal candidiasis, 100% (4/4) with oropharyngeal candidiasis and 87% (13/15) with invasive candidiasis. Caspofungin was generally well tolerated; one serious drug-related adverse event was reported.

Conclusion: In this study, caspofungin was an effective alternative for patients with refractory candida infections.

Keywords: Candida, echinocandins, novel antifungal treatment


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
For many years, amphotericin B has served as the mainstay for the treatment of serious candida infections.1 However, infusion-related toxicity, nephrotoxicity and electrolyte disturbances have traditionally limited its use.1,2 Recently, fluconazole has played a predominant role in the treatment of mucosal candidiasis and candidaemia.2 However, non-albicans candida, accounting for approximately half the cases of candidaemia worldwide, are relatively less susceptible to fluconazole.3

A medical need remains for novel agents in the treatment of candidiasis. Caspofungin, a parenteral echinocandin, manifests fungicidal activity against candida.4,5 Comparator-controlled trials demonstrate caspofungin to be an effective first-line agent for oesophageal and invasive candidiasis;69 however, less is known about its role in patients failing traditional antifungal regimens. We present results from a compassionate-use study, wherein 37 patients with candida infections received caspofungin as second-line therapy.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population

The caspofungin compassionate-use study, a worldwide patient-named trial, was conducted before its licensure. Patients with a documented candida infection were eligible provided they had no other mechanism to receive caspofungin.

Inclusion in the study necessitated that adult patients, between 18 and 80 years, have mucosal (oesophageal or oropharyngeal) or invasive candidiasis. Patients with oesophageal/oropharyngeal candidiasis had clinical symptoms accompanied by either a positive culture for candida or histopathological evidence of candida infection from the site of infection (endoscopic biopsy/brushing or oral swab). Patients with invasive candidiasis had at least one culture for candida from blood or another invasive site accompanied by fever/hypothermia, hypotension, or inflammatory signs from a candida-infected site. All patients were either refractory to or intolerant of an intravenous (iv) amphotericin formulation (amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid-complex, or amphotericin B colloidal-dispersion). Refractory was defined as clinical or microbiological progression of disease or lack of improvement despite at least 7 days of prior amphotericin therapy. Intolerance included patients who developed a serum creatinine >=2.5 mg/dL or systemic intolerance while receiving amphotericin. Written, informed consent was obtained from all patients or their families.

Study design

The compassionate-use study was conducted as a non-comparative, open-label, multicentre trial. Patients with oesophageal and/or oropharyngeal candidiasis were treated with caspofungin 50 mg/day. Patients diagnosed with invasive candidiasis received caspofungin 50 mg/day, following a 70 mg loading dose. Treatment duration was individualized based on the patient’s clinical/microbiological response. In general, patients with mucosal candidiasis were treated for a minimum of 7 days and at least 72 h following the resolution of symptoms/signs. Conversely, patients with invasive candidiasis were treated until resolution of clinical findings and at least 14 days after the last positive culture for candida.

Efficacy and safety evaluations

The primary assessment of response was carried out in each patient by the investigator at the end of caspofungin therapy. For patients with oesophageal candidiasis, a favourable response required the absence or significant reduction of clinical symptoms; follow-up endoscopy was encouraged, but not required, to document clearance. In patients with oropharyngeal candidiasis, a favourable response required the absence of oropharyngeal symptoms and a normal follow-up oropharyngeal exam. A favourable response for patients with invasive candidiasis required resolution/significant improvement of signs/symptoms, resolution/significant improvement of radiographic evidence of disease, and negative follow-up cultures.

For all candida infections, a favourable response included either ‘complete response’ or ‘partial response’. Such distinction was determined by the investigator based on the extent of the signs/symptoms of disease, radiographic evidence, or culture results at the end of caspofungin therapy. Unfavourable response included all patients not fulfilling the definition of a favourable response.

The safety of caspofungin was evaluated by determining the presence of adverse events. Serious clinical and laboratory adverse events and selected non-serious adverse events (including all drug-related adverse events) were reported. All patients receiving one dose of caspofungin were evaluated for safety. Although patients were monitored 14 days post-therapy to evaluate for toxicity, efficacy assessments were not collected at this later time-point.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Baseline characteristics

The trial was conducted between September 1999 and September 2002. Thirty-two investigators from seven countries (USA, Belgium, Italy, Greece, Switzerland, Sweden and Luxembourg) enrolled a total of 37 patients, including 21 with mucosal infections (17 oesophageal, four oropharyngeal) and 16 with various invasive candida infections.

All but two (91%) of the 21 patients with oesophageal/oropharyngeal candidiasis had HIV disease as the underlying risk factor. Eleven (65%) of the 17 patients with a primary diagnosis of oesophageal candidiasis also had thrush on oropharyngeal examination. The sites of invasive candidiasis were diverse; most patients had a non-blood site (63%) or multiple sites of infection (25%). Four patients had chronic disseminated candidiasis.

Enrolment reason

Nineteen (91%) of the 21 patients with mucosal candidiasis were refractory to prior antifungal therapy. Fourteen had failed multiple prior antifungal agents (including 13 refractory to both polyenes and triazoles). Eleven (58%) of the 19 refractory patients had disease progression on the prior regimen(s); the remainder showed no meaningful improvement during prior therapy.

Similarly, 15 (94%) of the 16 patients with invasive candidiasis were refractory to at least one antifungal agent. Twelve had failed multiple antifungal agents (including 11 refractory to both polyenes and triazoles). Eleven (73%) of the 15 refractory patients demonstrated progression of their invasive infection before receiving caspofungin.

Therapy duration

Caspofungin was administered for a mean duration of 31.4 days (range 7–101 days). Overall, 14 (38%) of the 37 patients received greater than 28 days of caspofungin. The duration of caspofungin therapy in patients with mucosal candidiasis (mean 32.0, range 7–101 days) and patients with invasive candidiasis (mean 30.6 days, range 9–57 days) was similar.

Efficacy

Successful outcomes were noted with caspofungin in 86% of the patients with mucosal candidiasis, including 14 (82%) of 17 with oesophageal candidiasis and all four with oropharyngeal candidiasis. The outcomes were consistent across all underlying factors (Table 1). Notably, 13 (93%) of the 14 patients who were refractory to multiple prior antifungals responded favourably. Interestingly, 10 of the 11 patients who had previously failed fluconazole responded favourably to caspofungin.


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Table 1. Efficacy in patients with mucosal (oesophageal/oropharyngeal) candidiasis
 
Favourable responses were demonstrated in 13 (87%) of the 15 patients with invasive candidiasis. Responses were consistent across all sites of infection (Table 2). Two of three patients with chronic disseminated candidiasis manifested symptomatic and radiographic improvement during caspofungin therapy; another patient with candidaemia and chronic disseminated candidiasis at study entry had complete resolution of all findings. Eighty-three percent of patients failing multiple antifungals responded favourably, including nine (90%) of 10 fluconazole-refractory patients and nine (82%) of 11 amphotericin-refractory patients.


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Table 2. Efficacy in patients with invasive candidiasis
 
Mortality

Six (16%) patients, including three each with mucosal and invasive candidiasis, died during the study. The three patients with mucosal candidiasis died in the follow-up period from either opportunistic infections or complications of their underlying disease. All three deaths in the invasive candidiasis cohort occurred while on caspofungin; each was related to non-fungal, infectious complications. None of the deaths was attributed to either the candida infection or caspofungin.

Safety

Among all patients, one (3%) serious drug-related adverse event was reported; this patient with pre-existing HIV-related thrombocytopenia developed a further decrement in platelet count during caspofungin therapy, ultimately leading to its discontinuation. This represented the only patient who discontinued caspofungin therapy as a result of toxicity. Three other patients (8%) developed non-serious adverse events: phlebitis, increased serum AST, and headache/pruritis in one patient each.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Before its licensure, we initiated this compassionate-use study to provide caspofungin to patients who warranted alternative antifungal therapy but could not receive the echinocandin through alternate means. Although several comparator-controlled studies have confirmed the efficacy of caspofungin as first-line treatment in oesophageal and invasive candidiasis,69 this study represents, to our knowledge, the first prospective trial employing an echinocandin as salvage therapy for candidiasis. Despite its compassionate-use nature, study inclusion required microbiologically- or histopathologically-confirmed cases of oesophageal, oropharyngeal, or invasive candidiasis, as defined in recent consensus guidelines.10 Patients also satisfied standardized definitions of refractoriness or intolerance to standard antifungal therapy.

Although the study mandated patients were refractory to an iv amphotericin preparation, the majority were refractory to both polyenes and azoles (either as sequential or combination therapy). Caspofungin was highly effective in the treatment of all infections, with favourable responses noted in >85% of the patients with either mucosal or invasive candidiasis. For both diseases, the outcomes remained consistent across a number of independent variables, including underlying disease, neutropenic status, enrolment reason and candida pathogen. Additionally, caspofungin was generally well tolerated with a low incidence of toxicity. The favourable safety findings are consistent with results obtained in comparator-controlled studies involving caspofungin.69

Notably, the outcomes with caspofungin were not predicated on the type of prior antifungal therapy. Fundamentally, this finding is consistent with the known differences in the mechanism of action between the echinocandins, which target the fungal cell wall, and the azoles and polyenes, which target the cell membrane.2,4,5 However, the susceptibility patterns of the candida isolates in this study were not routinely evaluated; therefore, it is impossible to ascertain whether the lack of activity of prior regimens was due to azole- or polyene-resistant strains or other clinically relevant host factors.

In summary, the experience from this study lends further support for the efficacy and safety of caspofungin in patients with mucosal or invasive candidiasis. Although the number of patients was limited, the results indicate that caspofungin is an effective, well-tolerated alternative for difficult-to-treat candida infections.


    Acknowledgements
 
We wish to acknowledge the following investigators who enrolled patients with candida infections in this study: Belgium—R. Colebunders (University Hospital Antwerp, Edegem), P. Damas (Centre Hospitalier Universitaire de Liège, Liège), C. Doyen (Cliniques Universitaires de Mont, Yvoir), F. Jacobs (Hôpital Université Erasme, Brussels); Greece—J. Christakis (Anticancer Hospital of Thessaloniki, Thessaloniki), G.L. Petrikkos (Laiko General Hospital, Athens); Luxembourg—J. Schmit (Centre Hospitalier de Luxembourg, Luxembourg); Italy—R. Fanin (University of Udine, Udine), A. Lazzarin (Osperdale San Rafaele, Milano), L. Pagano (Policlinico Gemelli, Roma), S. Sollima (Osperdale Luigi Sacco, Milano), C. Tascini (Cisanello Hospital, Pisa); Sweden—P. Anderson (Sahlgrenska University Hospital, Sahlgrenska); Switzerland—B.J. Hirschel (Hôpital Cantonal Universitaire, Geneva); USA—B. Alexander (Duke University Medical Center, Durham, NC), M. Antalek (Kaleida Suburban Hospital, Snyder, NY), R. Betts (The University of Rochester School of Medicine and Dentistry, Rochester, NY), S. Brown (Bronx VA Medical Center, Bronx, NY), J. Feinberg (University of Cincinnati Medical Center, Cincinnati, OH), P. Frame (University of Cincinnati Medical Center, Cincinnati, OH), G. Gonzalez (VA Medical Center, San Juan, PR), M. Gottlieb (Beer Medical Group, Los Angeles, CA), J.R. Graybill (University of Texas Health Science Center, San Antonio, TX), M.C. Hosseinipour (The University of North Carolina at Chapel Hill, Chapel Hill, NC), V. Jimenez (VA Medical Center, Northport, NY), J.I. Jones (private practice, New York, NY), D.H. Loughran (Doylestown Hospital, Doylestown, PA), H.G. Morse (Anderson Area Medical Center, Anderson, SC), K. Murphy (Sierra Infectious Diseases, Reno, NV), T. Musgrave (Pikeville Methodist Hospital, Pikeville, KY), J. Perfect (Duke University Medical Center, Durham, NC), W. Webster (Christ Hospital, Cincinnati, OH). Financial support for this study was made available by Merck Research Laboratories, Merck & Co., Inc. All listed authors are employees of Merck Research Laboratories.


    Footnotes
 
* Corresponding author. Tel: +1-484-344-7301; E-mail: nicholas_kartsonis{at}merck.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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