Miconazole Therapy for Treatment of Fungal Infections in Cancer Patients

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1 NTIMICROBIL GENTS ND CHEMOTHERPY, Dec. 1979, p ol. 16, No /79/12-792/6$2./ Miconazole Therapy for Treatment of Fungal Infections in Cancer Patients WILLIM M. JORDN, GERLD P. BODEY,t* ICTORIO RODRIGUEZ,t STEEN J. KETCHEL,4 ND JNE HENNEY Department of Deelopmental Therapeutics, Uniersity of Texas System Cancer Center, M. D. nderson Hospital and Tumor Institute, Houston, Texas 773 Receied for publication 13 September 1979 The effectieness of miconazole was ealuated in 37 documented fimgal infections, 32 of which were major infections. ll patients were receiing therapy for adanced malignancy, with 28 patients haing acute leukemia. The oerall cure rate was 41% and it was also 41% for major fungal infections. Nine of 22 patients with Candida albicans infections were cured, and 3 of 11 patients with Candida tropicalis infections were cured. total of 183 patients who receied miconazole for presumed or documented fungal infection were ealuated for toxicity. Nausea and omiting and central nerous system toxicity were the most common side effects, occurring in 25 and 16% of the patients, respectiely. Oerall, the drug was tolerated well, with only four patients requiring the drug to be permanently discontinued because of toxicity. Due to the improements in the treatment of malignancy, an increasing number of patients with cancer are achieing remissions and, ultimately, extended surial and cure (15). Unfortunately both the therapeutic regimens and the malignant process may often seerely compromise host defense mechanisms. The need for improed supportie care in the compromised host is well recognized. The opportunistic infections, including fungal infections, which occur in these patients, constitute a major problem. Often these patients fail to respond to appropriate antimicrobial therapy. This is especially true for patients with hematological malignancies who deelop major fungal infections (2). One of the frustrating problems in the management of fungal infections in cancer patients is the difficulty in establishing a diagnosis early in the course of the infection. The infecting organism is cultured from blood specimens from only 25% of patients with disseminated infections (2), and aailable diagnostic serological methods hae lacked consistent reliability (9). This has resulted in administering of antifungal treatment on presumptie clinical eidence. The treatment of fungal infections in cancer patients is often unsuccessful and associated t Present address: 1132 Nix Professional Building, San ntonio, TX i Present address: 164 North Country Club Road, Tucson, Z Present address: National Cancer Institute, Bethesda, MD 225. with excessie toxicity. mphotericin B, the most widely used systemic antifungal agent, is not uniformly effectie in the compromised host. In neutropenic patients with disseminated Candida infections there is, at most, a 25% response to amphotericin B, with response seldomly obsered unless there is recoery from myelosuppression (2). Higher responses to amphotericin B hae been reported in patients who deelop fungal infection as a postoperatie complication (5). The use of amphotericin B is frequently limited by its toxicity. In patients receiing chronic drug administration, azotemia has been reported in 8%, hypokalemia in 2%, and anemia in 8% (8). The use of other nephrotoxic agents for treatment of preceding or concomitant bacterial infection may further potentiate the nephrotoxicity of amphotericin B. Miconazole, a new imidazole antifungal agent, has a broad spectrum of actiity in itro against arious fungal organisms (1, 14). It has been used successfully with minimal toxicity in the therapy of disseminated coccidioidomycosis (11, 12), candidiasis (6) and Petriellidium boydii infections (7). In addition, miconazole has been used successfully in treatment of fungal meningitis (4, 13). Because of its actiity and minimal toxicity, we hae ealuated miconazole in patients with adanced malignancies. The study was designed to include all patients with presumed or proen fungal infection; howeer, only those patients with well-documented infections and Torulopsis gla- caused by Candida spp. brata were analyzed for response. 792 Downloaded from on June 16, 218 by guest

2 OL. 16, 1979 MICONZOLE FOR FUNGUS IN CNCER PTIENTS 793 MTERILS ND METHODS ll patients entered into this study had adanced malignant disease and were undergoing chemotherapy in the Department of Deelopmental Therapeutics at the Uniersity of Texas System Cancer Center, M. D. nderson Hospital and Tumor Institute. Patient characteristics are shown in Table 1. total of 183 patients with suspected or proen fungal infection were eligible for entry into the study. One hundred forty-six patients were inealuable either because of lack of strict documentation of fungal infection (122 patients), infections caused by fungi other than Candida spp. or T. glabrata (8 patients), or an inadequate trial of therapy (16 patients), defined as less than 5 days of miconazole therapy. The majority of patients with documented fungal infections had acute leukemia. The median age was 4. total of 37 documented fungal infections caused by Candida spp. or T. glabrata could be ealuated for response. Only patients with microbiologically or histologically proen fungal organisms or both were included, with no presumed infections being considered as ealuable. Fungal pneumonia was defined as clinical and radiographic eidence of pneumonia which failed to respond to antibacterial agents with recoery of a fungal isolate from pulmonary tissue or associated with other eidence of disseminated infection. Patients were not included if organisms were recoered by standard sputum or throat cultures only. Fungal esophagitis was diagnosed only after direct endoscopic biopsy or at autopsy. No diagnosis was made only on clinical findings or X-ray changes. The diagnosis of fungemia was considered to be established after the recoery of a fungal isolate from multiple blood culture or from a single blood culture plus eidence of tissue inasion. Patients were also considered to hae disseminated fungal infection if they deeloped characteristic skin lesions from which the organism was identified and cultured (3). Superficial skin infections were not included. The diagnosis of fungal infection from other sites was made on similar strict criteria either by antemortem or postmortem culture and histological examination. TBLE 1. Patient characteristics Patients registered... Patients inealuable... No documented fungal infection Inadequate trial (<5 days)... Fungi other than Candida or Torulopsis... Patients ealuable... Number of major fungal infections. Number of minor fungal infections. Median age in years (range)... Males/females... Primary malgnancy cute leukemia... Chronic leukemia... Lymphoma... Small cell lung... Gastric carcinoma... Soft tissue sarcoma (86%) 5 (14%) 4 (16-83) 2/ Major infections were considered to be present when fungi were cultured from an organ such as the lier, lung, kidney, or spleen, from the central nerous system, or from the blood or multiple skin sites, indicating disseminated disease (3). Esophagitis and joint infections were considered to be minor infections. Cure was defined as complete microbiological, histological, and clinical resolution of the infection. Miconazole was kindly proided for this study by Janssen R & D, Inc., New Brunswick, N.J. The drug was administered in doses ranging from 6 to 1,2 mg eery 8 h. Each dose was dissoled in 2 ml of 5% dextrose solution and infused intraenously oer 1 to 2 h. The infusion time was increased in some patients who deeloped toxicity during drug administration. Toxicity was ealuated in all 183 patients who receied the drug. Complete blood counts, SM 12, and urinalysis were performed in all patients before the administration of the first dose of miconazole, during treatment, and on the last day of treatment. Multiple attempts to further document the presence of fungal infection were made during treatment in all patients. RESULTS Response. Table 2 summarizes all cases which responded to treatment with miconazole. Table 3 summarizes all cases which failed to respond. Response related to the fungus isolated from the site of infection is shown in Table 4. Of the 37 documented fungal infections, 41% responded to miconazole therapy. Candida albicans was the most common fungus isolated, representing 59% of all cases. Forty-one percent of the 22 cases of C. albicans infection responded, and 27% of the 11 cases of Candida tropicalis infection responded. Candida parapsilosis was isolated from one patient and this infection responded, whereas one episode of a nonspeciated Candida infection failed to respond. Both of the infections caused by T. glabrata were cured with miconazole. Eight patients with other fungal infections (four spergillus spp., two Penicillium spp., one Mucor sp., and one Cryptococcus neoformans) were treated with miconazole and none responded. Three patients that failed to respond to miconazole subsequently responded to amphotericin B as follows: C. albicans esophagitis, C. albicans arthritis, and C. tropicalis sepsis. Two patients that preiously failed to respond to amphotericin B also failed to respond to miconazole therapy. Thirteen (41%) of 32 major infections and two of fie minor infections responded to miconazole therapy (Table 4). Of 15 responses, 13 (87%) were major infections and of 22 failures, 19 (86%) were major infections. Thirteen (41%) of the 32 major fungal infections occurred in patients whose neutrophil count was <1/mm3 and 2 (63%) occurred in Downloaded from on June 16, 218 by guest

3 794 JORDN ET L. I. m cq 4 z4 8 9 } dg.5 -S *a.1 t go X~~ ' 44X44>>XXrr*GoGo o (i Mlss. co m m C4 i- m "-4oq~ I.; ~ o ct aac - 4; - - ]3r tij] Xtem3iZ S~~~~~~~ SS k~~ C 1 3 LO 9 it3zo- co NTIMICROB. GENTS CHEMOTHER. patients whose neutrophil count was <1,/ mm3. Table 5 shows response of major infections related to the patients' initial neutrophil counts. There was a 67% cure rate when the neutrophil count was >1,/mm3, whereas there was only a 38% cure rate when the neutrophil count was <1/mm3 on the first day of therapy. Patients whose neutrophils increased during therapy had a higher response rate than patients whose neutrophils remained unchanged during therapy (47 ersus 33%). Only 2 of 7 patients whose neutrophil count remained <1/mm3 were cured of their infection. Toxicity. Table 6 summarizes toxicity which was ealuated in all 183 patients who receied miconazole. Nausea or omiting or both occurred in 46 patients (25%) and appeared to be affected by the infusion rate, being less seere during slower infusions. Twenty-nine patients (16%) had central nerous system toxicity which included three cases of grand mal seizure necessitating discontinuance of the drug. Respiratory arrest occurred in one patient at the beginning of infusion of the first dose but may not hae been due to miconazole. Other toxicity included pruritic rash, dyspnea, and hypotension. No case of direct pulmonary, renal, hepatic, or cardiac toxicity was noted. DISCUSSION. Miconazole was chosen for inestigation as an * antifungal agent in patients with seere compro- 3 mised host defense mechanisms because results ^ with other antifungal agents hae been unsatis- O factory. Furthermore, toxicity, especially neph- 2. rotoxicity, makes the use of amphotericin B difficult in these complex situations. Of 183 patients entered in the study, 122 pa- < tients (67%) were inealuable because of failure to document infection with a fungal organism., This reflects the difficulty in documentation of ' this type of infection. It is likely that some of t these patients did, indeed, hae a fungal infec-, tion and were cured with miconazole een though the diagnosis could not be established. I Some of these patients had clinical eidence of fungal infection in the lung or esophagus which responded to miconazole but were not included. Other patients with similar clinical findings, failec to respond to miconazole and a docu- 2 mented fungal infection was diagnosed at autopsy. These patients, of course, were ealuable O for response and classified as failures. In this setting, the reported response rate is probably lower than the actual response rate would be if more reliable methods of diagnosis were aail- < able. This is especially true since blood cultures are positie in only 25% of patients with dissem- Downloaded from on June 16, 218 by guest

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5 JORDN ET ET L. L.~~~~~~NTIMICROB. GENTS CHEMOTHER. TBLE 4. Response relatie to infecting fungus and seerity of infection Infection No. treated No. cured C. albicans C. tropicalis C. parapsilosis Candida (nonspeciated)... 1 T. glabrata Major infections Minor infections TBLE 5. Response relatie to neutrophil count' Neutrophils/mm' No. treated No. cured < to 1, 7 >1, 12 8 Decreased or unchanged 15 5 Increased 17 8 <1, Unchanged 7 2 a Major infections only. TBLE 6. Miconazole toxicity Number of patients ealuable. 183 Nausea or omiting or both.46 (25%) Central nerous system toxicity 29 (16%) Tremors. 9 Confusion. 8 Dizziness. 7 Seizure. 3 Hallucinations. 2 Rash... 5 Dyspnea Hypotension. 2 Respiratory arrest. 1 inated fungal infections (2), and serological testing has not been reliable (9). Sixteen patients were considered inealuable because they receied less than 5 days of therapy. Fie days was arbitrarily chosen as a reasonable time to judge a response to miconazole, although it is likely that some fungal infections, especially in neutropenic patients, require more time before objectie response can be expected. Since the compromised host cannot mount an adequate inflammatory response, infection frequently disseminates widely before the diagnosis can be established. Consequently, some patients may be irreersibly infected before therapy is initiated. Fifteen of 37 patients who receied at least 5 days of miconazole therapy were cured of their infection. Thirteen of the 32 patients with major fungal infections were cured. s expected, C. albicans was the most frequently isolated fungus and responded to miconazole more frequently than C. tropicalis. T. glabrata is being recognized increasingly as an etiological agent in opportunistic infections (1). Both patients with Torulopsis infections were cured with miconazole. The most significant toxicity from miconazole was nausea or omiting or both which occurred in 25% of the patients. This side effect frequently interfered with nutrition and occasionally was felt to potentiate the gastrointestinal side effects of chemotherapeutic agents. When miconazole was used concomitantly with trimethoprim-sulfamethoxazole, potentiation of this toxicity also was obsered. The degree of nausea could generally be reduced or alleiated by increasing infusion time of miconazole to 2 h or more. Central nerous system toxicity was seen in 29 patients, and the drug was discontinued in 3 patients who had grand mal seizures while receiing miconazole. In all three patients, the seizure actiity was preceded by seeral days of progressie fine tremors. Miconazole was discontinued in one other patient who had a sudden respiratory arrest associated with the first dose of miconazole. The patient was easily resuscitated, although the exact mechanism for the arrest was unclear. In general, the drug was well tolerated, and the -side effects were easily controlled. This study suggests that miconazole is a useful agent for the treatment of Candida spp. and T. glabrata infections in patients with adanced malignancy. lthough the cure rate is low, it is comparable to that obsered with amphotericin B in these patients and is associated with much less serious toxicity. spergillus infections hae not responded to the drug clinically. Responses to miconazole were not seen in other fungal infections, although no conclusions can be made regarding these organisms due to the small numbers. Further studies are needed to compare miconazole with amphotericin B in this difficult group of patients. CKNOWLEDGMENT This study was supported in part by Public Health Serice grant C 5831 from the National Cancer Institute. LITERTURE CITED 1. isner, J., S. C. Schimpff, J. C. Sutherland,. M. Young, and P. H. Wiernik Torulopsis glabrata infections in patients with cancer. Increasing incidence and relationship to colonization. m. J. Med. 61: Bodey, G. P Fungal infection complicating acute leukemia. J. Chronic Dis. 19: Bodey, G. P., and M. Luna Skin lesions associated with disseminated candidiasis. J. m. Med. ssoc. 229: Deresinski, S. C., R. B. Lilly, H. B. Leine, J. N. Galgiani, and D.. Steens Treatment of Downloaded from on June 16, 218 by guest

6 OL. 16, 1979 MICONZOLE FOR FUNGUS IN CNCER PTIENTS 797 fungal meningitis with miconazole. rch. Intern. Med. 137: Gaines, J. D., and J. S. Remington Disseminated candidiasis in the surgical patient. Surgery 72: Katz, M. E., and P.. Cassileth Disseminated candidiasis in a patient with acute leukemia. Successful treatment with miconazole. J. m. Med. ssoc. 237: Lutwick, L., ML W. Rytel, J. P. Ya-Nez, J. N. Galgiani, and D.. Steens Deep infections from Petriellidium boydii treated with miconazole. J. m. Med. ssoc. 241: Miller, R. P., and J. H. Bates mphotericin B toxicity. nn. Intern. Med. 71: Rodriguez,., G. P. Bodey, and E. J. Freireich Bacterial and fungal infections during cancer chemotherapy. Recent Results Cancer Res. 49: Shadomy, S., L Paxton,. Espinel-Ingroff, and H. J. Shadomy In itro studies with miconazole and miconazole nitrate. J. ntimicrob. Chemother. 3: Steens, D.., HL B. Leine, and S. C. Deresinski Miconazole in coccidioidomycosis. II. Therapeutic and pharmacologic studies in man. m. J. Med. 6: Sung, J. P Treatment of disseminated coccidioidomycosis with miconazole. West. J. Med. 124: Sung, J. P., J. G. Grendahl, and H. B. Leine Intraenous and intrathecal miconazole therapy for systemic mycosis. West. J. Med. 126: an Cutoem, J. M., and D. Thienpont Miconazole, a broad-spectrum antimycotic agent with antibacterial actiity. Chemotherapy 17: Zubrod, C. G Health Memorial ward Lecture: Contributions of chemotherapy to the control of cancer, p. 7. In nderson Hospital (ed.), Cancer chemotherapy: fundamental concepts and recent adances. Year Book Medical Publishers, Inc., Chicago, III. Downloaded from on June 16, 218 by guest