MYCOSES
ACCEPTED: SEPTEMBER20, 199 I
35, 1-8 (1992)
REVIEW ARTICLE
Oral candidosis: treatment with absorbable and non-absorbable antifungal agents in children Die Behandlung der oralen Candidose mit resorbierbaren und nicht-resorbierbaren An timyze tika bei Kindern F. Dhondt', J. Ninane', K. De Beule3, A. Dhondt3 and G. Cauwenbergh3 Key words. Candidosis, oral infection, antimycotic chemotherapy. Schliisselworter. Candidose, orale Infektion, antimykotische Chemotherapie.
Summary. Oral candidosis in neonates and children is a common infection which occurs often during the first few months after birth, but occasionally also in older children with certain predisposing factors. In neonates, oral candidosis is usually benign, although the symptoms of such an acute infection can be disturbing to both the patient and the parents. In older children developing oral candidosis, specific predisposing factors may be present (e.g. immunodeficiency, chemotherapy, etc.) . In such cases, the infection may constitute a source for further dissemination, leading to occasionally fatal Cundidu sepsis or to widespread chronic mucocutaneous candidosis. Treatment modalities to date include drugs with limited or no absorption from the gastrointestinal tract (e.g. nystatin and miconazole) and agents that are absorbed, combining local effect with systemic therapy (e.g. clotrimazole, ketoconazole, itraconazole and fluconazole) . Overall, it appears that treatment of neonatal oral candidosis should be performed with nonabsorbable drugs, while the systemically active agents should be used primarily if a risk of dissemination exists or if widespread disease is present. In general, side-effects and toxicity are not 'St Norbertus Hospital, Duffel, 'Department of Pediatric Haematology and Oncology, Clinical University St Luc, Brussels, and 3Janssen Research Foundation, Beerse, Belgium.
Correspondence: Dr Annik Dhondt, Janssen Research Foundation, B-2340 Beerse, Belgium.
major causes of concern with non-absorbed or absorbed antifungals in children with oral candidosis, since treatment is usually of relatively short duration. When the systemically active agents are used in premature infants with suboptimal liver function, the risk of drug-induced liver toxicity may be increased. Zusammenfassung. Die orale Candidose bei Neugeborenen und Kindern ist eine haufige Infektion, die oft in den ersten Monaten nach der Geburt auftritt, gelegentlich aber auch bei alteren Kindern mit gewissen pradisponierenden Faktoren. Bei Neugeborenen verlauft die orale Candidose gewohnlich gutartig, obgleich die Symptome einer solchen akuten Infektion sowohl den Patienten wie auch die Eltern erheblich belasten konnen. Bei anderen Kindern rnit oraler Candidose konnen besondere pradisponierende Faktoren vorliegen, wie Immundefekte, Chemotherapie u.a. In solchen Fallen kann die Infektion eine Disseminierungsquelle darstellen, die gelegentlich zu todlicher Cundida-Sepsis oder zur generalisierten mukokutanen Candidose fuhrt. Derzeitige Behandlungsstrategien umfassen Antimykotika mit geringer oder keiner Resorbierbarkeit im Gastrointestinaltrakt (z.B. Nystatin und Miconazol). Bei den resorbierbaren Wirkstoffen dagegen ist die lokale Wirkung mit der systemischen kombiniert (Clotrimazol, Ketoconazol, I traconazol, Fluconazol) . Die Behandlung der oralen Candidose bei Neugeborenen sollte mit nicht-resorbierbaren Wirkstoffen durchgefuhrt werden, wahrend die systemisch wirksamen Anti-
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F. DHONDT ET AL.
mykotika im wesentlichen den Patienten mit Disseminierungsrisiko oder schon generalisierter Candidose vorbehalten bleiben sollten. Nebenwirkungen und Toxizitatsrisiken sind keine wesentlichen Anwendungshindernisse nichtresorbierbarer und resorbierbarer Antimykotika bei der Therapie der oralen Candidose des Kindes, zumal die Therapie gewohnlich nur kurzzeitig erfolgt. Systemisch wirksame Antimykotika bei Fruhgeborenen mit suboptimaler Leberfunktion bergen freilich das Risiko Wirkstoffinduzierter Lebertoxizitat in sich. Introduction
From birth on, species of Candida, mainly Candida albicans, colonize the oral cavity. The presence of the yeast in newborns may originate from intrauterine infection, inoculation in transit through the contaminated vagina or contamination by the neonatal environment [l-31. Data about the frequency of oral Candida prevalence in children are rather divergent, but there is no doubt that in most instances the candidal population in the mouth is commensal [4]. In children, Candida albicans is also responsible for an important series of pathological conditions. The best example of this is oral candidosis in premature infants or neonates. Another superficial Candida pathology in children is chronic mucocutaneous candidosis, a widespread infection involving mucosa, skin, hair and nails [5-71. In general, this disease often results in major malformations. The underlying cause of chronic mucocutaneous candidosis is an immune defect. This indicates that different species of Candida will turn into pathogens when the host or the environment allows them to do so. A variety of iatrogenic factors are known which may cause this transition, e.g. broad-spectrum antibiotics, chronic use of steroids and immunosuppressive agents, chemotherapy and radiotherapy etc. [2]. This is the reason why in adults, and also in children receiving this kind of therapy, oral and oesophageal candidosis may develop. In such patients, however, the infection may not be limited to the gastrointestinal tract. The likelihood of systemic dissemination, because of the impaired immunity, is high, sometimes resulting in the death of the patient [2, 81. The therapeutic approach in the management of oral candidosis depends on the type of patient. The armamentarium to treat oral candidosis in children includes the older non-absorbed polyenes like amphotericin B tablets or nystatin tablets or suspension, an imidazole with limited absorption
(miconazole) and azole derivatives with good to excellent absorption (clotrimazole, ketoconazole, itraconazole and fluconazole) .
T h e drugs Amphotericin
B [9]
This is a broad-spectrum polyene antimycotic which is not absorbed after oral intake. An intravenous formulation is needed to combat systemic fungal infections. For treatment and prophylaxis of oral candidosis, amphotericin B is formulated as 50 mg tablets. Gastrointestinal disturbances are the most commonly reported side-effects and the taste of the drug usually precludes compliance. In general, oral amphotericin B has little use in children except for prevention in patients treated with chemotherapy. Nystatin [lOJ Like amphotericin By nystatin belongs to the group of the polyene antimycotics. The drug is extracted from an actinomycete, Streptomyces noursei. Nystatin is not absorbed after oral intake, and the therapeutic use of the oral form is therefore limited to treatment of the oral cavity and the gastrointestinal tract. At higher doses, gastrointestinal problems, including nausea and vomiting, are fairly common. Nystatin can be used orally as a suspension (100,000 U g- ') to be given four times daily. Miconatole [ll] This imidazole derivative has a broad spectrum of activity. After oral administration, systemic absorption is limited. The best-known formulations of miconazole include a whole range of products for dermatological and gynaecological use, as well as an intravenous form for systemic mycoses. I n addition to these formulations, miconazole is also available as tablets (250 mg per tablet) and, very important for its paediatric use, as an oral gel (20mg per g) with good adhesive properties to the oral mucosa. Miconazole oral gel is usually administered four times a day. Clotrimatole [12] Like miconazole, this molecule is also a first generation imidazole derivative. It has initially been developed as an orally active agent. After multiple doses, clotrimazole induces its own metabolism resulting in reduced plasma levels. mycoses 35, 1-8 ( 1992)
TREATMENT OF ORAL
This effect on hepatic metabolism also results in a 10-15y0 incidence of liver enzyme increases. Clotrimazole is available as oral troches, but the high incidence of raised liver enzymes combined with a relatively high incidence of gastrointestinal side-effects has limited its use in children with oropharyngeal candidosis.
CANDIDOSIS
3
oral solution is currently under development. Side-effects of itraconazole therapy are minimal, with headache and nausea reaching an incidence of about 1%. Raised liver enzymes have been observed in about 2% of patients. Itraconazole is a more selective inhibitor of cytochrome P450 and is therefore devoid of effects on the mammalian steroidogenesis.
Ketoconazole [13] This second generation imidazole is the first broad-spectrum antifungal which has shown consistent and sustained absorption after chronic oral administration. The drug has been extensively studied in dermatology, gynaecology and internal medicine. Excretion of ketoconazole in saliva is good, suggesting a therapeutic role in the management of oral candidosis. The overall side-effect profile of ketoconazole is relatively benign. Nausea and headache are most frequently reported with a 3-5% incidence. Serious side-effects have been reported in a limited number of patients. Hepatitis is the best-known example with an overall incidence of 1 in 15,000 patients treated. Generalized allergic reactions have occurred in a few instances. Finally, ketoconazole at higher doses also interferes with the endocrine system. In general, this does not result in clinical sideeffects with normal antifungal doses. Ketoconazole is available as 200 mg tablets and as a suspension (20 mg ml-'). One millilitre of the drug is given three times a day to very small children (below 10 kg in body weight). In older children and in adults, treatment is given once daily (5 or 10 ml) . Oral ketoconazole is regularly used in children with oral candidosis. A preference for use in compromised patients seems to prevail.
Ilraconazole [141 In contrast to previous azole derivatives, itraconazole is a triazole derivative. Like the imidazoles its mechanism of action consists of the inhibition of the cytochrome P450 isozyme responsible for the oxidative demethylation of methylsterols to ergosterol, the natural sterol of the fungal cell membrane. Itraconazole has only limited excretion in saliva, but its lipophilic character results in high mucosal tissue levels of the drug, protecting well against invasion of the tissue by Candzda hyphae. Like ketoconazole, itraconazole is widely used in dermatology, gynaecology and internal medicine. To date, only one form of the drug is available: capsules containing 100 mg itraconazole in a pelleted formulation. This form has also been used successfully in children. An mycoses 35, 1-8 (1992)
Fluconazole [IS] Fluconazole is a water-soluble bis-triazole derivative with a low protein binding capacity. I t has a weak in vitro activity against a wide range of fungi and the clinical efficacy has been studied primarily in yeast infections. Fluconazole has reasonable efficacy in dermatological infections but seems to be inferior to itraconazole. In vaginal candidosis and oral candidosis, fluconazole and itraconazole appear to be equivalent. The full therapeutic spectrum of fluconazole in systemic mycoses is being investigated. Fluconazole, like itraconazole, is well tolerated. Increases in liver enzymes have been reported in 7-10% of patients treated. Studies in rats have indicated that fluconazole may induce a number of enzymes in the liver. Large studies in children are performed with fluconazole and its use in paediatric patients is presently limited. In mycoses other than candidosis, it appears that fluconazole is not active against Aspergillus but, on the other hand, very active against Cryptococcus.
Review of the studies In selecting the studies, a review of the last 15 years has been made, searching only for drugs that are to date accepted or studied for paediatric use. Consequently only studies with nystatin, miconazole, ketoconazole and itraconazole have been included; one must, however, be aware that randomized prospective studies with fluconazole in children are presently performed but not yet published. Twenty-three studies on the paediatric use of antifungals for treatment or prevention of oral candidosis from nine different countries have been included in this review. Belgium and Germany contributed four studies each. Three studies from France, Italy, the U K and the USA were included, while The Netherlands, Switzerland and Spain contributed one study each. Nystatin was used in three studies, miconazole oral gel was discussed in nine studies, ketoconazole suspension in 12 studies and itraconazole in two studies.
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F. DHONDT ET AL.
A more complete listing of these studies is given in Tables 1 to 3. A summary of the response rates and the incidence of side-effects is given in Table 4. This data summary shows that nystatin, the only polyene of the series;appears to have a response rate about 20% lower than the imidazole derivatives. For itraconazole the response rate also seems to be somewhat lower (81%), but analysis of the individual reports (Table 1) shows that the itraconazole studies were conducted in very high risk patients treated for malignancies. In addition the type of study with itraconazole was different (prophylaxis), which may also account for the difference in response. Both miconazole gel and ketoconazole suspension gave over 90% response in children with oral candidosis. The tables listing individual studies show that the response rates have been fairly homogeneous in the different trials. Overall, responses are close to 100yo when non-immunocompromised children with oral candidosis are treated. Treatment lengths in these patients are short (1 to 2 weeks). Children with chronic mucocutaneous candidosis also seem to respond well to azole treatment. Obviously, therapy is much longer and chronic intermittent treatment may be needed to keep the patients free of reinfection or relapse.
Response rates become lower when neutropenic children are treated therapeutically or prophylactically or when conditions other than oral thrush, e.g. systemic candidosis, are treated [ 161. Treatment lengths are more prolonged under these conditions. The treatment schedules that have been used in the different studies show some variation. Nystatin was used fairly uniformly as 100,000 units four times daily. The total daily dose of miconazole oral gel fluctuated between 100 and 200 mg daily divided over two or four daily intakes. The total dose was based on body weight. The four times daily dosing scheme has been used most frequently. With ketoconazole, the daily dose has often been calculated on a mg kg-' basis. Depending upon the infection treated, doses from 5 to 10 mg kg-' were used. For small children with oral thrush, a dose of 20 mg three times daily was most frequently administered. The overall side-effect incidence is of course of concern in such studies. Three nystatin-treated patients (5.2%) reported side-effects: one vomiting and two nausea. Seventeen of the 289 miconazole-treated children had side-effects (5.9%). Nausea occurred in 8 children, vomiting in 4 and diarrhoea in 2, and 3 children complained of bad taste of the medication. With the ketoconazole
Table 1. Paediatric studies with nystatin or itraconazole in treatment or prophylaxis of oral candidosis Author
Country
No. of patients
Typeof patients
Median age
Dose/day
Duration
Response
Nystatin neonates < 1 month 100,000 u 1-4 weeks 8/15 Boon [I81 Netherlands 15 immunocomp. 1 month 100,000 u 2-4 weeks 18/24 Schaad [19] Switzerland 24 100,000 u 2-4 weeks 15/19 19 children 2 months Germany Freitag [20] I traconazole 1 CMC 11 years 100-300 mg continuous Burke [21] USA 1/1 34/42 50-100 mg 4 weeks Ninane [22] Belgium 42 profyl neutro. 6.5 years CMC: chronic mucocutaneous candidosis; profyl neutro: prophylactic treatment of neutropenic patients.
~~
~
~
~
~~
Side-effects
1 vomiting
2 nausea none none none
~
Table 2. Paediatric studies with miconazole oral gel in treatment or prophylaxis of oral candidosis Author
Country
No. of patients
Type of patients
Median age
Dose/day
Duration
Response
Sideeffects
Fandre [23] Bamberger [24] Schaad [ 191 Freitag [20] Behrens [25] Eickschen [26] Reading [27]
France France Switzerland Germany Germany Germany UK
48 18 23 19 28 30 35
newborn children immunocomp. children children children children
5 days 1-7 years
100 mg b i d .
80 mg b i d .
1 month
100 mg b.i.d.
2 months 2-3 months 3 months 17 months
2 weeks 1-3 weeks 1-2 weeks 2 weeks
25 mg q.i.d. 25-50 rng q.i.d. 1 week 25-50 mg q.i.d. 12 days 25 mg q.i.d. 1 week
46/48 16/18 23/23 17/19 28/28 29/30 35/35
Kessel [28] Casneuf [29]
UK Belgium
2 86
children children
3-10 years 2 months
50-100 mg
continuous 1 week
2/2 83/86
none none 8 nausea none none none 3 bad taste none 4 vomit/ 2 diarr.
100 mg q.i.d.
t.i.d.
mycoses 35, 1-8 (1992)
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wl c
I
03
I
I
Table 3. Paediatric studies with ketoconazole suspension in treatment or prophylaxis of oral candidosis Author
Country
No. of patients
Type of patients
Netherlands 20 neonates Boon [ 181 Italy 20 children Martinelli [30] 10 premat. sys. can. Germany Saule [31] Italy 26 child or. + sys. Bardare [32] Griscelli [33] France 9 immunocomp. Cauwenbergh [34] Belgium 32 children Belgium 39 profyl neutro. Ninane [35] Berkowitz [36] USA 16 profyl BMT UK 1 CMC Murphy [371 Ginsburg [38] USA 1.2 child derm. D’Argenio [39] Italy 23 children Molted0 [I71 Spain 143 children LFT: abnormal Liver Function Tests; mpk: mg per kg; profyl BMT: prophylactic
Median age
Dose/day
Duration
20 mg t.i.d. 1 week 1 week 1 week 20 mg t.i.d. 4 months 4 weeks 6-9 mpk 1 week 8 mpk I week-1.5 years 0.6-14 years 8 mpk 1 month 1-9 years 2 weeks 7 months 20 mg t.i.d. 10 mpk 4 weeks 4 years 4 weeks 50-200 mg 10 years 100 mg 1 month 20 months 5 rnpk 3-8 weeks 6 years 1 week 20 mg t.i.d. 4 months 20 mg t.i.d. 2-7 weeks 1 year treatment of Bone Marrow Transplant patient.
Response
20120 20/20 10/10
22/26 9/9 30132 35/39 13/16 111
11/12 22/23
1371143
Side-effects
none none 3 hep., 1 LFT 4 nausea none 1 rash none none none none none 1 nausea
6
F. DHONDT ET
AL.
observed during paediatric use of nystatin, miconazole gel, ketoconazole or itraconazole in a review of 23 studies on oral candidosis in children Treatment
Response rate
Side-effects
Nystatin Miconazole Ketoconazole
41/58 (71%) 279/289 (96%) 330/351 (94%)
3/58 (5%) 17/289 (6%) 10/351 (3%)'
Itraconazole*
35/43 (81%)
0/43 (0%)
*In contrast to the other drugs, all patients except one in the itraconazole group were neutropenic children receiving antifungal prophylaxis.
suspension, the side-effect incidence is somewhat lower than with the non-absorbed antifungals (2.5y0), but the side-effect spectrum is different, reflecting also the systemic activity of the drug. Nausea was observed in 5 children, 1 child experienced an allergic rash, and 4 premature infants with pre-existing liver dysfunction had further liver problems during therapy. None of the itraconazole-treated patients experienced any objective or subjective side-effect or laboratory abnormality. It should be kept in mind, however, that the sample of the itraconazole-treated children is much smaller than that for miconazole or ketoconazole. Further investigation will be needed to evaluate the side-effect incidence and profile of this new triazole in children. When side-effects are evaluated in the different studies separately, it becomes clear that more side-effects are seen in immunocompromised children or in children with more severe infections. For the four drugs combined, 30 side-effects were reported. Of those, 16 were in the group of 70 immunocompromised children or children with systemic fungal infection (22.9%). The other 14 patients with side-effects belong to the group of nonimmunocompromised patients ( n = 7 17) with oral thrush (2%). Discussion
Children with oral candidosis can be subdivided in two categories: ( 1 ) children who develop oral candidosis because of environmental conditions, e.g. neonates who are contaminated at the time of birth, or children receiving more prolonged courses of antibiotic therapy, and (2) children with underlying immune problems who develop the infection either because of the underlying immune deficiency (e.g. chronic mucocutaneous candidosis) or because of the required immunosuppressive therapy.
The available treatments for oral candidosis in children can also be subdivided in two groups: the non-absorbed antifungals (e.g. polyenes and miconazole) and the systemically active agents (e.g. ketoconazole, itraconazole) . This review of paediatric studies emphasizes some important points, discussed below. First, treatment with polyenes is efficacious, but response rates are apparently lower than those obtained with azole derivatives. This is not a completely unexpected finding. Indeed, evidence exists that also in other types of mucosal candidosis (e.g. vaginal candidosis) polyenes consistently give lower response rates than azole derivatives [2]. Studies on the prophylaxis of fungal infections in immunocompromised patients have also suggested such a difference in favour of azole molecules [8]. Second, treatment of oral thrush in children without serious predisposing factors is satisfactory. Even polyenes usually result in 80% or more response in these cases. Azole derivatives give consistently more than 90% response. The good results with both classes of antifungals are probably due to the normal immune function. Third, treatment of oral candidosis in children with serious underlying predisposing factors is more difficult and response rates are generally lower in this patient population. In addition, inadequate response to treatment of local infections in patients with impaired immunity bears a risk of potentially fatal dissemination of the infection. Fourth, neonates and children tolerate the existing antifungals well. The side-effect incidence in non-predisposed children is very low (2y0), while immunocompromised children and children with systemic fungal disease show a substantially higher side-effect incidence (23%). This difference may be related to the underlying condition, often requiring multiple concomitant treatments, or to the treatment lengths needed with the antifungal, often exceeding the 1-2week treatment courses given to non-compromised children. These four observations, derived from the studies in this review, lead to some suggestions or guidelines for the use of antifungal drugs for treatment of oral candidosis in children. I t seems obvious that non-systemically active drugs should be used in children without major underlying conditions, predisposing for the infection. Indeed, results with non-absorbed agents, especially with miconazole oral gel, in this patient population are such that the use of orally absorbed drugs is questionable. This review also suggests that children with serious underlying conditions, predisposing for widespread or dismycoses 35, 1-8 ( 1992)
TREATMENT OF ORAL
seminated disease, should be given systemically active agents. The broader spectrum agents should be preferred, especially in neutropenic children, since selective decontamination for Candida spp. may lead to a shift towards Aspergillus infections [8]. The use of systemically active agents in children, more predisposed to sideeffects and potential toxicity, implies careful monitoring of blood biochemistry. The fact that all 10 premature infants with systemic disease responded well to oral ketoconazole speaks for the efficacy of the drug; however, the fact that three of these premature children also developed transient jaundice during therapy, and that a fourth child had increases in liver enzymes, indicates that systemic agents should be used with caution in children. It is true, however, that the systemically active agents seem to be well tolerated when used in children without pre-existing liver dysfunction or not receiving multiple concomitant medications. In conclusion, therapy for oral candidosis in neonates and children is satisfactory in terms of efficacy and tolerance. Non-absorbed drugs should be preferred in non-predisposed children, while systemically active agents should be reserved for widespread disease or for children with impaired immunity, whether congenital or due to immunosuppressive treatment. The broader spectrum agents should be preferred in view of the potential shift in pathogens from Candida albicans to non-albicans species of Candida or to Aspergillus in immunocompromised patients. With systemic agents, careful monitoring should be performed during the more prolonged treatment courses. Acknowledgement
The authors wish to thank Hilde Dergent for preparing this manuscript for publication. References 1 Borderon, J. C., Guillon, M., Soutoul, J. M. et al. (1976)
2 3 4 5
Friquence de la contaimination mire-enfant par Candida albicans lors de l’accouchement. Arch. Fr. Pediatr. 33, 477-484. Odds, F. (1988) Candida and Candidosis, 2nd edn. London: BailliPre-Tindall. Schirar, A. C., Rendu, J., Vielh, P. el al. (1974) Congenital mycoses. Biol. Neonate 24, 273-288. Russell, C. & ‘Lay, K. M. (1973) Natural history of Candida species and yeasts in the oral cavities of infants. Arch. Oral Biol. 18, 957-962. Kirkpatrick, Ch. & Sohnle, P. G. (1981) Chronic mucocutaneous candidiasis. In: Safai, B. & Good, R . A. (eds) Immunodermatology. New York: Plenum Press, 1981, pp. 495-514.
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6 Schoof, A. (1983) Mundsoor und hefebedingte Windeldermatitis bei Sauglingen und Kleinkindern. iozialpadiatrie 5, 174-1 79. 7 Shrand, H. (1961) Thrush in the newborn. Br. Med. J . 1530-1533. 8 Cauwenbergh, G. (1986) Prophylaxis of mycotic infections in irnmunocompromised patients: a review of 27 reports and publications. Drug Exp. Clin. Res. 12, 419-427. 9 Bratjburg, J., Kobayashi, D., Medoff, G. et al. (1982) Antifungal action of amphotericin B in combination with other polyene or imidazole antibiotics. J . Infect. Dis. 146, 138-146. 10 Hamilton-Miller, J. M. T. (1973) Chemistry and biology of the polyene macrolide antibiotics. Bact. Rev. 37, 166- 196. 11 Graybill, J. R. & Craven, P. C. (1983) Antifungal agents used in systemic mycoses: activity and therapeutic use. Drugs 25, 41-62. 12 Borgers, M. (1980) Mechanism of action of antifungal drugs with special reference to the imidazole derivatives. Rev. Infect. Dis. 2, 520-534. 13 Levine, H. B. (1982) Ketoconazole in the Management of Fungal Disease. New Zealand: Adis Press. 14 Cauwenbergh, G., De Doncker, P., Stoops, K. et al. ( 1 987) Itraconazole in the treatment of mycoses in man; a review of 3 years of clinical experience. Rev. Infect. Dis. 9, 146-152. 15 Troke, P. F., Andrews, R. J., Brammer, K. W. rt al. (1985) Efficacy of fluconazole against Candida albicans experimental infections in mice. Antimicrob. Ag. Chemother. 28, 815-818. 16 Tricot, G., Joosten, M. & Boogaerts, M. (1987) Ketoconazole vs. itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of 2 nonrandomized studies. Rev. Infect. Dis. 9, 94-99. 17 Moltedo, J., Pettinatto, E., Linari, N. et al. (1983) Ketoconazol suspesion oral en el tratamiento de la candidiasis en el recien nacido de termino, pretermino y lactante. Pediatria 7, 1.61-164. 18 Boon, J. M., Lafeber, H. N., ’t Mannetje, A. H. et al. (1989) Comparison of ketoconazole suspension and nystatin in the treatment of newborns and infants with oral candidosis. Mycoses 32, 3 12-3 15. 19 Schaad, U. B. & Bachmann, D. (1983) Prospectiver Vergleich von Miconazol-Gel und Nystatin-Suspension in der Therapie des Mundsoors. Schweiz Med. Wschr. 113, 1356-1362. 20 Freitag, V., Schumacher, G. & Sternowsky, H. J. (1983) Soor im Mund-und Windelbereich. Der Kinderarzt 14, 177-178. 21 Burke, W. A. (1989) Use of itraconazole in a patient with chronic mucocutaneous candidiasis. 3. Am. Acad. Dermatol. 21, 1309-1310. 22 Ninane, J., Sluysmans, T., Vermylen, C. et al. (1988) Itraconazole vs ketoconazole for the prophylaxis of fungal infection in neutropenic children: results of 2 consecutive nonrandornized studies. Ped. Hematol. Oncol. 6 , 349-353. 23 Fandre, M., Hellouin de Menibus, A., Lasfargues, B. et al. (1983) Miconazole oral gel, itude multicentrique ouverte d a m le mueuet de l’enfant. Clin Res Reb 1983. v Janssen Research Foundation, Belgium. 24 Bamberger, J. C. (1983) Miconazole oral gel, etude ouverte d’orientation dans le muguet de I’enfant. Clin Res Rep 1983, Janssen Research Foundation, Belgium. 25 Behrens, R. & Helwig, H. (1983) Behandlung des Mundsoors mit Miconazol-Gel. Der Kinderarzt 13, 587.
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26 Eickschen, H. & Jouck, Th. (1982) Behandlung von Sprosspilzinfektionen des Mund- und Rachenraumes bei Sauglingen und Kleinkindern. Clin Res Rep R 18134132 1982, Janssen Research Foundation, Belgium. 27 Reading, J. H., Clifford, P. D., Coles, R. W. el al. (1981) An open assessment of miconazole oral gel in the treatment of pediatric oral candidosis in general practice. Curr. Ther. Res. 30,605-609. 28 Kessel, L. J. & Taylor, W. D. (1980) Chronic mucocutaneous candidiasis-treatment of the oral lesions with miconazole. BY.J . Oral. Surg. 18, 51-56. 29 Casneuf, J., de Loore, F., Dhondt, F. et al. (1980) Oral thrush in children treated with miconazole gel. Mycosen 23, 75-78. 30 Martinelli, V. ( 1982) Relazione sull'impiego del ketoconazole in pediatria: gocce 20 mg/ml. Clin Res Rep 1982, Janssen Research Foundation, Belgium. 31 Saule, H. ( 1983) Behandlung schwerer Candida-Infectionen mit Ketoconazol bei Neugeborenen und jungen Sauglingen. Dtsch. Med. Wschr. 108, 1676-1680. 32 Bardare, M., Tortorano, A. M., Pietrogrande, M. C. et al. (1984) Pharmacokinetics of ketoconazole and treatment evaluation in candidal infections. Arch. Dis. Childhood 59, 1068- 1071.
33 Griscelli, C. ( 1985) Expertise clinique: ketoconazole suspension buvable. Clin Res Rep 1985, Janssen Research Foundation, Belgium. 34 Cauwenbergh, G., Casneuf, J., de Loore, P. et al. (1981) Treatment of infant thrush with ketoconazole, a new broad spectrum antimycotic. Curr. Chemother. Zmmunother., Proc. 12th Int. Congress Chemother., Florence. 35 Ninane, J., Vangyseghem, S., Michel, M. et 01. (1988) Ketoconazole prophylaxis of fungal infections in the neutropenic child. Gun. Ther. Res. 43, 851-856. 36 Berkowitz, R. J., Hughes, C., Rudnick, M. el al. (1985) Oropharyngeal Candida prophylaxis in pediatric bone marrow transplant patients. Am. 3. Ped. Hemat. Oncol. 7, 82-86. 37 Murphy, J. F., Jones, M. & Thompson, E. (1984) Oesophageal candidiasis and croup in a child with defective neutrophil motility. J . Znfect. 8, 247-250. 38 Ginsburg, C. M., McCracken, G. H. & Olsen, K. (1983) Pharmacology of ketoconazole suspension in infants and children. Antimicrob. Ag. Chemother. 23, 787-789. 39 D'Argenio, P., Morino, G., Fanelli, A. et al. (1984) Una nuova terapia orale della candidiasi mucocutanea in pediatria: ketoconazole sospensione. La Clinica 39, 95- 100.
mycoses 35, 1-8 ( 1992)
ACCEPTED: SEPTEMBER20, 199 I
35, 1-8 (1992)
REVIEW ARTICLE
Oral candidosis: treatment with absorbable and non-absorbable antifungal agents in children Die Behandlung der oralen Candidose mit resorbierbaren und nicht-resorbierbaren An timyze tika bei Kindern F. Dhondt', J. Ninane', K. De Beule3, A. Dhondt3 and G. Cauwenbergh3 Key words. Candidosis, oral infection, antimycotic chemotherapy. Schliisselworter. Candidose, orale Infektion, antimykotische Chemotherapie.
Summary. Oral candidosis in neonates and children is a common infection which occurs often during the first few months after birth, but occasionally also in older children with certain predisposing factors. In neonates, oral candidosis is usually benign, although the symptoms of such an acute infection can be disturbing to both the patient and the parents. In older children developing oral candidosis, specific predisposing factors may be present (e.g. immunodeficiency, chemotherapy, etc.) . In such cases, the infection may constitute a source for further dissemination, leading to occasionally fatal Cundidu sepsis or to widespread chronic mucocutaneous candidosis. Treatment modalities to date include drugs with limited or no absorption from the gastrointestinal tract (e.g. nystatin and miconazole) and agents that are absorbed, combining local effect with systemic therapy (e.g. clotrimazole, ketoconazole, itraconazole and fluconazole) . Overall, it appears that treatment of neonatal oral candidosis should be performed with nonabsorbable drugs, while the systemically active agents should be used primarily if a risk of dissemination exists or if widespread disease is present. In general, side-effects and toxicity are not 'St Norbertus Hospital, Duffel, 'Department of Pediatric Haematology and Oncology, Clinical University St Luc, Brussels, and 3Janssen Research Foundation, Beerse, Belgium.
Correspondence: Dr Annik Dhondt, Janssen Research Foundation, B-2340 Beerse, Belgium.
major causes of concern with non-absorbed or absorbed antifungals in children with oral candidosis, since treatment is usually of relatively short duration. When the systemically active agents are used in premature infants with suboptimal liver function, the risk of drug-induced liver toxicity may be increased. Zusammenfassung. Die orale Candidose bei Neugeborenen und Kindern ist eine haufige Infektion, die oft in den ersten Monaten nach der Geburt auftritt, gelegentlich aber auch bei alteren Kindern mit gewissen pradisponierenden Faktoren. Bei Neugeborenen verlauft die orale Candidose gewohnlich gutartig, obgleich die Symptome einer solchen akuten Infektion sowohl den Patienten wie auch die Eltern erheblich belasten konnen. Bei anderen Kindern rnit oraler Candidose konnen besondere pradisponierende Faktoren vorliegen, wie Immundefekte, Chemotherapie u.a. In solchen Fallen kann die Infektion eine Disseminierungsquelle darstellen, die gelegentlich zu todlicher Cundida-Sepsis oder zur generalisierten mukokutanen Candidose fuhrt. Derzeitige Behandlungsstrategien umfassen Antimykotika mit geringer oder keiner Resorbierbarkeit im Gastrointestinaltrakt (z.B. Nystatin und Miconazol). Bei den resorbierbaren Wirkstoffen dagegen ist die lokale Wirkung mit der systemischen kombiniert (Clotrimazol, Ketoconazol, I traconazol, Fluconazol) . Die Behandlung der oralen Candidose bei Neugeborenen sollte mit nicht-resorbierbaren Wirkstoffen durchgefuhrt werden, wahrend die systemisch wirksamen Anti-
2
F. DHONDT ET AL.
mykotika im wesentlichen den Patienten mit Disseminierungsrisiko oder schon generalisierter Candidose vorbehalten bleiben sollten. Nebenwirkungen und Toxizitatsrisiken sind keine wesentlichen Anwendungshindernisse nichtresorbierbarer und resorbierbarer Antimykotika bei der Therapie der oralen Candidose des Kindes, zumal die Therapie gewohnlich nur kurzzeitig erfolgt. Systemisch wirksame Antimykotika bei Fruhgeborenen mit suboptimaler Leberfunktion bergen freilich das Risiko Wirkstoffinduzierter Lebertoxizitat in sich. Introduction
From birth on, species of Candida, mainly Candida albicans, colonize the oral cavity. The presence of the yeast in newborns may originate from intrauterine infection, inoculation in transit through the contaminated vagina or contamination by the neonatal environment [l-31. Data about the frequency of oral Candida prevalence in children are rather divergent, but there is no doubt that in most instances the candidal population in the mouth is commensal [4]. In children, Candida albicans is also responsible for an important series of pathological conditions. The best example of this is oral candidosis in premature infants or neonates. Another superficial Candida pathology in children is chronic mucocutaneous candidosis, a widespread infection involving mucosa, skin, hair and nails [5-71. In general, this disease often results in major malformations. The underlying cause of chronic mucocutaneous candidosis is an immune defect. This indicates that different species of Candida will turn into pathogens when the host or the environment allows them to do so. A variety of iatrogenic factors are known which may cause this transition, e.g. broad-spectrum antibiotics, chronic use of steroids and immunosuppressive agents, chemotherapy and radiotherapy etc. [2]. This is the reason why in adults, and also in children receiving this kind of therapy, oral and oesophageal candidosis may develop. In such patients, however, the infection may not be limited to the gastrointestinal tract. The likelihood of systemic dissemination, because of the impaired immunity, is high, sometimes resulting in the death of the patient [2, 81. The therapeutic approach in the management of oral candidosis depends on the type of patient. The armamentarium to treat oral candidosis in children includes the older non-absorbed polyenes like amphotericin B tablets or nystatin tablets or suspension, an imidazole with limited absorption
(miconazole) and azole derivatives with good to excellent absorption (clotrimazole, ketoconazole, itraconazole and fluconazole) .
T h e drugs Amphotericin
B [9]
This is a broad-spectrum polyene antimycotic which is not absorbed after oral intake. An intravenous formulation is needed to combat systemic fungal infections. For treatment and prophylaxis of oral candidosis, amphotericin B is formulated as 50 mg tablets. Gastrointestinal disturbances are the most commonly reported side-effects and the taste of the drug usually precludes compliance. In general, oral amphotericin B has little use in children except for prevention in patients treated with chemotherapy. Nystatin [lOJ Like amphotericin By nystatin belongs to the group of the polyene antimycotics. The drug is extracted from an actinomycete, Streptomyces noursei. Nystatin is not absorbed after oral intake, and the therapeutic use of the oral form is therefore limited to treatment of the oral cavity and the gastrointestinal tract. At higher doses, gastrointestinal problems, including nausea and vomiting, are fairly common. Nystatin can be used orally as a suspension (100,000 U g- ') to be given four times daily. Miconatole [ll] This imidazole derivative has a broad spectrum of activity. After oral administration, systemic absorption is limited. The best-known formulations of miconazole include a whole range of products for dermatological and gynaecological use, as well as an intravenous form for systemic mycoses. I n addition to these formulations, miconazole is also available as tablets (250 mg per tablet) and, very important for its paediatric use, as an oral gel (20mg per g) with good adhesive properties to the oral mucosa. Miconazole oral gel is usually administered four times a day. Clotrimatole [12] Like miconazole, this molecule is also a first generation imidazole derivative. It has initially been developed as an orally active agent. After multiple doses, clotrimazole induces its own metabolism resulting in reduced plasma levels. mycoses 35, 1-8 ( 1992)
TREATMENT OF ORAL
This effect on hepatic metabolism also results in a 10-15y0 incidence of liver enzyme increases. Clotrimazole is available as oral troches, but the high incidence of raised liver enzymes combined with a relatively high incidence of gastrointestinal side-effects has limited its use in children with oropharyngeal candidosis.
CANDIDOSIS
3
oral solution is currently under development. Side-effects of itraconazole therapy are minimal, with headache and nausea reaching an incidence of about 1%. Raised liver enzymes have been observed in about 2% of patients. Itraconazole is a more selective inhibitor of cytochrome P450 and is therefore devoid of effects on the mammalian steroidogenesis.
Ketoconazole [13] This second generation imidazole is the first broad-spectrum antifungal which has shown consistent and sustained absorption after chronic oral administration. The drug has been extensively studied in dermatology, gynaecology and internal medicine. Excretion of ketoconazole in saliva is good, suggesting a therapeutic role in the management of oral candidosis. The overall side-effect profile of ketoconazole is relatively benign. Nausea and headache are most frequently reported with a 3-5% incidence. Serious side-effects have been reported in a limited number of patients. Hepatitis is the best-known example with an overall incidence of 1 in 15,000 patients treated. Generalized allergic reactions have occurred in a few instances. Finally, ketoconazole at higher doses also interferes with the endocrine system. In general, this does not result in clinical sideeffects with normal antifungal doses. Ketoconazole is available as 200 mg tablets and as a suspension (20 mg ml-'). One millilitre of the drug is given three times a day to very small children (below 10 kg in body weight). In older children and in adults, treatment is given once daily (5 or 10 ml) . Oral ketoconazole is regularly used in children with oral candidosis. A preference for use in compromised patients seems to prevail.
Ilraconazole [141 In contrast to previous azole derivatives, itraconazole is a triazole derivative. Like the imidazoles its mechanism of action consists of the inhibition of the cytochrome P450 isozyme responsible for the oxidative demethylation of methylsterols to ergosterol, the natural sterol of the fungal cell membrane. Itraconazole has only limited excretion in saliva, but its lipophilic character results in high mucosal tissue levels of the drug, protecting well against invasion of the tissue by Candzda hyphae. Like ketoconazole, itraconazole is widely used in dermatology, gynaecology and internal medicine. To date, only one form of the drug is available: capsules containing 100 mg itraconazole in a pelleted formulation. This form has also been used successfully in children. An mycoses 35, 1-8 (1992)
Fluconazole [IS] Fluconazole is a water-soluble bis-triazole derivative with a low protein binding capacity. I t has a weak in vitro activity against a wide range of fungi and the clinical efficacy has been studied primarily in yeast infections. Fluconazole has reasonable efficacy in dermatological infections but seems to be inferior to itraconazole. In vaginal candidosis and oral candidosis, fluconazole and itraconazole appear to be equivalent. The full therapeutic spectrum of fluconazole in systemic mycoses is being investigated. Fluconazole, like itraconazole, is well tolerated. Increases in liver enzymes have been reported in 7-10% of patients treated. Studies in rats have indicated that fluconazole may induce a number of enzymes in the liver. Large studies in children are performed with fluconazole and its use in paediatric patients is presently limited. In mycoses other than candidosis, it appears that fluconazole is not active against Aspergillus but, on the other hand, very active against Cryptococcus.
Review of the studies In selecting the studies, a review of the last 15 years has been made, searching only for drugs that are to date accepted or studied for paediatric use. Consequently only studies with nystatin, miconazole, ketoconazole and itraconazole have been included; one must, however, be aware that randomized prospective studies with fluconazole in children are presently performed but not yet published. Twenty-three studies on the paediatric use of antifungals for treatment or prevention of oral candidosis from nine different countries have been included in this review. Belgium and Germany contributed four studies each. Three studies from France, Italy, the U K and the USA were included, while The Netherlands, Switzerland and Spain contributed one study each. Nystatin was used in three studies, miconazole oral gel was discussed in nine studies, ketoconazole suspension in 12 studies and itraconazole in two studies.
4
F. DHONDT ET AL.
A more complete listing of these studies is given in Tables 1 to 3. A summary of the response rates and the incidence of side-effects is given in Table 4. This data summary shows that nystatin, the only polyene of the series;appears to have a response rate about 20% lower than the imidazole derivatives. For itraconazole the response rate also seems to be somewhat lower (81%), but analysis of the individual reports (Table 1) shows that the itraconazole studies were conducted in very high risk patients treated for malignancies. In addition the type of study with itraconazole was different (prophylaxis), which may also account for the difference in response. Both miconazole gel and ketoconazole suspension gave over 90% response in children with oral candidosis. The tables listing individual studies show that the response rates have been fairly homogeneous in the different trials. Overall, responses are close to 100yo when non-immunocompromised children with oral candidosis are treated. Treatment lengths in these patients are short (1 to 2 weeks). Children with chronic mucocutaneous candidosis also seem to respond well to azole treatment. Obviously, therapy is much longer and chronic intermittent treatment may be needed to keep the patients free of reinfection or relapse.
Response rates become lower when neutropenic children are treated therapeutically or prophylactically or when conditions other than oral thrush, e.g. systemic candidosis, are treated [ 161. Treatment lengths are more prolonged under these conditions. The treatment schedules that have been used in the different studies show some variation. Nystatin was used fairly uniformly as 100,000 units four times daily. The total daily dose of miconazole oral gel fluctuated between 100 and 200 mg daily divided over two or four daily intakes. The total dose was based on body weight. The four times daily dosing scheme has been used most frequently. With ketoconazole, the daily dose has often been calculated on a mg kg-' basis. Depending upon the infection treated, doses from 5 to 10 mg kg-' were used. For small children with oral thrush, a dose of 20 mg three times daily was most frequently administered. The overall side-effect incidence is of course of concern in such studies. Three nystatin-treated patients (5.2%) reported side-effects: one vomiting and two nausea. Seventeen of the 289 miconazole-treated children had side-effects (5.9%). Nausea occurred in 8 children, vomiting in 4 and diarrhoea in 2, and 3 children complained of bad taste of the medication. With the ketoconazole
Table 1. Paediatric studies with nystatin or itraconazole in treatment or prophylaxis of oral candidosis Author
Country
No. of patients
Typeof patients
Median age
Dose/day
Duration
Response
Nystatin neonates < 1 month 100,000 u 1-4 weeks 8/15 Boon [I81 Netherlands 15 immunocomp. 1 month 100,000 u 2-4 weeks 18/24 Schaad [19] Switzerland 24 100,000 u 2-4 weeks 15/19 19 children 2 months Germany Freitag [20] I traconazole 1 CMC 11 years 100-300 mg continuous Burke [21] USA 1/1 34/42 50-100 mg 4 weeks Ninane [22] Belgium 42 profyl neutro. 6.5 years CMC: chronic mucocutaneous candidosis; profyl neutro: prophylactic treatment of neutropenic patients.
~~
~
~
~
~~
Side-effects
1 vomiting
2 nausea none none none
~
Table 2. Paediatric studies with miconazole oral gel in treatment or prophylaxis of oral candidosis Author
Country
No. of patients
Type of patients
Median age
Dose/day
Duration
Response
Sideeffects
Fandre [23] Bamberger [24] Schaad [ 191 Freitag [20] Behrens [25] Eickschen [26] Reading [27]
France France Switzerland Germany Germany Germany UK
48 18 23 19 28 30 35
newborn children immunocomp. children children children children
5 days 1-7 years
100 mg b i d .
80 mg b i d .
1 month
100 mg b.i.d.
2 months 2-3 months 3 months 17 months
2 weeks 1-3 weeks 1-2 weeks 2 weeks
25 mg q.i.d. 25-50 rng q.i.d. 1 week 25-50 mg q.i.d. 12 days 25 mg q.i.d. 1 week
46/48 16/18 23/23 17/19 28/28 29/30 35/35
Kessel [28] Casneuf [29]
UK Belgium
2 86
children children
3-10 years 2 months
50-100 mg
continuous 1 week
2/2 83/86
none none 8 nausea none none none 3 bad taste none 4 vomit/ 2 diarr.
100 mg q.i.d.
t.i.d.
mycoses 35, 1-8 (1992)
W
wl c
I
03
I
I
Table 3. Paediatric studies with ketoconazole suspension in treatment or prophylaxis of oral candidosis Author
Country
No. of patients
Type of patients
Netherlands 20 neonates Boon [ 181 Italy 20 children Martinelli [30] 10 premat. sys. can. Germany Saule [31] Italy 26 child or. + sys. Bardare [32] Griscelli [33] France 9 immunocomp. Cauwenbergh [34] Belgium 32 children Belgium 39 profyl neutro. Ninane [35] Berkowitz [36] USA 16 profyl BMT UK 1 CMC Murphy [371 Ginsburg [38] USA 1.2 child derm. D’Argenio [39] Italy 23 children Molted0 [I71 Spain 143 children LFT: abnormal Liver Function Tests; mpk: mg per kg; profyl BMT: prophylactic
Median age
Dose/day
Duration
20 mg t.i.d. 1 week 1 week 1 week 20 mg t.i.d. 4 months 4 weeks 6-9 mpk 1 week 8 mpk I week-1.5 years 0.6-14 years 8 mpk 1 month 1-9 years 2 weeks 7 months 20 mg t.i.d. 10 mpk 4 weeks 4 years 4 weeks 50-200 mg 10 years 100 mg 1 month 20 months 5 rnpk 3-8 weeks 6 years 1 week 20 mg t.i.d. 4 months 20 mg t.i.d. 2-7 weeks 1 year treatment of Bone Marrow Transplant patient.
Response
20120 20/20 10/10
22/26 9/9 30132 35/39 13/16 111
11/12 22/23
1371143
Side-effects
none none 3 hep., 1 LFT 4 nausea none 1 rash none none none none none 1 nausea
6
F. DHONDT ET
AL.
observed during paediatric use of nystatin, miconazole gel, ketoconazole or itraconazole in a review of 23 studies on oral candidosis in children Treatment
Response rate
Side-effects
Nystatin Miconazole Ketoconazole
41/58 (71%) 279/289 (96%) 330/351 (94%)
3/58 (5%) 17/289 (6%) 10/351 (3%)'
Itraconazole*
35/43 (81%)
0/43 (0%)
*In contrast to the other drugs, all patients except one in the itraconazole group were neutropenic children receiving antifungal prophylaxis.
suspension, the side-effect incidence is somewhat lower than with the non-absorbed antifungals (2.5y0), but the side-effect spectrum is different, reflecting also the systemic activity of the drug. Nausea was observed in 5 children, 1 child experienced an allergic rash, and 4 premature infants with pre-existing liver dysfunction had further liver problems during therapy. None of the itraconazole-treated patients experienced any objective or subjective side-effect or laboratory abnormality. It should be kept in mind, however, that the sample of the itraconazole-treated children is much smaller than that for miconazole or ketoconazole. Further investigation will be needed to evaluate the side-effect incidence and profile of this new triazole in children. When side-effects are evaluated in the different studies separately, it becomes clear that more side-effects are seen in immunocompromised children or in children with more severe infections. For the four drugs combined, 30 side-effects were reported. Of those, 16 were in the group of 70 immunocompromised children or children with systemic fungal infection (22.9%). The other 14 patients with side-effects belong to the group of nonimmunocompromised patients ( n = 7 17) with oral thrush (2%). Discussion
Children with oral candidosis can be subdivided in two categories: ( 1 ) children who develop oral candidosis because of environmental conditions, e.g. neonates who are contaminated at the time of birth, or children receiving more prolonged courses of antibiotic therapy, and (2) children with underlying immune problems who develop the infection either because of the underlying immune deficiency (e.g. chronic mucocutaneous candidosis) or because of the required immunosuppressive therapy.
The available treatments for oral candidosis in children can also be subdivided in two groups: the non-absorbed antifungals (e.g. polyenes and miconazole) and the systemically active agents (e.g. ketoconazole, itraconazole) . This review of paediatric studies emphasizes some important points, discussed below. First, treatment with polyenes is efficacious, but response rates are apparently lower than those obtained with azole derivatives. This is not a completely unexpected finding. Indeed, evidence exists that also in other types of mucosal candidosis (e.g. vaginal candidosis) polyenes consistently give lower response rates than azole derivatives [2]. Studies on the prophylaxis of fungal infections in immunocompromised patients have also suggested such a difference in favour of azole molecules [8]. Second, treatment of oral thrush in children without serious predisposing factors is satisfactory. Even polyenes usually result in 80% or more response in these cases. Azole derivatives give consistently more than 90% response. The good results with both classes of antifungals are probably due to the normal immune function. Third, treatment of oral candidosis in children with serious underlying predisposing factors is more difficult and response rates are generally lower in this patient population. In addition, inadequate response to treatment of local infections in patients with impaired immunity bears a risk of potentially fatal dissemination of the infection. Fourth, neonates and children tolerate the existing antifungals well. The side-effect incidence in non-predisposed children is very low (2y0), while immunocompromised children and children with systemic fungal disease show a substantially higher side-effect incidence (23%). This difference may be related to the underlying condition, often requiring multiple concomitant treatments, or to the treatment lengths needed with the antifungal, often exceeding the 1-2week treatment courses given to non-compromised children. These four observations, derived from the studies in this review, lead to some suggestions or guidelines for the use of antifungal drugs for treatment of oral candidosis in children. I t seems obvious that non-systemically active drugs should be used in children without major underlying conditions, predisposing for the infection. Indeed, results with non-absorbed agents, especially with miconazole oral gel, in this patient population are such that the use of orally absorbed drugs is questionable. This review also suggests that children with serious underlying conditions, predisposing for widespread or dismycoses 35, 1-8 ( 1992)
TREATMENT OF ORAL
seminated disease, should be given systemically active agents. The broader spectrum agents should be preferred, especially in neutropenic children, since selective decontamination for Candida spp. may lead to a shift towards Aspergillus infections [8]. The use of systemically active agents in children, more predisposed to sideeffects and potential toxicity, implies careful monitoring of blood biochemistry. The fact that all 10 premature infants with systemic disease responded well to oral ketoconazole speaks for the efficacy of the drug; however, the fact that three of these premature children also developed transient jaundice during therapy, and that a fourth child had increases in liver enzymes, indicates that systemic agents should be used with caution in children. It is true, however, that the systemically active agents seem to be well tolerated when used in children without pre-existing liver dysfunction or not receiving multiple concomitant medications. In conclusion, therapy for oral candidosis in neonates and children is satisfactory in terms of efficacy and tolerance. Non-absorbed drugs should be preferred in non-predisposed children, while systemically active agents should be reserved for widespread disease or for children with impaired immunity, whether congenital or due to immunosuppressive treatment. The broader spectrum agents should be preferred in view of the potential shift in pathogens from Candida albicans to non-albicans species of Candida or to Aspergillus in immunocompromised patients. With systemic agents, careful monitoring should be performed during the more prolonged treatment courses. Acknowledgement
The authors wish to thank Hilde Dergent for preparing this manuscript for publication. References 1 Borderon, J. C., Guillon, M., Soutoul, J. M. et al. (1976)
2 3 4 5
Friquence de la contaimination mire-enfant par Candida albicans lors de l’accouchement. Arch. Fr. Pediatr. 33, 477-484. Odds, F. (1988) Candida and Candidosis, 2nd edn. London: BailliPre-Tindall. Schirar, A. C., Rendu, J., Vielh, P. el al. (1974) Congenital mycoses. Biol. Neonate 24, 273-288. Russell, C. & ‘Lay, K. M. (1973) Natural history of Candida species and yeasts in the oral cavities of infants. Arch. Oral Biol. 18, 957-962. Kirkpatrick, Ch. & Sohnle, P. G. (1981) Chronic mucocutaneous candidiasis. In: Safai, B. & Good, R . A. (eds) Immunodermatology. New York: Plenum Press, 1981, pp. 495-514.
mycoses 35, 1-8 ( 1992)
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7
6 Schoof, A. (1983) Mundsoor und hefebedingte Windeldermatitis bei Sauglingen und Kleinkindern. iozialpadiatrie 5, 174-1 79. 7 Shrand, H. (1961) Thrush in the newborn. Br. Med. J . 1530-1533. 8 Cauwenbergh, G. (1986) Prophylaxis of mycotic infections in irnmunocompromised patients: a review of 27 reports and publications. Drug Exp. Clin. Res. 12, 419-427. 9 Bratjburg, J., Kobayashi, D., Medoff, G. et al. (1982) Antifungal action of amphotericin B in combination with other polyene or imidazole antibiotics. J . Infect. Dis. 146, 138-146. 10 Hamilton-Miller, J. M. T. (1973) Chemistry and biology of the polyene macrolide antibiotics. Bact. Rev. 37, 166- 196. 11 Graybill, J. R. & Craven, P. C. (1983) Antifungal agents used in systemic mycoses: activity and therapeutic use. Drugs 25, 41-62. 12 Borgers, M. (1980) Mechanism of action of antifungal drugs with special reference to the imidazole derivatives. Rev. Infect. Dis. 2, 520-534. 13 Levine, H. B. (1982) Ketoconazole in the Management of Fungal Disease. New Zealand: Adis Press. 14 Cauwenbergh, G., De Doncker, P., Stoops, K. et al. ( 1 987) Itraconazole in the treatment of mycoses in man; a review of 3 years of clinical experience. Rev. Infect. Dis. 9, 146-152. 15 Troke, P. F., Andrews, R. J., Brammer, K. W. rt al. (1985) Efficacy of fluconazole against Candida albicans experimental infections in mice. Antimicrob. Ag. Chemother. 28, 815-818. 16 Tricot, G., Joosten, M. & Boogaerts, M. (1987) Ketoconazole vs. itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of 2 nonrandomized studies. Rev. Infect. Dis. 9, 94-99. 17 Moltedo, J., Pettinatto, E., Linari, N. et al. (1983) Ketoconazol suspesion oral en el tratamiento de la candidiasis en el recien nacido de termino, pretermino y lactante. Pediatria 7, 1.61-164. 18 Boon, J. M., Lafeber, H. N., ’t Mannetje, A. H. et al. (1989) Comparison of ketoconazole suspension and nystatin in the treatment of newborns and infants with oral candidosis. Mycoses 32, 3 12-3 15. 19 Schaad, U. B. & Bachmann, D. (1983) Prospectiver Vergleich von Miconazol-Gel und Nystatin-Suspension in der Therapie des Mundsoors. Schweiz Med. Wschr. 113, 1356-1362. 20 Freitag, V., Schumacher, G. & Sternowsky, H. J. (1983) Soor im Mund-und Windelbereich. Der Kinderarzt 14, 177-178. 21 Burke, W. A. (1989) Use of itraconazole in a patient with chronic mucocutaneous candidiasis. 3. Am. Acad. Dermatol. 21, 1309-1310. 22 Ninane, J., Sluysmans, T., Vermylen, C. et al. (1988) Itraconazole vs ketoconazole for the prophylaxis of fungal infection in neutropenic children: results of 2 consecutive nonrandornized studies. Ped. Hematol. Oncol. 6 , 349-353. 23 Fandre, M., Hellouin de Menibus, A., Lasfargues, B. et al. (1983) Miconazole oral gel, itude multicentrique ouverte d a m le mueuet de l’enfant. Clin Res Reb 1983. v Janssen Research Foundation, Belgium. 24 Bamberger, J. C. (1983) Miconazole oral gel, etude ouverte d’orientation dans le muguet de I’enfant. Clin Res Rep 1983, Janssen Research Foundation, Belgium. 25 Behrens, R. & Helwig, H. (1983) Behandlung des Mundsoors mit Miconazol-Gel. Der Kinderarzt 13, 587.
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26 Eickschen, H. & Jouck, Th. (1982) Behandlung von Sprosspilzinfektionen des Mund- und Rachenraumes bei Sauglingen und Kleinkindern. Clin Res Rep R 18134132 1982, Janssen Research Foundation, Belgium. 27 Reading, J. H., Clifford, P. D., Coles, R. W. el al. (1981) An open assessment of miconazole oral gel in the treatment of pediatric oral candidosis in general practice. Curr. Ther. Res. 30,605-609. 28 Kessel, L. J. & Taylor, W. D. (1980) Chronic mucocutaneous candidiasis-treatment of the oral lesions with miconazole. BY.J . Oral. Surg. 18, 51-56. 29 Casneuf, J., de Loore, F., Dhondt, F. et al. (1980) Oral thrush in children treated with miconazole gel. Mycosen 23, 75-78. 30 Martinelli, V. ( 1982) Relazione sull'impiego del ketoconazole in pediatria: gocce 20 mg/ml. Clin Res Rep 1982, Janssen Research Foundation, Belgium. 31 Saule, H. ( 1983) Behandlung schwerer Candida-Infectionen mit Ketoconazol bei Neugeborenen und jungen Sauglingen. Dtsch. Med. Wschr. 108, 1676-1680. 32 Bardare, M., Tortorano, A. M., Pietrogrande, M. C. et al. (1984) Pharmacokinetics of ketoconazole and treatment evaluation in candidal infections. Arch. Dis. Childhood 59, 1068- 1071.
33 Griscelli, C. ( 1985) Expertise clinique: ketoconazole suspension buvable. Clin Res Rep 1985, Janssen Research Foundation, Belgium. 34 Cauwenbergh, G., Casneuf, J., de Loore, P. et al. (1981) Treatment of infant thrush with ketoconazole, a new broad spectrum antimycotic. Curr. Chemother. Zmmunother., Proc. 12th Int. Congress Chemother., Florence. 35 Ninane, J., Vangyseghem, S., Michel, M. et 01. (1988) Ketoconazole prophylaxis of fungal infections in the neutropenic child. Gun. Ther. Res. 43, 851-856. 36 Berkowitz, R. J., Hughes, C., Rudnick, M. el al. (1985) Oropharyngeal Candida prophylaxis in pediatric bone marrow transplant patients. Am. 3. Ped. Hemat. Oncol. 7, 82-86. 37 Murphy, J. F., Jones, M. & Thompson, E. (1984) Oesophageal candidiasis and croup in a child with defective neutrophil motility. J . Znfect. 8, 247-250. 38 Ginsburg, C. M., McCracken, G. H. & Olsen, K. (1983) Pharmacology of ketoconazole suspension in infants and children. Antimicrob. Ag. Chemother. 23, 787-789. 39 D'Argenio, P., Morino, G., Fanelli, A. et al. (1984) Una nuova terapia orale della candidiasi mucocutanea in pediatria: ketoconazole sospensione. La Clinica 39, 95- 100.
mycoses 35, 1-8 ( 1992)
