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IMMUNOLOGY AND

MEDICAL

MICROBIOLOGY

FEMS Immunology and Medical Microbiology 23 (1999) 75-78 ELSEVIER

Short Communication

Invasive infections due to Clavispora lusitaniae

Vladimir Krcmery Jr. al*, Frantisek Mateicka a, Sylvia Grausova ', Alena Kunova b,

Jan Hanzen '

a University oj' Trnava, School of Public Health and Postgraduate Medical School, 917 43 Tmava, Slovak Republic

" Department qf Oncology. Department of Microbiology, National Cancer Institute and St. Elisabeth's Cuncer Institute, Bratislava.

Slovak Republic

' Llepartment of Microbiology, HP Microbiology Centre. 841 01 Bratislava, Slovak Republic

Received 22 May 1998; received in revised form

24 August 1998; accepted 6 October 1998

Abstract

Three cases of Cluvispora Zusitaniue invasive fungal infections are reported. All three infections appeared in cancer patients

presented with fungaemia, one additionally with meningitis. Two of them were breakthrough - they developed during therapy

with conventional amphotericin B with a dose of 0.5 mg kg-' day -I. All three were cured: two with intravenous fluconazol and

one with an increasing dose (1 mg kg-' day-') of amphotericin B. In one of two breakthrough cases the sensitivity of the strain

to antifungals was tested against antifungal agents and showed in vitro resistance to amphotericin B (MIC 2 qg ml-'). 0

1999 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.

1. Introduction

Clavispora lusitaniae (named until 1996 Candida

(C.) lusitaniae) were emerging fungal organisms and the first cases of infection in humans were described in 1979 [1,2]. Since 1979, 5 cases and 1 review of fungaemias due to Clavispora lusitaniae have been published [3-71 which suggested that this yeast can cause systemic infection and even death. Before the introduction of antineoplastic therapy in cancer pa- tients, the incidence of Clavispora Iusitaniae among fungal isolates from blood cultures was very low [1,8]. Large studies on the epidemiology of fungal infections showed a 14% incidence of Clavispora * Corresponding author. Heydukova 10, Bratislava 812 50,

Slovak Republic. Tel.: +4.21 (7) 324 308;

Fax: +421 (7) 5311278. lusitaniae among all isolates until 1990. After 1990 the incidence of this pathogen increased to 2-8% [10P13]. Since Clavispora lusitaniae is known to de- velop secondary resistance to AmB [1,2] and some strains may be primary resistant [7,8], extensive use of non-absorbable polyenes in the prophylaxis and the large use of amphotericin B (AmB) in therapy may play a role in selection of less susceptible or 'polyene-tolerant' yeasts (Clavispora lusitaniae, C. quillermondii, C. parapsilosis, C. rugosa, Trichosporon beigelli) [1,8]. There are no data on comparable vir- ulence of Clavispora lusitaniae to other non-candida spp. yeasts such as Trichosporon beigelli or Candida albicans. However, at least 6 reports document inva- sive Clavispora lusitaniae infection in immunocom- promised humans, mainly those with haematologic malignancies. Here we report another 3 cases of in- vasive infection (3 fungaemias, one with meningitis)

0928-8244/99/$19.00 0 1999 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.

PII: SO928-8244(98)001 10-2 Downloaded from https://academic.oup.com/femspd/article/23/1/75/491184 by guest on 24 October 2023

16 Table 1 V. Krcrnery Jr. et al. IFEMS Immunology and Medical Microbiology 23 (1999) 75-78 Three fungaemias due to Cl. lusitaniae - risk factors, therapy, complications and outcome Age Underlying Risk factors Breakthrough" Source of disease (thlprophld) fungaemia Therapy Compli- cations Out- come

22 NHL Cathe- ter

29 Testicular +

cancer

3 CNS +

tumour ATB Ster- ATB pro- Neutro- th. oids phylaxis penia + - _ + AmB 0.5 mg kg-' Unknown AmB+CR 10 days None Cured

6 days 0.7 mg kgg' and

1 mg kg-' day-'

_ + AmB 0.5 mg kgg' Unknown FLU 5 mg kg-' None Cured

5 days 20 days

_ _ AmB 0.5 mg kgg' VP-shunt FLU 6 mg kg-' Meningitis Cured

11 days 28 days

"Drug, daily dose, length of therapy.

VP: ventriculoperitoneal; CR: catheter removal; FLU: fluconazole; AmB: amphotericin B; NHL: non-Hodgkin's lymphoma; CNS: central

nervous system. due to Cluvispora lusitaniae and briefly review the recent literature.

2. Patients and methods

2.1. Ident$cation of isolates

Identification was carried out with Vitek Jr. Sys- tem (Bio Merieux, Hazelwood, USA) and confirmed either by API-32 ID (Bio Merieux) or Mycotube (Roche) rapid identification systems. Only in one case (number 3) the isolate was in vitro tested for antifungal susceptibility with E-test [7] as recom- mended by the manufacturer (AB BIODISK, Solna,

Sweden) with RPM1 1640 agar. Zones were deter-

mined with automatic BIOMIC video. The strain showed MIC to AmB 2 ug ml-' and fluconazole

1 yg ml-l which represents resistance to convention-

al AmB but sensitivity to fluconazole according to NCCLS standards [14]. Susceptibility to fluconazole was reconfirmed with disc diffusion method on Mill- er Hinton's agar with 2% glucose and 5 pg ml-' methylene blue, with inoculum adjusted to density

0.5 MC Farland. Fluconazole discs 25 pg (Becton

Dickinson) were used. Inarbation was at 35°C for

24 h.

2.2. Cases studied

All three cases appeared in 1995-1997 in our can- cer institute with 220 beds but were sporadic (6 months difference among case 1 and 2 and 8 months between case 2 and 3) (Table 1). From 3 fun- gaemias, two appeared in young adults, one in a child. The underlying diseases were malignancy in all 3 cases. Two out of the three received antineo- plastic chemotherapy, all received antibiotics (third generation cephalosporines all three, two aminogly- cosides, one vancomycin). In the first two cases, fun- gaemia developed during therapy with conventional amphotericin B (dose 0.5 mg kg-' day-l) on day 5 and day 6 of therapy, respectively, who received con- ventional AmB because of non-responding neutro- penic fever. In the first, the dose was increased to

0.7 and 1 mg kg-' day-l later on, and the patient

was cured. In the second and third patient, AmB therapy was stopped and fluconazole was adminis- tered at 6 mg kg-l day-' for 20 and 28 days. All patients survived although one case of fungae- mia (number 3) was complicated with meningitis. In this case with meningitis both in vitro (MIC for

AmB 2 mg ml-l) and clinical (absence of response

to therapy with conventional AmB 0.5 mg kg-' day-l after 11 days) resistance was observed. The third child with fungaemia and meningitis had ven- triculoperitoneal shunt insertion after removal of a neuroblastoma and was cured after 8 days therapy with 6 mg kg-l day-'. The first two strains isolated from case 1 and 2 were not tested in vitro because no standard method for susceptibility testing of yeasts

in Slovakia was available until 1997. Downloaded from https://academic.oup.com/femspd/article/23/1/75/491184 by guest on 24 October 2023

Table 2 V. Krcmery Jr. et al. I FEMS Immunology and Medical Microbiology 23 (1999) 75-78 Review of invasive infections due to Clavispora Iusitaniae

References

No. of cases Sensitivity to AmB Type of infection Outcome

Guinet et al. [5]

Hadfield et al. [6]

Christenson et al. [4]

Merz et al. [3]

Pappagianis et al. [2]

Favel et al. [7] 1 Resistant

2 ND 1 ND

Review Various

1

Resistant

1 Sensitive Fungaemia

Fungaemias

Fungaemia

Fungaemias

Fungaemia

Fungaemia Death Cured Cured

Review

Cured Cured

3. Discussion and review of the literature

The incidence of Cluvispora lusitaniae before intro- duction of aggressive cytotoxic therapy (and empiric therapy with AmB or prophylaxis with oral polyenes during neutropenia) was minimal, and varied from

0 to 1% [l-3,9]. After 1990, the majority of large

epidemiologic studies [lo-13,161 showed a l-8% in- cidence of Clavisporu hktuniae, which was lower in general hospitals or ICUs (O-3%) than in cancer centres (3-S%) [8-131. In addition, in paediatric can- cer centres [19] the incidence was higher (337%) than in adults, probably because children with cancer are treated with more non-absorbable nystatin or oral amphotericin B than adults, who are exposed more to fluconazole (which was licensed in most European countries for paediatrics only after 1993). Clavispora lusituniue was not reported before 1979 to cause in- vasive infection in humans. After the first reported case in 1979 [2], one review [3] and 6 additional cases have been published [2-71 including 6 fungaemias (Table 2). Two of them were caused by AmB resist- ant Clavispora lusitaniae, one by organisms sensitive to AmB and in other cases susceptibility was not tested. However, antifungal susceptibility testing ac- cording to NCCLS [14] methods was only performed in one case [7]. Themfore, the clinical outcome of other cases where strains were either not tested [3,4,6] or were in vitro sensitive to AmB [7] may predict in the rest of lungaemias that strains of Cla- vispora lusitaniae in those cases (except 2 and 5) were probably AmB sensitive. However, correlation of in vitro susceptibility testing to clinical outcome in many non-Candida albicans spp. is not clear [ 15,17,18]. In addition, a paper published on antifun- gal susceptibility testing [7] showed that 35 tested strains were susceptible in vitro to AmB. However,

at least two reports [2.,5] clearly showed emergence of AmB resistance during therapy with AmB. Wingard

[l] in his review suggested emergence of AmB resist- ance in cancer centres and in patients receiving anti- neoplastic chemotherapy and empiric AmB, but not in the non-cancer patient population. All three of our patiens had fungaemia which appeared during empirical therapy with AmB but the strain was tested only in one and was resistant in vitro (MIC

2 ng ml-l). In two other cases of breakthrough fun-

gaemia, Clavispora lusitaniae was not tested against antifungals.

All our 3 patients survived and were successfully

treated, two with fluconazole and one with increas- ing doses of amphotericin B from 0.5 to 0.7 mg kg-' day-i and later with 1 mg kg-l day-'. In 6 cases published in 5 clinical reports or letters and 1 review, only 1 case died. The data extracted from various epidemiologic studies on the incidence or prevalence of Clavispora lusitaniae among other yeasts or Can- dida spp. fungaemias do not present mortality sepa- rately for Clavispora lusitaniae [8-13,161. When add- ing 3 of our cases to 6 previously published cases, only one of 9 (11.1%) died despite the fact that all patients were immunocompromised. This may sug- gest that the outcome of patients infected by Cluvi- spora lusitaniae in comparison to C. albicans or Tri- chosporon spp. is better and that Clavispora lusitaniae is probably less virulent than C. albicans [l].

References

[l] Wingard, J. (1995) Importance of Candida spp. other than C. albicnns as pathogens in oncology patients. Clin. Infect. Dis.

20, 115-125.

[2] Pappagianis, D., Collins, MS.. Hector, R. and Remington, J. (1979) Development of resistance to amphotericin B in Can- dida hrsitaniae infections in human. Antimicrob. Agents Che-

mother. 16, 1233126. Downloaded from https://academic.oup.com/femspd/article/23/1/75/491184 by guest on 24 October 2023

78 V. Krcmery Jr. et al. IFEMS Immunology and Medical Microbiology 23 (1999) 75-78

[3] Merz. W.G. (1984) Candida hsitaniae, frequency of recovery colonisation. infection, and amphotericin B resistance. J. Clin.

Microbial. 20. 11941195.

[4] Christenson. J.C., Guruswamy. A., Mukwaya. G. and Rettig, P.J. (1987) Candido lusitaniue, an emerging human pathogen.

Pediatr. Infect. Dis. J. 6. 755-757.

[S] Guinet, R., Chanas. J., Goulier, A.. Bonnefoy, G. and Ambroise-Thomas. P. (1983) Fatal septicaemia due to ampho- tericin B resistant Candida lusitaniae. J. Clin. Microbial. 18.

443444.

[6] Hadfield, T.L., Smith, M.B., Winn, RI?., Rinaldi, M.G. and Guerra. C. (1987) Mycoses caused by Candido lusitaniae. Rev.

Infect. Dis. 9, 10061012.

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