Copyright ª Blackwell Munksgaard 2006
Clin Transplant 2006: 20: 318–324 DOI: 10.111/j.1399-0012.2005.00484.x
Oral candidiasis prevention in transplantation patients: a comparative study Elad S, Wexler A, Garfunkel AA, Shapira MY, Bitan M, Or R. Oral candidiasis prevention in transplantation patients: a comparative study. Clin Transplant 2006: 20: 318–324. ª Blackwell Munksgaard, 2006 Abstract: Aim: Oral candidiasis occurs commonly in haematopoietic –stem cell transplantation (HSCT) patients carrying a risk of systemic candidemia and mortality. The aim of this pilot study was to design an effective protocol that prevents oral candidiasis and improves tolerability. Methods: A prospective, randomized, longitudinal study with two treatment groups, (A) chlorhexidine (CHX) and (B) CHX combined with medium-dose amphotericin B (AMB), was performed. The investigators were blinded to the treatment arm. Results: No clinical signs of oral candidiasis were observed in any of the 20 patients. All patients experienced neutropenia and were treated with antibiotics. The duration of antibiotic treatment was longer in group A than that in group B. The difference in systemic anti-fungal treatment was insignificant. Compliance was achieved in both groups, although tolerability was better in group A than that in group B. Conclusion: Effective oral anti-fungal prevention based on topical AMB was suggested. CHX mouthwash was also suggested to be effective as a single topical agent for the prevention of oral candidiasis in HSCT patients. The combination of topical CHX and medium-dose AMB-prophylactic protocol may achieve the same level of candidial prevention with better tolerability than that by AMB alone. More research is warranted.
Oral candidiasis is a frequently reported complication in patients undergoing haematopoietic stem cell transplantation (HSCT). The major risk of oral candidiasis in the severely immunocompromised is the development of candidemia. Disseminated fungal infections were the cause of death in 22– 56% of HSCT patients at autopsy (1). Candidiasis develops because of decreased host defenses following the conditioning regimen of HSCT, consisting of immunosuppressive and cytotoxic therapy with or without total body irradiation. This regimen damages the oral mucosa, which usually functions as a protective barrier to infection and causes neutropenia. The combination of prolonged neutropenia and empiric broad-spectrum antibiotic treatment disrupts the balance of ecologic oral flora, enhancing the proliferation of Candida (2).
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Sharon Elada, Alon Wexlera, Adi A. Garfunkela, Michael Y. Shapirab, Menachem Bitanb and Reuven Orb a Department of Oral Medicine, School of Dental Medicine, Hebrew University-Hadassah, Jerusalem, Isreal, bDepartment of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel
Key words: candidasis – prevention – transplantation Corresponding author: Sharon Elad, Department of Oral Medicine, School of Dental Medicine, Hebrew University-Hadassah, POB 12272, Jerusalem 91120, Israel. Tel.: +972-2-6777735; fax: +972-2-6411116; e-mail:
[email protected] Accepted for publication 9 November 2005
The importance of effective anti-fungal prophylaxis is clear; however, to date, no uniform prophylactic protocol has been established (3–5). The literature presents various approaches to the prevention of fungal infections, such as: systemic treatment (6–8); topical oral treatment (9–11) using azoles or polyenes anti-fungals. Systemic azole prophylaxis was shown to be highly effective (7). However, the consistent emergence of non-albicans-resistant Candida species limits its preventive use (12–15). Therefore, several management strategies for fluconazole-resistant cases have been suggested. A recent study focused on topical amphotericin B (AMB) application (16). This strategy is supported by the data about reduced mortality achieved with systemic AMB (17). The results suggest that AMB may provide control of Candida colonization, yet the authors
Oral candidiasis prevention pointed at the poor tolerability to AMB (16). In addition, in certain geographic niches, polyenes are microbiologically preferred compared to azolebased protocols. Here, we present a strategy for the prevention of oral candidiasis, which will continue this line of AMB research and will extend it to other dose range and combination protocol. Chlorhexidine (CHX) is widely used as a standard oral care agent (18). CHX is also known to have both anti-fungal and anti-bacterial effects (19, 20). In this study, we have evaluated the combination of CHX and a medium-dose AMB for anti-fungal prophylaxis. The tolerability to the protocol was the main second end-point. In addition, the efficacy of CHX as a prophylactic agent was evaluated in order to compare its anti-fungal efficacy.
(Pipracin, Vitamed Co., Binyamina, Israel)]. If no improvement was observed within 72 h, the empiric antibiotic protocol was changed, with the supplement of intravenous (i.v.) AMB 1 mg/kg/d (Fungizone, Bristol-Myers Squibb Co., Epernon, France). Prophylactic protocols started seven d before HSCT and ended at the time of discharge from hospital. Patients were evaluated clinically for the presence of signs and symptoms of oral candidiasis (reviewed in Ellepola and Samaranayake (20)) on a twice-weekly basis from day –7 (before the HSCT) until one month after discharge. Patients’ reports about side-effects related to these anti-fungal protocols were documented twice a week. A shift from the prophylactic protocol to anti-fungal treatment was based on clinical signs of oral candidiasis. Mycologic laboratory monitoring
Patients and methods Study design and clinical setting
A randomized, controlled, prospective, longitudinal, double-blind trial was designed. Ethical approval was obtained and each patient signed an informed consent form. HSCT candidates, examined to rule out oral infection foci, with no known allergy to CHX or AMB were included in the study. A total of 20 patients undergoing HSCT were randomly enrolled into one of two equal groups: (a) 10 mL CHX 0.2% mouth-rinse ·4/d (Tarodent, Taro Co., Haifa Bay, Israel); (b) 10 mL CHX 0.2% mouth-rinse ·2/d combined with 10 mg AMB lozenges ·4/d (Fungilin, BristolMyers Squibb Co., Middlesex, UK). The attending physician evaluated the patients clinically. Fever (>38C) was initially treated with an empiric antibiotic protocol [Cefazolin (Kefazin, Vitamed Co., Binyamina, Israel), Gentamicin (Gentamicin, Teva Co., Petach Tikva, Israel), Piperacillin
Mycologic laboratory monitoring was conducted in an 11 patient sample of the study population randomly selected from group A or B (six or five, respectively). Tests performed included: a smear (Fluorescent Brightener 28, Sigma Chemical Co., St Louis. MO, USA); and a culture (Emmon’smodified sabouraud dextrose agar) and typing on CHROMAgar Candida medium (CHROMAgar, Paris, France). The oral sample for laboratory analysis was taken from the dorsum of the tongue before daily prophylactic therapy during active hours of the day. The combination of the smear and the culture results yields the oral Candida status of the patient, as (Table 1): ÔNo Candida within oral flora (non-carrier)Õ; ÔCandida as a normal oral flora (carrier)Õ; Ômarginal subclinical proliferationÕ and Ôsubclinical proliferationÕ. The diagnosis of oral candidiasis was based on the clinical signs and supported by the laboratory proliferation, and was termed Ôclinical candida proliferationÕ.
Table 1. Laboratory candida status of the patients Staining
Culture No pseudohypha or yeast growth after a month Poor yeast growth Yeast growth
No pseudohypha or yeast
Few yeasts
Few pseudohypha and yeasts
Numerous pseudohypha and yeasts
Non-carrier
Carriera
–
–
Carrierb Carrierb
Carrier Carrier
– Marginal subclinical proliferation
– Without clinical signs: subclinical proliferation With clinical signs: clinical candida proliferation
a A combination of a positive staining result with a negative culture result may occur following anti-fungal treatment or due to a sampling error. Yeast can be seen in staining but were not vital and did not grow in culture. b A combination of a negative staining result with a positive culture result may occur with a low fungal load. Yeasts are not seen in staining but are detected after one month of incubation.
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Elad et al. Haematologic laboratory monitoring
Clinical candidiasis and serious adverse events
Haematologic laboratory monitoring was conducted daily. Two parameters defined were: engraftment day, when the polymorph-nuclear (PMN) cell count was greater than 500/mm3 for two sequential days; days at high risk for the development of oral candidiasis, PMN 90 d). In group A, the prolonged hospitalization was because of delayed engraftment of an autologous graft (patient no. 9); and in group B, the extended hospitalization was because of aspergillosis and prolonged anti-fungal treatment (patient no. 10). All patients developed a fever >38C and were treated with empiric antibiotics. The initiation of the first empiric antibiotic protocol in group A was earlier than that in group B (on average, day +2.3 post-HSCT vs. day +5 post-HSCT, p ¼ 0.19). Similarly, the percentage of hospitalization days with antibiotic treatment was higher in group A than that in group B (Table 3). Seven patients from group A (70%) and five patients from group B (50%) required administration of empiric anti-fungal treatment (i.v. AMB) (fever over 38C that did not decrease 48–72 h after broad-spectrum antibiotics). In one of these patients from group B (patient no. 12), treatment with empiric i.v. AMB was necessary despite the combination of topical oral antifungal prophylaxis with systemic prophylaxis using fluconazole (systemic fluconazole prophylaxis was supplemented in two out of 20 patients, both from group B). Empiric systemic anti-fungal treatment was administered earlier in group A than that in group B (on average, day +6.4 post-HSCT vs. day +9.2 post-HSCT, p ¼ 0.53). Additionally, the percentage of hospitalization days with systemic AMB treatment was higher in group A than in group B (Table 3).
Autologous (3) Autologous (5) CHX, chlorhexidine; AMB, amphotericin B; AML, acute myelogenous leukaemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin’s lymphoma; CLL, chronic lymphocytic leukaemia; MM, multiple myeloma; CML, chronic myelogenous leukaemia; ALL, acute lymphoblastic leukaemia.
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Day of engraftment, days at high risk and graft matching
The engraftment day was later in group A than in group B (on average, day +20.6 post-HSCT vs. days +15.7 post-HSCT, p ¼ 0.53).
Oral candidiasis prevention Table 3. Antibiotic and anti-fungal treatment during the hospitalization (averages ± SD)
Days at high riskb,c Hospitalization days covered with antibiotics – % (days)c Hospitalization days covered with systemic anti-fungal treatment (i.v. AMB) – % (days)c
Group Aa: CHX
Group Ba: CHX+AMB
p value
21.3 ± 18.6 60.94 ± 17.04 (25.3 ± 18.1) 49.11 ± 11.47 (22.8 ± 14.7)
12.1 ± 6.9 44.02 ± 20.05 (16.2 ± 10.5) 44.94 ± 21.29 (24.0 ± 22.6)
0.17 0.09 1.00
a
n ¼ 10. Polymorphonuclear
