Introduction
Pathophysiology of invasive candidiasis
Neutropenic and bone marrow transplant recipients
Solid organ transplant recipients
Nonsurgical critically ill patients
Critically ill patients recovering from abdominal surgery
Critically ill patients with Candida isolated from the respiratory tract
Candida colonization
Candida colonization index: the missing link
Colonization index
Index | Definition | Formula |
---|---|---|
Colonization index (CI) | Ratio of the number of distinct non-blood body sites colonized by Candida spp. to the total number of body sites cultured. With the exception of blood cultures, samples collected from body sites other than those routinely screened are also considered. Only strains of Candida spp. with identical electrophoretic karyotypes are considered when calculating the CI |
\({\text{CI}}\,{ = }\;\frac{{{\text{Number}}\;{\text{of}}\;{\text{sites}}\;{\text{colonized}}}}{{{\text{Number}}\;{\text{of}}\;{\text{sites}}\;{\text{cultured}}}}\)
|
Corrected colonization index (CCI) | Product of the CI and the ratio of the number of distinct body sites showing heavy growth (+++ from semi-quantitative culture or ≤105 in urine or gastric juice) to the total number of body sites with Candida spp. heavy growth |
\({\text{CCI}}\;{ = }\;\frac{{{\text{Number}}\;{\text{of}}\;{\text{sites}}\;{\text{colonized}}}}{{{\text{Number}}\;{\text{of}}\;{\text{sites}}\;{\text{cultured}}}}\; \times \;\frac{{{\text{Number}}\;{\text{of}}\;{\text{sites}}\;{\text{with}}\;{\text{heavy}}\;{\text{growth}}}}{{{\text{Total}}\;{\text{positive}}\;{\text{sites}}}}\)
|
Use of the CIa
| In patients perceived to be at risk of developing an invasive candidiasis: twice weekly surveillance culture of the following sitesb: - Oropharynx swab or tracheal secretions - Gastric fluid - Perinea swab or stool sample - Urine sample - Surgical wound swab or drained abdominal fluids - Catheter insertion sites |
Corrected colonization index
Overview of the usefulness of the colonization index
Reference | Type of patient; study design | Number of patients | Number of invasive candidiasis cases | CI monitoring | Number of surveillance cultures | Main CI findings | Authors’ conclusion |
---|---|---|---|---|---|---|---|
General studies (n = 7) | |||||||
Tran et al. [51] | Cardiac surgery; prospective | 81 | 7 | Preoperatively, day 6 or at discharge | 773 (mean, 8.8/patient); 116 (16.3 %) positive | CI ↑ in 57 % developing IC, 23 % uninfected; CI associated with female sex (45 vs. 21 %), catheter duration (13 vs. 11 days), length of ICU stay (5.7 vs. 4.9 days) CI did not change in 43 % developing IC, 72 % uninfected | “This study showed that three epidemiological factors—duration of the intravascular catheterization and medical devices, length of stay in the SICU and the sex of the patient—were associated in elective cardiovascular surgical patients with an increase of the Candida spp. colonization index, which helps to identify high-risk patients for Candida infections” |
Yazdanparast et al. [52] | Cardiac surgery; prospective | 131: coronary artery bypass grafting with (n = 72) and without (n = 59) extracorporeal circulation | 0 | Preoperatively, postoperatively (day not specified) | 147 | In patients requiring extracorporeal circulation, ↑ CI associated with more antibiotic use (1.50 ± 0.83 vs. 1.08 ± 0.40; different agents; p = 0.0055) | “Epidemiological data obtained from this study show that coronary artery bypass grafting with extracorporeal circulation procedure is associated with an increase in the use of antibiotics and subsequently a higher risk of Candida colonization-infection” |
Charles et al. [37] | Mixed ICU, patients with candidemia; retrospective | 51: 20 MICU, 32 SICU (p < 0.05) | 51 | Daily for 7 days before candidemia | Not specified (mean, 3.2/patient before candidemia) | Mean CI in 46 assessed: 0.56 ± 0.39 CI ≥ 0.50 in 21 (45.6 %) MICU 0.74 ± 0.31 vs. SICU 0.45 ± 0.40 (p = 0.01) Mean CI in survival 0.46 vs. death 0.63 (p = 0.04) Better ICU outcome associated with prior surgery [HR, 0.25 (0.09–0.67)], antifungal treatment [HR, 0.11 (0.04–0.30)], absence of neutropenia [HR, 0.10 (0.02–0.45)] | “Candidemia occurrence is associated with a high mortality rate among critically ill patients. Differences in underlying conditions could account for the poorer outcome of the medical patients. Screening for fungal colonization could allow identification of such high-risk patients and, in turn, improve outcome” |
Charles et al. [38] | Medical ICU, stay >7 days; prospective | 92 | 1 (septic shock with typical maculopapular rash, positive skin biopsy) | Weekly (mean, 3.2/patient) | 1,696 (mean, 18.4/patient) | CI ≥ 0.50 in 36 (39.1 %), almost all with detectable fungal colonization on ICU admission Predictors of CI ≥ 0.5: Candida colonization at admission [OR 18.80 (5.21–67.79)], >2 days bladder catheterization [OR, 10.44 (1.61–67.85)] CI ↑ associated with days on broad-spectrum antibiotics [β = 0.01 (0.01–0.02)], hematological malignancy [β = 0.41 (0.09–0.73)], candiduria [β = 0.2 (0.09–0.31)] Empirical antifungal treatment prescribed in 14/36 (39 %) with CI ≥ 0.5, 7/56 (13 %) with CI < 0.5 (p = 0.007) | “Candida spp. multiple-site colonization is frequently reached among the critically ill medical patients. Broad spectrum antibiotic therapy was found to promote fungal growth in patients with prior colonization. Since most of the invasive candidiasis in the ICU setting are thought to be subsequent to colonization in high-risk patients, reducing antibiotic use could be useful in preventing fungal infections” |
Eloy et al. [53] | Mixed ICU, risk factors (antibiotics or hospital stay >8 days, neutropenia); prospective | 75: 46 MICU, 29 SICU | 4 MICU (2 respiratory tract, 2 urinary); 5 SICU (4 peritonitis, 1 urinary) | At admission, weekly | 901; 469 (52 %) positive | Accuracy of CI > 0.5 in predicting IC in MICU: sens, 75 %; spec, 35 %; PPV, 10 %; NPV, 94 % In SICU: sens, 100 %; spec, 50 %; PPV, 29 %; NPV, 100 % | “Serological tests failed to differentiate infected from non-infected patients. The Pittet’s CI identified infected surgical patients (Fisher exact test, 0.052), which are in the population with CI > 0.5” |
Agvald-Ohman et al. [54] | Mixed ICU, stay >7 days; prospective | 59 | 10 | At admission, then weekly | 401; 149 (37 %) positive | 32 (54 %) received antifungals: 10 with IC [mean CI, 0.7; 8 had digestive surgery, 7 had CIs > 0.5 (<0.8 in 6)]; 22 without IC (mean CI, 0.26; 7 had digestive surgery, 9 had CIs > 0.5) 17/25 (68 %) with CIs ≥ 0.5 on day 7 received antifungals Predictors of IC: CI > 0.5 (OR, 19.1 [2.4–435]), digestive surgery [OR, 60 (2.4–infinity)] | “High colonization index and recent extensive gastro-abdominal surgery were significantly correlated with IC. The results indicate that ICU patients exposed to extensive gastro-abdominal surgery would benefit from early antifungal prophylaxis” |
Massou et al. [55] | Medical ICU, stay >2 days and at least one risk factor; prospective | 100 | 15 | At admission, then weekly | 816 (including 143 blood cultures) | CI ≥ 0.5 in 53 (53 %), predicted only by corticosteroids [OR, 5.1 (1.02–25.2)] Accuracy of CI > 0.5 in predicting IC: sens, 93 %; spec, 48 %; PPV, 26 %; NPV, 98 % Only neutropenia predicted invasive candidiasis [OR, 18.3 (2.9–114)] | “CI has the advantage to provide quantified data of the patient’s situation in relation to the colonization. But, it isn’t helpful with patients having an invasive candidiasis in medical intensive care unit” |
Candiduria studies (n = 5) | |||||||
Chabasse [56] | 15 mixed ICUs, one major or two minor risk factors and candiduria; prospective | 135 | 0 | At time of candiduria and/or candidemia | Not available | Candiduria: <103, 56 (42 %); 103–104, 21 (16 %); >104, 56 (42 %) CI > 0.5 in 36/76 tested (65 % with candiduria >104, 31 % with candiduria <104; p = 0.003) | “Quantification of candiduria could be useful to select patients at high risk for disseminated candidiasis” |
Dubau et al. [57] | Surgical ICU, stay or antibiotics >7 days or postoperative fistula and CRP > 100 mg/ml; prospective | 89 | 1/35 empirically treated with CIs ≥ 0.5; 0 with CIs < 0.5; 22 candiduria | On inclusion, then weekly | 2,238 | Absence of candiduria: CI = 0.3–0.47 (p = 0.008) Presence of candiduria: CI = 0.57–0.87 (p = 0.0001) | “The presence of a candiduria was significantly associated with an increased invasive candidiasis” |
Sellami et al. [58] | Mixed ICU, stay >3 days; prospective | 162 | 6; 56 candiduria | On inclusion, then weekly | Not available | Candiduria: <103, 12 (21 %); 103–104, 16 (29 %); >104, 28 (50 %) Mean CI = 0.47 candiduria, 0.8 IC (n = 6) CI > 0.5 in 67 % candiduria >104
| “Candiduria superior or equal to 104 UFC/ml associated with risk factors may predict invasive candidiasis in critically ill patients” |
Charles et al. [38] | Medical ICU, stay > 7 days; prospective | 92 | 9 | Weekly | 1,696 (mean, 18.4/patient) | ↑ CI associated with: days on broad-spectrum antibiotics [β = 0.01 (0.01–0.02)], hematological malignancy [β = 0.41 (0.09–0.73)], candiduria [β = 0.2 (0.09–0.31)] | “Since most of the invasive candidiasis in the ICU setting are thought to be subsequent to colonization in high-risk patients, reducing antibiotic use could be useful in preventing fungal infections” |
Ergin et al. [59] | Mixed ICU, stay >7 days; prospective | 100 | 9 (5 candidemia, 4 urinary); 42 candiduria | On inclusion, then weekly | 1,691 (mean, 17/patient) | CI > 0.2, 42 (42 %); CI > 0.2 and <0.5, 34 (34 %); CI ≥ 0.5, 8 (8 %) Accuracy of CI ≥ 0.5 in predicting invasive candidiasis: sens, 100 %; spec, 64 %; PPV, 21 %; NPV, 100 % | “Candida colonization and Candida colonization index may be used as useful parameters to predict invasive Candida infections” |
Prophylaxis studies (n = 6) | |||||||
Laverdière et al. [60] | Neutropenia (leukemia or BMT); prospective, double-blinded, randomized: prophylaxis (fluconazole, 400 mg/day orally) vs. placebo | 266 | 41: 9/135 (6.7 %) fluconazole, 32/131 (24.4 %) placebo (p < 0.001) | On randomization, at end of prophylaxis | 1,904; 458 (21 %) positive | Colonization ↓ (39–36 %) fluconazole, ↑ (37–73 %) placebo (p < 0.0001) CI ↓ (0.18–0.16) fluconazole, ↑ (0.18–0.39) placebo (p < 0.001) Accuracy of CI ≤ 0.25 in predicting IC at baseline: sens, 39 %; spec, 82 %; PPV, 28 %; NPV, 88 % At end of prophylaxis: sens, 76 %; spec, 69 %; PPV, 69 %; NPV, 94 % | “Fluconazole prevented and reduced fungal colonization of the alimentary tract and subsequent invasive fungal infections… In cancer patients, a colonization index ≤0.25 at the initiation of chemotherapy clearly predicts a low risk of invasive fungal infection” |
Garbino et al. [40] | Mixed ICU, >2 days mechanical ventilation and expected continuation for ≥72 h; prospective, double-blinded randomized: prophylaxis (fluconazole, 100 mg/day iv) vs. placebo plus selective digestive decontamination (polymyxin B, neomycin, vancomycin) | 204 | 6/103 (5.8 %) fluconazole, 16/101 (16 %) placebo (p < 0.001) | Daily | Not available | Colonization: 29/55 (53 %) fluconazole, 40/51 (78 %) placebo (p = 0.01) CI ↓ (0.26–0.13) fluconazole, ↑ (0.26–0.50) placebo (p < 0.001) Mean pre-infection CI in patients with candidemia (n = 10): 0.89 | “…fluconazole prophylaxis in selected, high-risk critically ill patients decreases the incidence of Candida infection, in particular, candidemia” |
Normand et al. [61] | Mixed ICU, >2 days mechanical ventilation; prospective, open-label, nystatin vs. placebo | 98 | 0 | On randomization, then every 3 days | Not available | Colonization: 0/51 nystatin, 12/47 (25 %) placebo (p < 0.01) CI ↓ (0.1–0.05) nystatin, ↑ (0.1–0.25) placebo (p < 0.05) | “Oral nystatin prophylaxis efficiently prevented Candida spp. colonization in ICU patients at low risk of developing invasive candidiasis” |
Senn et al. [46] | Surgical ICU, recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis; prospective, non-comparative, caspofungin prophylaxis | 19 | 1 (6–8 expected in this high-risk group without prophylaxis) | On inclusion, then twice in week 1, then weekly until end of follow-up | Not available (median, 4 sites/patient screened) | CI ↓ (0.5–0.3) during prophylaxis (p = 0.03) | “Despite limitations such as the open single-center non-comparative design and the small sample size, the observations of this proof-of-concept study suggest that caspofungin may be efficacious and safe for prevention of intra-abdominal candidiasis in surgical patients with a high-risk profile” |
Giglio et al. [62] | Surgical/trauma ICU, >2 days mechanical ventilation; prospective, randomized, open-label: prophylaxis (oral nystatin, 3 × 1 million U/day) vs. placebo | 99 | 0 | On inclusion, then every 3 days until end of follow-up (day 15) | 2,569; 746 (29 %) positive | Overall: CI ↓ (0.12–0.0) nystatin, ↑ (0.2–0.44) placebo (p < 0.05) Colonization at entry: CI ↓ (0.1–0.0) nystatin, ↑ (0.2–0.42) placebo (p < 0.05) | “The present trial shows that nystatin pre-emptive therapy in surgical/trauma ICU patients significantly reduces fungal colonization, even in those colonized at admission” |
Chen et al. [63] | Mixed ICU, mechanical ventilation; prospective, randomized, open-label: prophylaxis (oral nystatin, 3 × 1 million U/day) vs. placebo | 124 | 8: 3/60 (0.5 %) nystatin, 5/64 (7.8 %) placebo (p > 0.05) | On inclusion, every 3 days until end of follow-up (day 9) | Not available; 874 positive | CCI at day 6: 0.19 nystatin, 0.39 placebo (p < 0.05) At day 9: 0.0 nystatin, 0.45 placebo (p < 0.05) Length of ICU stay: 9.6 ± 3.5 days nystatin, 11.9 ± 6.3 days placebo (p < 0.05) | “Nystatin might reduce the colonization by Candida albicans and was associated with shorter ICU stay” |
Reference | Type of patient; study design | Number of patients | Number of invasive candidiasis cases | CI monitoring | Number of surveillance cultures | Main CI findings | Authors’ conclusion |
---|---|---|---|---|---|---|---|
Interventional studies (n = 4) | |||||||
Dubau et al. [57] | Surgical ICU, stay or antibiotics >7 days or -postoperative fistula and CRP >100 mg/ml; prospective, open, non-randomized: empirical antifungal treatment for CI >0.5 | 89 | 1/35 with CI > 0.5 receiving empirical antifungal treatment | On inclusion, then weekly | 2,238 | CI > 0.5: week 1, 6 %; week 2, 25 %; week 3, 40 %; week 4, 55 %; week >4, 59 % CI ↓ rapidly after start of empirical antifungal treatment in 34/35 patients | “A treatment was started whenever a colonization index >0.5 was associated with severe clinical or biological signs. This involved an increase of the expense of antifungal drugs. The potential benefits could not be evaluated from our study” |
Piarroux et al. [64] | Surgical ICU, stay ≥5 days; prospective, open, non-randomized: empirical antifungal treatment for CCI > 0.4 | 478 | Overall IC: 18 [3.8 %; 2/455 (7.0 %) in historical controls] ICU-acquired: 0 [10/455 (2.2 %) in historical controls; p < 0.001) | On inclusion, then weekly | 6,682 | With empirical treatment: CCI > 0.4, 96/117; CCI < 0.4 and CI ≥ 0.5, 11/66; CCI < 0.4 and CI < 0.5, 5/230 ~160 complete mycological screenings and 10 preemptive treatments needed to prevent at least one proven SICU-acquired candidiasis | “Preemptive treatment of highly colonized patients may efficiently prevent SICU-acquired proven candidiasis. Our results demonstrate the feasibility and benefits of implementing a large systematic mycological screening of SICU patients” |
Eren et al. [65] | Mixed ICU, inclusion criteria not specified; prospective observational, intervention not specified (antifungal treatment for CI > 0.5?) | 37 | 0 | Not specified | 191 | 26 (70 %) with C. albicans colonization CI ≥ 0.5 in 7 (5 with IgM, IgG positivity) CI < 0.5 in 19 (3/12 tested with IgM, IgG positivity) IgM, IgG found in 0/7 patients tested without colonization, out of 11 | “…follow-up of the ICU patients in terms of C. albicans CI and IgM would be effective for the prevention of serious Candida infections” |
Wang et al. [66] | 5 mixed ICUs, APACHE score > 10; prospective randomized: empirical antifungal treatment for CCI ≥ 0.4 (intervention group) or (control group) | 110 | Not specified | Not specified | Not available; 575 positive | Antifungal treatment for sepsis started at 0.9 ± 0.7 days in CCI ≥ 0.4, 3.8 ± 3.6 days in control (p < 0.05) | “Application of CCI may enhance the accuracy of timely preemptive treatment for invasive candidiasis and facilitate the collection of epidemiological data of Candida in critically ill patients” |
Comparison of the colonization index with other predictive tools
References | Type of patient; study design | Number of patients | Number of invasive candidiasis | CI monitoring | Performance of CI | Performance of comparators | Authors’ conclusion |
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Leon et al. [67] | 36 mixed ICUs, stay ≥7 days; prospective, observational cohort | 1,107 | 58; 18/240 in whom BG could be performed | At inclusion, then weekly (4,198 cultures) | 892 with Candida spp. colonization or invasive candidiasis Development of invasive candidiasis: CI < 0.5, 16/411 (3.9 %); CI ≥ 0.5, 42/481 (8.7 %) Sens, 72 %; spec, 47 %; PPV, 9 %; NPV, 96 %; AUC, 0.633 20.8 needed to treat to avoid one episode of invasive candidiasis | 892 with Candida spp. colonization or invasive candidiasis Development of invasive candidiasis: Candida score <3, 13/565 (2.3 %); Candida score ≥3, 45/327 (13.8 %) Sens, 78 %; spec, 66 %; PPV, 14 %; NPV, 98 %; AUC, 0.774 8.7 needed to treat to avoid one episode of invasive candidiasis | “In this cohort of colonized patients staying >7 days, with a CS <3 and not receiving antifungal treatment, the rate of IC was <5 %. Therefore, IC is highly improbable if a Candida-colonized non-neutropenic critically ill patient has a Candida score <0.3” |
Ellis et al. [68] | Hematological patients with febrile neutropenia and >3 days broad-spectrum antibiotics; prospective, usefulness of serial analysis for mannans/anti-mannans, β-glucans | 86 | 12 (14 %) | Twice a week | CI ≥ 0.5 in 52/86 (60 %), 8/9 (89 %) IC Accuracy not determined | Mannans/anti-mannans (33 patients (2 consecutive positive tests): sens, 73 %; spec, 80 %; PPV, 0.36; NPV, 0.95 Positive correlation of invasive candidiasis with β-glucans (r = 0.28, p = 0.01) | “Serial assays for mannans and anti-mannans in patients at risk for invasive candidiasis may usefully contribute to the management of such patients” |
Caggiano et al. [69] | Neurological ICU, stay ≥7 days; prospective, link between colonization and invasive candidiasis | 51 | 3 candidemia | At admission, then every 3 days (to day 15) | Colonization: 76 % at study entry, 92 % on day 15 CI ≥ 0.5: 16.6 % at study entry, 75 % on day 15 (all IC) CCI: 0.34 at study entry, 0.60 on day 15 | No mannan/anti-mannan detected in patients without candidemia Mannans: sens, 66.6 %; spec, 100 % Anti-mannans: sens, 100 %; spec, 100 % | “Thus, our experience suggests that monitoring CI could be helpful in identifying patients at risk of invasive fungal infection. In addition, complementing this with anti-Candida antibodies detection in immunocompetent patients with CI ≥ 0.5 increases the positive predictivity for infection allowing an early diagnosis of candidemia” |
Posteraro et al. [70] | Mixed ICU, stay ≥5 days; prospective, single-center, observational: diagnostic value of BG assay, Candida score, CI | 95 | 16 (14 invasive candidiasis) | At entry, day 3, and then weekly | CI ≥ 0.5: overall, 35 %; IC, 56 %; no IC, 30 % (p = 0.04) Sens, 64 %; spec, 70 %; PPV, 27 %; NPV, 92 %; AUC, 0.63 (0.57–0.79) |
Candida score ≥3: overall, 22 %; IC, 75 %; no IC, 11 % (p < 0.001). Sens, 86 %; spec, 87 %; PPV, 57 %; NPV, 97 %; AUC, 0.80 (0.69–0.92) BG positivity: overall, 21 %; IC, 94 %; no IC, 6 % (p < 0.001). Sens, 94 %; spec, 94 %; PPV, 75 %; NPV, 99 %; AUC, 0.98 (0.92–1.00)
Candida score ≥3 and BG positivity: sens, 100 %; spec, 84 %; PPV, 52 %; NPV, 100 % | “A single-point BG assay based on a blood sample drawn at the sepsis onset, alone or in combination with Candida score, may guide the decision to start antifungal therapy early in patients at risk for Candida infection” |
Peman et al. [71] | 6 mixed ICU, high risk of invasive candidiasisa; prospective, usefulness of CAGTA | 53 | 0 | Not specified | CCI ≥ 0.4: 23/53 (43 %) at study entry, 41/53 (77 %) at end of study | CAGTA positivity: 22/53 (42 %) at study entry, 47/53 (90 %) at end of study | “This study identified previous surgery as the principal clinical factor associated with CAGTA-positive results (serologically proven candidiasis) and emphasises the utility of this promising technique, which was not influenced by high Candida colonization or antifungal treatment” |
Hall et al. [72] | Mixed ICU, severe acute pancreatitis; retrospective, diagnostic value of BG assay, Candida score, CI | 101 | 18 (5 died) | Not specified | Colonization: 16/18 (89 %) IC, 37/83 (45 %) no IC (p = 0.0006). Colonization for IC: OR, 4.33 (1.07–17.5); p = 0.04 CI ≥ 0.5: sens, 67 %; spec, 79 %; PPV, 43 %; NPV, 91 %; AUC, 0.79 (0.69–0.87) |
Candida score: sens, 23 %; spec, 85 %; PPV, 39 %; NPV, 72 %; AUC, 0.62 (0.52–0.71) Predictive ruleb: sens, 61 %; spec, 49 %; PPV, 21 %; NPV, 85 %; AUC, 0.59 (0.49–0.69) | “In this study the Candida colonisation index score was the most accurate and discriminative test at identifying which patients with severe acute pancreatitis are at risk of developing candidal infection. However its low sensitivity may limit its clinical usefulness” |
Tissot et al. [44] | Surgical ICU, recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis; prospective, accuracy of BG antigenemia for diagnosis of intra-abdominal candidiasis | 89 | 2 | On admission, then twice a week | CI ≥ 0.5: sens, 26 %; spec, 76 %; PPV, 35 %; NPV, 67 %; AUC, 0.67 CCI ≥ 0.4: sens, 14 %; spec, 77 %; PPV, 23 %; NPV, 65 %; AUC, 0.43 | BG > 80 pg/ml (2×): sens, 66 %; spec, 83 %; PPV, 73 %; NPV, 78 %; AUC, 0.79
Candida score ≥3: sens, 86 %; spec, 50 %; PPV, 54 %; NPV, 84 %; AUC, 0.61 | “BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture-negative intra-abdominal candidiasis” |