Prophylaxis of candidiasis in patients with leukemia and bone marrow transplants

Prophylaxis of candidiasis in patients with leukemia and bone marrow transplants Joel B. Epstein, D M D , MSD, a Alison Ransier, BSc, R D H , b Ruth Lunn, C D A , R D H , ID, c Edward Chin, d Jed J. Jacobson, DDS, MS, MPH, e Nhu Le, PhD, f and D o n n a Reece, BS, MD,g Vancouver, BC, Canada, and A n n Arbor, Mich. VANCOUVER HOSPITAL AND HEALTH SCIENCES CENTRE, BC CANCER AGENCY, VANCOUVER COMMUNITY COLLEGE, UNIVERSITYOF BRITISH COLUMBIA, AND UNIVERSITYOF MICHIGAN SCHOOL OF DENTISTRY

Objectives. The increased risk for systemic fungal infection and the potential fatal consequences of disseminated candidiasis in bone marrow transplant patients has prompted study of prophylaxis and early treatment of candida colonization and infection. Study design. Patients with leukemia who received fluconazole prophylaxis were compared with a concurrent group of patients not given prophylaxis for fungal organisms. Results. A trend to reduction of oropharyngeal colonization by Candida albicans was seen (p = 0.07) although no significant differences in systemic candidiasis were seen. In patients with documented systemic candidiasis, oral colonization was present and systemic infection was identified after the development of ulcerative oral mucositis. Conclusions. Our results support the potential of fluconazole to reduce oropharyngeal colonization caused by Candida albicans, however, we did not show prophylaxis of oral candidiasis or systemic candidiasis. These findings and reports of fluconazole-resistant candidal species and a rising number of cases of infection as a result of Candida krusei indicate the need for further studies of prophylaxis of candidal infection in patients who are anticipated to develop profound neutropenia. (ORAt SURGORALMED ORAL PATHOLORAt RADIOL FNDOD 1996;81:291-6)

Up to 50% o f all oral infections in patients with acute leukemia have been reported to be o f fungal cause, primarily candidal speciesJ -5 The oral cavity can serve as a site o f colonization and the majority o f cases of systemic candidiasis m a y follow colonization of the oral cavity or occur in patients who have preexisting oropharyngeal colonization by candidal species.6 Risk factors for systemic candidiasis include the severity and duration o f neutropenia, the use of aMedicaUDental Staff of the BC Cancer Agency; Head, Department of Dentistry, Vancouver Hospital and Health Sciences Centre; Clinical Professor, University of British Columbia, Vancouver; Research Assistant Professor, University of Washington, Seattle. bDental Hygienist, Vancouver Hospital and Health Sciences Centre. CDental Hygienist, BC Cancer Agency, and Dental Hygiene Instructor, Vancouver Community College. aDental Student, University of Michigan School of Dentistry. ~AssociateProfessor/Directorof Admissions,Universityof Michigan School of Dentistry. fStatistician, Department of Epidemiology, Biometry, and Occupational Oncology, BC Cancer Agency. gHematologyDepartment, Vancouver Hospital and Health Sciences Centre, BC Cancer Agency. Received for publication Mar. 22, 1995;returned for revision June 5, 1995; accepted for publication Oct. 11, 1995. Copyright 9 1996 by Mosby-Year Book, Inc. 1079-2104/96/$5.00 + 0 7/13/69986

broad spectrum antibiotics, and the n u m b e r o f sites colonized by fungi. 7-9 Mortality a m o n g bone marrow transplant (BMT) patients as determined at autopsy was due to disseminated fungal infections in 22% to 56% o f patients. 7 A m o n g 665 patients w h o underwent bone m a r r o w transplantation, systemic candidiasis was diagnosed in 76 (11.4%) patients and contributed to the death in one third o f those patients. 1~ In leukemic patients who undergo transplantation, invasive fungal infection m a y account for as m a n y as 30% of deaths? Fungal infections in B M T recipients are also c o m m o n after neutropenia has resolved, 11 however, the risk o f systemic infection decreases with recovery o f i m m u n e competence. Prevention o f colonization o f the oropharynx and prevention o f clinical infection (oropharyngeal candidiasis) m a y be of critical importance in the prevention o f systemic candidiasis. 6' 7, 9, 12 Prophylaxis is justified because of the potential for increased morbidity and mortality in neutropenic patients. 1l The prophylactic use of topical and systemic antifungal agents has been studied, but each agent appears to be limited in efficacy or by toxicity. 2, 6, s, 9, 11-44 The triazole antifungals are active systemically, are well absorbed by mouth, and possess a long halflife. 45-47 Fluconazole inhibits the synthesis o f ergos-

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terol in the fungal cell wall and results in the accumulation of 14-alpha-methyl sterols that have fungicidal activity.48 Fluconazole is well tolerated and has produced clinical responses in patients with systemic fungal infections who are refractory to amphotericin B. 47 Fluconazole is widely distributed in the body including the cerebrospinal fluid, is secreted in saliva resulting in local effect, and causes reduced adherence of candidal species to human buccal epithelial cells. 49 In addition, fluconazole has been shown in studies of neutropenic animals to prevent candidiasisS~ in studies of neutropenic B M T patients, it may prevent both superficial and systemic fungal infections. 51 An advantage of fluconazole in BMT patients is its lack of significant interraction with cyclosporine. 52, 53 In cases of fungal resistance to fluconazole, increased doses may overcome antifungal resistance. 54 The high incidence of candidemia in neutropenic patients who receive antibacterial agents justifies aggressive empiric use of amphotericin B, but some of these infections may be prevented by prophylaxis with fluconazole. 5, 11,45,54-58 Systemic fungal infections developed in 15.8% of patients who received placebo as compared with 2.8% of those who received fluconazole. 54 Of patients who received placebo, 9 of 10 deaths were attributed to fungal infection. 5~ A multicenter study of 536 patients scheduled to receive chemotherapy, radiotherapy, or B M T for treatment of malignant disease and who were expected to become neutropenic randomly received fluconazole (50 mg/day), oral amphotericin B (2 gm/day, four times daily), or nystatin (4 x 106 units/day). 55 Oropharyngeal candidiasis was documented in 1.6% of the fluconazole group and 8.6% of the polyene group and colonization by candida was decreased (p < 0.001), however, no difference in systemic infection was seen and use of amphotericin B was not altered. Once a day fluconazole prophylaxis (50 mg) was shown to be more effective than oral polyenes for the prevention of oropharyngeal candidiasis. 55 In another trial, 257 adult patients undergoing chemotherapy for acute leukemia were given fluconazole (400 mg/day) or a placebo. 56 Fluconazole decreased fungal colonization by approximately 50% (p = 0.001), superficial fungal infections were decreased (6% versus 15%, p = 0.01), and invasive fungal infections were reduced (4% versus 8%, p = 0.3). Fluconazole was more effective in eliminating candidal species other than Candida krusei and aspergillus; isolation of these species and the empiric use of amphotericin B 56 was similar between groups. The purpose of this study was to assess the efficacy of fluconazole in the prevention of oropharyngeal

colonization by candidal species and prevention of oropharyngeal and systemic candidiasis.

METHODS Sixty-three consecutive patients admitted to the Hematology/Bone Marrow Transplant service were followed weekly for up to 8 weeks during their admission. All patients were older than 15 years of age and received chemotherapy or B M T that produced severe neutropenia. All patients received nursing care in single rooms in a facility with high-efficiency particulate air filtration. Empiric broad-spectrum antibiotics were routinely given when fever of more than 38 ~ C developed and the absolute neutrophil count was less than 1.0 x 109 cells/L. Empiri c amphotericin B was begun if fever persisted more than 72 hours while on broad-spectrum antibiotics. Patients received blood products irradiated to 1500 cGy to maintain a hemoglobin of more than 90 gm/L and a platelet count of more than 20 x 109 cells/L. Forty-four patients were provided fluconazole prophylaxis (400 rag/day) at the time of the clinical study. No specific criteria were in place at the time for selection of patients to receive prophylaxis but varied with the attending physician; this resulted in some patients receiving prophylaxis and others not. The patients taking fluconazole prophylaxis before transplantation were maintained on the drug for a mean of 3.64-_+ 1.37) weeks. Four patients were placed on amphotericin B because of fever unresponsive to broad-spectrum antibiotics. Patients were routinely given a chlorhexidine rinse (0.2% in aqueous solution) to be used as an oral rinse 10 ml four times daily. 35 Forty percent of patients were unable or unwilling to continue with regular use of chlorhexidine rinse because of the taste or nausea during chemotherapy. All patients received a complete oral examination conducted weekly between 11:00 AM and 2:30 PM. Examination of the oral mucosa included an assessment of erythema, ulceration, and pseudomembranes as previously described. 35, 58, 59 The medical records of each patient were reviewed including discharge summaries to extract data related to the admission. Oral cultures were conducted for all patients at each weekly visit. Culture for candidal species was conducted in the laboratory with standard microbiologic techniques. 5s Briefly, oral cultures were obtained by swab technique of buccal mucosa, palatal mucosa, and dorsal tongue, transferred to blood agar and Sabouraud's dextrose agar, and incubated at 37 ~ C for up to 5 days. Candidal species were identified by germ tube analysis and reported as semiquantitative colony counts were recorded as light, moderate, or heavy growth. A diagnosis of candidiasis was made

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Volume 81, Number 3

Table I. Medical diagnosis at admission

Table II. Medical management of primary malignant disease

Patient group

Systemic antifungal prophylaxis

Diagnosis

Flueonazole

No systemic antifungal

Acute myelogenous leukemia Chronic myelogenous leukemia Hodgkins Reticulosarcoma Multiple myeloma Malignant lymphoma Aplastic anemia Other Total

30

10

40

5

3

8

1 1 3 2 -2 44

1 1 2 --

2 2 5 2

Total

1

1

1 19

3 63

Table III. Medical management of patients primary disease Patient Group Fluconazole I No fluconazole Chemotherapy Bone marrow transplant Autologous Allogenic

Total

17

9

26

4 23

3 7

7 30

Fluconazole Chemotherapy Cytarabine, mitoxantrone, etoposide vincristine, adriarnycin, daunorubicin Bone marrow transplant conditioning Carboplatin, busulphan Cyclophosphamide, busulphan, melphalan Busulphan, cytoxan Ara-C, busulphan Ara-C, etoposide, mitoxantrone Etoposide, cisplantin, cyclophosphamide, carmustine Etoposide, total body irradiation Cyclophosphamide, total body irradiation Total number of patients

None

17

7

--

2

2 2

2 l

12 3 1

3 ---

--

1

2

1

5

2

44

19 (63 total)

Table IV. Colonization of the oral cavity in patient groups on the basis of the oral examination and the presence of a positive laboratory culture as previously described.S4, 55 Diagnosis of candidemia was based on positive culture of Candida in the blood, and systemic fungal infection was based on the presence of tissue infection as documented in blood culture or in tissue specimen. Data were entered on D-Base III+ (Ashton-Tate, Torrence Calif.), and analyzed with nonparametric statistical tests namely, the Kruskal-Wallis rank sum test. 60

RESULTS Sixty-three consecutive patients were included in this study. The mean age of the study population was 45.4 years (range, 15 to 75), 35 males and 28 females. The medical diagnosis groups are shown in Table I, and the management of the primary medical conditions are shown in Tables lI and III. The mean age of those undergoing transplantation was 38.9 years (range, 15 to 60 years) and those receiving chemotherapy was 50.0 years (range, 17 to 75 years). Of the B M T patients, 10 received conditioning that included total body irradiation (TBI), the remaining patients were conditioned with chemotherapy alone. Fluconazole prophylaxis was provided to 44 patients (25 males, 19 females), whereas 19 patients (10 males, 9

Treatment groups

Number of Cases with Cases with patients [ Candida albicans Candida krusei

No antifungal Fluconazole plus chlorhexidine Fluconazole Cblorhexidine Total

15 31

2 2

-1

10 7 63

1

--

2 7

l 2

Kruskal test p = 0.17.

females) did not receive fluconazole prophylaxis. The mean age of those provided fluconazole prophylaxis is 46 years (standard deviation, 17 years) and the nontreated group 44 years (standard deviation, 14 years). Two patients given fluconazole prophylaxis developed documented candidemia, one as a result of Candida albicans and the other Candida krusei. One patient not given fluconazole prophylaxis developed systemic infection; no patients in the fluconazole group were diagnosed with systemic infection (p = 0.13). When the use of chlorhexidine was assessed in the two groups of patients, no significant differences were seen (p = 0.17) (Table IV). Three cases of oral candidiasis were diagnosed on the basis of clinical signs and positive culture; of these, one

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March 1996 used chlorhexidine only, one took fluconazole prophylaxis only, and one took fluconazole, systemic arnphotericin B, and chlorhexidine rinse. Two cases of oral candidiasis were due to Candida albicans and one was due to Candida krusei. Candida had colonized in 9 patients (14%) (Table III). Of those patients taking fluconazole, 4 of 44 had positive cultures for Candida, and 5 of 19 (p = 0.07) without fluconazole were candidal positive. Two patients died with systemic candidiasis (Candida albicans); one was taking fluconazole prophylaxis, the other was not on antifungals and was diagnosed at postmortem. Oral mucositis developed in 62% (39 of 63) of the patients. Oral ulcerative mucositis was present in 26% (16 of 63) of all patients. No relationship between the use of antifungals, candidal colonization, and oral mucositis was seen. In both of the patients with documented systemic candidiasis, ulcerative oral mucositis and oral colonization by Candida were seen. Of the 63 patients, 77% were alive without evidence of the primary disease or graft-versus-host disease at the end of their admission. Eight percent of patients were free of the primary disease but were undergoing treatment for documented graft-versushost disease. At the end of the study period, nine (14%) patients had died. The cause of death was attributed to Candida in two (3%) cases, organ failure in six (9%) cases, and recurrent disease in one (2%) patient.

DISCUSSION In our study, candidal species had colonized in the oropharynx in 19% (9 of 63) of patients during admission for treatment of their primary disease. Reduction in oral colonization by Candida was seen in patients on fluconazole, however, this did not reach statistical significance (p = 0.07). These findings are in general agreement with previously reported resuits.SO, 55, 56 Of the three cases of culture-confirmed oral candidiasis, no differences were seen between the use of fluconazole, chlorhexidine, or amphotericin B. In the two patients with documented systemic candidiasis, the oral cavity was culture positive and oral ulcerative mucositis was present supporting the contention that oral ulcerative mucositis may increase the risk of systemic infection. 57' 61, 62 It is not clear whether use of chlorhexidine can affect the development of oral mucositis as suggested in some studies31-34, 63 because prevention or reduction has not been demonstrated in other studies. 35-37 In the current study, we did not detect any relationship between candidal colonization, use of chlorhexidine, and the development of ulcerative mucositis. We were unable to eliminate oral colonization by can-

didal species with the use of fluconazole, chlorhexidine, and amphotericin B either alone or in combination. Although there were five cases in whom the clinical differential diagnosis included candidiasis, when the results of oral culture were assessed candidiasis was confirmed in three cases. Candidemia was documented in two cases; one was taking fluconazole prophylaxis, the other was not taking any systemic or topical antifungal at the time and subsequently died. The reasons why Candida albicans is not completely eradicated with the use of fluconazole have not been elucidated. One possibility is fluconazole resistance that has been reported in patients immunocompromised as a result of HIV infection who have chronically used antifungals. 64-67 Unfortunately, in a vitro sensitivity testing of fungal isolates is not standardized, and the results do not always correlate with in vitro activity. 64' 65 However, infections by resistant fungal species have been seen only in HIV-infected patients who receive fluconazole. 6~-67 In AIDS, treatment failure may also be attributed to drug interactions (for example, fluconazole and rifamprin), and the continuing deterioration of a patient with AIDS may prevent the effectiveness of this antifungal. Hence, in cases in which fluconazole has not been effective, clinicians should consider the possibility of fluconazole-resistant organisms, possible drug interactions, and deteriorating immune status. In cases in which prophylaxis fails, treatment with amphotericin B or itraconazole may be considered. One concern with the use of fluconazole has been the emergence of nonalbicans species. In one center, this has led to the empiric addition of flucytosine to amphotericin B in BMT. 54 In this study, fungemia caused by Candida krusei was identified in 12.5% of cases, however, Torulopsis (Candida) glabrata was the cause of fungemia in 75% of patients who had received fluconazole prophylaxis. In another prospective study of fluconazole prophylaxis, treatment failed in 3 of 22 neutropenic pediatric patients, one each due to Candida krusei, Torulopsis (candida) glabrata, and Aspergillus. 6s In these cases of failure of prophylaxis, patients responded to other antifungals. In our study, oral colonization by Candida albicans was seen in seven cases and by Candida krusei in two cases. Clinical infection was attributed to Candida albicans in two patients and Candida krusei in one. Candidemia was diagnosed in two cases, one each from Candida albicans and krusei. These findings highlight the possible changing pattern of fungal infections when fluconazole is used. Because amphotericin B has served as the gold standard for antifungal treatment, 69 any trials of an-

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Volume 81, Number 3 t i f u n g a l p r o p h y l a x i s i n n e u t r o p e n i c p a t i e n t s m u s t accommodate the common practice of the early use of a m p h o t e r i c i n B. E a r l y d i a g n o s i s o f i n v a s i v e f u n g a l i n f e c t i o n i n n e u t r o p e n i c p a t i e n t s is o f t e n d i f f i c u l t a n d unreliable, therefore, until a reliable and sensitive test for rapid diagnosis of invasive fungal infection becomes clinically available, empiric amphotericin B is f r e q u e n t l y u s e d w h e n t h e r e is s u s p e c t e d f u n g a l i n fection.5, 8, 47, 54, 68, 70 The available data suggest that in BMT recipients, fluconazole used prophylactically may reduce oropharyngeal colonization clinical oropharyngeal candidiasis and reduce the incidence of disseminated fungal i n f e c t i o n a n d r e l a t e d m o r t a l i t y . 1~ 55, 56 T h e r e s u l t s o f our study suggest that prophylactic use of fluconazole m a y r e d u c e o r a l c o l o n i z a t i o n b y Candida albicans. N o r e l a t i o n s h i p b e t w e e n o r a l m u c o s i t i s a n d o r a l colo n i z a t i o n o r i n f e c t i o n b y Candida w a s s e e n . O u r findings support the contention that oral ulcerative mucositis may increase the risk of systemic infection by candidal species in patients who have colonization in the oropharynx.

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54. Pizzo PA, Robichand KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982;72: 101-11. 55. Philpott-Howard JN, Wade JJ, Mufti GJ, Brammer KW, Ehninger G. Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia: multicentre study group. J Antimicrob Chemother 1993;31:973-84. 56. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, doubleblind, multicenter trial. Ann Intern Med 1993;118:495-503. 57. Wingard JR. Oral complications of cancer therapies: infectious and non-infectious systemic consequences. NCI Monogr 1990;9:21-6. 58. Epstein JB, Freilich MM, Le ND. Risk factors for oropharyngeal candidiasis in patients who receive radiation therapy for malignant conditions of the head and neck. ORALSUR6 ORAL MED ORAL PATHOL 1993;76:169-74. 59. Epstein JB, Pearsall NN, Truelove EL. Oral candidiasis: effects of antifungal therapy upon clinical signs and symptoms, salivary antibody, and mucosal adherence of Candida albicans. ORAL StrRG ORAL MEDORAL PATHOL 1981;51:32-6. 60. Lehamann EL. Non-parametrics: statistical methods based on ranks. New York: McGraw Hill, 1975:205-10. 61. Donnelly JP, Muus P, Horrevorts AM, Sauerwein RA, De Pauw BE. Failure of clindamycin to influence the course of severe oromueositis associated with streptococcal bacteraemia in allogeneic bone marrow transplant recipients. Scand J Infect Dis 1993;25:43-50. 62. Donnelly JP, Muus P, Schattenberg A, De Witte T, Horrevorts A, DePauw BE. A scheme for daily monitoring of oral mucositis in allogenic BMT recipients. Bone Marrow Transplant 1992;9:409-13. 63. Ferretti GA, Raybould TP, Brown AT, et al. Chlorhexidine prophylaxis for chemotherapy and radiotherapy-induced stomatitis: a randomized double-blind trial. ORAL SURG ORAL MED ORAL PATHOL 1990;69:331-8. 64. Fan-Harvard P, Capano D, Smith SM, Mangia A, Eng RHK, Development of resistance in Candida isolates from patients receiving prolonged antifungal therapy. Antimucrob Agents Chemother 1991;35:2302-5. 65. Gallagher PJ, Bennett DE, Henman MC, et al. Reduced azole susceptibility of oral isolates of Candida albicans from HIVpositive patients and a derivate exhibiting colony morphology variation. J Gen Microbiol 1992;138:1901-11. 66. Heinic GS, Stevens DA, Greenspan D, et al. Fluconazole-resistant Candida in AIDS patients: report of two cases. ORAL SURG ORAL MED ORAL PATHOL 1993;76:711-5. 67. Galgiani JN. Antifungal susceptibility tests. Antimicrob Agents Chemother 1987;31:1867-70. 68. Cap J, Mojzesova A, Kayserova E, et al. Fluconazole in children: first experience with prophylaxis in chemotherapy-induced neutropenia in pediatric patients with cancer. Chemotherapy 1993;39:438-42. 69. EORTC international antimicrobial therapy cooperative group: empiric antifungal therapy in febrile granulocytopenic patients. Am j Med 1989;86:668-72. 70. Schaison G, Baruchel A, Arlet G. Prevention of gram positive and Candida albicans infections using teicoplanin and fluconazole: a randomized study in neutropenic patients. Br J Hematol 1990;76(suppl 2):24-6. Reprint requests: Dr. J.B. Epstein Department of Dentistry 600 West 10th Avenue Vancouver, BC V5Z 4E6