La tunisie Medicale - 2019 ; Vol 97 ( n°04 ) : 579-587
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Introduction: Le traitement de la candidose invasive (CI) demeure un défi en réanimation. L’administration tardive des antifongiques étant un facteur indépendant de mortalité. La prescription irraisonnable de ces agents est une source d’émergence de souches résistantes. Objectif: évaluer l’effet d’un traitement antifongique empirique (TAFE) sur la survie à J 28 et sur la survenue  de candidémie chez les patients septiques sans infection candidosique prouvée.
Méthodes: étude de cohorte monocentrique, rétrospective sur 8 ans, comparant deux bras de patients septiques non neutropéniques sans infection fongique prouvée selon l'administration ou non d'un TAFE. Les 2 critères de jugement sont  la mortalité à 28 jours et l'apparition de la candidémie. L'analyse a été ajustée sur le score APACHE II, le Candida score, la ventilation invasive et le cathétérisme central.
Résultats: 247 patients ont été inclus (groupe TAFE, n = 125 et groupe non TAFE, n = 122). Aucune amélioration de la survie à 28 jours n'a été trouvée. Ces résultats étaient concordants à l'analyse brute et après ajustement sur les facteurs mentionnés ci-dessus. Aucun effet préventif sur la survenue de candidémie. Un effet bénéfique du TAFE sur la survie a été observé chez des patients ayant un score APACHE II <16: OR= 0,68; IC 95% [0,53-0,87]; p=0,002.
Conclusions: aucun effet bénéfique d'un TAFE sur la survie à 28 jours ni sur la prévention de l'apparition d’une candidémie chez les patients septiques non neutropéniques de réanimation. Chez les patients ayant un score APACHE II <  16, il y avait un effet bénéfique sur la survie.

Mots Clés

In critically ill patients, invasive candidiasis (IC) incidence’s is growing and this is explained as a result of invasive procedures and the over-use of antibacterial and antifungal agents (1-3). Despite the development of effective and safer drugs, IC and candidemia remain associated with high mortality, namely when it is complicated by septic shock (4-7).
IC stills a major challenge in critically ill patients with unresolved sepsis. Indeed, the diagnosis of IC is usually late and confirmed by a positive blood culture for Candida species but the diagnosis of IC without candidemia is less evident. Recent guidelines recommend research of mannan antigen/ antibody with especially an excellent negative predictive value (8,9). But this is not always easy to reveal the IC. Furthermore, biomarkers such beta-D-glucan, not available at all the time.
Therefore, antifungal are increasingly used as empirically, mainly in patients at risk for IC or patients with unresolved sepsis. Some tools may help in selection of patients with high risk of IC, such the Candida score (10,11). The optimal management of Candida species infections includes an earlier selection of patients at risk of IC, a control of the infection source, and the administration of appropriate antifungal (7-9,12,13). Several recent investigations demonstrated that inappropriate empiric or delayed antifungal therapy was related to mortality in septic shock due to Candida infection (14-16).  Unreasonable administration of antifungal led to the emergence of non-albicans Candida infections and resistant candida strains (17,18).
The impact of an empiric antifungal therapy (EAFT) on prognosis was suggested by several studies (19-21), but without formal proof.
We aimed to evaluate whether EAFT improved survival and reduced the number of ICU acquired candidemia in septic critically ill patients without proven Candida infection.

 Study Design and Location:  it was monocentric, retrospective double cohort study conducted in a medical ICU with the collaboration of mycology and parasitolgy department over 8-years period (January 2008–December 2015) in the university hospital center of la Rabta.
Patients and Data Collection: non neutropenic patients with an ICU stay of more than seven days who developed a sepsis without documented bacterial or fungal infection were eligible for inclusion in our study. Patients who received a targeted antifungal for a proven Candida infection and those with neutropenia (neutrophil count of less than 500/mm3) were excluded. Thus, two groups were compared according to the administration or not of an EAFT (EAFT versus non EAFT).
Patient specific baseline characteristics as well as the follow-up of clinical, biological and microbiological data were collected from the hospital medical record. The predisposing factors of invasive candidiasis were collected as well as the outcome criteria (length of stay in ICU and 28 day mortality). The subsequently documented infections with the isolated pathogens and received antibiotics were also recorded. 
Definitions: To be included in the analysis, patients had to meet criteria for sepsis, severe sepsis or septic shock without documented fungal infection. Sepsis, severe sepsis or septic shock criteria were based on definitions of Surviving Sepsis Campaign 2012 (22). The Timing of EAFT was determined from the interval between the onset of sepsis or septic shock and administration of the first intravenous dose of antifungal. The prescription was considered empirical when it occurred within 24 hours of the onset of sepsis or septic shock. Confounding factors that we have adjusted our analysis were: APACHE II score, Candida score, invasive ventilation and central catheterisation. The Acute Physiology and Chronic Health Evaluation (APACHE) II was calculated based on clinical data present during the 24 hours of the beginning of sepsis (23).
Outcome assessment:  The primary end point was survival at day 28. The stratified analysis was assessed in predefined subgroups (APACHE II <16 vs > 16, candida score <3 or ≥3, mechanical ventilation vs not, central catheterization vs not). The secondary end point was the number of candidemia.
Statistical analysis:
Sample Size Calculation: As previously published, the mortality varied from 30 to 50% (19,20,24-26) in invasive candidiasis if not treated earlier, and the candidemia-related mortality
in case of early treatment would be 12% instead of 35% when the treatment is delayed (current practice, equivalent to a reduction percentage of 65% (7,21). We estimated that 124 evaluable patients per group were needed to take into account the expected the decreasing of mortality of 65% with a two-sided α risk of 5% and a power of 80% to compute sample size,.
Quantitative variables were expressed by means or medians and compared by the Student t-test or the Mann-Whitney U-test, as appropriate. Qualitative data were expressed as percentages and compared by the χ2 or Fisher’s Exact test, as appropriate. The measures of association between the EAFT and the 28-day survival were expressed by the odds ratio. The adjustment on predefined covariates was performed by the method of Mantel Hansel. The survival rates over time were represented by the Kaplan-Meier survival curves and compared by the log-rank test. The confidence interval was fixed at 95%. Data processing was done using SPSS Version 20 software.
Ethics statement: This study was approved by our local institutional review boards, and written patient consent was not required because of the retrospective nature of this study.

Patient’s clinical characteristics:
During the study period, 1762 patients were admitted to the medical ICU and among them 247 have met our inclusion criteria (EAFT group, n=125 and non EAFT group: n=122), the distribution of studied population is displayed in figure 1.
Our groups were comparable on demographic criteria, APACHE II score, co-morbidities and admission reason. The major identified predisposing factors of invasive candidiasis were central catheter; mechanical ventilation; previous antimicrobial therapy and less frequent the parenteral nutrition and hemodialysis (Table 1). The all five patients who had abdominal surgery received an EAFT. No difference was shown between groups regarding the risk factors, mainly the Candida colonisation before inclusion (36.8% versus 26.2%, p=0.1). The mean Candida score was superior in the intervention group without a real difference (4.33 ± 0.5 versus 3.09 ± 1.3, p=0.08). The prescribed antibiotics were directly against the multidrug resistant bacteria and were administered similarly between the groups. The median days on mechanical ventilation and ICU stay did not differ (Table 1).

Infectious data:
The microbiological follow up showed that a documented infection was identified among 81.6% of the intervention group and 78% of control group. The median delay required to the microbiological documentation was at 4 versus 5 days in the intervention and control groups respectively. The observed infections were classified in bacterial (51.2% vs 48.5%, p=1), fungal (30.4% vs 29.5%, p=0.8) and not documented infection (18.4% vs 22%, p=0.96) in the EAFT and non EAFT groups respectively. The most frequent infection was ventilator associated pneumonia (VAP) and the most common isolated pathogens were Acinetobacter baumannii (EAFT: 44% and non EAFT: 52%) and Candida albicans (EAFT: 63% and non EAFT: 58%). The distribution did not differ between the study groups.
When considering the total number of screened patients, the overall incidence of Candida infection was 21.5 per 1000 admissions for candidemia and 20.4 per 1000 admissions for Candida colonisation. No cases of complicated intra-abdominal infections were diagnosed.

Effect on survival of EAFT: 
In our series, we did not find an improvement in 28- day survival both in crude analysis and stratified analysis OR = 0.94; CI 95% [0.77-1.15]; p = 0.34 and OR= 0.54; CI 95% [0.7-1.95]; p= 0.63. However, a protective impact of the EAFT on 28 day-survival was found in the subgroup of moderate severity with an APACHE II score lower than 16: OR= 0.68; CI95% [0.53-0.87] and p=0.002 (Table 2).
The mortality in the EAFT group was 36% and that of non EAFT group was 40.2% without significant difference (p=0.51). Similarly, survival times were comparable to 28 days with median survival time of 25 days [21-28] in EAFT group and 22 days [19-24] in non EAFT group.  The survival analysis using the Kaplan-Meier curves tended to significance but without real difference between the two groups (p = 0.07) (Figure 2).
Nevertheless, stratified survival analysis on APACHE II score has regained that EAFT  improved survival time for the sub group with APACHE II score lower than 16 : median of 19 days [16-23] versus 15 days [9-17]  with p = 0.017  (Figure 3).

EAFT and prevention of new candidemia or Candida colonisation:
No difference was shown on the number of new proven candidemia between the two groups [21 (17%) among EAFT group versus 17 (14%) among non EAFT group, p=0.8]. Consequently, the EAFT did not prevent the occurrence of candidemia (OR= 0.96; CI 95% [0.68-2.07], p=0.5). Similarly, the Candida colonisation did not differ between our study groups [17 (13.6%) among EAFT group versus 19 (15.5%) among non EAFT group, p=0.88].  

Prescription of anti-fungal agents and central venous catheter removal:
The prescribed antifungal in the EAFT+ group were: fluconazole (58%), voriconazole (14.5%), amphotericin B (19.5%) and caspofungin (8%). The EAFT was maintained when the isolated strain was susceptible to the initial antifungal (19/21 candidemia) and changed in the two other cases. Its continuation was discussed case by case in the following situations (catheter-related infection (CRI) without candidemia, candiduria and undocumented infection); and this depending on the underlying diseases and hemodynamic status. It was continued in 27/40 and stopped in 13/40 of cases. Otherwise, empiric antifungal was stopped for a documented bacterial infection in 64 among a total of 125 cases.
Regarding the non EAFT group, the anti-fungal were administered only in case of proven fungal infection [22/122 (18%): 17 cases of candidemia and 5 cases of catheter related infection (CRI); because of the worsening of hemodynamic status. The median delay of antifungal introduction was 4 days after sepsis onset. In this later situation, antifungal therapy was targeted depending on the isolated Candida strain and antifungal susceptibility. The most prescribed antifungal was fluconazole since the sensitivity of isolated strains was almost exclusive to fluconazole (18/22: 82%) followed by amphotericin B and caspofungin in 2 cases each.
The central venous catheter was removed routinely in all cases of sepsis.

                Our study showed that empiric antifungal therapy (EAFT), when administered in patients with late-onset sepsis without documented fungal infection did not improved survival nor prevented candidemia. Nonetheless, a beneficial effect of an EAFT on survival was showed with the subgroup of patients with moderate severity at inclusion (APACHE II score < 16).
The management of invasive candidiasis in critically ill patients is clear when candidemia is confirmed (9). Early treatment and appropriate antifungal in candidemia is related to a better prognosis had shown to reduce mortality in patients with candidemia (7,17,18, 27,28). Preemptive therapy in colonized patients and in those with high-risk of candidemia and unresolved sepsis despite broad broad-spectrum antibacterial therapy remains unclear (29,30). Despite these arguments, the findings of some robust trials (such the INTENSE study: European/American exploratory, multicenter, randomized, double-blind, placebo-controlled trial) were enables to provide evidence that pre-emptive administration of an echinocandin was effective in preventing IC in high-risk surgical ICU patients with intra-abdominal infections (31). Indeed, in that study, the IC incidence was 8.9% and 11.1% for placebo and micafungin arms respectively with a difference at 2.24% [95% CI, (-5.52-10.20)]. Our results were in accordance with these findings concerning the failure of pre-emptive antifungal therapy in preventing candidemia.
Accordingly, clinicians should continue to use predictive scores to identify critically patients who are susceptible to benefit from empirical antifungal treatment. Although it is recognized as a strong risk factor, the candida colonization, which may occur early after ICU admission, does not justify the start of empirical antifungal treatment (32). In our series, adjusted analysis on candida score (<3 vs > 3) didn’t show a significant benefit on survival. It is therefore suggested to revise the interest of Candida score among the medical patients. Also, invasive ventilation and central venous catheterization, commonly known as a major risk factors for candidemia (3,33), have not changed the impact of an EAFT on 28-day survival.
Overall, our results were similar to those of a multicenter French study (5 ICUs included in the French Outcome Rea group and 1491 patients) (34) in non-neutropenic, non-transplanted ICU patients.  In the AmarCand study that  described the management of IC in French ICUs, despite the clinical enhancing after empiric antifungal in 70% among cases of suspected IC, mortality rate remains high and similar in the proven IC group (31.6% vs 34.4%, p=0.42) (25).
Likewise, the EMPIRICUS clinical Trial of Timsit JF et al (21) that was designed to evaluate benefits of early introduction of micafungin in critically ill patients with ICU acquired severe sepsis and Candida colonization failed to conclude in a real survival improvement of such therapy. Indeed, 68% patients in the micafungin group vs 60.2% in the placebo group were alive and free from invasive fungal infection at day 28 (HR=1.35 [95%CI,0.87-2.08]. Nevertheless, the results regarding various predefined subgroups were in favour of micafungin group for patients with     [1-3]-β-D-glucan levels >80 pg/mL, [1-3]-β-D-glucan levels of 250 pg/mL, Candida scores at ≥3, and colonization index ≥ 50% (21). Similarly, no significant difference was observed between the 2 groups for the secondary endpoints (day-28 and 90 survivals, the number of organ failure–free days, the rate of ventilator-acquired pneumonia and the serum B-D glucan serum titers evolution) (21). But another interesting and different result emerges from this study: the use of empirical micafungin decreased the rate of new invasive fungal infection in 3% among the micafungin group vs 12% among the placebo group (p=0.008) (21). Our result on this endpoint was not concordant. Indeed, we observed a rate of candidemia in 17% among EAFT group versus 14% among non EAFT group (p=0.8).
In our series the benefit of EAFT on survival improvement was found in the subgroup of patients with moderate severity: APACHE II score <16 (OR= 0.68, CI 95% [0.53-0.87], p=0.002). But, the signification of such result is debatable and requires to be consolidated by further studies with larger series. Probably, the response to an EAFT when it is early introduced in moderately severe patients without multiple organ failures or underlying diseases is more favourable and consequently the gain on survival is greater.
Furthermore, in the latest systematic review on the untargeted antifungal, there was moderate grade evidence that untargeted antifungal treatment did not significantly reduce or increase total mortality (RR=0.93, 95% CI: 0.79 -1.09, p=0.36; participants = 2374; studies = 19). With regard to the outcome of proven invasive fungal infection, there was low grade evidence that untargeted antifungal treatment significantly reduced the risk (RR=0.57, 95% CI: 0.39-0.83, p=0.0001; participants = 2024; studies = 17). The only probable benefit was the reduction of fungal colonization risk (RR=0.71, 95% CI: 0.52-0.97, p= 0.03; participants = 1030; studies = 12) but the quality of evidence was low (35).
In addition to the uncertain improvement of survival by the introduction of an EAFT, it was reported that excessive use of antifungal contributes to the emergence of less sensitive Candida species to antifungal agents and Higher minimal inhibition concentration (MIC) for sensitive Candida species (17). Previous use of azoles and candines increase the risk of fungemia to species with higher antifungal MICs. E. Azoulay (18) described a significant relationship between antifungal consumption and probability of being colonized by yeasts with higher antifungal MICs. in ICU patients.
Our findings support the hypothesis that early empiric antifungal therapy did not improve survival and did not prevent a new episode of candiemia. This should lead to a rationalization of the antifungal use among non-neutropenic critically ill patients with ICU-acquired sepsis.  The weakness of our study was the retrospective and monocenter design and the nature of the used antifungal (fluconazole). While echinocandins are recommended as first line antifungal therapy, the most common agents used were fluconazole and amphotericin B which remain the two most prescribed agents in underdeveloped countries.

No benefits were found of empirical antifungal therapy both in improving survival at 28 day or in preventing a new candidemia among non-neutropenic critically ill patients with a late-onset sepsis. Nevertheless, a beneficial impact on the survival has been objectified at 28 days, in moderately ill patients (APACHE II < 16). Further studies are necessary to resolve the uncertainties around this question. This should lead to improving diagnostic strategies in order to surmount the diagnostic delay of fungal infections and excessive administrations of antifungals without a real benefit.

Declarations of interest: none
Ethics statement: This study was approved by our local institutional review boards, and written patient consent was not required because of the retrospective nature of this study.

Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Figure 1. Patient’s flow chart

Figure 2. Survival Analysis at 28 days of the study groups

Figure 3. Stratified survival analysis on APACHE II score
Table I: Patient's baseline characteristics

EAFT: empiric antifungal therapy, APACHE II:  Acute Physiology and Chronic Health Evaluation II, SOFA: Sequential Organ Failure Assessment. ICU: intensive care unit, SD: standard deviation, *: candida colonisation was considered when colonisation index was higher than 0.5

Table II.  Impact of EAFT on 28-day survival: crude and stratified analysis

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