Invasive fungal infections (IFIs) are frequently diagnosed and managed by the ICU physicians in both immunocompromised or not immunocompromised patients. Despite different antifungal agents having been developed to combat these infections, fungi are a leading cause of mortality among critically ill patients admitted to ICUs [1,2]. The rise of IFIs in critically ill patients can be related to the presence of complex medical and surgical problems, disruption of natural barriers, multiple invasive procedures, and the wide use of devices. In addition, many ICU patients are treated with prolonged antibiotic therapies for real or presumed bacterial infections and this favors the onset of fungal infections. The majority of these life-threatening infections are caused by Candida species, mostly Candida albicans[3▪]. Invasive candidiasis includes candidemia, disseminated candidiasis with deep organ involvement and chronic disseminated candidiasis. Candidemia is frequently associated with a high attributable mortality, increased length of hospital stay and cost [4▪]. Stratifying ICU patients for mortality scores, the interaction between cause, resistance to antifungal therapy, biofilm production, and appropriate therapy plays an essential role in determining the outcome of patients with candidemia [5–9]. In particular, recent studies indicate that inadequate antifungal therapy and inadequate source control combined with the disease severity were the most important determinants of outcome among patients with septic shock attributable to Candida infection with positive blood cultures [10,11▪▪].
Although the leading fungal infection is candidemia, pulmonary aspergillosis has been recently reported as an additional important complication in ICU patients also without the classical risk factors, and other pathogens, including yeast-like and other filamentous fungi, have emerged as additional causes of severe infections [12▪▪].
Timely diagnosis is essential for a favorable outcome and apart from blood cultures, several laboratory tests have been developed in the last years to facilitate an earlier detection of fungal infections. In particular, biomarkers-based diagnostic approaches give, at the same time, the possibility to early detect the ongoing infection and reduce inappropriate antifungal therapy in nonconfirmed cases. The antifungal armamentarium has also been expanded and physicians can now choose among the old class of polyenes, the older and newer azoles and the echinocandins for the treatment of proven cases, but clinicians should carefully consider the risk of treatment failure and the availability of new monitoring and therapeutic tools .
In this review, we will focus on the advances in treatment and diagnosis of invasive fungal infections encountered in ICU patients.
ADVANCES IN DIAGNOSIS
The diagnosis of invasive candidiasis in critically ill patients is a challenging task for ICU physicians. Blood culture positivity still represents the diagnostic gold standard for Candida spp. bloodstream infections, but the suboptimal sensitivity (<50%) and the long incubation time significantly delay the prompt initiation of an adequate antifungal treatment [14,15]. Indeed, several clinical scores have been largely proposed with the aim to predict invasive candidiasis occurrence and promptly start antifungals . Among these, in the last ten years, ‘Candida Colonization Index’ (CCI) and ‘Candida Score’ have been widely adopted in the clinical practice [17▪,18]. However, despite their undoubted usefulness as negative predictive tools, both lack diagnostic accuracy. Hence, more recently, a growing interest has been focused on new laboratory diagnostic methods.
(1–3)-β-D-Glucan is a cell wall content of Candida spp. and other fungi. Although several confounding factors are potentially able to influence patients’ plasma level [19▪], its usefulness as early diagnostic tool has been largely proven in several studies on patients with hematological malignancies . However, an increasing body of evidence in favor of its use in the ICU setting has been recently documented [21▪]. In one of the first ICU observational studies, including 16 invasive candidiasis, a single point (1–3)-β-D-glucan sampling showed higher positive and negative predictive values, compared with CCI and Candida Score (72.2% versus 57.1% and 27.3%; and 98.7% versus 97.2% and 91.7%, respectively)  (Fig. 1). These data have been recently confirmed by a multicenter cohort study of 434 critically ill surgical patients , in which (1–3)-β-D-glucan showed high accuracy for the early detection of blood culture negative abdominal candidiasis. Less consensus exists regarding the optimal cutoff level. For instance, increasing the threshold value from 80 to 350 and 800 pg/ml, Poissy et al.[24▪] observed an opposite relationship between specificity (from 0.31 to 0.86) and sensitivity (from 0.97 to 0.30). Nevertheless, (1–3)-β-D-glucan levels at invasive candidiasis diagnosis and their kinetic over time have been also described to be correlated with the clinical outcome [25–27].
During recent years, other rapid tests have been proposed and compared with (1–3)-β-D-glucan assay. Despite previous encouraging data , in a recent prospective investigation, single values of either Mannan-Anti-Mannan or Cand-Tec Candida antigen (a new latex agglutination test) assays were characterized by fairly low specificity and sensitivity values . However, the combination of more than one serological biomarker may result in significantly higher overall positive and negative predictive values. This effect was clearly observed by Leon et al. after combining, in a large population of ICU patients at risk of invasive candidiasis, (1–3)-β-D-glucan results with Candida albicans germ tube antibody positivity.
Nuclear acids Candida detection from the blood is one of the new targets for innovative diagnostic approaches. Despite some drawbacks regarding the possibility of false-positive results, the absence of standardized techniques and the limited commercial availability, over the last few years numerous clinical studies have addressed this topic. A meta-analysis of 54 studies evaluating the diagnostic accuracy of PCR methods to detect Candida spp. in the whole blood showed a pool sensitivity and specificity of 0.95 (confidence interval 0.88–0.98) and 0.92 (0.88 0.92), respectively . A multiplex nested PCR approach, which enables the detection up to seven Candida species, has been recently used in 54 critically ill pediatric patients at risk of invasive candidiasis, showing rapid and highly sensitive fungal detection, compared with blood culture results [32▪].
Finally, a new nanodiagnostic approach (T2 magnetic resonance) that directly analyzes blood specimens has showed encouraging results in a recent multicenter clinical trial [33▪▪], providing an overall specificity per assay of 99.4% and a mean time to negative results of 4.2–0.9 h.
The diagnostic gold standard for invasive aspergillosis is the direct histopathological identification in tissue biopsies. Frequently, in the critically ill setting, this criterion may not be satisfied and other elements should trigger the initiation of an antimold treatment . In patients with hematological malignancies, current guidelines stratify invasive aspergillosis into proven, probable and possible, matching clinical, radiological, and microbiological findings . However, in nonneutropenic ICU patients, the absence of classical risk factors and the low specificity of radiological findings impair the reliability of such approach [36▪]. Interestingly, a new clinical algorithm has been developed in order to discriminate Aspergillus spp. colonization from invasive pulmonary aspergillosis (IPA) in the intensive care setting (Table 1). Its application in a multicenter study involving 524 critically ill patients provided a 32% higher diagnosis rate, with a specificity of 61% and a sensitivity of 92% .
Among nonculture techniques, galactomannan assay is commonly tested in blood or other body fluids. This is a cell-wall component of Aspergillus spp., able to provide a rapid and accurate detection of actively growing molds [38,39]. However, its specificity and sensitivity may vary according to the cutoff level used [usually 0.5 and 1 of optical density index in the blood and bronchoalveolar lavage (BAL), respectively] . Further, galactomannan positivity from BAL has shown high sensitivity, compared with serum galactomannan and respiratory cultures, for detecting IPA in ICU patients with chronic obstructive pulmonary disease . On the contrary, the reliability of this assay in patients undergoing antimold prophylaxis/treatment is under debate. In an interesting 4-year study involving 262 hematological malignancies patients undergoing posaconazole prophylaxis, positive predictive value of the test was only 12%, especially during the preemptive surveillance phase [42▪▪]. Recent investigations have addressed the potential predictive role of galactomannan trend over time during invasive aspergillosis treatment. The post-hoc analysis of a randomized trial showed how the decline of serum galactomannan index in patients undergoing voriconazole therapy was significantly associated with a good clinical response after 12 weeks [43▪].
As for invasive candidiasis, molecular diagnosis of invasive aspergillosis is challenged by the wide range of adoptable measurement approaches (i.e., targets, primers, amplification, and extraction). In hematological patients, there is growing evidence supporting the usefulness of PCR or other nuclear acid-based diagnostic methods, but robust data are still lacking in the ICU setting .
The relative simplicity of performing BAL in critically ill intubated patients is now fostering investigators to focus on molecular diagnosis of IPA by the direct detection of Aspergillus spp. nuclear acid in the epithelial lining fluid . In a recent prospective study, involving 77 ICU and hematological patients, a new multiplex real-time PCR assay was compared with galactomannan . The performance of the test in terms of sensitivity and specificity was high (ranging between 80 and 96%), also allowing fast differentiation of wild type from resistant strains, despite the negative results of traditional BAL cultures.
A novel test for IPA (‘Aspergillus lateral-flow device’) diagnosis has been recently tested in 221 patients with underlying respiratory diseases [47▪], providing better diagnostic performance than (1–3)-β-D-glucan and standard BAL cultures but lower accuracy compared with galactomannan.
However, as noted in invasive candidiasis, the combination of more than one biomarker, whenever possible, might represent the optimal diagnostic strategy. This concept has been recently shown in a multicenter trial in which 219 hematological malignancies high-risk patients were randomized to adopt a galactomannan versus galactomannan PCR surveillance approach for prompt detection and treatment of invasive aspergillosis [48▪]; not surprisingly patients allocated to the galactomannan PCR had higher proven or probable invasive aspergillosis free survival (P = 0.027).
Other fungal infections
Although less common, also invasive fungal infections other than Candida/Aspergillus deserve rapid, accurate, and affordable new diagnostic tools .
Serum (1–3)-β-D-glucan detection may be considered a helpful tool for the diagnosis of Pneumocystis jirovecii pneumonia (PCP) in the ICU setting. In a recent clinical study, involving 260 PCP cases diagnosed by BAL microscopic or nuclear acid detection, (1–3)-β-D-glucan resulted the most accurate serologic marker followed by ‘Krebs von den Lungen-6’ antigen, lactate dehydrogenase, and S-adenosylmethionine. The use of (1–3)-β-D-glucan/Krebs von den Lungen-6 combination was associated with 94.3% sensitivity and 89.6% specificity . Furthermore, (1–3)-β-D-glucan testing can be efficiently performed in BAL specimens .
Rapid diagnosis of cryptococcal invasive diseases relies on cryptococcal antigen detection from serum or cerebrospinal fluid, but a new reliable point of care assay is now available. This test (the dip-stick-formatted cryptoccal antigen lateral flow assay) has been compared with standard cultures and serological diagnostic approaches, showing very high sensitivity and specificity (both above 97%) .
Conventional histological mucormycosis diagnosis is improved by the adoption of advanced molecular amplification systems and antigen detection assays [53▪]. The use of quantitative PCR targeting different Mucurales species has been recently proposed as new tool for early diagnosis of mucormycosis. Although very attractive, the cost-effectiveness of such strategies in the ICU setting is the major issue limiting their clinical application.
ADVANCES IN TREATMENT
Given the high morbidity and mortality rate of invasive Candida infection (ICI) in critically ill patients, a prompt and effective therapeutic approach, in the ICU setting, is strongly warranted. It is noteworthy how early initiation of an appropriate antifungal regimen is able to significantly improve the clinical outcome of such patients [5,7,8]. Indeed, many strategies have been recently implemented aiming to obtain this target. Apart from the prophylactic use of antifungals for a few peculiar scenarios, ICU physicians may adopt an empirical approach relying on clinical risk factors, signs, and symptoms of infection in absence of any identified pathogen [54–56]. Otherwise laboratory tests or radiographic findings may guide a preemptive therapy when a conclusive histopathological proof of invasive fungal infection is not available yet. Current guidelines suggest the use of empirical antifungal agents in critically ill patients at high risk of ICI, preferring a fungicidal agent in life-threatening conditions . Currently, there is only one randomized controlled trial that addressed the efficacy of using empirical antifungals in ICU patients . The study did not find any difference in terms of resolution of fever, presence of IFI, and major adverse events. Furthermore, recently, the empirical systemic antifungal approach failed to provide any clinical benefit in a large cohort of critically ill patients [59▪▪]. The low efficacy of this approach led clinicians to rely on more specific risk factors for ICI and new biomarkers. Hence, new preemptive approaches, especially (1–3)-β-D-glucan-driven strategies, are certainly attractive in the ICU setting and they appear a concrete alternative to the less cost-effective empirical therapy.
A preliminary randomized pilot study compared prophylactic antifungal approach versus (1–3)-β-D-glucan-guided preemptive therapy, using anidulafungin, in 64 ICU patients . Preemptive anidulafungin was well tolerated and associated with a significant effect on (1–3)-β-D-glucan concentrations (P < 0.001) and excellent clinical response. In a recent larger trial, 222 ICU patients at risk for ICI were monitored with twice weekly (1–3)-β-D-glucan and treated with caspofungin according to a prophylactic/preemptive strategy [61▪]. This approach resulted well tolerated and associated with lower ICI rates for both prophylactic and preemptive approach (9.8% versus 16.7%, P = 0.14 and 18.8% versus 30.4%, P = 0.04, respectively). Also micafungin has been tested as preemptive therapeutic tool in 241 high-risk surgical patients. However, despite a reduction in the rate of Candida colonization, there were no differences between the two arms (micafungin versus placebo) in terms of ICI rate, mortality, and improvement of organ failures [4▪].
It is noteworthy that, given the high negative predictive value of (1–3)-β-D-glucan results, this biomarker may be also used as a tool for antifungal sparing strategies, avoiding unuseful empirical therapies only based on clinical risk factors.
Regarding the treatment of proven infections, the last European guidelines  recently updated the previous approach , recommending the use of fungicidal agents (echinocandins or lipid-based polyenes) for the initial treatment of ICI, and reserving azoles deescalations for stable patients with susceptible isolates. This approach is supported by the evidence of echinocandins’ superiority over fluconazole for the early therapeutical management of ICI, especially in critically ill patients . However, while treating severe infections, antifungals’ plasmatic concentrations are potentially influenced by interindividual variability and this drawback may be managed only by using therapeutic drug monitoring [63▪]. On the contrary, polyenes treatment is preferred for end-organ infections (meningitis, endocarditis, and osteomyelitis) or whenever other fungal pathogens (i.e., Aspergillus spp. or Mucor spp.) are suspected or documented.
There is no evidence supporting the use of combined antifungal regimens for ICI except for anecdotal cases wherein such approach has been successfully adopted as salvage therapy . Once source control has been obtained, antifungal therapy should be prolonged for 14 days from the last negative blood culture . In light of recent data on the use of (1–3)-β-D-glucan kinetic as a marker of treatment response [25,26], treatment duration could be shortened in those cases wherein a rapid and significant negative slope is observed. However, up to date, this approach is not supported by clinical evidence yet.
Early treatment at the stage of ‘possible’ Aspergillus spp. infection has been demonstrated to be associated with improved outcome [56,64]. In a recent observational investigation on ICU patients with invasive aspergillosis, each 1 day lag before initiating antifungal therapy was associated with 1.28 days’ longer hospital stay and 3.5% increase in costs (P < 0.0001 for both) . Recently, a multicenter cohort study showed that half of the ICU patients with a positive Aspergillus culture had either putative or proven invasive aspergillosis, sharing immunosuppression status and higher mortality rate [12▪▪]. Despite this, likewise for the prevention of ICI, anti-Aspergillus spp. prophylaxis is not recommended in the ICU setting, with the exception of deep immunosuppressed patients .
Indeed, it is quite unclear when to start an empirical treatment relying on the suspicion of a mold infection: nonneutropenic ICU patients are less likely to show symptoms but they share similar sensitivity regarding microbiological samples, antigen assays, and radiological findings . In the ICU population a preemptive approach based on microbiological biomarkers (galactomannan or Aspergillus nuclear acid) should be adopted for early detection and prompt treatment of suspected invasive infections . When using galactomannan with a preemptive therapeutic aim, BAL detection is more accurate than serum determinations. In a Spanish study including 51 patients, a cutoff value of 1 showed 100% sensitivity and 89.4% specificity for proven IPA; in addition, these values did not differ between neutropenic and nonneutropenic patients . Azoles (voriconazole, itraconazole, and posaconazole), amphotericin B, and echinocandins are the three classes of drugs active in invasive aspergillosis. Voriconazole is the first-line treatment recommended by current guidelines, preferring intravenous administration in critically ill patients. The superiority of this drug compared with polyenes dates back to more than 10 years ago when, in a large randomized controlled trial, its use was associated with significantly higher successful rate and lower side-effects . Recently, in a study on 67 ICU patients with acute respiratory failure and pulmonary isolation of Aspergillus spp., voriconazole use was associated with lower mortality rate, confirming its primary role in the management of invasive aspergillosis . Similarly in a large prospective surveillance study conducted in North America between 2004 and 2008 voriconazole was the main antifungal used . Even though this drug has an excellent oral bioavailability, the intravenous administration (loading bolus followed by maintenance multiple administrations) allows to achieve therapeutical levels as early as possible. In addition, it has an excellent tissue distribution: in a recent pharmacokinetic study very high epithelial-lining fluid concentrations were found in a cohort of lung transplant recipients, after oral administration . Voriconazole is metabolized by CYP2C19 P450 enzyme and several drug–drug interactions have been reported. Anyway, mainly interacting molecules are well known, so they may be avoided or administered according to therapeutical drug monitoring (i.e., cyclosporine and tacrolimus) . In patients with renal failure (creatinine clearance <50 ml/min), intravenous voriconazole should be carefully used, due to the potential toxic accumulation of sulfobutylether-β-cyclodestrin (SBECD). However, in critically ill patients, during continuous renal replacement therapy this drug may be safely used as the ultrafiltration process is able to efficiently remove this toxin [72▪]. On the contrary, the only way to optimize voriconazole therapy consists in monitoring drug plasma levels. Because of obvious cost implications such strategy might be advocated in peculiar conditions such as treatment failure, possible suboptimal dosing, suboptimal absorption, or suspected toxicity related to overdosing .
L-Amphotericin B still plays a role in the management of invasive aspergillosis when voriconazole may not be used for any reason . All three ehinocandins are ‘in-vitro’ active against Aspergillus spp. but only caspofungin is approved for the treatment of invasive aspergillosis .
Limited experience is available on antifungal combinations [75▪]. Triazole–amphotericin combination should be avoided because of possible antagonistic interactions but voriconazole–echinocandins association may be used as salvage therapy in first-line nonresponsive cases .
Optimal duration of invasive aspergillosis therapy is not known. Biomarkers kinetic, radiological response, and baseline clinical conditions are the key elements to decide when stopping the treatment. Experts’ opinion suggests to discontinue the antifungal therapy only when the patient is clinically stable and the complete resolution of radiographic abnormalities has been definitely obtained [34,36▪,39].
Other fungal infections
Trimethoprim–sulfamethoxazole (CTX) still represents the mainstay treatment of pneumonia caused by P. jirovecii. Pentamidine is considered a second-line choice in nonresponding patients or when CTX is contraindicated. Animal models support the possible use of CTX–echinocandins combination as first-line therapy in severe cases, but clinical evidence supporting a real benefit of this approach is still lacking . Steroids are strongly recommended in patients with severe PCP and HIV infection but their usefulness has not been demonstrated in other categories of immunocompromised patients. However, in severe community-acquired pneumonia methylprednisolone use has been recently demonstrated to improve clinical outcome and radiological picture . The recent mapping of the P. jirovecii genome represents a crucial starting point for advanced therapeutic opportunities such as new targets of folic acid biosynthesis pathway .
Treatment against cryptococcosis is essentially limited to three old drugs: 5-flurcytosine, liposomial amphotericin B, and fluconazole. Cryptococcal meningitis is frequently complicated by raised intracranial pressure and it sometimes deserves temporary ventricular drains . Disseminated infections may be complicated by exaggerated systemic inflammatory response while the immune system progressively recovers (immune reconstitution inflammatory syndrome). In such conditions, steroids use, as well as other immunomodulatory therapies, may be taken into account: a large trial investigating this approach in HIV-infected patients with cryptococcal meningitis is ongoing (CRYPTODEX, www.controlled-trials.com/ISRCTN59144167).
Mucorales spp. treatment relies on three basic approaches: surgical management of primary focus, high-dose polyenes administration (up to 10 mg/kg of liposomial amphotericin B), and optimal control of underlying clinical conditions. Any new therapies have been recently approved for clinical use .
IFIs still represent a clinical challenge for ICU physicians. Critically ill patients may suffer from different patterns of immunosuppression (both host-related or ICU-acquired), being at high risk for fungal infections. Candida spp. infections represent the most frequent invasive fungal disease in the ICU: rapid diagnosis and prompt adequate therapy are of paramount importance to reduce disease-related morbidity and mortality. Biomarkers-based preemptive approaches (especially (1–3)-β-D-glucan-driven strategies) have been successfully used in critical settings, with the advantage to reduce inappropriate or delayed treatments. Echinocandins are the first-line drugs during ICI and a step down azole therapy may be considered only in stable patients. Aspergillus spp. invasive infections are increasing in the ICU setting, frequently affecting nonhematological patients. In absence of histopathological findings, IPA diagnosis may be difficult but the combination of host-specific risk factors, serum/BAL biomarkers (especially galactomannan) and peculiar radiological finding may support clinicians in the ‘real life’ practice. Voriconazole is the drug of choice for the treatment of invasive aspergillosis, but possible drug interactions should be carefully considered. Combination schemes may be adopted, without the support of strong clinical evidence though. Other IFIs are not so common in ICU patients but they may cause serious systemic and local diseases that deserve appropriate and aggressive treatments.
Financial support and sponsorship
This study did not receive any funding.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Shoham S, Marwaha S. Invasive fungal infections in the ICU. J Intensive Care Med 2010; 25:78–92.
2. Limper AH. Clinical approach and management for selected fungal infections in pulmonary and critical care patients. Chest 2014; 146:1658–1666.
3▪. Bassetti M, Merelli M, Righi E, et al. Epidemiology, species distribution, antifungal susceptibility, and outcome of candidemia across five sites in Italy and Spain. J Clin Microbiol 2013; 51:4167–4172.
A large epidemiological overview on Candida bloodstream infection in five European centers.
4▪. Weiss E, Timsit JF. Management of invasive candidiasis in non neutropenic ICU patients. Ther Adv Infect Dis 2014; 2:105–115.
Recent and complete literature revision on the issue of treating Candida invasive infections in critically ill patients.
5. Vincent JL, Rello J, Marshall J, et al. EPIC II Group of InvestigatorsInternational study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302:2323–2329.
6. Tumbarello M, Posteraro B, Trecarichi EM, et al. Biofilm production by Candida species and inadequate antifungal therapy as predictors of mortality for patients with candidemia. J Clin Microbiol 2007; 45:1843–1850.
7. De Rosa FG, Trecarichi EM, Montrucchio C, et al. Mortality in patients with early- or late-onset candidaemia. J Antimicrob Chemother 2013; 68:927–935.
8. Hsu DI, Nguyen M, Nguyen L, et al. A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in nonimmunocompromised adult patients. J Antimicrob Chemother 2010; 65:1765–1770.
9. Tumbarello M, Fiori B, Trecarichi EM, et al. Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS One 2012; 7:e33705.
10. Kollef M, Micek S, Hampton N, et al. Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 2012; 54:1739–1746.
11▪▪. Bassetti M, Righi E, Ansaldi F, et al. A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med 2014; 40:839–845.
A large multicenter observational study involving 216 patients with septic shock due to Candida infection. The role of source control and early appropriate antifungal therapy results of outstanding importance.
12▪▪. Taccone FS, Van den Abeele AM, Bulpa P, et al. AspICU Study InvestigatorsEpidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care 2015; 19:7.
A large observational study on 563 patients with a positive culture for Aspergillus, classified according to recently validated criteria. In addition to an overall high mortality rate, patients with either putative or proven aspergillosis showed greater severity of illness and higher degree of organ support.
13. Matthaiou DK, Christodoulopoulou T, Dimopoulos G. How to treat fungal infections in ICU patients. BMC Infect Dis 2015; 15:205.
14. Hope WW, Castagnola E, Groll AH, et al. ESCMID Fungal Infection Study GroupESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida
spp. Clin Microbiol Infect 2012; 18 (Suppl 7):38–52.
15. Pappas PG, Kauffman CA, Andes D, et al. Infectious Diseases Society of AmericaClinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:503–535.
16. Horn DL, Ostrosky-Zeichner L, Morris MI, et al. Factors related to survival and treatment success in invasive candidiasis or candidemia: a pooled analysis of two large, prospective, micafungin trials. Eur J Clin Microbiol Infect Dis 2010; 29:223–229.
17▪. Eggimann P, Pittet D. Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later. Intensive Care Med 2014; 40:1429–1448.
A very interesting revaluation of the original study by Pittet et al. after 20 years from the original publication.
18. León C, Ruiz-Santana S, Saavedra P, et al. Cava Study GroupUsefulness of the ‘Candida score’ for discriminating between Candida colonization and invasive candidiasis in nonneutropenic critically ill patients: a prospective multicenter study. Crit Care Med 2009; 37:1624–1633.
19▪. Hammarström H, Kondori N, Friman V, Wennerås C. How to interpret serum levels of beta-glucan for the diagnosis of invasive fungal infections in adult high-risk hematology patients: optimal cut-off levels and confounding factors. Eur J Clin Microbiol Infect Dis 2015; 34:917–925.
An observational study in which a higher cut-off for β-glucan is suggested for the diagnosis of IFIs in adult high risk hematology patients.
20. Marchetti O, Lamoth F, Mikulska M, et al. European Conference on Infections in Leukemia (ECIL) Laboratory Working Groups. ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients. Bone Marrow Transplant 2012; 47:846–854.
21▪. León C, Ostrosky-Zeichner L, Schuster M. What's new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Intensive Care Med 2014; 40:808–819.
A comprehensive review on the diagnosis of invasive candidiasis in ICU patients.
22. Posteraro B, De Pascale G, Tumbarello M, et al. Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1→3)-β-D-glucan assay, Candida score, and colonization index. Crit Care 2011; 15:R249.
23. Blot Tissot F, Lamoth F, Hauser PM, et al. Fungal Infection Network of Switzerland (FUNGINOS). β-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med 2013; 188:1100–1109.
24▪. Poissy J, Sendid B, Damiens S, et al. Presence of Candida cell wall derived polysaccharides in the sera of intensive care unit patients: relation with candidaemia and Candida colonisation. Crit Care 2014; 18:R135.
A retrospective study where the combination of mannan and β-glucan are efficiently used to guide preemptive antifungal therapy in the ICU.
25. Jaijakul S, Vazquez JA, Swanson RN, Ostrosky-Zeichner L. (1,3)-β-D-glucan as a prognostic marker of treatment response in invasive candidiasis. Clin Infect Dis 2012; 55:521–526.
26. Sims CR, Jaijakul S, Mohr J, et al. Correlation of clinical outcomes with β-glucan levels in patients with invasive candidiasis. J Clin Microbiol 2012; 50:2104–2106.
27. De Pascale G, Posteraro B, Cutuli SL, et al. Why should we monitor (1-3)-β-D-glucan levels during invasive candidiasis? Just ask your ophthalmologist! J Clin Microbiol 2013; 51:1645–1646.
28. Mikulska M, Calandra T, Sanguinetti M, et al. Third European Conference on Infections in Leukemia Group. The use of mannan antigen and antimannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Crit Care 2010; 14:R222.
29. Held J, Kohlberger I, Rappold E, et al. Comparison of (1->3)-β-D-glucan, mannan/antimannan antibodies, and Cand-Tec Candida antigen as serum biomarkers for candidemia. J Clin Microbiol 2013; 51:1158–1164.
30. León C, Ruiz-Santana S, Saavedra P, et al. Value of β-D-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions. Intensive Care Med 2012; 38:1315–1325.
31. Avni T, Leibovici L, Paul M. PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol 2011; 49:665–6670.
32▪. Taira CL, Okay TS, Delgado AF, et al. A multiplex nested PCR for the detection and identification of Candida species in blood samples of critically ill paediatric patients. BMC Infect Dis 2014; 14:406.
A new molecular-based approach for the diagnosis of Candida bloodstream infection in critically ill patients.
33▪▪. Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, et al. T2 Magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis 2015; 60:892–899.
A revolutionary approach for the diagnosis of candidemia in septic patients. A step forward to a new era of molecular diagnostics.
34. Bassetti M, Righi E, De Pascale G, et al. How to manage aspergillosis in nonneutropenic intensive care unit patients. Crit Care 2014; 18:458.
35. De Pauw B, Walsh TJ, Donnelly JP, et al. European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus GroupRevised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813–1821.
36▪. Koulenti D, Garnacho-Montero J, Blot S. Approach to invasive pulmonary aspergillosis in critically ill patients. Curr Opin Infect Dis 2014; 27:174–183.
A complete review on the management of invasive aspergillosis in ICU patients.
37. Blot SI, Taccone FS, Van den Abeele AM, et al. AspICU Study InvestigatorsA clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012; 186:56–64.
38. Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med 2008; 177:27–34.
39. Koulenti D, Vogelaers D, Blot S. What's new in invasive pulmonary aspergillosis in the critically ill. Intensive Care Med 2014; 40:723–726.
40. Zou M, Tang L, Zhao S, et al. Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis. PLoS One 2012; 7:e433–e447.
41. He H, Ding L, Sun B, et al. Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. Crit Care 2012; 16:R138.
42▪▪. Duarte RF, Sánchez-Ortega I, et al. Serum galactomannan-based early detection of invasive aspergillosis in hematology patients receiving effective anti mold prophylaxis. Clin Infect Dis 2014; 59:1696–1702.
Interesting observational study in which the role of serum galactomannan, as marker of invasive aspergillosis, is evaluated in hematology patients undergoing antimold prophylaxis.
43▪. Chai LY, Kullberg BJ, Earnest A, et al. Voriconazole or amphotericin B as primary therapy yields distinct early serum galactomannan trends related to outcomes in invasive aspergillosis. PLoS One 2014; 9:e90176.
Post-hoc analysis on 147 patients, receiving voriconazole or amphotericin B, wherein galactomannan kinetic is analyzed according to the therapeutical regimen used. Voriconazole regimen was associated with earlier decreases in galactomannan serum level.
44. Li Y, Gao L, Ding Y, et al. Establishment and application of real-time quantitative PCR for diagnosing invasive aspergillosis via the blood in hematological patients: targeting aspecific sequence of Aspergillus 28S-ITS2. BMC Infect Dis 2013; 13:255.
45. Torelli R, Sanguinetti M, Moody A, et al. Diagnosis of invasive aspergillosis by a commercial real-time PCR assay for Aspergillus DNA in bronchoalveolar lavage fluid samples from high-risk patients compared to a galactomannan enzyme immunoassay. J Clin Microbiol 2011; 49:4273–4278.
46. Chong GM, van de Sande WW, Dingemans GJ, et al. Direct detection of Aspergillus and azole resistance of Aspergillus fumigatus on bronchoalveolar lavage fluid. Validation of a new Aspergillus real-time PCR. J Clin Microbiol 2015; 53:868–874.
47▪. Prattes J, Flick H, Prüller F, et al. Novel tests for diagnosis of invasive aspergillosis in patients with underlying respiratory diseases. Am J Respir Crit Care Med 2014; 190:922–929.
Interesting comparative study on β-glucan, galactomannan and Aspergillus-specific lateral flow test, for the diagnosis of invasive aspergillosis.
48▪. Aguado JM, Vázquez L, Fernández-Ruiz M, et al. PCRAGA Study Group; Spanish Stem Cell Transplantation Group, the Study Group of Medical Mycology of the Spanish Society of Clinical Microbiology and Infectious Diseases, and the Spanish Network for Research in Infectious DiseasesSerum galactomannan versus a combination of galactomannan and polymerase chain reaction-based Aspergillus DNA detection for early therapy of invasive aspergillosis in high-risk hematological patients: a randomized controlled trial. Clin Infect Dis 2015; 60:405–414.
Randomized controlled trial wherein a combined monitoring strategy (galactomannan and Aspergillus DNA) was associated with an earlier diagnosis and a lower incidence of invasive aspergillosis in high-risk hematology patients.
49. Arvanitis M, Anagnostou T, Fuchs BB, et al. Molecular and non molecular diagnostic methods for invasive fungal infections. Clin Microbiol Rev 2014; 27:490–526.
50. Esteves F, Calé SS, Badura R, et al. Diagnosis of Pneumocystis pneumonia: evaluation of four serologic biomarkers. Clin Microbiol Infect 2014; [Epub ahead of print].
51. Rose SR, Vallabhajosyula S, Velez MG, et al. The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections. J Infect 2014; 69:278–283.
52. Tang MW, Clemons KV, Katzenstein DA, Stevens DA. The cryptococcal antigen lateral flow assay: a point-of-care diagnostic at an opportune time. Crit Rev Microbiol 2015; 23:1–9.
53▪. Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical MycologyESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect 2014; 20:5–26.
Current guidelines for the diagnosis and treatment of mucormycosis.
54. Tumbarello M, Fiori B, Trecarichi EM, et al. Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS One 2012; 7:e33705.
55. Kollef M, Micek S, Hampton N, et al. Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 2012; 54:1739–1746.17.
56. Pagano L, Caira M, Nosari A, et al. on behalf of the HEMA e-Chart Group, ItalyThe use and efficacy of empirical versus preemptive therapy in the management of fungal infections: the HEMA e-Chart Project. Haematologica 2011; 96:1366–1370.
57. Cornely OA, Bassetti M, Calandra T, et al. ESCMID Fungal Infection Study GroupESCMID* guideline for the diagnosis and management of Candida diseases 2012: nonneutropenic adult patients. Clin Microbiol Infect 2012; 18:19–37.
58. Schuster MG, Edwards JE Jr, Sobel JD, et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med 2008; 149:83–90.
59▪▪. Bailly S, Bouadma L, Azoulay E, et al. Failure of empirical systemic antifungal therapy in mechanically-ventilated critically ill patients. Am J Respir Crit Care Med 2015; 191:1139–1146.
Interesting observational study where empirical systemic antifungal therapy did not show any outcome benefit in critically ill mechanically ventilated patients.
60. Hanson KE, Pfeiffer CD, Lease ED, et al. β-D-glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS One 2012; 7:e42282.
61▪. Ostrosky-Zeichner L, Shoham S, Vazquez J, et al. MSG-01: A randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 2014; 58:1219–1226.
A randomized controlled trial where caspofungin prophylaxis, followed by preemptive therapy, in high-risk critically ill patients resulted to be well tolerated and showed a trend to reduce the incidence of invasive candidiasis.
62. Andes DR, Safdar N, Baddley JW, et al. Mycoses Study GroupImpact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 2012; 54:1110–1122.
63▪. Sinnollareddy MG, Roberts JA, Lipman J, et al. DALI Study authorsPharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study. Crit Care 2015; 19:758.
First pharmacokinetic multicenter pharmacokinetic study on antifungal use in critically ill patients.
64. Nivoix Y, Velten M, Letscher-Bru V, et al. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis 2008; 47:1176–1184.
65. Baddley JW, Stephens JM, Ji X, et al. Aspergillosis in Intensive Care Unit (ICU) patients: epidemiology and economic outcomes. BMC Infect Dis 2013; 13:29.
66. Herbrecht R, Denning DW, Patterson TF, et al. Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study GroupVoriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408–415.
67. Trof RJ, Beishuizen A, Debets-Ossenkopp YJ, et al. Management of invasive pulmonary aspergillosis in nonneutropenic critically ill patients. Intensive Care Med 2007; 33:1694–1703.
68. Acosta J, Catalan M, del Palacio-Peréz-Medel A, et al. A prospective comparison of galactomannan in bronchoalveolar lavage fluid for the diagnosis of pulmonary invasive aspergillosis in medical patients under intensive care: comparison with the diagnostic performance of galactomannan and of (1→ 3)-β-d-glucan chromogenic assay in serum samples. Clin Microbiol Infect 2011; 17:1053–1060.
69. Burghi G, Lemiale V, Seguin A, et al. Outcomes of mechanically ventilated haematology patients with invasive pulmonary aspergillosis. Intensive Care Med 2011; 37:1605–1612.
70. Azie N, Neofytos D, Pfaller M, et al. The PATH (Prospective Antifungal Therapy) Alliance® registry and invasive fungal infections: update 2012. Diagn Microbiol Infect Dis 2012; 73:293–300.
71. Heng SC, Snell GI, Levvey B, et al. Relationship between trough plasma and epithelial lining fluid concentrations of voriconazole in lung transplant recipients. Antimicrob Agents Chemother 2013; 57:4581–4583.
72▪. Kiser TH, Fish DN, Aquilante CL, et al. Evaluation of sulfobutylether-ß-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy. Crit Care 2015; 19:32.
Interesting pharmacokinetic study that demonstrates that SBECD does not accumulate during voriconazole treatment in patients undergoing continuous renal replacement therapy.
73. Cornely OA, Maertens J, Bresnik M, et al. AmBiLoad Trial Study GroupLiposomal amphotericin B as initial therapy for invasive mould infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44:1289–1297.
74. Walsh TJ, Anaissie EJ, Denning DW, et al. Infectious Diseases Society of AmericaTreatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:327–3260.
75▪. Raad II, Zakhem AE, Helou GE, et al. Clinical experience of the use of voriconazole, caspofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies. Int J Antimicrob Agents 2015; 45:283–288.
Observational study in which combined antifungal strategies are used as salvage therapy in hematological patients with invasive aspergillosis.
76. Garbati MA, Alasmari FA, Al-Tannir MA, Tleyjeh IM. The role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review. Int J Infect Dis 2012; 16:e76–e81.
77. Kim T, Hong HL, Lee YM, et al. Is caspofungin really an effective treatment for Pneumocystis jirovecii pneumonia in immunocompromised patients without human immunodeficiency virus infection? Experiences at a single center and a literature review. Scand J Infect Dis 2013; 45:484–488.
78. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015; 313:677–686.
79. Luraschi A, Cissé OH, Monod M, et al. Functional characterization of the Pneumocystis jirovecii potential drug targets dhfs and abz2 involved in folate biosynthesis. Antimicrob Agents Chemother 2015; 59:2560–2566.
80. Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: what do we know now. Fungal Genet Biol 2015; 78:49–54.
81. Ibrahim AS, Kontoyiannis DP. Update on mucormycosis pathogenesis. Curr Opin Infect Dis 2013; 26:508–515.