1 Centre National de Référence Mycologie et Antifongiques, Institut Pasteur, Paris and Hôpital Necker, Paris; 2 Cemka-Eval, Bourg la Reine; 3 Centre Hospitalier Universitaire de Tours; 4 Hôpital Européen Georges Pompidou, Paris; 5 Hôpital Pitié-Salpêtrière, Paris; 6 Hôpital de Ravenel, Mirecourt; 7 Hôpital de la Timone, Marseille; 8 Hôpital Saint-Antoine, Paris; 9 Centre Hospitalier Universitaire de Rouen; 10 Département d'Hématologie et d'Oncologie, Hôpital Hautepierre, Avenue Molière, 67098 Strasbourg and the French Cooperative Study Group, France
Received 13 February 2004; returned 28 March 2004; revised 26 May 2004; accepted 3 June 2004
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Abstract |
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Patients and methods: Cases of invasive fungal infections (IFI) were identified retrospectively over a 1 year period. Data on underlying condition, IFI diagnosis, antifungal treatment and outcome were collected on the last five cases in each centre. Factors associated with first line therapy and with death were identified by multivariate analysis.
Results: Two hundred and nine cases were included (102 aspergillosis, 86 candidiasis, 15 cryptococcosis). Amphotericin B, in different formulations, was the first line therapy in 60%, azoles in 32%, combinations in 8%. Haematological malignancies and neutropenia were associated with less frequent initial prescription of azoles [OR = 0.3 (0.10.8) and OR = 0.3 (0.10.9), respectively]. In aspergillosis, younger age and neutropenia were associated with less frequent initial prescription of azoles [OR = 0.03 (0.0020.6) and OR = 0.09 (0.030.3), respectively] and previous history of IFI was associated with a higher probability of azole prescription [OR = 17.2 (2.4124.3)]. In candidiasis, haematological malignancy and co-prescription of nephrotoxic agents were associated with a less frequent initial prescription of azoles [OR = 0.1 (0.040.4) and OR = 0.2 (0.060.9), respectively]. Three factors were associated with a lower risk of death: cryptococcosis [OR = 0.16 (0.030.98)], hospitalization in infectious diseases units [OR = 0.40 (0.160.97)] and recent surgery [OR = 0.26 (0.080.80)]. Severe renal insufficiency was associated with a higher probability of death [OR = 8.77 (1.9738.97)].
Conclusions: Our results emphasize factors associated with the antifungal therapeutic decision and with the outcome of IFI.
Keywords: aspergillosis , candidiasis , cryptococcosis , pharmacoepidemiology
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Introduction |
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Over the 1990s, antifungal therapy has evolved with a broader choice between conventional amphotericin B (c-AMB), azole antifungal agents, new formulations of amphotericin B such as liposomal (L-AMB) and lipid-complex (ABLC) formulations. This has resulted in antifungal therapeutic strategies becoming more complex. However, resistance to antifungals is emerging, some fungal species being intrinsically resistant or less susceptible to antifungals.1618 In addition, patient characteristics are evolving (underlying diseases, risk factors, concomitant treatments with more patients managed in intensive care units and presenting with impaired renal function and devastating fungal infections). As opposed to bacterial infection, the diagnostic strategy of IFI remains suboptimal and heterogeneous among centres,19 which makes evaluating the global therapeutic decision process difficult. Well-designed therapeutic trialsof optimal performance in selected populationsare being used to study the clinical development of systemic antifungals. However, these cannot always translate into the reality of general medical practice. Furthermore, protocols do not take into account the medical process leading to the therapeutic decision. Thus, therapeutic practice has to be evaluated through pharmacoepidemiological studies. Pharmacoepidemiology is the evaluation of a morbid phenomenon in the population. It takes into account the drug as an informative factor supposed to influence the patient's health status to an extent similar to other factors, such as biological, behavioural, environmental parameters or the infectious agent itself.20 Such studies also provide a scientific basis for therapeutic strategy guidelines and the development of new anti-infectives. Although pharmacoepidemiological studies have been performed for antibacterial agents, such an approach had not been used for evaluating the prescription of systemic antifungals.
This multicentre pharmacoepidemiological study of systemic antifungals in France describes the medical practice and therapeutic strategies used in IFI, as well as factors involved in the therapeutic decision during the period 19981999 in France.
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Patients and methods |
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This 1 year study included patients treated for IFI during 1 November 199831 October 1999 in a randomized sample of haematology, intensive care (ICU) and infectious diseases wards of all university hospitals in France. Distribution of randomization was based on antifungal agent prescription figures, according to the above cited medical specialties: 50% of systemic antifungals are prescribed in haematology units (Gilead France, internal data). Forty-eight wards, including 27 [adult (20) and paediatric (7)] haematology units, 10 ICU and 11 infectious diseases units, were selected and all agreed to participate in the study. Investigators had to identify, retrospectively, the last five successive cases of IFI observed during the study period from their centre files. No IFI definitionwhether clinical or mycologicalwas given to investigators, as the objectives were to study current clinical practice. IFI cases collected were thereafter analysed using the EORTC/MSG criteria released recently. Patients receiving empirical antifungal therapy, as recommended in persistently febrile neutropenia, patients with superficial fungal infection or having mucosal colonization were not included. At the time of the study, amphotericin B colloidal dispersion, voriconazole, caspofungin and the intravenous formulation of itraconazole were not licensed in France.
Data collection
The following data were collected by two medical clinical research assistants in an anonymous questionnaire: demographics, underlying diseases, potential risk factors for IFI, antifungal prophylaxis, fungal pathogen(s) isolated, localization of infection and systemic antifungal therapies used for the episode. The latter included choice criteria, outcomes (cure, improvement or failure) as assessed by the physicians and tolerance of the treatment. Choice criteriaincluding drug spectrum, clinical criteria, infection site, underlying renal function, lack of possibility of oral treatment, intolerance, ward protocols, expert advicewere also retrospectively recorded.
A scientific committee involving haematologists, infectious diseases or solid-organ transplantation specialists, mycologists and pharmacists involved in the management of invasive fungal infections, reviewed the data collection form and validated the analysis and study report. Monitoring and statistical analysis was provided by a clinical research organization specializing in pharmacoepidemiology (Cemka-Eval, Bourg la Reine, France).
Definitions
Neutropenia at baseline was defined as a neutrophil count of <500 cells/µL, or a history of a neutrophil count <500 cells/µL for more than 10 days within 2 months before the first symptoms of IFI.
Pre-existing renal insufficiency was considered when the baseline serum creatinine level was >115 µmol/L (13.0 mg/dL) in men and 90 µmol/L (10.2 mg/dL) in women, or if the creatinine clearance estimated by the Cockcroft formula was <80 mL/min.21 Renal dysfunction occurring during treatment was defined by the serum creatinine level if it increased the baseline value by >1.5.
Antineoplastic chemotherapy was retained at baseline if it had been prescribed during the previous 3 months. The choice of nephrotoxic drug was via a pre-defined list of 21 drugs (cyclosporin, tacrolimus, non-steroidal anti-inflammatory agents, iodine, contrast medias, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aminoside, vancomycin, sulfamethoxazole and trimethoprim, sulfadiazine, foscarnet, pentamidine, aciclovir, indinavir, ritonavir, platinum salts, ifosfamide, methotrexate, IL-2, OKT3 antibody).
All records were reviewed by the Scientific Committee and IFI were classified as proven, probable or possible according to the EORTC/MSG definition criteria.22 These criteria, initially defined for oncology and haematology patients, were extended to all cases as no other standardized criteria were available for non-cancer patients.
Statistical analysis
Statistical analysis was performed using SAS statistical software. Comparison of qualitative variables was performed with the 2 test and that of quantitative variables with the ANOVA test. A P value of <0.05 was considered significant.
Multivariate analysis by logistic regression was applied to study the independent factors influencing the first line antifungal therapy, retaining all factors significantly associated to first line therapy in bivariate analysis, and to study independent factors associated with death within 3 months following first symptoms of IFI.
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Results |
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Overall, 209 patients who met the study criteria were recruited in 48 medical wards during the study period. Their characteristics and factors predisposing to IFI are summarized in Table 1. Solid tumours and haematological malignancies were progressive in 51% of the patients.
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Before the occurrence of IFI, prophylactic antifungal treatment was prescribed in 43.5% (91/209) of patientsmore frequently in haematology (62%) than in ICU (20%) or in infectious diseases wards (15%) (P<0.001). A similar number received prophylactic amphotericin B and/or azoles: 38 patients received c-AMB, 39 azoles, 12 c-AMB associated with an azole and two received L-AMB.
Initial renal insufficiency was present in 49% of patients (103/209) and was more frequent in ICU patients (77.5%) than in those hospitalized in haematology (42%) or infectious diseases wards (56%) (P<0.001). No relationship was found between baseline renal insufficiency and any particular IFI. At the time of the initiation of systemic antifungal therapy, 16 patients presented with a creatinine clearance <30 mL/min and 40 between 3060 mL/min.
Fungal pathogen and site of infection
Characteristics of patients according to fungal disease are described in Table 2. Invasive aspergillosis was diagnosed in 102 patients (49%), including 53 (52%) in whom Aspergillus spp.43 Aspergillus fumigatus and 10 other Aspergillus specieswere isolated. Pulmonary aspergillosis was the most frequent localization (87/102, 85%); 10 patients had sinusitis (four associated with pulmonary lesions compatible with invasive aspergillosis), seven developed a disseminated infection, one a central nervous system infection and one an osteomyelitis. Diagnosis was based on culture or microscopy in 57/102 cases, repeated galactomannan detection in serum (55/102) or histopathology (5/102). Two of these 102 patients had mixed infections: one with Aspergillus sp. and Candida sp. (fungaemia) and another with Aspergillus sp. and Mucor sp.
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Based on the classification of IFI through EORTC/MSG criteria, cases were more frequently proven in infectious diseases units (29/47, 62%) than in ICU (19/40, 48%) or in haematology wards (46/122, 38%), (P<0.001) (Table 2).
Children 16 years did not differ from adults except for higher frequencies of neutropenia (68% in children versus 44% in adults), concomitant nephrotoxic therapy (100% in children versus 75% in adults) and administration of prophylactic antifungals (68% in children versus 40% in adults).
First line antifungal therapy
Antifungal therapy was initiated within a mean of 4 days after the beginning of symptoms related to IFI. First line antifungal therapy included amphotericin B formulations in 60% of the cases (126/209) and azole antifungal agents in 32% [66/209; itraconazole (17), fluconazole (49)]. Combinations were used in 8% (17/209) consisting of the association of amphotericin B and flucytosine (eight patients), amphotericin B and azoles [seven patients; itraconazole (five), fluconazole (two)] or the association of two azoles (two patients). Among the various amphotericin B formulations, c-AMB was prescribed in 33% (69 patients), amphotericin B mixed with intralipid 20% (c-AMB-IL) in 12% (26 patients), L-AMB in 9% (18 patients) and ABLC in 6% (13 patients). Among the azoles, fluconazole was more often prescribed (49 patients) than itraconazole (17 patients) (Table 3).
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According to the investigators, criteria for first line antifungal therapy dependedfor 70% of themon the spectrum of the drug; on clinical criteria suggestive of any particular fungal infection (45%); on ward policy (20%); on localization of IFI (19%); on baseline renal function (16%); on fear of intolerance (6%); on impossibility of oral therapy (4%); and referent's recommendation (3%).
Median duration of first line therapy was 13 days with c-AMB (range 1199 days) and c-AMB-IL (range 144 days), 18 days for L-AMB (range 184 days), 10 days for ABLC (range 1126 days), 15 days and 16 days with fluconazole (range 1173 days) and itraconazole (range 1340 days), respectively. Combination therapy was more often prescribed in cases of proven IFI (15/17).
Results of bivariate analysis of factors associated with first line antifungal therapy are reported in Table 3. First line therapy was influenced by the type of fungal infection (P<0.001): amphotericin B and particularly c-AMB were more often prescribed for aspergillosis, azoles were more often prescribed for candidiasis, and combinations were most often proposed in patients with cryptococcosismostly the association of amphotericin B and flucytosine. When looking to the influence of the place of hospitalization, amphotericin B was more often prescribed in those hospitalized in haematology, and azoles more frequently in those staying in ICU or in infectious diseases units (P<0.001). When looking to potential differences between children and adults, more c-AMB or L-AMB were prescribed in children compared with adults (P<0.001) and no combination therapy was prescribed for children.
The administration of amphotericin B as a first line therapy was associated with haematological malignancy (P<0.001), recent administration of antineoplastic chemotherapy (P<0.001), neutropenia (P<0.001) or a previous administration of prophylactic antifungals (P=0.01).
L-AMB was significantly more often prescribed when patients received a haematopoietic stem cell transplant (P=0.04), corticosteroid therapy (P=0.02), cyclosporin (P=0.009) or presented graft versus host disease (P<0.001). Azoles were more often prescribed during AIDS (P<0.001) or in patients with solid organ transplantation (P=0.047).
The administration of concomitant nephrotoxic therapy other than cyclosporin did not influence the prescription of any amphotericin B formulation. Cancer, recent radiotherapy, tacrolimus therapy, diabetes mellitus, recent antibiotic use, recent surgery, presence of a central venous catheter, previous history of IFI, known Candida species mucosal colonization and baseline renal insufficiency did not influence the type of first line therapy; the EORTC/MSG criteria classification was not retrospectively evaluated.
Logistic regression analysistaking into account all factors retained after bivariate analysiswas applied to individualize factors independently associated with the initial prescription of azoles compared with amphotericin B formulations, both as a single therapy. Haematological malignancies and neutropenia were associated with a less frequent initial prescription of azoles [OR = 0.3 (0.10.8); P=0.02, and OR = 0.3 (0.10.9); P=0.04, respectively]. In patients with invasive aspergillosis, two factors were independently associated with a less frequent initial prescription of azoles: age [OR = 0.03 (0.0020.6); P=0.02] (the younger the patient the more often polyenes were prescribed) and neutropenia [OR = 0.09 (0.030.3); P<0.001] and one factor was independently associated with a higher probability of azole prescription: previous history of IFI [OR = 17.2 (2.4124.3); P=0.005]. In cases of systemic candidiasis, two factors were independently associated with a less frequent initial prescription of azoles: presence of haematological malignancy [OR = 0.1 (0.040.4); P<0.001] and concomitant prescription of nephrotoxic agents [OR = 0.2 (0.060.9); P=0.04].
Among patients with invasive aspergillosis and treated with one of the amphotericin B formulations, those with graft verus host disease were more likely to receive a lipid formulation as a first line therapy (P=0.01).
Second line therapy
Sixty-five patients (31%) received only a first line antifungal therapy, whereas 144 patients (69%) received at least a second line therapy, including 62 (30% of the total number of patients) who received a third line therapy or more. There was no significant relationship between the number of lines and subsequent mortality due to IFI.
When the first line therapy was amphotericin B, the switch to a second therapy was for the prescription of an azole in 61%, to another preparation of amphotericin B in 37% and for the addition of flucytosine in 2%. When the first line therapy consisted of an azole, the second line was most often amphotericin B formulations (90%), another azole in 5% and the addition of flucytosine in 5%. For 72/144 (50%), the reason for starting a second line therapy could be documented by the investigator. The reason was an intolerance for 23/72 (32%) including 16 cases of renal insufficiency, clinical failure in 19 (26%), results of mycological investigations in 12 (17%) or others, such as the need to switch to an oral therapy, clinical or radiological improvement and ward policy for the remaining 18 (17%).
Outcome
Cure or improvement, as assessed by the local physician, were observed in 38% and 25% of patients, respectively, and treatment failure was notified in 37%. The proportion of antifungal-treatment failures was higher in haematology (43%) and in ICU (42%) than in infectious diseases wards (18%) (P=0.04). Mycological outcome was documented in 97 patients (46%), consisting of persistence of fungal pathogen (52%) or eradication (48%) regardless of the fungi involved.
Median follow-up after IFI diagnosis was 4 months. Death was reported in 98/209 patients (47%) among whom 90 succumbed during the 3 months following the first symptoms of IFI. Fifty-two percent of the deaths were considered to be directly caused by IFI. Mortality within the first month following the initial appearance of symptoms was 27%, and cause of death was IFI in 60% according to the investigator's assessment. Survival analyses at 12 weeks, according to the fungal disease, are presented in Figure 1. Survival curves were similar for proven and probable IFI.
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Discussion |
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A high proportion of patients received prophylactic antifungal treatment: 56% for aspergillosis, 30% for candidiasis and 27% for cryptococcosis. The indications for prophylaxis or empirical therapy for aspergillosis and candidiasis were not clearly defined in France at the time the study started.
The results of the present study allow some interesting comments on current antifungal therapeutic practices, which appear to depend more on the suspected fungal agent than on speciality ward or host-related criteria, both in terms of first and second line therapy. Indeed, the choice of the first line antifungal agent was determined by the spectrum (70%) long before any other decision criteria, such as clinical orientation (45%) or renal risk (16%). This explains the major prescription of amphotericin B conventional formulation as the first line in haematology (44% versus 17% in ICU) whatever the renal status at baseline (49% with renal dysfunction at baseline) and nephrotoxic agents co-prescribed. Of note, the success rate of first line therapy was low (38% complete responses and 25% partial responses), at least for aspergillosis, but in accordance with the literature.31
Polyenesas a first line prescriptionwere independently associated with more severe disease and high risk of aspergillosis, and, despite its toxicity, c-AMB remained the most prescribed antifungal agent in IFI during the study period. Nearly half the patients had increased creatinine at baseline, with nephrotoxic agents co-prescribed for 80% of them. Twenty-seven (27%) of all patients developed subsequent renal failure, with a trend towards a higher risk with C-AMB-IL (42%), ABLC (38%) compared with L-AMB (28%) (P=0.06).
The number of associated factors explains the difficulty in determining patient profiles related to first line prescription. Nevertheless, L-AMB prescription was more frequently used than ABLC in young patients, but the number of patients did not allow any pertinent comparison of the two lipid formulations in multivariate analysis. Despite arguments about the lack of benefits provided by c-AMB-IL and its potential pulmonary side effects related to fat overload, or the incompatibility of the two drugs,32,33 this compound was prescribed in one third of medical centres involved in the studyas a less expensive alternative to the new formulations of amphotericin B.
A change in antifungal strategy was frequent (at least two lines for 69%) especially for intolerance but with no correlation with survival.
The mortality rate relating to fungal infection was high: 27% of deaths during the first month, 60% of which were attributed to IFI. Death rates due to invasive aspergillosis observed here appear similar to what was observed in the amphotericin B arm of the recent randomized comparative study performed in invasive aspergillosis,34 but were lower than the rates reported in published studies.24 Similarly, the mortality of cryptococcosis was identical to that recorded during another multicentre study running in parallel in a much larger population11 as well as that of candidiasis. The mortality did not significantly vary in patients with confirmed infections in comparison with those with probable or possible infections. However, the methodology we used here was not designed specifically to analyse outcomes and mortality. Regarding candidiasis, the mortality rate was high, but the selection of invasive fungal cases must be taken into account.3538 Despite the small numbers of patients, patients with severe IFI and numerous risk factors who were treated with L-AMB appeared to have better survival, particularly compared with patients receiving c-AMB-IL. When looking to factors independently associated with deaths occurring within 12 weeks, we found the presence of severe renal insufficiency at baseline, thereby confirming its negative impact, which had been demonstrated by others in terms of mortality and economic burden.39,40
This study shows the low level of relevant criteria for diagnosing fungal infection in clinical practice in order to define patient profiles regarding morbidity status. The decision of prescription followed a presumptive judgement, but the drug choice did not take into account toxicological consequences or the early risk of death.
The future variety of therapeutic strategies, guided by recent studies with the new formulations of amphotericin B, new azoles and the introduction of echinocandins will challenge physicians to change their practice and improve in parallel their decision criteria for prescription and their therapeutic practice, both for aspergillosis and candidiasis.
Further prospective studies should be developed to compare efficacy and toxicity according to the different types of strategy schedules. Homogeneous sub-populations should be targeted, prior to recommendations for systemic antifungal therapy according to individual risk.
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Acknowledgements |
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Participating Investigators
M. Boasson, Centre Hospitalier Universitaire, Angers; A.M. Peny, Centre François Baclesse, Caen; F. Déméocq, C. Paillard, Hotel Dieu, Clermont Ferrand; J.J. Sotto, F. Garban, J.P. Stahl, C. Contamin, Hôpital A. Michallon, Grenoble; D. Bordessoule, P. Turlure, Hôpital Dupuytren, Limoges; D. Peyramond, Hôpital de la Croix Rousse, D. Fière, A. Thiébaut, Hopital Edouard Herriot, Lyon; O. Bastien, Hôpital Louis Pradel, Bron; B. Coiffier, D. Espinousse, A. Lepape, Hôpital Lyon Sud, Pierre Bénite; G. Michel, Hôpital de la Timone, P. Fuentès, M. Reynaud-Gaubert, Hôpital Sainte Marguerite, Marseille; J. Reynes, Hôpital Gui de ChauliacHopital Saint Eloi, D. Rieu, F. Montoya, J.F. Rossi, Hôpital Lapeyronie, Montpellier; N. Milpied, P. Moreau, Hôtel-Dieu, Nantes; J.P. Cassuto, E. Rosenthal, P. Dellamonica, S. Chaillau, J.G. Fuzibet, W. Lescaut, Hôpital de l'Archet, Nice; C. Carbon, V. Jolly, Hôpital Bichat, A. Fischer, S. Dupuis, P. Hubert, B. Varet, B. Arnulf, Hôpital Necker, F. Bricaire, P. Bossi, J.P. Vernant, N. Dhedin, Hôpital Pitié-Salpêtrière, E. Vilmer, R. Larchée, Hôpital Robert Debré, A. Najman, F. Isnard-Grivaud, Hôpital Saint Antoine, A. Baruchel, Y. Reguerre, L. Degos, H. Dombret, E. Gluckman, P. Ribaud, Hôpital Saint-Louis, G. Huchon, A. Rabbat, J.P. Marie, A. Vekhoff, Hotel-Dieu, Paris; C. Camus, P.Y. Le Prisé, Hôpital de Pontchaillou, Rennes; H. Tilly, A. Stamatoulas, Centre Henri Becquerel, F. Caron, Y. Debab, J. Leroy Giraud, J.P. Vannier, B. Veber, R. Gillet, Hôpital Charles Nicolle, Rouen; F. Lucht, A. Frésard, Hôpital Bellevue, Saint-Etienne; P. Dufour, R. Herbrecht, Hôpital de Hautepierre, Strasbourg; D. Durand, G. Bordes, P. Massip, E. Bonnet, J. Pris, F. Huguet, Hôpital Purpan, Toulouse; P. Canton, C. Rabaud, A. Gérard, P. Léderlin, B. Witz, Centre Hospitalier Universitaire, Vandoeuvre les Nancy.
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Footnotes |
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