J. Med. Microbiol. - Vol. 41 (1994), 295-310 0 1994 The Pathological Society of Great Britain and Ireland

REVIEW ARTICLE: CLINICAL MYCOLOGY

Candida krusei: biology, epidemiology, pathogenicity and clinical manifestations of an emerging

YUTHIKA H. SAMARANAYAKE and L. P. SAMARANAYAKE”

Department of Pathology (Oral), Faculty of Medicine and Ord diology Unit, Faculty of Dentistry, University of Hong Kong, 34 Hospital Road, Hong Kong

Summary. Early reports of krusei in man describe the organism as a transient, infrequent isolate of minor clinical significance inhabiting the mucosal surfaces. More recently it has emerged as a notable pathogen with a spectrum of clinical manifestations such as fungaemia, endophthalmitis, arthritis and endocarditis, most of which usually occur in compromised patient groups in a nosocomial setting. The advent of human immunodeficiency virus infection and the widespread use of the newer triazole to suppress fungal infections in these patients have contributed to a significant increase in C. krusei infection, particularly because of the high incidence of resistance of the to this drug. Experimental studies have generally shown C. krusei to be less virulent than C. albicans in terms of its adherence to both epithelial and prosthetic surfaces, proteolytic potential and production of phospholipases. Furthermore, it would seem that C. krusei is significantlydifferent from other medically important Candida spp. in its structural and metabolic features, and exhibits different behaviour patterns towards host defences, adding credence to the belief that it should be re-assigned taxonomically. An increased awareness of the pathogenic potential of this yeast coupled with the newer molecular biological approaches to its study may facilitate the continued exploration of the epidemiology and pathogenesis of C. krusei infections.

Introduction as a human pathogen during the last two to three decades. For instance, from 1960 onwards, > 65 There are nearly 150 asporogenous yeast species articles have been published implicating C. krusei as an presently classified in the genus Candida. Of these, aetiological agent in human disease. Although this C. albicans, C. tropicalis and C. glabrata comprise may be due partly to increased awareness of the > 80% of clinical Candida isolates whle others such organism and improvements in laboratory identifi- as C. krusei, C. parapsilosis, C. guilliermondii and cation methods, there is little doubt that a true C. kefyr are isolated sporadically and are thought to be increase in the numbers of C. krusei infections has less virulent.’ Nonetheless, their importance as medi- occurred during this period. This review emphasises cally important fungi has been recognised from the the features that distinguish C. krusei from other early twentieth century2* and recent data indicate members of the genus, its pathogenicity, epidemiology that > 30 YOof nosocomial candida infections are due and clinical manifestations. to species other than C. albicans.* The belonging to the genus Candida were first Biology discovered by Langenbeck5 in 1839 from buccal aphthae in a patient with typhus, but the suggestion In contrast to a majority of other Candida spp. that C.krusei may cause disease in man was proposed which are ovoid in shape, the cells of C. krusei are by Castellani‘ more than 75 years later. Since then, this generally elongated and have the appearance of “long organism has been generally recognised as a com- grain rice” (fig. I), a feature which they share with C. mensal in warm-blooded animals with very low kejyr (formerly C. pseudotropicalis) amongst clinically pathogenicity and vir~lence.~.However, there has important Candida spp. C. krusei (Castellani been a remarkable increase in the reports of C. krusei Berkhout) measures 2-2-56 x 4.3-1 5.2 pm, with wide variations in the length and the breadth of the isolates (fig. 1). Variation in colony morphology of Received 8 Feb. 1994; accepted 10 May 1994. * Correspondence should be sent to Dr L. P. Samaranayake. C. krusei has also been observed.’

295 2%) Y. H. SAMARANAYAKE AND L. P. SAMARANAYAKE

Fig. 1. Scanning elecrronmtcrographsof three oral isolates of C krusei. a+, varying blastospore size of different isolates together with, b, the hyph,iI phase ot the organ~sins Note the presence of an extracellular material which appears to link the individual blastospores in c. Miercwop> uas performed on colonies of isolates after growth for 18 h on Sabouraud's dextrose agar. Magnification x 5000.

The ultrastructure of C. krusei has been described in cell membrane. The outer layer of flocculent material one article."' This study indicated a multilayered cell appears in abundance in some isolates as extracellular wall comprising six layers and a few intracytoplasmic extensions linking the individual cells, especially dur- organelles such as small vesicles. lipid droplets, ribo- ing growth of colonies on solid media (fig. lc). somes and groups of dense intra-cytoplasmic granules, The a-D-mannan of the cell wall of Candidu spp. is probably glycogen. The multilayered cell wall con- an important constituent of its structure as it acts as a sisted of an outer irregular coat of flocculent material, major antigen. The mannan usually has a (1 -6)-linked an electron-dense zone, a granular layer, a less main backbone with side chains containing (1-2) or (1- granular layer, a thin layer of dense granules and 3) linkages, or Although Nishikawa ct t7l.l:' another sparsely granular layer outside the trilaminar are of the opinion that C.krusei cell-wall mannans are CANDZDA KRUSEI: AN EMERGING PATHOGEN 297

Table I. The frequencies of oral isolation of C. krusei and C. albicans from various patient populations

Sampling technique C. krusei C. albicans Date Reference Patient group (%) (Oh)

1962 Mackenzie2? Hospi t a1 patients Swabs 2.4 65-9 1962 Stenderup and Hospital patients Swabs 1.1 75.6 Pederson2' 1968 Mahgoub2' Children (oral thrush) Swabs 4.0 44-0 1969 Pederson3' Obstetric patients Not stated 0-5 79.2 1969 Grodzka31 Dental patients Smears 2.8 61.1 1974 Denture stomatitis Imprint and smears 2.3 54.7 1974 Respiratory infections Not stated 2.1 801 1975 Budtz-Jorgensen Geriatric patients Swabs 1.7 65.9 et 1978 Odds et Diabetic patients Mouth wash 5.4 73.9 1979 Coudert et Psychiatric patients Not stated 3.0 33.3 1979 Shiprnan3? Cancer patients Saliva 3-1 84.4 1981 Martin et Oral cancer Swabs 1.9 65.8 1982 Staib et aL3' Denture stomatitis Not stated 3.1 62.5 1983 Martin and School children Swab + 71-0 Wilkinson4' 1984 MacFarlane41 Sjorgren's patients Swab + + 1985 Wright et Denture wearers Imprint cultures 6.1 46.9 1987 Fisher et al.43 Diabetic patients Oral rinse 2.8 89.0 1989 Samaranayake et a1.44 Burning mouth syndrome Oral rinse + +

+, no quantitative data. comparable with those of other Candida spp., Kogan is a genus of asexual yeasts,' C. krusei is very closely et al.14 have demonstrated recently that C. krusei related to a sexual species,l* and a sexual form- mannan is different from those of other Candida spp. termed Issatchenkia orientalis-has been proposed for in being lightly branched and containing (1-2) and (1- the organism.19 6) side chains in the ratio of 3 : 1.14 They have proposed a modified structure for a-D-mannan of C. krusei Growth and metabolism where the main chain is lightly branched and consists of 2- and 6-linked units in the ratio 3 : 1. The low cross- C. krusei grows at a maximum temperature of reactivity of C. krusei with antisera raised against 4345°C.Although most of the medically important other pathogenic Candida spp. and its weak immuno- Candida spp. require biotin for growth and some have genicity is more compatible with a short side chain additional vitamin requirements, only C. krusei can structure than with the highly branched 6-linked grow in vitamin-free media.' C. krusei assimilates and structure with longer side chains. Such differences in ferments only glucose out of a large panel of carbo- the cell wall may account for the variable behaviour of hydrate~.'~~2o The only other yeast sometimes isolated C. krusei in biological fluids such as saliva and from medical specimens which reacts similarly is C. bronchial lavage fluid (see section on Pathogenicity) pint01opesii.l~ However, of the medically important when compared with other Candida spp. Indeed, some Candida spp., C. krusei is perhaps the only species argue that C. krusei should be re-classified into a which grows on Sabouraud's dextrose agar as spread- different genus on the basis of its ultrastructure, cell ing colonies with a matt or a rough whitish yellow wall composition and co-enzyme Q numbers.15Recent surface, in contrast to the convex colonies of other molecular biological studies also tend to add credence Candida spp. This characteristic, together with its to this contention, as the average chromosomal num- " long grain rice " appearance on microscopy, helps ber of C. krusei appears to be eight, compared with 16 the definitive identification of the species.21 for C. albicans.16 Interestingly, Barns et aZ.,l' who A complex variety of fatty acids has been demon- evaluated the evolutionary relationship among strated as metabolites when C. krusei is grown in Candida spp., found C. krusei to be the most distantly culture media containing lactose,22it is also able to related to C. albicans of the medically important produce a~etoin.~~It also produces a number of short- Candida spp. Nonetheless, as only the medically chain carboxylic acids when cultured in saliva supple- important species were investigated in this taxonomic mented with glucose ; these include acetate, pyruvate, study, virtually excluding more than 100 other Candida succinate, propionate, formate and lactate.24 The spp. which comprise the genus, further research into biological role of these, if any, is as yet unknown. the true taxonomic position of C. krusei appears to be warranted. C. krusei is usually found in two basic morphological Epidemiology forms, as yeast and pseudohyphae. Both are frequently present simultaneously in growing cultures and may Compared to the medically important Candida spp;, not be separated easily. Despite the fact that Candida C. krusei has been isolated from a large variety of 298 Y. H. SAMARANAYAKE AND L. P. SAMARANAYAKE

Table 11. The frequencies of isolation of C. krusei and C.albicans from the gastrointestinal tract of various patient populations

C. krusei C. albicans Date Reference Patient group Sampling technique Po) ("0)

1968 Schonebeck4' With or without gastric Aspirated by catheter 0.9 52.6 diseases 1968 Bernhardt" Not stated Not stated 3.7 53.1 1969 Cohen ef al." Normal adults Aspirates from small 2.9 71.4 intestine 1974 Brooks et ~1.'~ Pre-vagotomy and post- Aspiration 10.3 79.5 vagotomy 1980 Gordon er al.49 Chronic lymphocytic Pus samples + - ieukaemic patient with intra-abdominal abscess 1985 Di Febo"' Gastric ulcer Biopsies of lesion 2.6 47.3 border

+, no quantitative data.

Table 111. The frequencies of isolation of C. krusei and C. albicans from various patient populations with and without symptoms of

krusei albicans Date Reference Patient group Sampling technique C. C. ("/.I ("/.I

Asymptomatic women 1962 Stenderup and Hospital patients Not stated 5.6 55.6 Pederson2' 1963 Sonck and Diabetic girls Swabs 9.7 55-4 Somersa10~~ 1963 Kearns and Grays2 Gy naecology Not stated 3.2 77.7 1964 Hurley and MorrP; Obstetrics Not stated 5.4 54.9 Hurleys4 1966 Timonen et al.j5 Gynaecology Smear 4.9 37.6 1967 Mahgoub" Pregnant women Swabs 47 60-9 1979 Knippenberger et Gynaecology Not st a ted 4.8 76.9 1981 Bergamashi er Asymptomatic Smear 11-7 83.3 1983 Schonheyder et Pregnant women Swabs 3.0 64.0 1984 Mendling and Pregnant women Not stated 2.7 73.6 Schnel15' 1986 Mondello er ~1.~~Asymptomatic Swabs 7-6 34.8 I986 Guaschino et al." Pregnant women Swabs 5.0 66.3 Symptomatic women 1972 Thiery et a1.62 Vaginal candidosis Swabs 12.5 77.2 1972 Proost et al.63 Vaginal candidosis Swabs 0.7 93.4 1972 Peeters et ~1.~~Vaginal candidosis Swabs 1-9 81.5 1973 Hurley et al." Pregnant women Charcoal swabs 04 90-4 1975 Sparks et ~1."~ Obstetrics Swabs 4-0 86.0 1985 Horowitz et al." Gynaecology Vaginal specimens 0.6 67.9 1986 Breuker ef ~1.~~Gynaecology Not stated 2.2 92.6 1986 Mondello et ~1.~' Gy naecology Swabs 16-1 29.0 1987 Sanz and Del Palaci~~~G ynaecology Not stated 1.7 91.7 1989 Poria ef al." Gynaecology Not stated 11.4 56.8 1989 Gugnani et al." Pregnant women Not stated 5-4 9.2

natural habitats such as the atmosphere, fruits, sewage, C. parapsilosis preceding it. In one large study, the I silage, soil, foods (including dairy and meat products, most common yeast combinations isolated from oral pickles, sugar and syrup-based products), wines and samples comprised C.albicans with one or more of the beer.25Hence it is widely distributed in nature and following: C. krusei, C. tropicalis or C. glabrutu.26 considered to be a facultative ~aprophyte.~~It is also Tables 1-111 summarise the frequency of isolation of found in chickens and seagulls.8 C. krusei from the oral cavity, gastrointestinal tract Generally, C. krusei is considered to be a transient and the vaginal-anorectal area, re~pectively.~~-~' commensal in man and has been isolated only in- frequently from the mucosal surfaces of various patient groups and as a mucosal inhabitant in healthy Pathogenicity individuals.* In his comprehensive review of the Virulencefactors literature on oral carriage of Candida spp., Odds' concluded that C. krusei is the fifth most dominant Candida spp. have several virulence attributes. Some species, with C. ulbicans, C.glabrata, C. tropicalis and of these include adherence to host surfaces, production CANDIDA KRUSEZ: AN EMERGING PATHOGEN 299

___ ~~ of phospholipases and proteinases and formation of of C. krusei and C. albicans, all C. krusei isolates were hyphae, which help evasion of the host immune c. 15 times less adhesive than the C. afbicans defences. Unlike the more pathogenic C. albicans, In a related clinical study where the adhesion of C. relatively few studies have been conducted to de- krusei and C. albicans isolates to BEC from healthy termine the virulence potential of C. krusei in man and individuals and bone marrow transplant patients were laboratory animals. An early investigation by Hurley compared, the adhesion of C. albicans to the latter cells and Stanley72compared the cytopathic effect of C. was three-fold lower than to the control cells, although krusei and other Candida spp. in cell cultures. C. adhesion of C. krusei remained the same.i7 This may krusei, C. kefyr and C. parapsilosis destroyed cultured possibly reflect a selective colonisation process which mouse renal epithelial cells in 48-72 h, whereas the may operate in these patients, possibly due to drug relatively more pathogenic C. albicans, C. tropicalis therapy (see section on C. krusei and antifungal and C. stellatoidea (now re-assigned as C. albicans) agents), and may explain to some extent the frequent induced degenerative changes rapidly, and totally isolation of C. krusei from the mouth in compromised destroyed the cultures in a much shorter period of patient groups.37*38943 24 h. A few workers have examined the adherence of C. Ho~lett~~determined the pathogenicity of C. krusei krusei to non-biological surfaces. T~bgi,~~for instance, with an in-vitro organ culture system comprising the found that the adhesion of C. krusei to denture acrylic dorsal tongue mucosa of neonatal Sprague Dawley strips was the lowest in comparison with several other rats.i3 In the tissues infected with C. krusei, the Candida spp.-including C. albicans. Other 79 grew in both the yeast and mycelial phases, but examining the relative adherence of different Candida generally showed less invasiveness than C. albicans or spp. to acrylic have confirmed these findings. However, C. tropicalis. C. albicans produced extensive epithelial a recent study, with 20 isolates of C. krusei, demon- invasion, penetrating all the layers of the epithelium strated that the adhesion of the latter to acrylic is but C. krusei did not penetrate the stratum corneum, significantly greater than that of C. albi~ans.~~ although a heavy growth of the yeast was observed on Although the variations in these results from different the superficial epithelium. However, a scanty growth centres could be attributable to differences in the of C. krusei into the connective tissues was observed at isolates, techniques and culture media, it is fair to the explant edges. Similar results were also obtained conclude that C. krusei is more adherent to inert for two other Candida spp.-C. parapsilosis and surfaces than to buccal epithelial cells. C. guilliermondii. Cell-surface hydrophobicity is considered to play a Although adhesion to host surfaces is an essential critical role in the initial events leading to colonisation prerequisite for colonisation and subsequent invasion, of host surfaces by Candida spp. and this property, very few workers have investigated the adhesion of C. together with adherence, may have clinical implica- krusei to host epithelial cells. In one early study by tions in fungal infections related to plastic devices such King et al.,74where the in-vitro adhesion of C. krusei as implants and catheters. Klotz et alsohave ranked and other Candida spp. to buccal epithelial cells (BEC) the hydrophobicity of different Candida spp. by was compared, it was observed that the adhesion of measurement of adherence to an aqueous- C. krusei was far less than that of C. albicans. Indeed, hydrocarbon two-phase system. The two C. krusei C. krusei failed to adhere to BEC whereas the other strains they studied were more hydrophobic than C. species tested-C. tropicalis, C. parapsilosis, albicans, C. tropicalis, C. kefyr, C. parapsilosis, C. C. guilliermondii and C. kefyr-adhered but demon- glabrata or C. lipolytica isolates. Otherss' have also strated lower values than C. albicans. In another found C. krusei to be more highly hydrophobic than investigation, Ray et al.75investigated the adhesion of the key, medically important Candida spp. Recently, five Candida spp.; C. albicans and C. stellatoidea we examined the cell surface hydrophobicity of 20 oral exhibited marked adhesion to BEC whereas C. isolates of C. krusei with the aforementioned biphasic tropicalis, C. parapsilosis, C. guilliermondii and C. assay system and found the hydrophobicity of the krusei showed little or no adhesion. However, all these latter to be five-fold greater than that of a panel of studies were conducted with only one or two isolates of C. albicans (Y. H. Samaranayake, unpublished data). C. krusei and hence it is not possible to conclude Minagi ct af.82also observed the cell surface hydro- whether intra-species differences exist amongst dif- phobicity of C. krusei to be similar to that of ferent Candida spp. C. glabrata and C. tropicalis but greater than that of Two recent investigations have employed a larger either C. albicans or C. parapsilosis. A significant number of C. krusei isolates to evaluate the adhesion positive correlation has been reported between the of the fungus to several surfaces. One of these, by adherence of Candida spp. to acrylic surfaces and their T~bgi,~~revealed that seven C. krusei isolates had the cell surface hydrophobicity. 78 However, when saliva- lowest affinity to BEC when compared with a number coated acrylic plates were used, the cell surface hydro- of other Candida spp. that adhered to oral epithelial phobicity as well as the adherence of C. krusei to cells in the following hierarchical order : C. albicans, C. acrylic was significantly decreased. Therefore, it would tropicalis, C. parapsilosis, C. glabrata, C. guilliermondii seem that, of the medically important Candida spp., C. and C. krusei. In a second study with five isolates each krusei is endowed with a greater ability to colonise 300 Y. H. SAMARANAYAKE AND L. P. SAMARANAYAKE

Fig. 2. Scanning electronmicrographs of: a. control : b, apo-lactoferrin-treated C. krusei isolates. Note the bleb-like surface changes and irregular cell surface of the apo-lactoferrin-treated cells. Magnification x 100oO. (From reference 94, with permission.) inert surfaces such as implants and catheters by virtue which either suppressed or promoted extracellular of its cell surface hydrophobicity. polysaccharide formation. One reason for this may be Once attached to an inert substrate, and if left the dual attributes of very high cell surface hydro- undisturbed and provided with adequate nutrition, phobicity and adherence of C. krusei to inert plastic organisms multiply and colonise surfaces with re- surfaces compared with other species (see above) sultant formation of thin pellicles or biofilms. This which may have facilitated biofilm development. phenomenon of biofilm formation by microbes on The ability to produce hydrolytic enzymes such as implant materials (such as urinary catheters, prosthetic phospholipases and proteinases is considered a puta- heart valves, cardiac pacemakers, silicone voice pros- tive virulence factor of Candida spp. However, C. theses. endotracheal tubes and cerebrospinal fluid krusei, in contrast to species such as C. albicans, does shunts) has received considerable attention in the last not possess the ability to produce either of these decade as there appears to be a direct relationship between the ability of an organism to form a biofilm From the foregoing review of the virulence attri- and its pathogeni~ity.'~In a recent study, Hawser and butes of C. krusei, it is evident that the organism is DouglasH4demonstrated, with an in-vitro model, that relatively less virulent than the commonly pathogenic the biofilm formation on the surface of different Candida spp. such as C. albicans. The following section catheter materials varied among Candida spp., and will further elucidate the relative vulnerability of also correlated to some extent with pathogenicity. C. krusei to host defence mechanisms. Thus, less pathogenic species such as C. parapsilosis, C. pseudotropicalis (now C. kelvr) and C. glabrata Host defence .factors produced significantly less biofilm than the more pathogenic C. albicans. Remarkably though, of the There are few studies on the effect of host defence Cundida spp. examined, C. krusei produced the most factors on C.krusei. These mainly relate to the effect of extensive biofilm on the surfaces of polyvinyl chloride constituents of biological fluids such as lysozynie and catheter disks irrespective of the growth medium, lactoferrin. Both are non-immune defence factors CANDZDA KRUSEZ: AN EMERGING PATHOGEN 301

8 8 8

3 8 8 8

8 8

8 Q 0 8 0 m

8 a 8 rn 8 8

glabmta albicans guilliemondii tropicalis parapbsis krusei

Candida spp. Fig. 3. The fungicidal activity of lysozyme (2 ,ug/ml) for different candidal isolates. The higher the Fly value the more sensitive the isolate is to lysozyme. Note the very high susceptibility of C. krusei to lysozyme when compared with the other species. (From reference 96, with permission.) present in human external secretions (e.g., saliva, milk, lysozyme in the following order : C. krusei > C. tears), mucosal surfaces and secondary granules of parapsilosis > C. tropicalis > C. guilliermondii > C. polymorphonuclear leucocytes.88ysg Lactoferrin is albicans > C. glabrata, the latter being the most highly bactericidal in nature and this activity is a direct resistant to lysozyme (fig. 3). Furthermore, C. krusei result of iron sequestration and deprivation of this pre-incubated in sucrose-supplemented media be- element that is essential for bacterial 91 comes highly sensitive to the killing effect of lysozyme Lactoferrin may also interact directly with bacteria, in comparison to C. albi~ans.~’As it is known that altering their perrneabilit~.~~Valenti et aLg3were the C. albicans produces an extracellular floccular layer first to examine the effect of iron-free lactoferrin on a during growth in sucrose-supplemented media,98the single isolate of C. krusei and they reported no increased sensitivity of C. krusei to lysozyme under inhibition of growth or adsorption of lactoferrin on to these conditions appears to be due to the absence of the fungal cell surface. However, a recent study such extracellular material. These data tend to confirm indicated varying degrees of susceptibility to lacto- the observations of Kogan et al.14 that the cell wall ferrin amongst C. albicans and C. krusei isolates.94The structure of C. krusei differs significantly from that of authors demonstrated that C. krusei was almost C. albicans (see above) while indicating that biological 50 % more sensitive to iron-free lactoferrin than fluids such as saliva may exert a selective colonisation C. aZbicansg4and, furthermore, they noted cell surface pressure on different Candida spp., thereby supp- changes such as bleb-like structures and efflux of ressing the growth of more susceptible species such as cellular protein into the test medium due to lactoferrin C. krusei. activity, implying that cell death may be a direct Samaranayake et al.” examined the fungicidal effect consequence of permeability changes (fig. Z).94 of murine bronchial lavage fluid to determine whether The inhibitory effects of lysozyme on C. krusei and respiratory secretions could protect the surfaces of the several other Candida spp. were first demonstrated by lower respiratory tract. Of the five different Candida Kama~a.’~Similar studies have been conducted by spp. examined, C. albicans was the most sensitive, Tobgi et al.,96 comparing the antifungal activity of whereas C. krusei and C.glabrata were highly resistant lysozyme against a battery of Candida spp. They to the activity of bronchial lavage fluid. showed that the Candida spp. were susceptible to After exposure to a primary barrage of anti-candidal 302 Y. H. SAMARANAYAKE AND L. P. SAMARANAYAKE defence factors in the biological fluids which bathe the section is an account of clinical manifestations that C. superficial mucosae, the subsequent disposal of the krusei may cause in hosts with such compromised yeast will be the remit of the immuno-effector cells defences. such as polymorphonuclear leucocytes (PMNLs). Although several investigators have reported the importance of phagocytosis in host defence against Clinical manifestations invasive, deep seated candidosis in general (for a Systemic infect ions review, see Odds') the protective role of phagocytes in C. krusei infections has been evaluated only sparsely. In parallel with the increase in superficial candida Vecchiarelli et ~1.'~~demonstrated the in-vitro kill- infections, there has been a surge in the incidence of ing of C. krusei and several other Candida spp. by systemic candida infections in recent years. This has murine phagocytic cells by means of a radiolabel been related to several predisposing factors, including release micro-assay and measurement of colony the use of immunosuppressive drugs, prolonged forming units. They observed that C. krusei, C. broad-spectrum antibiotic therapy, indwelling intra- quilliermondii and C. parapsilosis were killed by poly- vascular catheters, extensive periods of treatment in morphonuclear and bone marrow cells more rapidly intensive care units and the pandemic of human (1 h) than C. albicans, C. tropicalis and C. uiswanathi immunodeficiency virus (HIV) infecti~n.l~*-'~~ (4 h). Moreover, the effector to target cell ratio was Although C. albicans and C. tropicalis infections have significantly higher for the latter species. Another predominated in these patient populations, the emerg- interesting observation was that C. krusei, C. ence of the less virulent C. krusei as a systemic guilliermondii and C.parapsilosis were more vulnerable pathogen has been described in a number of patients to peritoneal resident macrophages and spleen cells, in with compromised host resistan~e.'~~-~~~ particular, whereas C. albicans and C. tropicalis were In one of the earliest studies in which C. krusei was not affected even in mice immunodepressed with implicated as a systemic pathogen, Young et al.'1° cyclophosphamide. A few other workers have shown a described 70 patients with fungal infections from the similar hierarchy of resistance to intracellular killing National Cancer Institute (Bethesda, MD, USA) of different Candida spp. by macrophages.lO' In a during the decade beginning 1962. Of these, 28 patients cytotoxic colorimetric assay, Borg et al.'O' demon- had C. albicans- and one had C. krusei-associated strated that C. krusei, C.guilliermondii, C.parapsilosis disseminated fungal disease; the rest of the infections and C. glabrata were associated with a lower degree of were other mycoses. C. krusei was observed histologi- cytotoxicity than C. albicans and C. tropicalis. In cally in one or more visceral organs that were not another report, in an in-vitro phagocytosis assay with considered to be the original portal of entry of the rat peritoneal macrophages, phagocytic indices fungus. This is perhaps the earliest documentation of obtained for C. krusei and C. uiswanathi were signifi- C. krusei fungaemia and systemic infection. cantly lower than those for C. albicans and A prospective investigation of surgical and autopsy C. t rop icalis. O2 specimens submitted to the Mycology Laboratory of In animal studies, Bistoni et al.'03 tested the relative the Veterans Administration Centre in Wisconsin, pathogenicity of C. albicans, C.krusei, C. parapsilosis, USA, from 1963 to 1973 was undertaken by Rose and C. tropicalis and C. uiswanathi in normal and Varkey"' to study patients with possible deep fungal cyclophosphamide-immunodepressed mice. In normal infections. Of 123 such patients, 55 (44.7 Oh) infections mice, only C. albicans, C. tropicalis and C. viswanathi were caused by Candida spp. and 28 (22.8%) by were pathogenic on intravenous challenge, with spp. There were 44 patients during the first increased virulence after cyclophosphamide treat- 5 years and 79 during the second period-an increased ment ; the mice were consistently resistant to challenge number which was related primarily to the marked with C. krusei, C. quilliermondii and C. parapsilosis, increase in deep-seated candida infections. The major despite increasing doses of cyclophosphamide. aetiological agent of the 55 patients with candida Although the foregoing data are limited, a consensus infection was C. albicans. Of the 46 patients with view that C. krusei is highly vulnerable to immuno- positive blood cultures, C. albicans was isolated from egector cells. when compared with C.albicans, appears 33 patients, C.parapsilosis from four, C. krusei from to be emerging. two, C. tropicalis from two and C.guilliermondii from Despite the limited information available on the one patient. The main underlying diseases among the pathogenic attributes of C. krusei and its host inter- 55 patients were general surgery, aspiration pneu- actions, it can be concluded that in both these aspects, monia and cerebral sclerosis, although they did not C. krusei appears to be a feeble pathogen when describe the condition of the patient with C. krusei compared with other Candida spp., especially C. infection."' albicms. Hence, the predominant motive force in its Disseminated candidosis was seen in 39 patients conversion from commensalism to parasitism is likely who attended the Presbyterian-University Hospital, to be related to the host within which it may lie USA between 1963 and 1975.'12 These investigators dormant and cause disease in the event of complete or observed a six-fold increase in the incidence of dis- partial failure of host antimicrobial defences. The next seminated candidosis during the last 4 years compared CANDZDA KRUSEI: AN EMERGING PATHOGEN 303 with the first 4 years of the study period. This high C. albicans fungaemias were evenly distributed be- incidence of disseminated candidosis occurred mainly tween patients with haematological and non- in patients with acute leukaemia. Of the 1 1 cases where haematological malignancies. It was also noted that speciation of Candida isolates was considered reliable, other factors such as neutropaenia, chemotherapy, C. krusei accounted for one case, C. stellatoidea for broad-spectrum parenteral antibiotics and oral eight, and C. albicans and C. tropicalis were identified nystatin therapy tended to precede C. krusei or in one patient each. C. tropicalis fungaemia. Sanford et ~1.l'~surveyed the presence of different Arguably, the landmark study that confirmed the species of yeasts in the urine, stool and respiratory importance of C. krusei fungaemia in compromised specimens of 89 immunocompromised patients ad- patients was that of Merz et ~l.~"They evaluated a mitted to the Johns Hopkins Oncology Centre, total of 868 patients admitted to the Oncology Centre Baltimore, MD, USA during the period 1977-1978. Of of the Johns Hopkins Medical Institution, Baltimore these, 37 were recipients of bone marrow transplants, MD, USA (1977-1985) and receiving time sequential 47 were patients with acute leukaemia and five had chemotherapy for haematological malignancies or other haematological malignancies. C. krusei was bone marrow transplantation, to determine the role of isolated from one urine, 13 stool and 17 respiratory C. krusei in systemic candidosis. The patients received cultures. It was also observed that 67 % of the patients chemotherapy that induced a period of profound were colonised by C. albicans and only 28% by C. granulocytopaenia (< 100/mm3)of at least 2 weeks, a tropicalis, C. krusei and C. glabrata. Of the six patients condition conducive to candida infection. They were which were colonised with C. krusei, three produced variably given platelet, blood and leucocyte trans- positive surveillance cultures for 2 weeks or longer. fusions and antibiotics, and urine, stool, rectal swabs Episodes of fungaemia due to various Candida spp. and throat swabs were examined for fungal growth. have been documented by Meunier-Carpenter et al.l14 The two criteria used to delineate C. krusei systemic at the Memorial Sloan Kettering Cancer Centre, USA, infection in this population were isolation of the yeast from 1974 to 1977. In total, there were three patients from two or more blood cultures collected within a with C. krusei fungaemia in comparison to 53 with 72-h period during granulocytopenia, and isolation of C. albicans, 29 C. tropicalis, 26 C. glabrata, 16 the organism and evidence of candidosis from histo- C. parapsilosis and one with C. kelyr (formerly C. pathological findings from tissues taken at biopsy or pseudotropicalis) fungaemia. The underlying diseases autopsy. for the C. krusei fungaemias were leukaemia (one C. krusei was isolated from a total of 108 (12.4 YO) patient) and solid tumour (two patients). They patients during this 9-year study. However, only 46 of surmised that the most important predisposing factors them had persistent colonisation and the number of in these patients were intravenous catheters, chemo- patients colonised each year with C. krusei ranged therapy, neutropenia and antibiotic administration ; from eight to 21. The gastrointestinal tract was most diabetes mellitus, adrenocorticosteroid treatment and frequently colonised (73 YO)followed by the upper radiation therapy accounted to a lesser degree. In respiratory tract (39%) and the urinary tract (6%). comparison to patients with infections due to other Seven of the patients died within 1 month of C. krusei Candida spp. who had multiple positive sites for the sepsis; systemic candidosis was seen in four patients respective organisms, all three C. krusei fungaemia on whom autopsies were performed. patients had only one positive site for the yeast other Finally, there is a single case report of disseminated than the blood cultures and in all cases this was their C.krusei fungaemia in a 23-year-old male patient who respiratory tract, as the yeasts were isolated from had acute lympho~arcorna."~ The patient was sputum. Although all three patients with C. krusei diagnosed as having disseminated candidosis and fungaemia died, it was difficult to attribute death to the treated with . A few days later C. krusei fungaemia. These early studies tended to suggest that was grown from blood and faecal cultures. After C. krusei is not merely an innocuous commensal but recovering completely the patient died 2 months later; has the potential to cause serious infection in patients post-mortem exaniination did not reveal any evidence with underlying immunosuppressive disease. of disseminated candidosis. Since the realisation of the importance of C. krusei A series of reports on C. krusei fungaemia in patients fungaemia in compromised patients, other studies who are on the newer triazole antifungal agent, have followed. Horn et allo6reported 200 episodes of fluconazole, has appeared. This has wide therapeutic fungaemia in 188 patients in the Memorial Sloan and clinical implications, as discussed in the pen- Kettering Cancer Institute, USA, between 1978 and ultimate section of this review. 1982, of which seven were due to C. krusei in comparison with 89 patients with C. albicans Ocular infections fungaemia. Whereas most episodes of C. krusei fungaemia occurred in patients with leukaemia, The most important ocular manifestation of C. lymphoma or aplastic anaemia, most episodes of C. krusei infection to date has been endophthalmitis. parapsilosis and C. glabrata fungaemia occurred in Previous citations on candidal endophthalmitis have patients with solid tumour or non-neoplastic diseases ; largely been related to infections with C. albicansl'" 11' 304 Y. H. SAMARANAYAKE AND L. P. SAMARANAYAKE although other species such as C. tropicalis, C. Miscellaneous infections purapsilosis, C. glabrata and C. guilliermondii have been reported sporadically to be associated with Arthritis due to Candida spp. is uncommon and the haematogenous endophthalmitis. '18 involvement of C. krusei as a causative agent is There are three case reports of C. krusei endoph- extremely rare. There has been a report of arthritis thalmitis. The first describes C. krusei fungaemia caused by C. krusei in a heroin addict who had together with endophthalmitis in a 70-year-old man leukaemia and was neutropenic. 120 The 4 1-year-old who was admitted for elective abdominoperineal patient was undergoing cytotoxic drug therapy for resection for a recurrent rectal adenocarcinoma."* relapse of acute myelogenous leukaemia. Following After surgery, total parenteral nutrition through a chemotherapy, he became neutropenic and was in an peripheral intravenous catheter was administered. The isolation chamber without prophylactic antibiotic or patient developed high fever 15 days after surgery and antifungal therapy. On the 10th day of hospitalisation, blood cultures yielded C. krusei. Endophthalmitis in C. krusei was grown from five sputum cultures and a the left eye due to C. krusei was diagnosed and the urine culture. However, blood cultures were negative patient recovered after receiving intravenous ampho- for fungi. Fever persisted and on the 21st day swelling tericin B. and tenderness of the right knee occurred and synovial In the second case, a 69-year-old man with acute fluid obtained by arthrocentesis revealed C. krusei. On myeloid leukaemia was found to have endophthalmitis the 27th day in hospital, after C. krusei was grown due to C. krusei."' The patient initially experienced from the second aspirate, intravenous amphotericin B recurrent fever despite negative culture, although he was started, On the 29th hospital day the patient was was persistently neutropenic. At this stage, pipera- discharged to receive amphotericin B intravenously cillin, gentamicin and induction chemotherapy was three times weekly as an outpatient. After cessation of administered. Blood cultures on the 20th day of the antifungal therapy, swelling and tenderness of the hospitalisation yielded C. krusei, although there was right knee recurred. Amphotericin therapy was re- no evidence of retinitis. Cultures of the central venous instituted and after 3 months there was no clinical line tip yielded a moderate growth of C. krusei. On day evidence of arthritis. Arthritis in this case was possibly 32, fundoscopic examination revealed two white a consequence of haematogenous spread, as the patient infiltrates near the macula of the right retina which was was colonised in the respiratory tract and the urinary consistent with candidal retinitis. However, the patient tract with C. krusei. It is noteworthy that arthritis recovered and by day 48 was no longer neutropenic. caused by C. albicans is more common as haema- When the patient died 3 months later, there was no togenous joint invasion complicating disseminated evidence of candidal infection. candidosis, although it is more often polyarticular A third case report of endophthalmitis due to C. than mono-articular. 21 krusei was in a man with acute myeloid leukaemia who Candidal endocarditis is a frequent occurrence was on induction The patient be- among intravenous drug abusers. In one survey Odds' came neutropenic, developed fever on day 20 and 2 estimated that one-fifth of candidal endocarditis days later several cutaneous lesions were observed. occurs in the latter group. C. afbicans and C. Two blood cultures obtained from a peripheral vein on purapsifosisaccounted for the vast majority of reported day 20 were positive for C. krusei. In spite of treatment cases,' but 3.7 Oh of 163 cases in the latter survey were with liposomal amphotericin B, the fever persisted and due to C. krusei. The detailed clinical features of these on day 32 the patient developed candidal endoph- case reports are sparse. Rubinstein et a1.lz2described a thalmitis. He subsequently recovered from endoph- case of C. krusei endocarditis in a 36-year-old male thalmitis, but several months later experienced a heroin addict who had fever and heart failure. relapse of leukaemia and died. Autopsy results Although the patient was treated with intravenous revealed no sign of recurrent fungal infection. amphotericin B he subsequently died. Autopsy exam- A corneal ulcer due to C. krusei has also been ination revealed myocardial abscesses, aortic vegeta- described in another report .'I9 A 45-year-old female tion and septic emboli due to C. krusei. farmer complained of pain, redness, swelling and Renal candidosis is usually seen in patients with pre- lacrimation in the left eye. Prior to the isolation of the existing renal pathology and diabetes is the most aetiological agent the patient was given penicillin, common single underlying condition. Candida in- oxytetracycline eye ointment and atropine drops and fection is usually obstructive, with fungal material chloramphenicol. The condition deteriorated with often referred to as "fungus balls" collecting in the swelling and diminution of vision and 10 days later renal pelvis. As in the case of other candida infections, fungal cultures were positive for C. krusei. The patient C. albicans is the most common species implicated in recovered her vision after topical and intravenous renal candidosis and C.krusei infection is still a rarity. amphotericin B therapy. Interestingly, in animal In a review of 74 cases of renal candida infection, 86 YO experiments, the C. krusei isolate produced endoph- were caused by C. albicans and 2.7 YOby C. krusei.' A thalmitis in three compromised albino rabbits. In- case report by Thomalla et represents a rare fection developed in all eyes that were tested within involvement of C. krusei leading to the ureteral 24-72 h after inoculation. obstruction. An immunosuppressed 29-year-old CANDIDA KRUSEI: AN EMERGING PATHOGEN 305

Table IV. Sensitivities of C. krusei and C. albicans to antifungal agents

Name of Number of MIC range Yeast References anti fungal isolates Olg/ml)

Amphotericin B C. krusei 133 0.05-> 6.25 Athar and Winner,124Bergan and Vangdal,125Hamilton- Miller,126Hopfer and Grosche1,12' King et a1.,12' Oblack et al.,12' Potel and Arndt,13' Seidenfeld et al.,131 Tortorano et C. albicans 2318 0.054 McGinnis and Ri~~aldi'~~ Nystatin C. krusei 105 0.5-25 Athar and Winner,124Bergan and Vangdal,125Potel and Arndt13' C. albicans 1642 0.78-> 100 McGinnis and Rinaldi133 Clotrimazole C. krusei 37 < 0.5-1 Akgun and Ak~it,l~~Bergan and Vangdal,125Hamilton- Miller,12' Jacob et ~l.,'~~Potel and Arndt,13' Saubolle and Hoepri~h,'~~Shadomy et all3' C. albicans 1200 0.0 1-50 McGinnis and Ri~~aldi,'~~ Econazole C. krusei 34 0 125-1 2.5 Bergan and Vangdal,125Potel and Arndt,13' Schar et ~1.l~' C. albicans 283 0.016-25 McGinnis and Ri~~aldi,'~~ Ketoconazole C. krusei 37 01-10 Bergan and Vangdal,125Drouhet and Dupont,13' Moody el al.,14' Odds et al.,141 Van Cut~eml~~ C. albicans 976 0*01-> 100 McGinnis and Ri~~aldi'~~ Miconazole C. krusei 40 < 0,063-6.25 Bergan and Vangdal,125Moody et al.,14' Potel and Arndt,13' Schar et al.13* C. albicans 1815 0-016-100 McGinnis and Rinaldi,133 Fluconazole C. krusei 7 0*019-100 Arzeni et ~l.,'~~Fisher et al.,144Morace et ~l.,'~~Wingard et ~1.''~ C. albicans 75 0.0 19-20 McGinnis and Ri~~aldil~~ I traconazole C. krusei 7 0.009-5 Arzeni et ~1.l~~ C. albicans 1474 0.063-1 28 McGinnis and Ri~~aldil~~ 5-Flurocytosine C. krusei 85 0*1-> 25 Bergan and Vangdal,'25 Drouhet et al.,146Hamilton-Miller,126 Hopfer et al.,14' Marks et al.,14' Pawlik and Barylak,14' Potel and Arndt,13' Speller and Davies,15' Tortorano et ~1.l~~ C. albicans 4382 0*016-> 100 McGinnis and Ri~~aldi,'~~ Pimaricin C. krusei 30 1-4 Potel and Amdt13' C. albicans 289 1-100 McGinnis and Ri~~aldi'~~

woman presented with renal dysfunction. On cysto- only one group has directly compared the scopic examination, an erythematous papillary lesion MICs for C.krusei with those of other Candida spp.,151 involving the ureteral orifice was observed; histo- and they too report higher MICs for C. krusei than for logical examination of a biopsy sample revealed other species. This issue has been further compounded chronic inflammation and oedema and C. krusei was by the discordant correlation of in-vitro testing with isolated on culture. The patient was given intravenous outcome in vivo (for a recent review see Rex et ~1.'~~). miconazole and bladder irrigation with amphotericin For the azole derivatives, especially, the outcome of B. The infection proved to be very difficult to eradicate the in-vitro susceptibility tests depends on the methods but resolved eventually after 11 weeks of combination and media used and also on other variables such as the therapy with ketoconazole, amphotericin B and endpoint definition, inoculum size, inoculum prep- flucytosine. aration, incubation conditions and the nutritional requirement of the 151-153 Another key prob- lem in interpreting antifungal susceptibility test results Antifungal agents is the partial inhibition of growth with azoles. Ac- cording to Odds et aZ.,154the activity of fluconazole The most widely used antifungal agents are the against Candida spp. in vitro appears to be the hardest polyenes and the azoles, which include the imidazoles to determine meaningfully, being heavily dependent and the newer triazoles. As it is beyond the scope of on the culture medium used. Hence, future workers this review to dwell in detail on the antifungal need to review the available data by means of a sensitivity patterns of C. krusei and their clinical standardised assay method such as the National implications, we provide for reference purposes, in Committee for Clinical Laboratory Standards table IV,124-150the relative MICs of various antifungal (NCCLS) reference method for MIC dete1minati0n.l~~ agents against C. krusei and C. albicans. However, Notwithstanding these reservations, there is an because of the generally expressed concerns of the emerging consensus that C. krusei isolates demonstrate emergence of fluconazole-resistant C. krusei isolates, a high level of resistance to fluconazole-widely used some aspects related to this problem are discussed in the empirical treatment of patients with immuno- below. deficiencies, especially HIV-infected individuals. The Although fluconazole MICs for individual C.krusei clinical implications of this problem are discussed in isolates have been reported as elevated by some some detail below. 306 Y. H. SAMARANAYAKE AND L. P. SAMARANAYAKE

et ul.16' also concluded that fluconazole can be krusei andflucoriazo/e fherapj7 c. administered effectively to reduce the incidence of Fluconazole is highly active against several patho- systemic mycoses in severely immunosuppressed gens that cause systemic mycoses.1J6 It is a triazole patients, although they noted a tendency towards with a low mol. wt and unique pharmacokinetics- increased isolation of C. krusei during therapy and good water solubility, weak protein binding, long more episodes of candidaemia due to C. krusei in half-life and high level of cerebrospinal fluid pene- patients who received this drug. tration. It is well absorbed after oral administration Other case reports of failure of fluconazole therapy and has been effective in treating both superficial157 include the following. Roder et described con- and systemic candida infections.'" It has emerged as sistent growth of C. krusei from at least six blood the drug of choice for prophylaxis of oropharyngeallJ9 cultures of a patient during treatment with fluconazole, and systemiclG0candidosis in HIV-infected patients. suggesting that this agent was ineffective against Despite the initial claims of the efficacy of fluconazole C. krusei. In another report reaffirming the failure in candida infections in general, studies in animals of C. krusei infection to respond to therapy with and man have now demonstrated both prophylactic fluconazole, Akova et quoted three immuno- and therapeutic failure of fluconazole against C. suppressed patients who developed oropharyngeal C. krusei,105.1<53. 161 168 Furthermore, it is possible that the krusei infection with ulceration after fluconazole treat- increase in colonisation and infection of human ment. Furthermore, the development of C. krusei patients by C. krusei which has been documented in sepsis in an HIV-infected patient during fluconazole the last few years is partly attributable to the treatment was described by Stellbrink et al."l widespread use of this drug as a prophylactic anti- Taken together, these data strongly indicate that the fungal agent. administration of fluconazole, especially in low doses, Immediately after the approval of its use in early as a prophylactic antifungal agent in immuno- 1990, fluconazoie was used as a prophylactic anti- compromised patients may result in the emergence of fungal agent in recipients of heart and bone marrow resistant C. krusei strains. Hence, controlled clinical transplants.'05,169 In one study conducted by Good- trials of prophylactic and therapeutic use of triazoles man el al.,'69patients receiving bone marrow trans- for disseminated candidosis appear to be warranted plants were randomly assigned to receive fluconazole before their widespread recommendation as a primary (400 mg daily) or placebo. By the end of the treatment therapeutic agent. Furthermore, it should now be period 28 of 177 patients in the placebo group mandatory to identify Candida isolates to species level developed systemic fungal infections, two of which whenever fluconazole is to be used for treatment of were due to C. krusei. In comparison, five of 179 systemic mycoses. patients who received fluconazole developed systemic fungal infections of which three were due to C. krusei. Conclusions This study demonstrated that although fluconazole prevents infection with most pathogenic Candida spp. The biology, epidemiology, pathogenicity and clini- it does not eradicate C. krusei. cal manifestations of C. krusei have been reviewed. In another retrospective study of 463 bone marrow The available data indicate that C. krusei is signifi- transplant and leukaemia patients, there was a seven- cantly different from other medically important fold greater incidence of blood stream or visceral Candida spp. in its structural and metabolic features infection with C. krusei in 84 patients who received and that it exhibits different behaviour patterns fluconazole prophylaxis than in 355 patients who towards host defences, thus adding credence to the received other modes of prophylaxis, including ampho- belief that it should be taxonomically re-assigned. tericin B, miconazole and ketoconazole, or no prophy- Experimental studies have generally shown that C. laxis.'05 The foregoing observations suggest that the krusei is less virulent than C. albicans in terms of its prophylactic use of fluconazole in immuno- adherence to epithelial and prosthetic surfaces, pro- compromised patients, while decreasing the frequency teolytic potential and production of phospholipases. of fungal infection caused by C. albicans and C. Early reports described this organism as a sporadic tropicalis may also promote the emergence of resistant isolate of minor clinical significance, but more recently such as C. krusei. it has emerged as an important nosocomial pathogen. Several other reports have documented the devel- The most common clinical manifestation of C. krusei opment of resistant strains of Candida spp. after the is disseminated fungaemia in compromised patients, use of fluconazole as a prophylactic agent or as especially leukaemia patients. The advent of HIV primary therapy for superficial candidosis.16G168.li0 A infection and the widespread use of the newer triazole recent study by Casasnovas et a1.l" also strongly fluconazole to suppress fungal infections in these supports these reports and suggests that fluconazole is individuals have contributed to a significant increase not the ideal antifungal agent for preventing C. krusei in C.krusei infection, particularly because of the high infections. The author observed a high incidence incidence of resistance of the yeast to this drug. Other (I I Oh) of C. krusei septicaemia in patients with focal infections due to C. krusei include endoph- neutropaenia who received fluconazole. Goodman thalmitis, arthritis and endocarditis, which are usually CANDIDA KRUSEI: AN EMERGING PATHOGEN 307 related to invasive procedures superimposed on a ecular biological approaches to its study should compromised host defence system. Thus the epithet enhance our understanding of the epidemiology and “an emerging pathogen” could justifiably be given to pathogenicity of this important nosocomial pathogen. this yeast, not least because of a putative increasing incidence of C. krusei infection, due partly to the HIV Y.H.S. was a recipient of a post-graduate studentship of the University of Hong Kong. Some of the unpublished studies quoted pandemic. An increased awareness of the pathogenic in the text were funded by a research grant from the Committee for potential of this yeast coupled with the newer mol- Research and Conference Grants of the University of Hong Kong.

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~ ~~

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