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Epidemiological shifts in opportunistic and nosocomial Candida infections: mycological aspects
INTERNmONAL
IOLRNII.
08
Antimicrobial Agents International Journal of Antimicrobial Agents 6 (1996) 141-144
Epidemiological shifts in opportunistic and nosocomial Candida infections: mycological aspects Frank C. Odds* Department of Bacteriology and Mycology, Janssen Research Foundation. B-2340 Beerse, Belgium
Accepted 13 November 1995
Abstract Increases in the prevalence: of yeast species other than C. albicuns as agents of disseminated and of fluconazole-resistant C. albicuns isolates from patients infected with HIV indicate
mycoses in immunosuppressed
patients
changes in the epidemiology of Cundida infections, The precise reasons for alterations in prevalence of various agents are difficult to pinpoint but changes in the types of host populations at risk of Cundida infection and selection of resistant yeast populations by widescale usage of certain antifungal agents seem to be factors involved in the process. Greater attention to speciation of clinical yeasts and standardized susceptibility test methods are needed for future epidex&ological surveillance Keywords:
Candida;
Pathogen shift; Azole resistance
1. Candida species as caulsal agents of nosocomial infections The
incidence
of
hospital-acquired
(nosocomial)
Candida infections has increased steadily since the 1970s.
This is probably the combined result of an ever larger number of patients rendered susceptible to mycoses by immunosuppressive procedures, including cancer chemotherapy and transplantation surgery, and a growing clinical awareness of the significance of yeasts and moulds as nosocomial pathogens. Surveys in the USA have shown Candida species as the third most common type of micro-organisms isolated from blood cultures, with an overall prevalence as high as lo-15% in some surveys [ 11. Candida albicans is the most commonly encountered pathogenic yeast: species such as C. glabrata, C. krusei, C. parapsilosis and C. tropicalis are usually isolated much less often than C. albicans. However, there is now evidence from some studies for a decrease in the relative prevalence of C. albicans as other Candida species are
*Tel. (+32-I) 460 3004; Fax (+32-l) 460 5403. 0924~8579/96/$32.00
SSDI
0 1996 Elsevier Science B.V. All rights reserved 0924-8579(95)00049-6
reported more frequently as isolates from neutropenic patients [24]. Moreover, the emergence both of less common Candida species [5-71 and of fluconazole-resistant C. albicans isolates [8-141 has now been documented in oropharyngeal Candida infections associated with AIDS. These changing trends in the epidemiology of opportunistic Candida infections are not always easy to monitor. The prevalence of various species of Candida isolated from clinical materials varies between countries, between institutions and between patient groups [15]. Meunier et al. [16], for example, showed a significantly higher prevalence of C. albicans and C. glabrata among bloodstream isolates from patients with solid tumors and a significantly higher prevalence of C. tropicalis and C. krusei among similar isolates from patients with haematological malignancies. Against such a highly variable background, global changes in species prevalence are inevitably difficult to demarcate precisely. Changes in the nature of the host population at risk and, anecdotally, changes in approaches to yeast identification can both lead to changes in the nature of Candida species causing infection. However, the best documented changes in Candida epidemiology are those attributed to antifungal drug usage.
142
EC. Oddsllnternational Journal of Antimicrobiul Agents 6 (1996) 141-144
2. Emergence of ‘non-albicans’ Candida species as clinical pathogens Candida lusitaniae is a species that was never reported as a cause of disease until after the antifungal agent amphotericin B began to be used very commonly in patients with neutropenia, both for prophylaxis and empirical therapy of sepsis, in the 1980s. C. lusitaniae strains often develop resistance to amphotericin B [17], a factor that may account circumstantially for their emergence as pathogens. The source of C. lusitaniae has been shown to be exogenous [18], whereas species such as C. albicans and C. glabrata are usually carried as endogenous commensals [ 151. Prophylactic use of ketoconazole in neutropenic patients led to the emergence of a higher prevalence of C. glabrata isolates among surveillance cultures in some surveys [19,20] but no similar phenomenon was reported among most prophylactic trials with this antifungal agent [21]. In one therapeutic trial, ketoconazole was found to be ineffective against disseminated C. tropicalis infections [22], however, no subsequent reports have documented an increase in colonization or infection with this species among groups of patients receiving ketoconazole prophylactically. It is impossible to judge the extent to which global pathogen shifts among neutropenic hosts may be attributable to ketoconazole usage, but the very small number of publications suggests that it is low. A more definitive link has been established in several studies showing a rise in the prevalence of C. glabrata and C. krusei as nosocomial pathogens in neutropenic patients treated prophylactically with fluconazole. These two Candida species have an inherently lower susceptibility to fluconazole than does C. albicans [23]. Price et al. [2] specifically incriminated fluconazole prophylaxis as the reason for the decrease in C. albicans bloodstream isolates seen in their hospital (Table 1). Between 1987, when no fluconazole was used in the hospital surveyed and 1992, when 7000 patient doses of the antifungal agent were given, the frequency of C. albicans in blood cultures fell from 87% to 31%. Wingard et al. [3] found all of 10 disseminated Candida infections among 84 patients undergoing bone marrow transplantation who received fluconazole prophylaxis were caused by species other than C. albicans. Of the 10 infections, 7 were caused by C. krusei. These figures compared with historical data showing 27 disseminated Candida infections among 335 similar patients who received no fluconazole, of which 10 were caused by C. albicans, 10 by C. tropicaiis, and only 4 by C. krusei. Studies that established the value and effectiveness of fluconazole in reducing the overall incidence of Candida infections among neutropenic patient populations also pointed to a tendency for species such as C. krusei and C. glabrata to emerge under prophylactic regimens. For example, Goodman et al. [24] prospectively demon-
strated a significant beneficial effect of fluconazole prophylaxis in terms of reduced Candida prevalence in surveillance cultures, superficial infections and disseminated infections. However, the only species not suppressed by fluconazole prophylaxis was C. krusei. which caused 3 systemic infections among the 179 patients receiving the antifungal and 2 among the 177 patients receiving placebo. Similarly, Philpott-Howard et al. [25], who compared prophylactic use of fluconazole and polyenes in neutropenia, encountered just 3 deep-seated Candida infections among the 256 patients on fluconazole prophylaxis as compared with 8 among 255 patients who received polyenes: but all the infections under fluconazole cover were caused by C. krusei. Among haematology patients, Coste et al. [4] reported an increase in C. glabrata isolations from 4.5% to 19.8%, a change they attributed to fluconazole prophylaxis. Emergence of both C. glabrata and C. krusei at higher frequencies in neutropenic patients treated prophylactically with fluconazole as compared with placebo [26,27], polyenes [28] or antiseptics [29] has now been widely confirmed in more recent studies. In one instance C albicans isolated in successive routine surveillance cultures from a neutropenic patient receiving fluconazole prophylaxis showed phenotypic development of resistance to fluconazole in vitro. The C. albicans strain type (determined by RAPD/PCR methods) remained constant despite the phenotypic change to resistance [30]. In contrast to this recent spate of reports describing increased prevalences of C. glabrata and C krusei among patient groups receiving fluconazole, some publications indicate no such change when fluconazole is used for prophylaxis or empirical treatment of presumptive fungal infection [31-331. In one of these studies [33] the average C. krusei prevalence of almost 15% is already much higher than the global average of 34% among cancer patients, calculated in two reviews of published data [ 15,341. The high inherent variation in prevalence of species such as C. glabrata and C. krusei in published surveys has been attributed to differences in patient types, antibacterial drug usage and common-source contamination episodes [34]. Wingard’s review of Candida species epidemiology [34] concluded that there is no definable global increase in prevalence of non-albicans Candida species among cancer patients. It is nevertheless Table 1 Prevalence of various Candida spp.in bloodstream isolates, 1987-1992: fluconazole usage grew from 0 in 1987 to 7000 patient doses per year in 1992 [7] Species
C. C. C. C.
albicans giabrata parapsilosis tropicalis
No. (%) isolated
in
.
1987
1988
1989
1991
1992
47 (87)
41 (75)
39 (85)
9 (15) 5 (8) 5 (8)
5 (11) 2 (4) 0 (0)
51 30 14 17
32 26 20 24
1 (2) 5 (9) 1 (2)
(46) (27) (13) (15)
(31) (26) (20) (24)
RC. Oddslhternational
Journal of Antimicrobial Agents 6 (1996)
noteworthy that only one of the six most recent surveys tabulated by Wingard reported no C. krusei isolates, and the prevalence of this species in the remaining five surveys ranged from 17 to 6 I%, as compared to 0 to 11% in the 32 earlier surveys and a global mean occurrence of 4% [34]. Among HIV-infected patients there has been less evidence of changes in the species of Candida causing oropharyngeal and oesophageal infection than among patients with neutropenia. H.owever, at least three publications have now documented the emergence of C. krusei and C. glabrata in association with fluconazole treatment in this patient group [5-71, so the possibility of selection for these species with low fluconazole susceptibility has to be regarded as a general phenomenon.
3. Emergence of fluconazole resistance among C. albicans strains
The more common finding among HIV-positive patients is the emergence of oral C. albicans strains resistant to fluconazole. This phenomenon has now been very well documented in several published case reports and in cross-sectional and longitudinal surveys [8-131. It has also been described in large numbers of abstracts at meetings [14]. Resistance development is predominantly seen in patients with low CD4 lymphocyte counts, i.e. late in the development of AIDS. Its incidence is estimated at around 10% among HIV-positive patients in some clinics [ 141. Some investigators have typed the C. albicans strains longitudinally as phenotypic resistance to fluconazole develops. In reports so far published, a total of 11 cases where successive C. albicws isolates have developed resistance have been typed at the DNA level: in 10 out of the 11 instances the strain type remained unchanged while the phenotype altered to resistance [35-371.
4. Conclusions
An increasing number of immunocompromised hosts at risk of opportunistic Candidu infections and more widespread use of antifungal agents are both factors that can influence the species and type of yeasts that arise as pathogens. While no specific global trends in yeast epidemiology are yet quantifiable, evidence is available to indicate that changes are occurring. In particular, the widespread use in recent years of fluconazole as a prophylactic and therapeutic antifungal agent in patients with neutropenia and with HIV infections has resulted in changes in the types of yeast causing infections in these clinical settings. The prevalence of ‘non-albicans’ Cundidu species has risen, particularly among patients with neutropenia, and fluconazole-resistant strains of C. albi-
141-144
143
cans have emerged in the course of fluconazole treatment. Similar occurrences were reported previously with ketoconazole usage but far less consistently and on a smaller scale. The current epidemiological trends in Candidu infection have two major implications for patient management. The first is a definitive requirement for identification of yeasts to the species level, at least for isolates from surveillance cultures of patients at risk of disseminated infection and from the oropharynx of HIV-positive patients. The second is for susceptibility testing of yeast isolates from patients at most risk to assist in determining appropriate antifungal agents and appropriate doses. The introduction of CHROMagar Candida, a chromogenic yeast isolation medium that facilitates recognition of some Candida spp. and aids in detection of mixed yeast flora [38] and the publication of a reference broth test for yeast susceptibility determinations [39] are technical advances that should make both requirements easier to fulfill.
References
111Pfaller
M, Wenzel R. Impact of the changing epidemiology of fungal infections in the 1990s. Eur J Clin Microbial Infect Dis 1992;11:287-291. PI Price MF, LaRocco MT, Gentry LO. Fluconazole susceptibilities of Candida species and distribution of species recovered from blood cultures over a 5-year period. Antimicrob Agents Chemother 1994;38:1422-1424. [31 Wingard JR, Merz WG, Rinaldi MG, John TR. Karp JE, Sara1 R. Increase in Candidu krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with Ruconazole. New Engl J Med 1991;325:1274-1277. 141Coste T, Barale T, Reboux G et al. Prophylaxie antifungique par fluconazole: son influence sur l’augmentation de la frequence d’isolement de Cundida glabratu. Bull Sot Fr Mycol M&d 1990;19:151-154. G, Gentschew G, Dohle M, Bottinger C, Helm EB, 151Just-Nubling Stille W. Fluconazole in the treatment of oropharyngeal candidosis in HIV-positive patients. Mycoses 1990:33:435440. WI Millon L. Manteaux A, Reboux G et al. Fluconazole-resistant recurrent oral candidiasis in human immunodeficiency virus-positive patients: persistence of Candidu albicans strains with the same genotype. J Clin Microbial 1994; 1115-1118. study of 171Chavanet P, Lopez J, Grappin M et al. Cross-sectional the susceptibility of Candida isolates to antifungal drugs and in vitro in vivo correlations in HIV-infected patients. AIDS 1994;8:945-950. PI DuPont B. Resistance trends in oral Candidu infections: the clinical challenge. Clinician 1993:11:19-22. [91 Cameron ML, Schell WA, Bruch S. Bartlett JA, Waskin HA, Perfect JR. Correlation of in-vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1. Antimicrab Agents Chemother 1993;37:2449-2453. [IO] Ruhnke M, Eigler A, Tennagen I, Geiseler B. Engelmann E, Trautmann M. Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. Antimicrob Agents Chemother 1994;32:2092-2098.
144
EC. Oddsllnterna~ional Journal of Antimicrobial Agents 6 (1996) 141-144
[11] Baily GG, Perry FM, Denning DW, Mandal BK. Fluconazoleresistant candidosis in an HIV cohort. AIDS 1994;8:787-792. [12] Willocks L, Leen CLS, Brettle RP. Urquhart D, Russell TB, Milne LJR. Fluconazole resistance in AIDS patients. J Antimicrob Chemother 1991;28:937-939. [13] Fox R, Neal KR, Leen CLS, Ellis ME, Mandal BK. Fluconazole resistant Candida in AIDS. J Infect 1991;22:201-204. [14] Denning DW, Ng TTC. Fluconazole-insensitive OPC in AIDS patients. J Infect 1994;28:223-232. [15] Odds FC. Candida and Candidosis (2nd ed). Bailliere Tindall, London 1988. [16] Meunier F, Aoun M, Bitar N. Candidemia in immunocompromised patients. Clin Infect Dis 1992;14(suppl l):Sl20-S125. [17] Hadfield TJ, Smith MB, Winn RE. Rinaldi MG, Ceuena C. Mycoses caused by Candida lusitaniae. Rev Infect Dis 1987;9: 1006 1012. [18] Sanchez V, Vazquez JA, Barth-Jones D, Dembry L, Sobel JD, Zervos MJ. Epidemiology of nosocomial acquisition of Cundida lusitaniae. J Clin Microbial 1992;30:300553008. [19] Shepp DH, Klosterman A, Siegel MS, Meyers JD. Comparative trial of ketoconazole and nystatin for prevention of fungal infection in neutropenic patients treated in a protective environment. J Infect Dis 1985;152:1257-1263. [20] Meunier F. Prevention of mycoses in immunocompromised patients. Rev Infect Dis 1987:9:408416. [21] Odds FC. Resistance of yeasts to azole-derivative antifungals. J Antimicrob Chemother 1993;3 1:4633471. [22] Fainstein V, Bodey GP, Elting L, Maksymiuk A, Keating M, McCredie KB. Amphotericin B or ketoconazole therapy of fungal infections in neutropenic cancer patients. Antimicrob Agents Chemother 1987;31:11-15. [23] Troke PF. In vitro and experimental in vivo activities of fluconazole against some fungi causing cutaneous mycoses, p. 199-214. In: Rippon JW, Fromtling RA (eds) Cutaneous Antifungal Agents. Marcel Dekker, New York, 1993. [24] Goodman JL, Winston DJ. Greenfield RA et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. New Engl J Med 1992;326:845-851. [25] 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. J Antimicrob Chemother 1993;31:973-984. [26] Ellis ME, Clink H, Ernst P et al. Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients. Eur J Clin Microbial Infect Dis 1994;13:3-11.
[27] Chandrasekar PH, Gatny CM. The effect of fluconazole prophylaxis on fungal colonization in neutropenic cancer patients. J Antimicrob Chemother 1994;33:309-318. [28] Akiyama H. Mori S, Tanikawa S, Sakamaki H, Onozawa Y. Fluconazole versus oral amphotericin B in preventing fungal infection in chemotherapy-induced neutropenic patients with haematological malignancies. Mycoses 1993;36:373-378. [29] Ellis ME, Hussain Qadri SM, Spence D et al. The effect of fluconazole as prophylaxis for neutropenic patients on the isolation of Candida spp. from surveillance cultures. J Antimicrob Chemother 1994;33:1223-1228. [30] Van Belkum A, Melchers W. De Pauw BE, Scherer S, Quint W, Meis JF. Genotypic characterization of sequential Candidu albicans isolates from fluconazole-treated neutropenic patients. J Infect Dis 1994; 169:1062-1070. [31] EORTC International Antimicrobial Therapy Cooperative Group. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989;86:6688672. [32] Winston DJ, Chandrasekar PH. Lazarus HM et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 1993;118:4955503. [33] Kunova A, Trupl J, Spanik S et al. Candida glabrata, Candidu krusei, non-albicans Candidu spp., and other fungal organisms in a sixty-bed national cancer center in 1989-1993: no association with the use of fluconazole. Chemotherapy 1995;41:3944. [34] Wingard JR. Importance of Candidu species other than C. albicans as pathogens in oncology patients. Clin Infect Dis 1995;20:115125. [35] Bart-Delabesse E, Boiron P. Carlotti A, DuPont B. Candida albicans genotyping in studies with patients with AIDS developing resistance to fluconazole. J Clin Microbial 1993;31:2933-2937. [36] Pfaller MA. Rhine-Chalberg J, Redding SW et al. Variations in fluconazole susceptibility and electrophoretic karyotype among oral isolates of Cundida albicans from patients with AIDS and oral candidiasis. J Clin Microbial 1994;32:59-94. [37] Vuffray A. Durussel C. Boerlin P et al. Oropharyngeal candidiasis resistant to single-dose therapy with fluconazole in HIV-infected patients. AIDS 1994;8:7088709. [38] Odds FC, Bernaerts R. CHROMagar Candida, a new differential isolation medium for presumptive identification of clinically important Candida species. J Clin Microbial 1994;32: 1923-1929. [39] Galgiani JN, Bartlett MS, Espinel-Ingroff A, Fromtling RA, Pfaller MA, Rinaldi MG. Reference method for broth dilution antifungal susceptibility testing of yeasts; proposed standard. NCCLS Pub1 M27-P, NCCLS, Villanova, PA, 1992.
IOLRNII.
08
Antimicrobial Agents International Journal of Antimicrobial Agents 6 (1996) 141-144
Epidemiological shifts in opportunistic and nosocomial Candida infections: mycological aspects Frank C. Odds* Department of Bacteriology and Mycology, Janssen Research Foundation. B-2340 Beerse, Belgium
Accepted 13 November 1995
Abstract Increases in the prevalence: of yeast species other than C. albicuns as agents of disseminated and of fluconazole-resistant C. albicuns isolates from patients infected with HIV indicate
mycoses in immunosuppressed
patients
changes in the epidemiology of Cundida infections, The precise reasons for alterations in prevalence of various agents are difficult to pinpoint but changes in the types of host populations at risk of Cundida infection and selection of resistant yeast populations by widescale usage of certain antifungal agents seem to be factors involved in the process. Greater attention to speciation of clinical yeasts and standardized susceptibility test methods are needed for future epidex&ological surveillance Keywords:
Candida;
Pathogen shift; Azole resistance
1. Candida species as caulsal agents of nosocomial infections The
incidence
of
hospital-acquired
(nosocomial)
Candida infections has increased steadily since the 1970s.
This is probably the combined result of an ever larger number of patients rendered susceptible to mycoses by immunosuppressive procedures, including cancer chemotherapy and transplantation surgery, and a growing clinical awareness of the significance of yeasts and moulds as nosocomial pathogens. Surveys in the USA have shown Candida species as the third most common type of micro-organisms isolated from blood cultures, with an overall prevalence as high as lo-15% in some surveys [ 11. Candida albicans is the most commonly encountered pathogenic yeast: species such as C. glabrata, C. krusei, C. parapsilosis and C. tropicalis are usually isolated much less often than C. albicans. However, there is now evidence from some studies for a decrease in the relative prevalence of C. albicans as other Candida species are
*Tel. (+32-I) 460 3004; Fax (+32-l) 460 5403. 0924~8579/96/$32.00
SSDI
0 1996 Elsevier Science B.V. All rights reserved 0924-8579(95)00049-6
reported more frequently as isolates from neutropenic patients [24]. Moreover, the emergence both of less common Candida species [5-71 and of fluconazole-resistant C. albicans isolates [8-141 has now been documented in oropharyngeal Candida infections associated with AIDS. These changing trends in the epidemiology of opportunistic Candida infections are not always easy to monitor. The prevalence of various species of Candida isolated from clinical materials varies between countries, between institutions and between patient groups [15]. Meunier et al. [16], for example, showed a significantly higher prevalence of C. albicans and C. glabrata among bloodstream isolates from patients with solid tumors and a significantly higher prevalence of C. tropicalis and C. krusei among similar isolates from patients with haematological malignancies. Against such a highly variable background, global changes in species prevalence are inevitably difficult to demarcate precisely. Changes in the nature of the host population at risk and, anecdotally, changes in approaches to yeast identification can both lead to changes in the nature of Candida species causing infection. However, the best documented changes in Candida epidemiology are those attributed to antifungal drug usage.
142
EC. Oddsllnternational Journal of Antimicrobiul Agents 6 (1996) 141-144
2. Emergence of ‘non-albicans’ Candida species as clinical pathogens Candida lusitaniae is a species that was never reported as a cause of disease until after the antifungal agent amphotericin B began to be used very commonly in patients with neutropenia, both for prophylaxis and empirical therapy of sepsis, in the 1980s. C. lusitaniae strains often develop resistance to amphotericin B [17], a factor that may account circumstantially for their emergence as pathogens. The source of C. lusitaniae has been shown to be exogenous [18], whereas species such as C. albicans and C. glabrata are usually carried as endogenous commensals [ 151. Prophylactic use of ketoconazole in neutropenic patients led to the emergence of a higher prevalence of C. glabrata isolates among surveillance cultures in some surveys [19,20] but no similar phenomenon was reported among most prophylactic trials with this antifungal agent [21]. In one therapeutic trial, ketoconazole was found to be ineffective against disseminated C. tropicalis infections [22], however, no subsequent reports have documented an increase in colonization or infection with this species among groups of patients receiving ketoconazole prophylactically. It is impossible to judge the extent to which global pathogen shifts among neutropenic hosts may be attributable to ketoconazole usage, but the very small number of publications suggests that it is low. A more definitive link has been established in several studies showing a rise in the prevalence of C. glabrata and C. krusei as nosocomial pathogens in neutropenic patients treated prophylactically with fluconazole. These two Candida species have an inherently lower susceptibility to fluconazole than does C. albicans [23]. Price et al. [2] specifically incriminated fluconazole prophylaxis as the reason for the decrease in C. albicans bloodstream isolates seen in their hospital (Table 1). Between 1987, when no fluconazole was used in the hospital surveyed and 1992, when 7000 patient doses of the antifungal agent were given, the frequency of C. albicans in blood cultures fell from 87% to 31%. Wingard et al. [3] found all of 10 disseminated Candida infections among 84 patients undergoing bone marrow transplantation who received fluconazole prophylaxis were caused by species other than C. albicans. Of the 10 infections, 7 were caused by C. krusei. These figures compared with historical data showing 27 disseminated Candida infections among 335 similar patients who received no fluconazole, of which 10 were caused by C. albicans, 10 by C. tropicaiis, and only 4 by C. krusei. Studies that established the value and effectiveness of fluconazole in reducing the overall incidence of Candida infections among neutropenic patient populations also pointed to a tendency for species such as C. krusei and C. glabrata to emerge under prophylactic regimens. For example, Goodman et al. [24] prospectively demon-
strated a significant beneficial effect of fluconazole prophylaxis in terms of reduced Candida prevalence in surveillance cultures, superficial infections and disseminated infections. However, the only species not suppressed by fluconazole prophylaxis was C. krusei. which caused 3 systemic infections among the 179 patients receiving the antifungal and 2 among the 177 patients receiving placebo. Similarly, Philpott-Howard et al. [25], who compared prophylactic use of fluconazole and polyenes in neutropenia, encountered just 3 deep-seated Candida infections among the 256 patients on fluconazole prophylaxis as compared with 8 among 255 patients who received polyenes: but all the infections under fluconazole cover were caused by C. krusei. Among haematology patients, Coste et al. [4] reported an increase in C. glabrata isolations from 4.5% to 19.8%, a change they attributed to fluconazole prophylaxis. Emergence of both C. glabrata and C. krusei at higher frequencies in neutropenic patients treated prophylactically with fluconazole as compared with placebo [26,27], polyenes [28] or antiseptics [29] has now been widely confirmed in more recent studies. In one instance C albicans isolated in successive routine surveillance cultures from a neutropenic patient receiving fluconazole prophylaxis showed phenotypic development of resistance to fluconazole in vitro. The C. albicans strain type (determined by RAPD/PCR methods) remained constant despite the phenotypic change to resistance [30]. In contrast to this recent spate of reports describing increased prevalences of C. glabrata and C krusei among patient groups receiving fluconazole, some publications indicate no such change when fluconazole is used for prophylaxis or empirical treatment of presumptive fungal infection [31-331. In one of these studies [33] the average C. krusei prevalence of almost 15% is already much higher than the global average of 34% among cancer patients, calculated in two reviews of published data [ 15,341. The high inherent variation in prevalence of species such as C. glabrata and C. krusei in published surveys has been attributed to differences in patient types, antibacterial drug usage and common-source contamination episodes [34]. Wingard’s review of Candida species epidemiology [34] concluded that there is no definable global increase in prevalence of non-albicans Candida species among cancer patients. It is nevertheless Table 1 Prevalence of various Candida spp.in bloodstream isolates, 1987-1992: fluconazole usage grew from 0 in 1987 to 7000 patient doses per year in 1992 [7] Species
C. C. C. C.
albicans giabrata parapsilosis tropicalis
No. (%) isolated
in
.
1987
1988
1989
1991
1992
47 (87)
41 (75)
39 (85)
9 (15) 5 (8) 5 (8)
5 (11) 2 (4) 0 (0)
51 30 14 17
32 26 20 24
1 (2) 5 (9) 1 (2)
(46) (27) (13) (15)
(31) (26) (20) (24)
RC. Oddslhternational
Journal of Antimicrobial Agents 6 (1996)
noteworthy that only one of the six most recent surveys tabulated by Wingard reported no C. krusei isolates, and the prevalence of this species in the remaining five surveys ranged from 17 to 6 I%, as compared to 0 to 11% in the 32 earlier surveys and a global mean occurrence of 4% [34]. Among HIV-infected patients there has been less evidence of changes in the species of Candida causing oropharyngeal and oesophageal infection than among patients with neutropenia. H.owever, at least three publications have now documented the emergence of C. krusei and C. glabrata in association with fluconazole treatment in this patient group [5-71, so the possibility of selection for these species with low fluconazole susceptibility has to be regarded as a general phenomenon.
3. Emergence of fluconazole resistance among C. albicans strains
The more common finding among HIV-positive patients is the emergence of oral C. albicans strains resistant to fluconazole. This phenomenon has now been very well documented in several published case reports and in cross-sectional and longitudinal surveys [8-131. It has also been described in large numbers of abstracts at meetings [14]. Resistance development is predominantly seen in patients with low CD4 lymphocyte counts, i.e. late in the development of AIDS. Its incidence is estimated at around 10% among HIV-positive patients in some clinics [ 141. Some investigators have typed the C. albicans strains longitudinally as phenotypic resistance to fluconazole develops. In reports so far published, a total of 11 cases where successive C. albicws isolates have developed resistance have been typed at the DNA level: in 10 out of the 11 instances the strain type remained unchanged while the phenotype altered to resistance [35-371.
4. Conclusions
An increasing number of immunocompromised hosts at risk of opportunistic Candidu infections and more widespread use of antifungal agents are both factors that can influence the species and type of yeasts that arise as pathogens. While no specific global trends in yeast epidemiology are yet quantifiable, evidence is available to indicate that changes are occurring. In particular, the widespread use in recent years of fluconazole as a prophylactic and therapeutic antifungal agent in patients with neutropenia and with HIV infections has resulted in changes in the types of yeast causing infections in these clinical settings. The prevalence of ‘non-albicans’ Cundidu species has risen, particularly among patients with neutropenia, and fluconazole-resistant strains of C. albi-
141-144
143
cans have emerged in the course of fluconazole treatment. Similar occurrences were reported previously with ketoconazole usage but far less consistently and on a smaller scale. The current epidemiological trends in Candidu infection have two major implications for patient management. The first is a definitive requirement for identification of yeasts to the species level, at least for isolates from surveillance cultures of patients at risk of disseminated infection and from the oropharynx of HIV-positive patients. The second is for susceptibility testing of yeast isolates from patients at most risk to assist in determining appropriate antifungal agents and appropriate doses. The introduction of CHROMagar Candida, a chromogenic yeast isolation medium that facilitates recognition of some Candida spp. and aids in detection of mixed yeast flora [38] and the publication of a reference broth test for yeast susceptibility determinations [39] are technical advances that should make both requirements easier to fulfill.
References
111Pfaller
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