Candidemia and invasive candidiasis in adults: A narrative review

EJINME-03269; No of Pages 8 European Journal of Internal Medicine xxx (2016) xxx–xxx

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Review Article

Candidemia and invasive candidiasis in adults: A narrative review Spinello Antinori a,b,⁎, Laura Milazzo b, Salvatore Sollima b, Massimo Galli a,b, Mario Corbellino b a b

Department of Clinical and Biomedical Sciences “Luigi Sacco”, University of Milano, Milano, Italy III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milano, Italy

a r t i c l e

i n f o

Article history: Received 26 March 2016 Received in revised form 12 June 2016 Accepted 22 June 2016 Available online xxxx Keywords: Candidemia Invasive candidiasis Diagnosis Antifungal therapy Resistance Guidelines

a b s t r a c t Candidemia and invasive candidiasis are major causes of morbidity and mortality, and their incidence is increasing because of the growing complexity of patients. Five species of Candida (Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei) account for more than 90% of all diagnosed cases, but their relative frequency varies depending on the population involved, geographical region, previous anti-fungal exposure, and patient age. The best evidence regarding the anti-fungal treatment for invasive candidiasis comes from randomized controlled trials in which more than 85% of the recruited patients had candidemia. In the case of less frequent forms of invasive candidiasis, the recommendations are based on retrospective studies, meta-analyses (when available) and experts' opinions. A pre-emptive approach based on biomarkers and clinical rules is recommended because of the high rate of infection-related mortality among critically ill patients. © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Candida spp. are the microorganisms responsible for the most frequently encountered invasive fungal infections among hospitalized patients in high-income countries [1]. Invasive candidiasis (IC) encompasses a spectrum of clinical conditions, the most frequent of which is candidemia, which is reported to be between the fourth and seventh most frequent causes of bloodstream infections (BSI) in USA and Europe, and it is associated with high crude mortality rate, prolonged hospital stays, and high healthcare costs [2–5]. Deep-seated candidiasis or IC is a more difficult clinical entity to diagnose as it is associated with various syndromes involving organs such as the liver, spleen, heart, eyes, peritoneum, kidney, bone, meninges and lungs with or without concomitant candidemia [6]. Traditionally, the most frequently affected patients are the critically ill patients in intensive care units (ICUs), those undergoing abdominal surgery and neutropenic patients, and the most frequent causes are Candida colonization of indwelling catheters, translocation from the gut to the bloodstream, or anastomotic leakage after laparotomy [1,7, 8]. However, there have been recent reports of a sharp increase in candidemia among patients admitted to internal medicine wards, mainly in Italy [9,10]. This may be due to the greater awareness of this infection among physicians working in internal medicine wards or the increasing admission of elderly patients who share many of the risk factors for invasive candidiasis, such as an indwelling central venous ⁎ Corresponding author at: Department of Clinical and Biomedical Sciences Luigi Sacco, University of Milano, Via GB Grassi 74, 20157 Milano, Italy. E-mail address: [email protected] (S. Antinori).

catheter (CVC), peripheral parenteral nutrition (PPN), total parenteral nutrition (TPN), urinary catheters, and broad-spectrum antibiotic therapy. Moreover, the elderly are frequently affected by multiple comorbidities such as diabetes mellitus, liver cirrhosis, solid neoplasia and malnutrition, that make them more similar to very complex ICU patients [1,10,11]. Interestingly, the increasingly worldwide epidemic of Clostridium difficile infection and colonization by carbapenemaseproducing Klebsiella pneumoniae among frequently hospitalized elderly patients have been indicated as possible new factors associated with the onset of candidemia [12–14]. 2. Methodology The studies were identified by searching PubMed for English language articles published between 1997 and March 2016 using the following keywords alone or in combination: candidemia, invasive candidiasis, Candida endocarditis, intra-abdominal candidiasis, epidemiology, diagnosis, drug resistance, treatment, and guidelines. Two authors (SA, LM) critically reviewed all of the studies retrieved, and selected those judged to be the most relevant. Studies of children and adolescents were excluded. 3. Epidemiology IC is a disease of medical progress therefore it is not surprising that its increasing incidence has paralleled advances in healthcare technology. A 10-year population-based study carried out in France found that the overall incidence of candidemia was 2.5 per 100,000 inhabitants per year, but it increased from 1.9 in 2001 to 3.6 in 2010 [1]. In the

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United States, the incidence of candidemia-related hospitalizations per 100,000 inhabitants rose by 52% from 2000 to 2005, and the incidence per 1000 hospitalizations rose by 14% [15]. In addition, the incidence of candidemia in ICU patients has been reported to be as high as 6.31 episodes/10,000 days of hospitalization (i.e., 5–10 times the incidence in general hospital wards) [3,8,15]. Although the list of Candida species cultured from patients with IC and candidemia is increasing, it has been clearly shown that only five species (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis and Candida krusei) account for more than 90% of the isolates [16–18]. Furthermore, although C. albicans remains as the most frequently isolated species worldwide (it is detected in 38–70% of the cases in population-based studies) but its incidence is decreasing [17]. The variability in the relative proportions of Candida isolates has been associated with factors such as age, underlying disease (cancer, hematological malignancies), geography, the extensive use of fluconazole prophylaxis, the use of specific antibiotics, and the failure of infection control measures (Table 1) [17,20–22]. C. glabrata is the second or third most isolated species in the USA and Europe, where it is particularly frequent among the elderly and cancer patients previously exposed to azole and echinocandins [19,20]. C. parapsilosis is predominant in neonates, in South America, southern Europe and Asia, and is especially associated with intravenous catheter and nosocomial outbreaks [17,18, 21]. In the latter case, the hands of healthcare workers are frequently the source of exogenous infections affecting the patients' skin or CVCs. C. krusei, a species that is intrinsically resistant to fluconazole, is the least frequently isolated of the 5 species and is associated with severe immunodeficiency. 4. Clinical syndromes Candidemia is by far the most frequent clinical presentation of all forms of IC, which may or may not be associated with deep tissue invasion [5]. A prospective observational study carried out in 180 ICUs in France between 2005 and 2006 found that isolated candidemia represented 39.5% of all cases, 32.1% had IC without any candidemia, and 28.4% candidemia associated with IC [22]. The patients with isolated candidemia more frequently had an underlying hematological malignancy, and those who were more frequently fungemic had received previous antibiotic treatment and had neutropenia [22]. Candidemia has been generally over-represented in all the recent randomized clinical

Table 1 Clinical condition or risk factor associated with different Candida species. Candida spp.

Clinical conditions/risk factors

Geographical distribution

Candida albicans

All populations (neonates, children, adults) Diabetes Cancer Hematological malignancies/ stem cell recipients Azole prophylaxis Older age Catheter-related conditions Neonates ICU patients

USA Northern and Central Europe USA Northern Europe (Denmark)

C. glabrata

C. parapsilosis

C. krusei

C. tropicalis

Azole prophylaxis Hematologic malignancies/ stem cell recipients Corticosteroid therapy Hematological malignancies Corticosteroid therapy

Based on references [17, 18, 21]. ICU: intensive care unit.

South America (Brazil) Australia Northern Africa Southern Europe (Spain) Kuwait Northern Europe (Finland)

Asia (China; Taiwan; Thailand; India) South America Northern Europe (Iceland)

trials (RCTs) comparing different echinocandins or an echinocandin with azole or amphotericin B, with frequencies ranging from 73.5% to 88.6% (Table 2) [23–28]. This is probably not only due to the difficulty in diagnosing non-candidemic IC, but also to the less frequent incidence of deep-seated candidiasis [29].As there is no characteristic constellation of clinical signs and symptoms to indicate a diagnosis of candidemia, its complication should be considered in any patients with known risk factors who present with persistent fever unresponsive to broad-spectrum antibacterial antibiotics. Septic shock is a possible presentation of candidemia, and accounted for about 19% of the cases in a point prevalence study [30]. In another study, patients with septic shock due to Candida spp. had a higher incidence of renal and hepatic failure, and lower levels of lactate dehydrogenase than patients with bacterial septic shock [31]. Intra-abdominal candidiasis is characterized by a spectrum of diseases encompassing abscesses, peritonitis, pancreatitis and cholangitis. The largest study published so far included 481 patients from 13 hospitals in Italy, Spain, Greece and Brazil, and found that abscesses and secondary and tertiary peritonitis accounted for about 80% of cases, with 40% of the patients developing septic shock [32]. The frequently polymicrobial nature of Candida peritonitis and the lack of standardized diagnostic criteria due to its many controversial aspects are among the factors associated with high mortality rates [32,33]. Concomitant candidemia has been observed in 14–28% of patients with abdominal candidiasis [32,33]. C. glabrata is the second most frequently isolated species in patients with intra-abdominal candidiasis, accounting for 16–20% of cases [31,32]. This is particularly worrying because of its high rate of resistance to fluconazole and the fact that it is also the species most frequently involved in cases of echinocandin resistance [34]. A recent study found that 24% of Candida isolates from patients with abdominal candidiasis (29% C. glabrata, 14% C. albicans) were FKS mutant (i.e., with point mutations within hot spots of the FKS genes encoding the echinocandin target enzyme β-1,3-D-glucan synthase, which is responsible for the reduced susceptibility or resistance of Candida species to all echinocandis) [35,36]. The authors suggested that prolonged subinhibitory echinocandin concentrations within the abdominal cavity, biliary tree or abscesses may be a source of hidden echinocandin resistance [35]. Although probably rare, spontaneous fungal peritonitis caused by Candida spp. is characterized by a high mortality rate among patients with liver cirrhosis [37]. Candida endocarditis (CE) is a rare but severe form of IC identified in 2–4% of cases of infective endocarditis [38]. It was once mainly observed among intravenous drug abusers (IDAs) and patients undergoing heart surgery [39,40], but a recent prospective French study found that 70% of cases do not involve IDAs, and that 86% are healthcare-associated, most frequently in older patients with major comorbidities in whom it has a worse outcome [41]. Prosthetic valves and short-term indwelling catheters are the more frequent risk factors among patients with a diagnosis of CE [38–43]. A retrospective study by Nasser et al. found that the risk of developing prosthetic valve endocarditis (PVE) after an episode of candidemia was 25% [44]. The patients were diagnosed some time after undergoing valve replacement, which suggests that the pathogenesis of this form of CE may involve two steps: 1) transient postoperative candidemia with colonization of the prosthesis; and 2) the subsequent formation of biofilm and the slow growth of vegetation [44,45]. The clinical presentation of CE is not specific, but generally similar to that of bacterial endocarditis (i.e., persistent fever, a new cardiac murmur, and vascular embolic events). Persistently positive blood cultures, extensive vegetation and a high frequency of embolization are considered to be highly suggestive of CE [41–43] but, in a recent Spanish retrospective study, Fernandez-Cruz et al. found that 30% of their cases of CE were clinically unsuspected in patients diagnosed with candidemia but without persistent positive blood cultures or previous heart valve disease, and therefore suggested that this severe complication may be overlooked unless echocardiography is routinely performed [46].

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Table 2 Distribution of candidemia and invasive candidiasis in six randomized comparative trials. Author, year, reference

Mora-Duarte [25]

Kuse [24]

Reboli [23],

Pappas [26]

Betts [27]

Kullberg [28]

Drugs

Caspofungin vs amphotericin B

Micafungin vs liposomal amphotericin B

Anidulafungin vs fluconazole

Micafungin vs caspofungin

Caspofungin (Hd) vs caspofungin (Sd)

Caspofungin vs isavuconazole

Candidemia, no. (%) Other sterile site, no. (%) Lung (biopsy proven), no. (%) Pleural fluid, no. (%) Pneumonia, no. (%) Peritoneal fluid, no. (%) Abscess Peritonitis, no. (%) Skin (biopsy proven), no. (%) Endocarditis, no. (%) Acute disseminated, no. (%) Bone, no. (%) Multiple sites, no. (%) Total

181 (80.8) – 1 (0.4) 3 (1.3) – 16 (7.1) 13 (5.8) – 1 (0.4) – – – 9b (4) 224

333 (84.9) – – – – 28 (7.1) 10 (2.5) – – 5 (1.3) 14 (3.6) 1 (0.2) – 391

219 (89.4) 18a (7.3) – – – – – – – – – – 8c (3.2) 245

492 (85.4) 84 (14.6) – – – – – – – – – – – 576

172 (85.6) 7d (3.5) – – 2 (0.9) 9 (4.5) – 5 (2.5) – – 13e (6.4) – – 208

333 (83) 67 (17) NR

NR

NR NR NR NR NR 400

Total N° (%)

1730 (84.7) 176 (8.6) 1 (0.04) 3 (0.01) 2 (0.09) 53 (2.6) 23 (1.1) 5 (0.2) 1 (0.04) 5 (0.2) 27 (1.3) 1 (0.04) 17 (0.8) 2044

Hd = high dose; Sd = standard dose; NR = not reported. a Defined as: peritoneal, intra-abdominal, pleural fluid; pelvis; and pancreas. b Five patients had candidemia and infection at another site; four patients had infections at two non-blood sites. c Defined as: blood plus bile; pleural fluid; skin, peritoneal fluid, or kidney. d 2 patients with non-Candida fungemia, 1 patient with empyema, 1 patient with pyelonephritis, 1 patient with chronic disseminated candidiasis. e 7 candidemia + endophthalmitis, 5 candidemia + peritonitis, 1 candidemia + empyema.

It was long questioned whether Candida pneumonia can be considered a clinical entity, and the hypothesis was finally refuted after the publication of an autoptic study of critically ill ICU patients by Meersseman et al. [47]. It is well known that both intubation and ventilation are associated with frequent tracheobronchial Candida colonization, and that its incidence increases with the duration of ventilation, although a large retrospective autopsy study from Japan found the presence of Candida foci in the lungs of 7.8% of the patients [48]. However, a recent review of 701 broncoalveolar lavage (BAL) specimens related to clinical cases by Schnabel et al. found Candida pneumonia in only 0.7% of all patients [49]. Although a definite diagnosis of Candida pneumonia can only be made on the basis of lung histology because even quantitative tracheal aspirates and BAL cannot distinguish colonization and true infection, the authors suggested that Candida pneumonia should be considered and treated in the presence of serious respiratory failure and radiographic evidence of pneumonia with no other growth except Candida in BAL fluid [49]. Ocular candidiasis following hematogenous seeding of the choroid and retina can cause chorioretinitis or endophthalmitis with vitritis, both of which may lead to devastating visual loss. The presenting symptoms include the subacute onset of blurred vision with photophobia and ocular injection [50]. It has been suggested that improvements in microbiological diagnoses and the timely treatment of candidemia have reduced the incidence of these complications. Two recent retrospective studies found ocular candidiasis in 4.8–7.9% of patients with diagnosed candidemia who underwent ophthalmological examination [50,51], but a prospective randomized trial comparing voriconazole with amphotericin B followed by fluconazole for the treatment of candidemia in which the patients underwent close fundoscopy monitoring found that 13% had ocular candidiasis at baseline and 3% developed it during treatment [52]. C. albicans and a longer duration of candidemia were both associated with ocular involvement. However, it should be noted that exogenous Candida endophthalmitis can occur as a complication of intraocular surgery or after a penetrating eye injury. Hepatosplenic candidiasis (HSC), also known as chronic disseminated candidiasis, is a well-known complication that is diagnosed in 2–9% of hematological patients who develop profound and prolonged neutropenia [53]. It is characterized by a fever unresponsive to broadspectrum antibiotics, abdominal pain, hepatosplenomegaly, and increased serum alkaline phosphatase levels. Target-like or “bull's eye” lesions revealed by contrast-enhanced computed tomography, and a

“wheel within a wheel” ultrasonographic pattern are considered consistent with a diagnosis of HSC [53]. It has been recently suggested that HSC may be an immune reconstitution inflammatory syndrome due to the recovery of neutrophils leading to a pro-inflammatory Th1/Th17 response [53]. Candida meningitis is rare: its cumulative incidence in an 8-year surveillance study carried out in England and Wales was 0.09/100,000 people and, contrary to what might have been expected, it was diagnosed in older patients and there was a high prevalence of non-albicans species [54]. Clinically, adult Candida meningitis can present as chronic meningitis with cerebrospinal fluid findings that resembles cryptococcal or tuberculous meningitis. Interestingly, it has been recently suggested that subjects with inherited caspase recruitment domain family member 9 (CARD9) deficiency may be prone to the development of Candida meningoencephalitis, and the authors suggest that this deficiency should be investigated even in previously healthy subjects with Candida central nervous system infections [55]. 5. Diagnosis and anti-fungal susceptibility testing The traditional gold standard for the diagnosis of candidemia and IC are cultures of blood or other sterile fluids or the histopathological demonstration of invasive tissue disease. Blood cultures usually perform well in patients with candidemia as they are positive in 93% of those with endocarditis, but their overall sensitivity in the case of deepseated candidiasis is estimated to be less than 50% [6,29,41]. The number of Candida colony-forming units (CFUs) is generally low in patients with candidemia: one study found that the median concentration of CFUs/mL in the first positive blood culture was 1, but more than 50% of the positive cultures had a concentration of b1 CFU/mL, which is below the detection threshold of DNA-based diagnostic tests [56]. Moreover, the bloodstream load depends on the species (it is highest for C. parapsilosis and lowest for C. glabrata) and the patient's age (there is a high burden in the pediatric population) [56]. In order to overcome the low sensitivity of blood cultures when diagnosing IC, non-culture diagnostic assays such as 1,3-β-D-glucan (BDG), a major constituent of fungal cell walls, the mannan/antimannan assay, and polymerase chain reaction (PCR) have been developed and evaluated [29] (Table 3). One comparative study found that PCR and BDG were both more sensitive than blood cultures in

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Table 3 Diagnostic tests available and their efficiency in diagnosing candidemia and invasive candidiasis. Diagnostic test

Candidemia

Invasive candidiasis

Comment

Blood culture 1,3-β-D-Glucan

Positive in 70–80% of patients Sensitivity 68%

Rarely positive Sensitivity 56%; specificity 73% [29]; sensitivity 65%, specificity 78%; PPV 68%, NPV 77%a [58]

Mannan Ag/anti-mannan antibodies

Sensitivity 59%; specificity 97%

Sensitivity 83%, specificity 86%

Considered the gold standard A pan-fungal marker (except for cryptococcosis and zygomicosis) Recommended cut-off level ≥80 pg/mL in 2 determinations May anticipate a diagnosis of intra-abdominal candidiasis by 5 days Sensitivity of mannan Ag higher for C. glabrata and C. tropicalis Recommended cut-off for Ag ≥125 pg/mL; antibody cut-off ≥10 AU/mL Very rapid (mean time for Candida detection and species identification 4.4 ± 1 h)

Very few data; it seems to detect Sensitivity 91.1%; specificity 99.4% [64] Sensitivity 92.3% C. albicans/C. tropicalis; 94.2% 100% of cases C. parapsilosis; 88.1% C. glabrata/C. krusei Polymerase chain reaction Sensitivity 59% [29] Sensitivity 80%; specificity 70%b Sensitivity 89%c [29] T2 MR Candida

Precedes a diagnosis of candidemia by a median of 3 days. Persistently positive results associated with death.

MR = magnetic resonance. a Intra-abdominal candidiasis. b Invasive candidiasis. c Deep-seated candidiasis.

diagnosing IC (89% and 66%, respectively), but less sensitive than blood cultures in patients with candidemia [29]. BDG results should be interpreted bearing in mind the heterogeneity of the patients at risk of developing IC, the chosen cut-off value (N60 or N80 pg/mL), the number of positive specimens (the best performance has been obtained using two consecutive positive results), and the possible causes of falsepositivity due to fungal colonization, hemodialysis, treatment with broad-spectrum antibiotics or blood components, and systemic bacterial infections [57]. Among patients with intra-abdominal candidiasis (IAC), it has been found that a BDG level of ≥ 80 pg/mL is superior to the Candida score (CS), the Candida colonization index (CI) and the corrected Candida colonization index (CCI) in discriminating IAC from colonization [58]. Interestingly, this biomarker was capable of anticipating a culture-based microbiological diagnosis by five days, and a level of N400 pg/mL or an increasing value correlated with worse outcomes [58]. The use of BDG has been suggested as a means of guiding preemptive treatment in ICU patients, and allowing empirical anti-fungal therapy to be safely withheld in BDG-negative patients because of its high negative predictive value [59–61]. The use of T2 magnetic resonance (T2MR) seems to be a promising new means of diagnosing candidemia [62]. It is based on particles coated with specific targets (DNA, proteins) that, when added to a sample containing the target, bind and cluster to it; the changes induced in the water environment of the sample alters the T2MR signal, thus indicating the presence of the target [63]. Preclinical studies comparing a T2 Candida panel with an automated blood culture system showed that the former detected all five major species of Candida at densities ranging from 2.8 to 11.1 CFU/mL and reduced the time necessary to obtain a positive result (3–5 vs 63.23 ± 30.27 h) [62]. On the basis of the results of a pivotal clinical study, it has been suggested that, in a study population with a 6% prevalence, the T2 Candida panel has a negative predictive value of 99.4% which, together with its rapidity (a mean time of 4.2 h to obtain a negative result), means that it is capable of greatly reducing the number of patients receiving empirical treatment [64]. The widespread use of azoles and echinocandins has been accompanied by the emerging drug resistance of clinical isolates of Candida spp. Both the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical Laboratory Standards Institute (CLSI) have developed reference methods and appropriate cut-off points for interpreting susceptibility results [65,66]. However, the reference procedures are generally labor intensive and performed in a microbroth dilution format that is not used in routine laboratory practice. A number of commercial techniques based on the principle of agar diffusion or a colorimetric indicator have been developed for everyday practice and have

good concordance with the reference methods [67,68]. It is beyond the scope of this review to describe the mechanisms of anti-fungal resistance and their acquisition in detail, but readers are referred to various, recently published and high-quality reviews [36,69,70]. Clinicians should be aware of the inherent resistance of C. krusei to azoles, and the frequent secondary resistance of C. glabrata, which is also the species that is raising the most concern about the development of echinocandins resistance [34]. The reason for the rapid development of the resistance of C. glabrata is unknown, but it is thought that its haploid state is a contributory factor. It should also be mentioned that C. parapsilosis harbors a naturally occurring FKS1 polymorphism that is responsible for higher MIC values against echinocandins [69,70].

6. Treatment Candidemia and IC are life-threatening diseases in critically ill patients, and associated with a crude mortality rate of approximately 45–50% [22]. However, retrospective analyses have shown that early anti-fungal treatment and adequate source control can improve outcomes [71,72] and, in the case of IC, this has been confirmed by a patient-level quantitative review of randomized trials [73]. In an attempt to overcome delayed diagnoses due to the lack of sensitivity of standard microbiological cultures, a number of clinical and microbiological predictive rules and scores have been proposed as means of identifying patients at high risk of developing IC (Fig. 1); however, although these models are characterized by very high negative predictive values (97–99%), their positive predictive values are low (4–57%) [74–77]. Only a few studies have been made concerning the real-life usefulness of predictive rules [76,78], and the lack of solid clinical data is responsible for the low quality of evidence assigned to them in the guidelines. Three recently published studies (respectively evaluating empirical anti-fungal therapy in mechanically ventilated critically ill patients, Caspofungin prophylaxis followed by pre-emptive therapy in ICU patients identified on the basis of risk factors, and pre-emptive therapy with Micafungin in patients requiring surgery for intra-abdominal infections) failed to demonstrate that any of these anti-fungal strategies offered any outcome benefit in patients without proven IC [79–81]. According to the recommendations of the most recently released guidelines of the Infectious Diseases Society of America (IDSA) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID), the initial targeted therapy for candidemia in nonneutropenic patients should be based on an echinocandin (Table 4) [82,83]. This recommendation is largely based on conclusions arising

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Fig. 1. Examples of the predictive rules proposed to improve the diagnosis of candidemia and invasive candidiasis. Candida score (CS) (reference [75]); Candida colonization index (Pittet Score, reference [74]); Ostrosky-Zeichner score (reference [77]); Nebraska Medical Score (NMC) (reference [76]). Sen: sensitivity; Spec: specificity; PPV: positive predictive value; NPV: negative predictive value.

Table 4 Comparison of ESCMID and IDSA guidelines for the treatment of invasive candidiasis. Clinical syndrome

IDSA 2016 [82]

ESCMID 2012 [83]

Candidemia, nonneutropenic patient

Echinocandin (Caspofungin 70/50 mg, Micafungin 100 mg, Anidulafungin 200/100 mg): strongly recommended; high-quality evidence Fluconazole 800 mg (12 mg/kg) then 400 mg/d: strongly recommended; high-quality evidencea Lipid formulation AMB (3–5 mg/kg/d): strongly recommended; high-quality of evidenceb Echinocandin (Caspofungin 70/50 mg, Micafungin 100 mg, Anidulafungin 200/100 mg): strongly recommended; moderate-quality evidence Fluconazole 800 mg (12 mg/kg) then 400 mg/d: weakly recommended; low-quality evidence Lipid formulation AMB (3–5 mg/kg/d) or an echinocandin for several weeks followed by oral fluconazole 400 mg/d: strongly recommended; low-quality evidence Lipid formulation AMB (3–5 mg/kg/d) ± flucytosine 25 mg/kg 4 times/d or high dose echinocandin (Caspofungin 150 mg/d; Micafungin 150 mg/d; Anidulafungin 200 mg/d): strongly recommended; low-quality evidence Same anti-fungal regimens: strongly recommended; low-quality evidence Chronic suppressive anti-fungal therapy with fluconazole (400–800 mg daily): strongly recommended; low-quality evidence Fluconazole 400 mg/d for 6–12 months or an echinocandin for at least 2

Echinocandin (Caspofungin 70/50 mg, Micafungin 100 mg, Anidulafungin 200/100 mg): SoR: A; QoE:I Liposomal amphotericin B 3 mg/kg/d: SoR: B; Qoe:I Voriconazole 6/3 mg/kg/d: SoR: B; Qoe:I Fluconazole 400–800 mg/d: SoR: C; Qoe:I

Candidemia, neutropenic patient

Chronic disseminated candidiasis (hepatosplenic) Candida endocarditis: native valve Candida endocarditis: prosthetic valve Candida osteomyelitis

weeks followed by fluconazole 400 mg/d for 6–12 months: strongly recommended; low-quality evidence Candida chorioretinitis without vitritis Candida chorioretinitis with vitritis

Central nervous system candidiasis

Fluconazolo 800 mg/d then 400–800 mg/d or voriconazole 400 mg × 2/d then 300 mg × 2/d for 4–6 weeks: strongly recommended; low-quality evidence Same as above plus intravitreal injection (AMB deoxycholate 5–10 μg/0.1 mL sterile water or voriconazole 100 μg/0.1 mL sterile water): strongly recommended; low-quality evidence Liposomal AMB 5 mg/kg) ± flucytosine 25 mg/kg 4 times/d followed by fluconazole 400–800 mg/kg/d: strongly recommended; low-quality evidence

Echinocandin (Caspofungin 70/50 mg, Micafungin 100 mg): SoR: A; Qoe: II Anidulafungin 200/100 mg/d: SoR: B; Qoe: II Liposomal amphotericin B 3 mg/kg/d: SoR: B; Qoe: II Lipid formulation AMB for 8 weeks: SoR: A; Qoe: III Fluconazole for 3 months; SoR: B; Qoe: III Liposomal amphotericin B ± flucytosine for 6–8 weeks followed by fluconazole: SoR: B; Qoe: II Surgery within 1 week: SoR: A; Qoe: II Liposomal amphotericin B 5 mg/kg/d: SoR: B; Qoe: III Surgery Fluconazole 400 mg/d for 6–12 months: SoR: A; Qoe: II Liposomal amphotericin B 3 mg/kg/d or lipid formulation 5 mg/kg/d for 2–6 weeks followed by fluconazole 400 mg/d for 5–11 months: SoR: A; Qoe: II Liposomal amphotericin B 5 mg/kg/d: SoR: B; Qoe: III

Same as above plus intravitreal injection (AMB deoxycholate 5–10 μg/0.1 mL sterile water): SoR: B; Qoe: II Same as above plus intravitreal injection (voriconazole 100 μg/ 0.1 mL sterile water): SoR: B; Qoe: III Liposomal AMB 3 mg/kg + flucytosine 150 mg/d for 10 weeks followed by fluconazole 3 mg/kg/d for 5 weeks: SoR: B; Qoe: III Liposomal AMB 3 mg/kg/d + fluconazole 6 mg/kg/d for 4 weeks: SoR: B; Qoe: III

IDSA: Infectious Diseases Society of America; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; SoR: strength of recommendation; QoE: quality of evidence; AMB, amphotericin B. a Acceptable alternative to an echinocandin in selected patients (those who are not critically ill and those considered to be unlikely to have fluconazole-resistant Candida species). b Reasonable alternative in the case of intolerance, limited availability, or resistance to other anti-fungal agents.

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from controlled clinical trials in which about 85% of the enrolled patients had candidemia (Table. 2) [23–28]. In the updated IDSA guidelines, fluconazole remains a valuable alternative in selected patients (those who are not critically ill and those not affected by resistant Candida species), whereas the ESCMID guidelines only marginally support its use [82,83]. The echinocandins (anidulafungin, caspofungin and micafungin) are preferred to fluconazole because of their demonstrated fungicidal activity, good biofilm penetration, good tolerability, and general lack of interactions with other drugs. The superiority of echinocandins over fluconazole has been demonstrated in a single head-to-head clinical trial of anidulafungin that showed significantly better overall response rates (76% vs 60%; P = 0.01) [23], and a further post hoc analysis showed better global responses (70.8% vs 54.1%) and reduced 14-day, all-cause mortality (10.1% vs 20.3%, P = 0.08) in critically ill patients [84]. However, it should be noted that the study was designed to assess the noninferiority of anidulafungin. A review of randomized clinical trials has demonstrated that treatment with an echinocandin and the removal of a central venous catheter were the two variables associated with decreased all-cause mortality [73]. It is worth noting that the echinocandins do not reach therapeutic concentrations in the eye, urine or central nervous system, and so they are considered inappropriate for the treatment of infections involving those sites. Against the recommendations of the cited guidelines and the opinions of the majority of experts, an analysis of 689 candidemic and ventilated patients in the Prospective Anti-fungal Therapy (PATH) Alliance Registry showed better 28-day survival among the patients receiving fluconazole rather an echinocandin as initial therapy [85]. However, although a number of confounding factors were analyzed, it is not known whether these findings were affected by any residual confounding or unmeasured variables. In an attempt to reduce the emergence of echinocandin resistance (a problem particularly in the case of C. glabrata) and avoid the high cost of echinocandin therapy, the IDSA and ESCMID guidelines both recommend switching to fluconazole (a step-down strategy) within 10 days in the case of clinically stable, non-neutropenic patients with negative blood cultures and a Candida isolate susceptible to fluconazole. The feasibility of early anti-fungal de-escalation (within 5 days) without any adverse outcome on mortality has been shown in three studies of critically ill patients [86–88]. The treatment of documented candidemia should be continued for 14 days after the first negative blood culture. It is difficult to draw any conclusions concerning the choice of antifungal agent and duration of treatment for the less common forms of IC because of the lack of good-quality studies. The recommendations are therefore based on retrospective case series, case reports, and the opinions of experts, particularly in the case of rare and difficult to treat condition such as endocarditis and osteomyelitis (Table 4). 7. Conclusions Candidemia and the other forms of IC represent an increasingly significant diagnostic and therapeutic challenge for physicians working outside ICUs. Early intervention strategies based on clinical prediction rules and non-culture-based diagnostic assays may improve the outcomes of these healthcare-associated complications. Funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interests The authors declare that they have no conflicts of interest. All of the authors had access to the data and played a role in writing the manuscript.

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