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Antimicrobial Agents and Chemotherapy, December 2004, p. 4808-4812, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4808-4812.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Liposomal Nystatin in Patients with Invasive Aspergillosis Refractory to or Intolerant of Amphotericin B

Fritz Offner,¹ Vladimir Krcmery,² Marc Boogaerts,³ Chantal Doyen,⁴ Dan Engelhard,⁵ Patricia Ribaud,⁶ Catherine Cordonnier,⁷ Ben de Pauw,⁸ Simon Durrant,⁹ Jean-Pierre Marie,¹⁰ Philippe Moreau,¹¹ Harry Guiot,¹² George Samonis,¹³ Richard Sylvester,¹⁴ Raoul Herbrecht,^15* and the EORTC Invasive Fungal Infections Group

UZ Gent, Ghent,¹ UZ Gasthuisberg, Leuven,³ Clinique Universitaire Mont Godinne, Yvoir,⁴ EORTC Data Center, Brussels, Belgium,¹⁴ St. Elisabeth Cancer Institute, Bratislava, Slovakia,² Hadassah University Hospital, Jerusalem, Israel,⁵ Hôpital Saint Louis,⁶ Hotel-Dieu, Paris,¹⁰ Hôpital Henri Mondor, Créteil,⁷ CHR Hotel-Dieu, Nantes,¹¹ Hôpital de Hautepierre, Strasbourg, France,¹⁵ University Medical Centre, Nijmegen,⁸ Leiden University Medical Center, Leiden, The Netherlands,¹² Royal Brisbane Hospital, Brisbane, Australia,⁹ University General Hospital, Heraklion, Greece,¹³

Received 31 December 2003/ Returned for modification 12 February 2004/ Accepted 25 June 2004

Top Abstract Introduction Materials and Methods Results Discussion References

 
We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Mold infections continue to be an important cause of death for patients with leukemia, allogeneic hematopoietic stem cell transplantation, and advanced stages of malignancy. The mortality rate of invasive aspergillosis (IA) ranges from 40 to 90% depending on the degree of underlying immune suppression and the institution of early therapy (5, 16).

Until the recent approval of voriconazole, standard treatment of IA consisted of intravenous amphotericin B given at doses of at least 1 mg/kg of body weight/day (11, 24). Amphotericin B is associated with considerable toxicity and frequent treatment failure, particularly in the case of advanced disease and prolonged neutropenia. The liposomal formulation of amphotericin B has allowed the administration of more than fivefold doses of the drug with considerable improvement in the safety profile (15, 25).

The liposomal encapsulation technique can, however, be extended to other antifungal agents that were previously excluded for treatment of systemic fungal infections due to the lack of a well-tolerated intravenous formulation. Nystatin is a naturally occurring product of Streptomyces noursei that has been used as a topical fungicidal drug since the 1950s. It is active against Candida, Cryptococcus, Histoplasma, Blastomyces, and Aspergillus spp. and has a spectrum of antifungal activity similar to that of amphotericin B (1, 4, 13, 22).

Early attempts at free drug administration resulted in dose-limiting toxicity. Recent studies have demonstrated that nystatin can be incorporated into liposomes with significant reductions in toxicity while preserving antifungal activity (4, 8, 10, 13, 18, 19, 22).

This approach has resulted in extensive animal testing, with good results in short- and long-term toxicity studies with healthy rodents and dogs (9, 19). Efficacy has been shown for experimental infections including aspergillosis: liposomal nystatin at doses of 2 and 4 mg/kg/day, but not at 1 mg/kg/day, prolonged survival for neutropenic rabbits and reduced tissue fungal burden (8). In an experimental murine aspergillosis study, liposomal nystatin at a dose of 5 mg/kg given four times within the first week of infection was as effective as liposomal amphotericin B and more effective than amphotericin B deoxycholate and amphotericin B lipid complex (7). Clinical studies are very limited and have not yet been published. They include a phase I maximal-tolerated-dose study, a compassionate-use study, and phase II and III trials for candidemia, for empirical therapy of persistent febrile neutropenia, and for cryptococcal meningitis (2, 14, 20). Doses used in clinical trials ranged from 2 to 4 mg/kg for empirical therapy of persistent febrile neutropenia and for candidemia (23, 26). To test the activity and safety of liposomal nystatin in documented or probable IA, the European Organisation for Research and Treatment of Cancer (EORTC) Invasive Fungal Infections Group undertook a clinical phase II study of liposomal nystatin for patients who had previously been treated with amphotericin B and found to be resistant or intolerant.

(This work was presented in part at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 17 to 21 September 2000.)

Top Abstract Introduction Materials and Methods Results Discussion References

 
The study is an open-label, noncomparative, multicenter salvage study to evaluate the safety and activity of liposomal nystatin for IA. Patients were enrolled between February 1997 and January 1999. The protocol was approved by the appropriate institutional review boards, and written informed consent was obtained from all patients or their parents or legal guardians.

Patient population. Patients aged 6 years or older were included if they were shown to have definite or probable Aspergillus infections, had either failed to respond to or were intolerant of conventional amphotericin B and/or a lipid formulation of amphotericin, and required continued antifungal therapy. Reasons for noninclusion were evidence of hepatic function impairment (baseline bilirubin level of 4 mg/dl or higher or baseline transaminase levels more than 5 times the upper limit of the normal value), severe renal dysfunction (4.5 mg of creatinine/dl or on dialysis), life expectancy of less than 14 days due to underlying disease, or pregnancy or lactation.

Definitions. In the absence of consensus definition criteria at the time the study was designed, the following criteria, which later proved to be close to the EORTC/MSG criteria published in 2002 (3), were used. Definite aspergillosis was defined as tissue histopathology showing septate acute branching hyphae with a positive culture for an Aspergillus sp. from the same site or, in the absence of histopathology, a positive culture from tissue obtained by an invasive procedure, such as transbronchial biopsy or percutaneous needle aspiration, from a consolidated tissue or closed body fluid.

Probable aspergillosis was defined in the context of neutropenia (<500 neutrophils/µl), administration of cytotoxic agents for a malignant or immunologic disease, a corticosteroid dosage of more than 10 mg of prednisone or the equivalent daily, or a congenital or acquired immunodeficiency. Patients with these preexisting conditions had probable aspergillosis if either of the following radiological signs was demonstrated in the presence of clinical signs and symptoms: (i) for pulmonary infection, chest radiography or computed tomography (CT) scan showing new nodular or cavitary lesions, in addition to two sputum cultures or one bronchoalveolar lavage (BAL) or brushing culture testing positive for Aspergillus species or cytologic examination of BAL fluid showing characteristic septate hyphae; (ii) for central nervous system infection, CT scan or magnetic resonance imaging demonstrating symptomatic lesions compatible with a previous diagnosis of definite aspergillosis elsewhere.

Patients were considered refractory to conventional treatment if they had received the equivalent of at least 5 days of amphotericin B (0.8 mg/kg/day), amphotericin B lipid complex (5 mg/kg/day), liposomal amphotericin B (3 mg/kg/day), or amphotericin B colloidal dispersion (3 mg/kg/day) and nevertheless showed no improvement upon radiographic assessment and/or showed persistence of fever (38.3°C) in the absence of any other cause.

Patients were considered intolerant of amphotericin B if they developed or had preexisting nephrotoxicity, indicated by a serum creatinine level of 2.5 mg/dl (>1.5 mg/dl for pediatric patients), or if they developed severe infusion-related adverse events not controlled by premedication.

Antifungal therapy. Liposomal nystatin was provided by Aronex Pharmaceuticals, Inc. (The Woodlands, Tex.). Patients were started on a 4-mg/kg/day dose of liposomal nystatin. Liposomal nystatin was reconstituted with saline to produce a 1-mg/ml solution and was delivered at an infusion rate of 2 mg/min once daily. For patients with preexisting renal impairment (baseline creatinine level, 2.5 mg/dl), the initial dosage level was 2 mg/kg/day.

The option to increase the daily dose to 6 mg/kg after at least 5 days of therapy at the initial dosage, or to decrease to 2 mg/kg, was left to the investigator's clinical assessment of response and tolerance. Patients continued treatment until failure or to a maximum of 40 days.

The initial dose was given without any premedication. In case of infusion-related side effects, the infusion of liposomal nystatin was temporarily interrupted and administration of paracetamol or meperidine was allowed. If shivering did not subside, the use of chlorpheniramine or steroids was left to the discretion of the investigator. Hypotension was treated with intravenous fluid replacement.

Systemic use of additional antifungal agents for treatment of aspergillosis or another fungal infection disqualified patients from this study.

Follow-up and evaluation. Patients were followed up clinically on a daily basis. Routine laboratory tests, creatinine clearance, and chest X rays were performed on the day of inclusion, days 3 and 5, and weekly thereafter. Safety was assessed by using modified National Cancer Institute (NCI) Common Toxicity Criteria.

Activity was assessed at the end of treatment, and survival was evaluated up to 1 month later. Case report forms and imaging were collectively reviewed by the two coordinators of the study and two site investigators in order to reach a consensus on eligibility and response evaluation. Response evaluation was as follows: complete response was defined as the resolution of all attributable symptoms and clinical and radiographic signs; partial response was defined as an improvement in attributable symptoms and clinical signs and a decrease of at least 50% in radiographic signs; a patient was considered to have stable disease if, at the end of the study, he or she was alive and had only minor or no improvement; failure was defined as deterioration in attributable clinical and/or radiographic abnormalities.

Statistical methods. The main end point in this trial was the response rate. A two-stage Simon design was followed such that if the true underlying response rate with liposomal nystatin was 20% or more, the probability of rejecting the drug for further study should be 0.05 (ß = 0.05), whereas if the true underlying response rate was 5%, the probability of rejecting the drug for further study should be 80% ( = 0.20).

Under these assumptions, 16 patients were initially entered into the study. If at least 1 success was observed among these 16, an additional 17 patients would be entered, for a total of 33. The drug could be rejected as being inactive if two or fewer responses were observed and should be considered of potential interest if three or more responses were observed.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Patient eligibility and evaluability. Thirty-three patients were entered into the study and received at least one dose of therapy. All were evaluated for drug toxicity. Of these, 26 (78.8%) were eligible. Reasons for ineligibility were absence of immune deficiency for two patients and insufficient mycological or radiological documentation for five patients. The characteristics of the 26 eligible patients with respect to age, sex, underlying condition, neutropenia, and Apache II score at inclusion are summarized in Table 1. One patient committed suicide on day 2 of therapy and was therefore excluded from activity and survival assessments. Therefore, 25 patients were finally evaluable.

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TABLE 1. Baseline demographics and characteristics of the 26 eligible patients

Infectious episode and response to amphotericin B. Table 2 shows the characteristics of infections at inclusion. Infection was localized to the lungs in a majority of patients (23 of 26). Infection was disseminated to at least two noncontiguous organs in the other three patients. Of 26 eligible patients, 23 met the criteria of probable IA and 3 had definite IA. Two patients were put on liposomal nystatin because they were intolerant of amphotericin B, one on the basis of renal insufficiency and the other on the basis of uncontrolled side effects at infusion. The majority of patients (24 of 26) were switched to liposomal nystatin because of disease progression under amphotericin B treatment. Of these, 21 showed repeat positive cultures and all had radiographic deterioration. The median duration of previous amphotericin B treatment was 16.5 days.

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TABLE 2. Characteristics of invasive aspergillosis at initiation of liposomal nystatin for the 26 eligible patients

Course of therapy for eligible patients and outcome. Liposomal nystatin was given for a median treatment duration of 22 days (range, 1 to 48 days). The median daily dose was 4 mg/kg (range, 1.5 to 5 mg/kg).

Among the 25 evaluable patients, 1 achieved a complete response. He was a 67-year-old man with colorectal cancer who was on a ventilator for pulmonary failure secondary to anaerobic sepsis following a colostomy. He developed fungal pneumonia, with cultures of the tracheal aspirate positive for both Aspergillus fumigatus and Aspergillus flavus. He received 70 mg of amphotericin B/day for 14 days while on dialysis and was switched to liposomal nystatin because of absence of clinical and radiological improvement and persistent positive cultures. He became asymptomatic and totally cleared CT scan abnormalities. There were six partial remissions and four patients with stable disease, three of whom progressed after discontinuation of liposomal nystatin. Fourteen patients failed despite 1 to 48 days of treatment. Thus, the overall favorable response rate was 7 of 25 (28%; 95% confidence interval, 12 to 49%).

Two patients underwent a lobectomy after achieving a partial response, one because of hemoptysis and one at the discretion of the investigator. Both remained disease free at 1 month posttreatment.

Treatment responses for the 25 evaluable patients with respect to definite or probable IA and intolerance or refractoriness to amphotericin B are shown in Table 3.

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TABLE 3. Responses of 25 evaluable patients to liposomal nystatin according to the degree of certainty and the reason for inclusion

Tolerance. Immediate toxicity was evaluated for 33 patients by using modified NCI Common Toxicity Criteria as shown in Table 4.

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TABLE 4. Adverse events reported for the 33 enrolled patients

Liposomal nystatin was initiated at a 4-mg/kg/day dose for all patients, but for three patients the dose was reduced to 2 mg/kg after 1, 2, and 5 days, respectively, because of mild renal impairment, and for one of these, the drug was discontinued. Twenty-two (67%) patients experienced at least one infusion-related adverse event. Infusion side effects included chills for 21 patients, shivering for 6, fever for 7, nausea for 3, and vomiting for 3. Hypertension during infusion was observed for one patient. Two patients experienced mild hypotension, and six had tachycardia. Severe dyspnea was observed for three patients. Side effects were usually controlled by holding the infusion. Premedication with paracetamol or antihistamines was given to 18 patients prior to each infusion thereafter, steroids were given to 3 patients, and meperidine was given for chills to another 3 patients.

For two patients, infusion-related toxicity was the reason for discontinuation of drug treatment; one experienced severe shivering, chills, and hypertension on the first infusion, and the other decided to discontinue in the middle of the second infusion because of respiratory distress and chills.

Non-infusion-related side effects included a decline in renal function for 10 patients (all with grade 1 toxicity), electrolyte disturbances (hypokalemia for 13 patients [8 with grade 1 and 5 with grade 2 toxicity] and grade 1 hypocalcemia for 4), liver toxicity for 8 patients (6 with grade 1 and 2 with grade 2 toxicity), and diarrhea for 4 patients. Arrhythmias were not noted in this study; neither were influences on glucose or fat metabolism. Hematological toxicity was not observed for 15 patients starting with normal blood counts. For the other patients, anemia, neutropenia, and thrombocytopenia were present at the start of treatment and were not noticeably influenced by liposomal nystatin. In a population with underlying hematological malignancies that are not in remission, any drug for refractory Aspergillus infection is difficult to score for hematological toxicity.

Survival and causes of death. Of the 25 eligible patients, 17 died and 8 remained alive at the end of treatment. All eight patients who were alive at the end of treatment remained alive 1 month thereafter. For nine patients the primary cause of death was IA, while eight patients died of underlying malignancy in spite of improvement of the fungal infection.

Top Abstract Introduction Materials and Methods Results Discussion References

 
This is the first published clinical trial of liposomal nystatin. Our study was designed to evaluate the potential of this new formulation of nystatin for further study in the treatment of IA. Because at least 1 response was observed among the first 16 patients, a total of 33 patients were included according to the design of this two-stage study. At least three responses had to be recorded in this trial in order to conclude that the drug was of potential interest. This criterion was fully satisfied, with seven complete or partial responses. As a consequence, further evaluation of liposomal nystatin in IA is warranted.

The severity of fungal disease in our patients needs to be stressed. All patients but two were refractory to previous conventional amphotericin B therapy and/or a lipid formulation of amphotericin B. Although patients could be included after only 5 days of amphotericin B therapy according to the design of the study, the median duration of previous therapy was much longer. This long duration and the high median cumulative dose of amphotericin B that was given prior to inclusion suggest true refractoriness and not an early and inappropriate conclusion of failure. In addition, the median Apache II score of 21 also confirms the severity of the underlying condition and/or of the fungal infection.

Interestingly, all 7 responses occurred in the subgroup of 23 patients refractory to previous amphotericin B therapy, leading to a 30.4% favorable response rate in this population of patients with severe disease. Only a few studies on salvage therapy with recently developed antifungal drugs have been specifically devoted to IA. The response rate for patients failing previous therapy is not always precisely indicated. The response rate we observed in this population is in the range of previously published results for caspofungin (39.4% in a group of 71 refractory patients), voriconazole (37.5% of 56 patients refractory to or intolerant of previous therapy), liposomal amphotericin B (45.5% of 11 patients in a single-center study), and a colloidal dispersion of amphotericin B (29.2% of 48 patients included in five phase I/II studies) (6, 12, 17, 21).

Infusion-related events, including chills, shivering, fever, hypo- or hypertension, and tachycardia are, as for amphotericin B, the most common adverse events during liposomal nystatin therapy. They remained mild or moderate in all but three cases. Liposomal nystatin was associated with nephrotoxicity, although limited in severity, in 10 patients. The investigator believed it was appropriate to reduce the daily dosage to 2 mg/kg in three cases. Hypokalemia was more common but never severe and did not limit the dose or duration of therapy. Anemia, thrombocytopenia, and leukopenia, including grade 3 and 4 toxicity, were frequently reported, but the relationship with the study drug cannot be ascertained, because all the patients affected by these events suffered from hematological malignancies and had abnormal blood cell counts at baseline. Such hematological adverse events are more likely due to the underlying condition than to the antifungal therapy.

This study demonstrates that liposomal nystatin at a daily dose of 4 mg/kg can be effective for salvage therapy of invasive aspergillosis. However, its administration is associated with frequent infusion-related adverse events and mild renal toxicity, which would, in the context of other currently available drugs, reduce its level of utility in the antifungal armamentarium.

 
Patients were treated in a clinical study sponsored by Aronex Pharmaceuticals, Inc.

We thank Ann Marinus and Stéphane Lejeune for assistance in analyzing the data and preparing the manuscript.

Members of the EORTC Invasive Fungal Infections Group are as follows: Liliana Baila (coordinating physician), Hamdi Akan, Mickael Aoun, Sibel Ascioglu, Daniel Benhammou, Zwi Berneman, Hartmut Bertz, Jacques Bille, J. Magnus Bjorkholm, Igor Wolfgang Blau, Angelika Boehme, Aida Botelho de Sousa, Patrick Boutard, Stephane Bretagne, Denis Caillot, Thierry Calandra, Bernadeta Ceglarek, Francois Chapuis, Jose Miguel Cisneros, Alain Cometta, Oliver Cornely, Robrecht de Bock, Siem de Marie, David W. Denning, Anna Dmoszynska, Peter Donnelly, C. Duhamel, Hermann Einsele, Michael Ellis, Zoran Erjavec, Peter Ernst, Edgar Faber, Bertrand Gachot, Jorge Garbino, E. Gautier, Mareva Giacchino, Raffaella Giacchino, Axel Glasmacher, Renee Grillot, Andrease Groll, Jan Haber, Petr Hamal, Ian Hann, Ulrich Jehn, Elizabeth Johnson, Alain Kentos, Winfried Kern, Chris C. Kibbler, Paul Kotoucek, Bart Jan Kullberg, Jean-Paul Latge, Bernadette Lebeau, Jean-Claude Legrand, R. Lindblad, Per Ljungman, Olivier Lortholary, Johan Maertens, Rodrigo Martino, Georg Maschmeyer, Jacques Meis, Francoise Meunier, Mauricette Michallet, Marco Montillo, Frank Michael Mueller, D. Nemet, Nicole Nolard-Tintigner, Karoly Pecze, George Petrikkos, Ray L. Powles, Elisabeth Presterl, C. Rayon, Jorg Ritter, Tom Rogers, Emmanuel Roilides, Montserrat Rovira, Markus Ruhnke, Stefan Schwartz, Dominique Selleslag, David G. Spence, Anne Thiebaut, Eckhard Thiel, Jan Tollemar, Janez Tomazic, Andrew J. Ullmann, Omrum Uzun, Catalina Vadell-Nadal, Bernard Vandercam, Paul Verweij, Claudio Viscoli, and Marianna Viviani.

 
* Corresponding author. Mailing address: Département d'Hématologie et d'Oncologie, Hôpital de Hautepierre, 67098 Strasbourg, France. Phone: 33 388 12 76 88. Fax: 33 388 12 76 81. E-mail: raoul.herbrecht{at}chru-strasbourg.fr.

Participants in the EORTC Invasive Fungal Infections Group are listed in Acknowledgments.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, December 2004, p. 4808-4812, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4808-4812.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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