Journal of Chemotherapy

ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20

Fluconazole and Ketoconazole in the Treatment of Oral and Esophageal Candidiasis in AIDS Patients F. Barchiesi, A. Giacometti, D. Arzeni, P. Branchesi, G. Crescenzi, F. Ancarani & G. Scalise To cite this article: F. Barchiesi, A. Giacometti, D. Arzeni, P. Branchesi, G. Crescenzi, F. Ancarani & G. Scalise (1992) Fluconazole and Ketoconazole in the Treatment of Oral and Esophageal Candidiasis in AIDS Patients, Journal of Chemotherapy, 4:6, 381-386, DOI: 10.1080/1120009X.1992.11739196 To link to this article: http://dx.doi.org/10.1080/1120009X.1992.11739196

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Date: 30 September 2016, At: 07:13

Journal of Chemotherapy

Fluconazole and Ketoconazole in the Treatment of Oral and Esophageal Candidiasis in AIDS Patients F. D. G. G.

BARCHIESI - A. GIACOMETTI ARZENI - P. BRANCHES! CRESCENZI - F. ANCARANI SCALISE

Summary ---------------------------------

In our study 77 AIDS patients suffering from oral and/or esophageal candidiasis were evaluated: 38 received fluconazole, 39 ketoconazole. We analyzed the rates of clinical and mycological responses, relapses and toxicities. In vitro susceptibility tests for both antifungal drugs were performed by evaluating their Minimal Inhibitory Concentrations (MICs). The azole drugs investigated show a good activity in the treatment of oropharyngeal and esophageal candidiasis also in advanced stages of HIV infection. Clinical cure or improvement were achieved in 29 (76.3%) and 31 (79.4%) of the patients treated with fluconazole or ketoconazole respectively. Clinical or laboratory adverse experiences related to fluconazole were seen in 7 (21.2%) patients while ketoconazole provoked adverse experiences in 9 (26.4%) patients. In vitro susceptibility tests, if repeated more than once, both in primary infection and relapses, could be important to demonstrate a probable sensitivity change or resistance of the tested strains. Key words: Fluconazole, Ketoconazole, Candidiasis, AIDS.

Institute of Infectious Diseases, University of Ancona, Italy. Corresponding Author: Francesco Barchiesi, M.D., Clinica Malattie Infettive, Ospedale Umberto 1°, L.go Cappelli, 1, 60121 Ancona, Italy. © Edizioni Riviste Scientifiche - Firenze

Vol. 4 - n. 6 (381-386) - 1992

INTRODUCTION

Candidiasis represents a common infectious complication in the immunocompromised host. This infection is primarily endogenous and may be either localized or widespread. While patients with leukemia or malignant tumors are at high risk of developing systemic candidiasis, life-threatening Candida infections are rarely seen in HIV patients 1 • However, nearly all patients in advanced stages of HIV-infection suffer from recurrent oral candidiasis. Studies in HIV-infected patients have shown a frequency of oral candidiasis ranging from 43 to 93% in patients with AIDS or AIDS-related complex (ARC) and 7 to 93% of patients who have LAS or are asymptomatic 2 • Severe pharyngeal Candida infection is painful, impairs the quality of life, and may result in a reduction in food or fluid intake. Moreover, extension of the infection from the oropharyngeal mucosa to the esophagus is a common complication 3 • There is no universal recommendation concerning treatment of AIDS-associated oropharyngeal and esophageal candidiasis. Systemic antifungal agents have been widely used in the treatment of oral candidiasis because of the poor response and rapid relapse with topically acting antifungal agents, such as amphotericin B or nystatin 4 • Much of the progress made in antifungal therapy has involved the imidazoles, which are potentially of extreme importance for the treatment of candidiasis in the immunocompromised host because of their activity against the Candida species and their greater tolerability than amphotericin B 5 • Among the oral systemic antifungal agents, ketoconazole was the first that appeared to be effective for the treatment of oropharyngeal candidiasis and has also been ISSN 1120-009X

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F . BARCHIESI - A. GIACOMETI'l - D. ARZENI - P . BRANCHES! - G. CRESCENZI - F . ANCARANI - G. SCALISE

shown to be effective against mucocutaneous candidiasis. However it occasionally causes hepatotoxicity, has a short half-life which requires twice-daily dosaging and in higher doses may inhibit androgen synthesis 6 • During the last decade several new imidazoles have been developed. A newly introduced triazole, fluconazole has proved to be effective for both the therapy and prophylaxis of orpharyngeal candidiasis in patients with AIDS as well as other immunocompromised patients. It differs markedly from other azoles in its pharmacokinetic properties and is available for both oral and intravenous administration 7 • We have therefore evaluated, on the grounds of our experience, fluconazole and ketoconazole efficacy in the treatment of oral and esophageal candidiasis in AIDS patients and analyzed the rates of clinical and mycological responses, relapses and toxicities. PATIENTS AND METHODS

During a 48-month period all HIV seropositive patients in advanced stage of infection (stage IV C 2 according to CDC classification) hospitalized at the Institute of Infectious Diseases, University of Ancona, were evaluated 8 • Patients were eligible for the study if they had symptoms (i.e. dysphagia, odynophagia) or clinical appearances (i.e. thrush, erythema) of oral and/or esophageal candidiasis. Whenever possible an esophagoscopy was performed to confirm the clinical suspicion. Exclusion criteria included impairment of renal function (serum creatinine level ~ 1.8 mg/mL) or hepatic function (alkaline phosphatase level > 50% of normal values, bilirubin level ~ 2 mg/mL) or a previous severe adverse hepatic reaction to imidazoles. A total of 93 patients were considered: 72 males, 21 females, mean age 32.7 years, range 22-74 years. Before patients started the azole therapy, symptoms and signs of oropharyngeal and/or esophageal infection were recorded, with mycologic confirmation by microscopy and culture of a sample within 48 hours of initiation of treatment. Mycologic assessment was carried out two times weekly during treatment and 10 days after the end of treatment. The patients were allocated for oral therapy in an alternating sequential manne~ to receive one

of the two antifungal agents. Fluconazole 200 mg/day and ketoconazole 400 mg/day were orally administered. Clinical assessment of the response to treatment was graded as clinical cure, improvement and failure. Clinical cure was defined as complete disappearance of complaints (i.e. dysphagia, odynophagia) with negative control culture 10 days after the end of treatment. Improvement was defined as eradication of all signs and symptoms of infection although the control culture obtained 10 days after the end of treatment showed a little growth of yeasts (s 10 2 cfu/mL in mouth washing). Failure was defined as persistence of signs and symptoms of infection with positive control culture during treatment. Disappearance of all signs and symptoms without an obtained contol culture was considered improvement. All yeast isolates were identified to species level by API 20 C Aux system (Bio Merieux) supplemented as needed with conventional morphologic and biochemical methods 9 • For the yeasts isolated in the last two years which were causative agents of the relapses, fluconazole and ketoconazole in vitro susceptibility tests were performed. The Minimal Inhibitory Concentrations (MICs) were determined using a previously described method 10 • 11 • In brief, fluconazole (Pfizer Inc.) and ketoconazole Ganssen Pharmaceutica) stock solutions were prepared by dissolving 20.0 mg of azole pure powder in 5.0 mL of dimethylsulfoxide (Merck), resulting in a concentration of 4000 mg/L. Each dilution was diluted 1:10 in sterile distilled water followed by doubling dilutions in water to provide concentrations from 400 to 0.02 mg/L. To each milliliter of solution were added 9 ml of semisolid agar, obtaining antimycotic dilutions from 40 to 0.002 mg/L. Sterile polystyrene plates with 24 wells (Cell Cult Flow, 15x17 mm) were used: samples of 1 ml of antifungal agents and agar preparation were dispensed into the wells. The inoculum was prepared from yeasts grown on Sabouraud dextrose agar from 24-48 hours: a homogeneous suspension was made in sterile 0.85% saline solution and adjusted to a turbidity which permits exactly 85% transmission of light at 5 30 nm. This suspension was further diluted in sterile saline to make the working inoculum. Each of the wells received 10 microliters of suspension. The plates were incubated at 37 °C until the control showed clearly visible

FLUCONAZOLE AND KETOCONAZOLE IN THE TREATMENT OF ORAL AND ESOPHAGEAL CANDIDIASIS, ETC.

growth. At this time the MIC was read. The MIC was the lowest concentration of drug preventing macroscopic growth of colonies. Our reference culture was a strain of Candida albicans (ATCC 10231) grown on Sabouraud dextrose agar for 48 h at 30° C. RESULTS

Of the original 93 patients considered in the study, 16 were excluded. In 5 patients the course of therapy was too short to permit an analysis of efficacy because their rapidly evolv- . ing diseases resulted in death within 3-5 days. Two other patients were transferred within 3-4 days after hospitalization. In another patient fluconazole was already discontinued and substituted by an amphotericin B plus flucytosine treatment because of a Cryptococcus neoformans meningitis diagnosed 3 days after hospitalization. In another eight subjects the intravenous route was the only possible administration route due to severe life-threatening conditions so that they were excluded from the study. In these patients intravenous fluconazole was administered at a dosage ranging from 100 to 600 mg/day according to severity of the fungal infection, for a mean duration of 10 days (range 6-15 days). The characteristics of 77 assessable patients, their clinical and microbiological evaluation, are summarized in Table 1. The two groups were similar with regard to underlyng infection, duration of therapy, and distribution of Candida species. Oropharyngeal candidiasis recurred in 58 patients (75.3%), oropharyngeal candidiasis plus esophagitis in 12 (15.5%), esophagitis in 7 (9.1%). The most commonly isolated strain was Candida albicans (83 .1%). Fluconazole 200 mg/day was orally administered to 38 patients for a mean duration of 14 days (range 6-46 days) . Ketoconazole 400 mg/day was administered to 39 patients for a mean duration of 12 days (range 6-33 days). Clinical cure and improvement were obtained respectively in 16 (42 .1%) and 13 (34.2%) patients treated with fluconazole, and in 18 (46.1%) and 13 (33.3%) patients treated with ketoconazole . Treatment failure occurred in 9 (23.6%) of the patients in the fluconazole group and in 8 (20.5%) in the ketoconazole group. In Table 2 clinical adverse effects are reported. Gastroin-

383

testinal disturbances were observed more frequently than other adverse effects with both drugs but were never too severe to discontinue the therapy. One patient treated with ketoconazole showed a moderate increase in hepatic enzymes. In Table 3 we report the MIC modification for the strains isolated from 14 patients in whom recurrent episodes of candidiasis occurred. It is possible to note a progressive increase in the MIC values from among the first episodes and relapses. In patients 3, 4, 7, 9,13 the infection was sustained by two or three Candida species. Generally the MIC values of Candida krusei and Torulopsis glabrata were higher than the values obtained for C. albicans strains contemporaneously isolated. T ABLE 1 - Characteristics of patients, clinical and microbiologic evaluation.

Category

Fluconazole Ketoconazole

N ° of patients (M/F)

38 (3 0/8)

39 (29/11)

31

27 7 5

Infection - O roph aryngeal candidiasis - Oroph . cand . and esophagitis - Esophagitis

5 2

Pathoge nic yeas ts

-

Candida albicans Candida kl'usei Tomlopsis glabrata Candida parapsilosis Candida pseudotropicalis

29 3 2 2 2

1 1

14 (6-46)

12 (6-33)

16 (42. 1) 13 (34.2) 9 (23.6)

18 (46. 1) 13 (33.3) 8 (2 0 .5)

- Mixed Medi an duration of therapy in days (range) Clinical evaluation (% ) - Cure - Improve ment - Failure

T ABLE

35

2 - Adverse effects due to antifungal agents.

Adverse effects nausea epigas tric pain vo mitin g diarrhea pruritus rash headache hepatic enzymes increase

Fluconazole

Ketoconazole

2

4 3

1 4

3

2 2

2

F . BARCHIESI - A. GIACOMETII - D. ARZENI - P. BRANCHES! - G. CRESCENZI - F. ANCARANI - G. SCALISE

384

TABLE 3 - Modifications of the MIC values during the relapses of Candida infections. MICs (mg/L) variations in the relapses ** Pt./Drug* 1 2

F/K F

3

F

4

F

7

F F F

8

F

9

F

10

F

11 12

13

K K/F K

14

K

5 6

Strains

C. C. C. C. T. C. T. C. C. C. C. C. C. C. T. C. C. C. C. T. C.

albicans albicans albicans krusei glabrata albicans glabrata albicans albicans albicans krusei albicans krusei albicans glabrata albicans albicans albicans albicans glabrata albicans

no

JO ( )*** 0.312 (24) 0.312 (8) 0.625 (24) 1.25 (24) 1.25 (24) 0.156 (26)

1.25 (16)

0.625 (24) 10 (2)

40

0.625 5 10 0.312 10 (4)

20 (4)

0.312 (32) 0.3 12 (30) 0.019 (2 8)

0.625 (32) 0.625 (28) 5 (10)

0.039 (8)

0.312 (2)

0.019 (32)

5 10 (4)

1.25 (1) 0.625 (24)

5

20 20 (10) 10 (10) 40 2.5 20

vo

IV 0 5/1.25 (16)

10/5

40 20 20 (8) ND

40

40

0.3 12 (26)

5 0.3 12 (24) 5 (16)

1.25 (20)

5

O.D78 (2)

mo

5/20 10 ND

* F Fluconazole, K Ketoconazole. ** I 0 • • • . V 0 indicate the relapses of Candida infection. *** The numbers in parentheses indi~ate the intervals in weeks, occurring among the recurrent episodes. ND not determined.

DISCUSSION

Oral candidiasis has been identified as the most common oral manifestation of HIV infection and AIDS in all patients at risk worldwide 12 • Candida albicans is the strain m·ost fre-· quently isolated from the oral mucosa of HIVinfected patients 1 • It is a commensal, found in more than 90% of the population, and may produce a variety of clinical le~ions, including pseudomembranous, erythematous and hyperplastic candidiasis, and angular cheilitis 12 • The esophageal involvement is predictive of progressive immunosuppression 13 • In our study we considered 77 seropositive patients, affected by oral and/or esophageal candidiasis, all in an advanced stage of infection and seriously immunocompromised (mean CD4 + count 192/mm3 ). Thirty-eight patient~ received_fluconazole, 39

ketoconazole. The clinical and microbiological response rates were similar in both groups of patients. The failures were found in 9 patients (23 .6%) treated with fluconazole and in 8 patients (20 .5go) treated with ketoconazole. The lack of response to the therapy of the strain·s isolated from the acute episodes of candidia-sis could be explained by a progressively reduce~ susceptibility to azoles. In fact all 17 patients failing therapy had already been subjected to a fluconazole prophylaxis (50/ 100 mg/day), at least once, because oral candidiasis episodes occurred in previous stages of HIV infection. Literature data report that strains of C. a/hicans resistant to azoles are highly unusual and they 'appear in clinical practice only with protracted exposure to the drug, like in patients affected by mucocutaneous candidiasis and always more frequently in those affected by

FLUCONAZOLE AND KETOCONAZOLE IN THE TREATMENT OF ORAL AND ESOPHAGEAL CANDIDIASIS, ETC.

AIDS 14 • 1 s. Hitchcock et al. reported C. albicans strains showing cross-resistance to all azole compounds tested: the mechanism of their resistance is suggested to be a lowered permeability to azoles 16 • 17 • 18 • Moreover in 7 of these 17 cases, strains other than C. albicans were isolated during the acute episode of infection: 3 C. krusei and 3 T. glabrata in the fluconazole group, 1 C. pseudotropicalis and 1 T. glabrata in the ketoconazole group. Recently, several studies in non-HIV immunocompromised patients have documented the failure of fluconazole therapy in C. krusei fungemia and the appearance of T. glabrata strains resistant to fluconazole and ketoconazole 19 • 20 • 21 . Wingard et al. indicate that the prophylactic use of fluconazole in immunocompromised patients may decrease the frequency of fungal infections caused by C. albicans and C. tropicalis, but it may also result in the emergence of resistant fungal pathogens, such as C. krusei 22 • Our data seem to suggest that the uncommon Candida strains represent a serious problem also in AIDS patients. Thus it appears to be of importance to introduce methods for testing antifungal agents. The current lack of standardization of in vitro susceptibility tests of fungi, makes recognition of resistant strains more difficult 23 • We used a semisolid agar dilution method described by Gordon et al. that permits reproducible MIC endpoints 10 • While the results of in vitro susceptibilities have poor value in absolute terms, it is more important to examine the modification of MIC values in a controlled follow-up. The progressive increase of MIC values for a yeast causing recurrent episodes of candidiasis can mean the presence of a strain that has begun to be resistant to that therapy. For a good correlation between in vitro and in vivo results Willocks et al. introduced the relative sensitivity or "resistant factor" of C. albicans isolates from cases of refractory oral candidiasis compared with those from a control group of patients. A relatively small "resistant factor" of four or greater may be significant 1 s. Concluding, both fluconazole and ketoconazole show good activity in the treatment of oropharyngeal and esophageal candidiasis even in advanced stages of HIV infection, although a complete clearance of the oral cavity is difficult to obtain. In spite of the poor general condition of our patients, both of the drugs were well

385

tolerated. The importance of performing in vitro susceptibility tests for azole antifungal agents to identify the emerging resistant strains must be emphasized. AcKNOWLEDGEMENTS - We thank Stefania Galeazzi for laboratory technical assistance. This work was partially supported by Ministero della Sanita, ISS, Progetto AIDS (1990), Roma, ltalia.

REFERENCES ' Meunier F. Candidiasis. Eur J Clin Microbial Infect Dis 1989; 8 (5):438-447. ' Dodd CL, Greenspan D, Ketz MH, Westenhouse JL, Feigal DW, GreenspanJL. Oral candidiasis in HIV infection: pseudomembranous and erythematous candidiasis show simi· Jar rates of progression to AIDS . AIDS 1991; 5(11): 1339· 1343. 1 Podzamcler D, Casanova A, Santamaria P, Benasco C, Gudil F. Esophageal candidiasis in the diagnosis of HIV· infected patients . JAMA 1988; 259 (9): 1328-1329. • De Vries-Hospers GH, Van Der Waaji D . Salivary concentrations of amphotericin B following its use as an oral lozenge. Infection 1980; 8: 63- 65 . 'Dismukes EW. Azole antifungal drugs: old and new. Ann Intern Med 1988; 109 (3): 177-179. 'Shaunak S, Cohen J . Clinical management of fungal infection in patients with AIDS. J Antimicrob Chemother 1991; 28 (Suppl. A): S67-S82. ' Galgiani JN. Fluconazole, a new antifungal agent. Ann Intern Med 1990; 113 (3): 177-181. 1 Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Morb Mort Wkly Rep 1987; 36 (Suppl. 1S): 3S-15S. 'Cooper BH, Silva-Hutner M. Yeasts of medical importance. In: Lennette EH, Baboa A, Hausler WJ, Shadomy NJ, eds. Manual of Clinical Microbiology. Washington DC 1985: 526-541. 10 Gordon MA, Lapa WE, Passero GP. Improved method for azole antifungal susceptibility testing. J Clin Microbiol 1988; 26 (9): 1874-1877. 11 Arzeni D, Barchiesi F, Ancarani F, Scalise G . Fluconazole, itraconazole and ketoconazole in vitro activity. A com· parative study. J Chemother 1991; 3 (3): 139-142. " Diamond RD. The growing problem of mycoses in patients infected with the human immunodeficiency virus. Rev Infect Dis 1991; 13: 480-486. 11 Gould E, Kory WP, Raskin JB, lbe MJ, Redlhammer DE. Esophageal biopsy findings in the acquired immunodefi· ciency syndrome (AIDS): clinicopathologic correlation in 20 patients. South Med J 1988; 81: 1392-1395 . "Hay RJ. Antifungal therapy and the new azole compounds. J Antimicrob Chemother 1991 ; 28 (Suppl. A): S35· S46. "Willocks L, Leen CLS, Brettle RP, Urquhart D, Russell TB, Milne LJR. Fluconazole resistance in AIDS patients. JAC 1991; 28 (6) : 937-939 . "Hitchcock CA, Barrett-Bee KJ, Russell NJ. The lipid composition of azote-sensitive and azote-resistant strains of Candida albicans. J Gen Microbic! 1986; 132: 242 1-2431. " Hitchcock CA, Barrett-Bee KJ, Russell NJ. The lipid composition and permeability to azote of an azole- and po·

386

F. BARCHIESI - A. GIACOMETTI - D. ARZENI

lyene-resistant mutant of Candida albicans. J Med Vet Mycol 1987; 25: 29-37. 11 Ryley JF, Wilson RG, Barrett-Bee KJ. Azole resistance in Candida albicans. Sabouraudia 1984; 22: 53-63 . •• Mcilroy MA. Failure of fluconazole to suppress fungemia in a patient with fever, neutropenia, and typhlitis. J Infect Dis 1991; 163: 420-421. 20 Warnock DW, Burke J, Cope NJ, Johnson EM, von Fraunhofer NA, Williams EW . Fluconazole resistance in Candida glabrata. Lancet 1988; 2: 1310. "Meunier F, Aoun M, Gerard M. Therapy for oropharyngeal candidiasis in the immunocompromised host: a rando-

P. BRANCHES! - G. CRESCENZI - F. ANCARANI - G. SCALISE

rnized double-blind study of fluconazole vs. ketoconazole. Rev Infect Dis 1990; 12 (Suppl. 3): S364-S368. "Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Sara! R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole . N EnglJ Med 1991; 325 : 1274-1277. " Shadomy S, Spinel-lngro££ A, Cartwright JR. Laboratory studies with antifungal agents: susceptibility tests and bioassay. In: Lennette EH, Baboa A, Hausler WJ, Shadomy NJ, eds. Manual of Clinical Microbiology. Washington DC 1985: 991-999.