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1.  Risk Factors for Invasive Candidiasis in Infants >1500 g Birth Weight 
We describe the incidence, risk factors, and outcomes of invasive candidiasis in infants >1500 g birth weight.
We conducted a retrospective cohort study of infants >1500 g birth weight discharged from 305 NICUs in the Pediatrix Medical Group from 2001–2010. Using multivariable logistic regression, we identified risk factors for invasive candidiasis.
Invasive candidiasis occurred in 330/530,162 (0.06%) infants. These were documented from positive cultures from ≥1 of these sources: blood (n=323), cerebrospinal fluid (n=6), or urine from catheterization (n=19). Risk factors included day of life >7 (OR 25.2; 95% CI 14.6–43.3), vaginal birth (OR 1.6 [1.2–2.3]), exposure to broad-spectrum antibiotics (OR 1.6 [1.1–2.4]), central venous line (OR 1.8 [1.3–2.6]), and platelet count <50,000/mm3 (OR 3.7 [2.1–6.7]). All risk factors had poor sensitivities, low positive likelihood ratios, and low positive predictive values. The combination of broad-spectrum antibiotics and low platelet count had the highest positive likelihood ratio (46.2), but the sensitivity of this combination was only 4%. Infants with invasive candidiasis had increased mortality (OR 2.2 [1.3–3.6]).
Invasive candidiasis is uncommon in infants >1500 g birth weight. Infants at greatest risk are those exposed to broad-spectrum antibiotics and with platelet counts of <50,000/mm3.
PMCID: PMC3578110  PMID: 23042050
candidiasis; candidemia; neonates; neonatal intensive care unit
2.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
PMCID: PMC3258271  PMID: 22144537
3.  Urine d-Arabinitol/l-Arabinitol Ratio in Diagnosis of Invasive Candidiasis in Newborn Infants 
Journal of Clinical Microbiology  2000;38(8):3039-3042.
Infants treated in neonatal intensive care units suffer an increased risk for invasive candidiasis, but the diagnosis is sometimes difficult. d-arabinitol is a metabolite of most pathogenic Candida species. An elevated urine d-arabinitol/l-arabinitol (DA/LA) ratio is a sensitive sign of invasive candidiasis in children with cancer, but the method has not been previously evaluated for newborn infants. We therefore enrolled 117 infants in a neonatal intensive care unit, and 411 urine samples were obtained on filter paper. The DA/LA ratio was measured by gas chromatography-mass spectrometry. For 81 infants with no suspicion of superficial or invasive candidiasis, the urine DA/LA ratio was 2.7 ± 0.7 (mean ± standard deviation [SD]). The upper cutoff level was set at 4.8 (mean plus 3 SD). Of 22 infants with mucocutaneous candidiasis and not given systemic antifungal treatment, two had elevated DA/LA ratios, which normalized after removal of intravascular catheters. Eight other infants were given empiric antifungal treatment but had negative cultures; five of these had repeatedly elevated DA/LA ratios. Six infants with culture-positive invasive candidiasis all had one or more samples with elevated ratios. For seven infants, three with suspected and four with confirmed invasive candidiasis (for which follow-up samples were available), ratios normalized during antifungal treatment. In conclusion, urine DA/LA ratio determination is a rapid test and can be used for newborns. It is possibly more sensitive than fungal blood cultures in the diagnosis of invasive candidiasis and can also be used for monitoring the effect of antifungal treatment.
PMCID: PMC87181  PMID: 10921974
4.  Invasive candidiasis in low birth weight preterm infants: risk factors, clinical course and outcome in a prospective multicenter study of cases and their matched controls 
BMC Infectious Diseases  2014;14:327.
This multicenter prospective study of invasive candidiasis (IC) was carried out to determine the risk factors for, incidence of, clinical and laboratory features, treatment and outcome of IC in infants of birth weight <1250 g.
Neonates <1250 g with IC and their matched controls (2:1) were followed longitudinally and descriptive analysis was performed. Survivors underwent neurodevelopmental assessment at 18 to 24 months corrected age. Neurodevelopmental impairment (NDI) was defined as blindness, deafness, moderate to severe cerebral palsy, or a score <70 on the Bayley Scales of Infant Development 2nd edition. Multivariable analyses were performed to determine risk factors for IC and predictors of mortality and NDI.
Cumulative incidence rates of IC were 4.2%, 2.2% and 1.5% for birth-weight categories <750 g, <1000 g, <1500 g, respectively. Forty nine infants with IC and 90 controls were enrolled. Necrotizing enterocolitis (NEC) was the only independent risk factor for IC (p = 0.03). CNS candidiasis occurred in 50% of evaluated infants, while congenital candidiasis occurred in 31%. Infants with CNS candidiasis had a higher mortality rate (57%) and incidence of deafness (50%) than the overall cohort of infants with IC. NDI (56% vs. 33%; p = 0.017) and death (45% vs. 7%; p = 0.0001) were more likely in cases than in controls, respectively. IC survivors were more likely to be deaf (28% vs. 7%; p = 0.01). IC independently predicted mortality (p = 0.0004) and NDI (p = 0.018).
IC occurred in 1.5% of VLBW infants. Preceding NEC increased the risk of developing IC. CNS candidiasis is under-investigated and difficult to diagnose, but portends a very poor outcome. Mortality, deafness and NDI were independently significantly increased in infants with IC compared to matched controls.
PMCID: PMC4063435  PMID: 24924877
Invasive candidiasis; Neurodevelopmental outcome; Risk factors; Neonatal; Prematurity
5.  Quantitative urine cultures do not reliably detect renal candidiasis in rabbits. 
Journal of Clinical Microbiology  1997;35(12):3292-3297.
The significance of quantitative urine cultures in patients at risk for hematogenous disseminated candidiasis is controversial. While various concentrations of Candida spp. in urine have been suggested as critical cutoff points in the diagnosis of renal candidiasis, other investigators consider quantitative cultures less critical in diagnosing upper tract infections. To determine the significance of quantitative urine cultures in renal candidiasis, we studied serial quantitative urinary cultures of Candida albicans in a rabbit model of hematogenous infection. Of 197 urine samples from 34 infected animals, 144 were culture positive, with a sensitivity of 73.1% for urine cultures and a lower limit of detection of 10 CFU/ml. The yield of urine cultures varied according to severity and duration of infection. The mean renal and urinary concentrations of C. albicans from rabbits with subacute candidiasis differed significantly from those from rabbits with acute candidiasis (P = 0.013 and P < or = 0.001, respectively). During the first 4 days of subacute renal candidiasis, more than one-half of all urine cultures were negative for C. albicans. Only 12 (8.1%) of 148 urine cultures in animals with subacute renal candidiasis had concentrations of > 10(3) CFU/ml, 2.7% had concentrations of > 10(4) CFU/ml, and none were > or = 10(5) CFU/ml. By comparison, all urine cultures from the animals with lethal acute renal candidiasis had higher concentrations of C. albicans and were positive throughout the course of infection. Urinary concentrations of C. albicans were not predictive of the amount of Candida in the kidney (r < or = 0.49) and did not correlate with survival (r = 0.0232). However, the renal concentration of C. albicans (in CFU/gram) inversely correlated with the duration of survival (in days) of rabbits with renal candidiasis (r = 0.76; P < 0.001). These findings indicate that a negative urine culture in rabbits does not preclude the presence of renal candidiasis. The interpretation of a urine culture positive at any concentration, on the other hand, must involve an analysis of the risk factors for renal candidiasis, for any urinary concentration of C. albicans may reflect kidney infection.
PMCID: PMC230165  PMID: 9399537
6.  Symptomatic and asymptomatic candidiasis in a pediatric intensive care unit 
This study aimed to examine the incidence, epidemiology, and clinical characteristics of symptomatic and asymptomatic candidiasis in a pediatric intensive care unit (PICU), and to determine the risk factors associated with symptomatic candidiasis.
This retrospective study included 67 patients from a 7-bed PICU in a tertiary care hospital that had Candida-positive cultures between April 2007 and July 2009. Demographic and clinical characteristics of the patients, Candida isolates, antimicrobial and antifungal treatments, and previously identified risk factors for symptomatic candidiasis were recorded, and symptomatic and asymptomatic patients were compared.
In all, 36 (53.7%) of the patients with Candida-positive cultures had asymptomatic candidiasis and 31 (46.3%) had symptomatic candidiasis. Candida albicans was the most common Candida sp. in the asymptomatic patients (n = 20, 55.6%), versus Candida parapsilosis in the symptomatic patients (n = 15, 48.4%). The incidence of central venous catheter indwelling, blood transfusion, parenteral nutrition, and surgery was higher in the symptomatic patient group than in the asymptomatic patient group (P < 0.5). Surgery was the only independent predictor of symptomatic candidiasis according to forward stepwise multivariate logistic regression analysis (OR: 6.1; 95% CI: 1.798-20.692).
Surgery was the only risk factor significantly associated with symptomatic candidiasis and non-albicans Candida species were more common among the patients with symptomatic candidiasis. While treating symptomatic candidiasis in any PICU an increase in the incidence of non-albicans candidiasis should be considered.
PMCID: PMC3227576  PMID: 22104492
Candida; candidiasis; pediatric intensive care unit
7.  Diagnosis of invasive candidiasis in the ICU 
Invasive candidiasis ranges from 5 to 10 cases per 1,000 ICU admissions and represents 5% to 10% of all ICU-acquired infections, with an overall mortality comparable to that of severe sepsis/septic shock. A large majority of them are due to Candida albicans, but the proportion of strains with decreased sensitivity or resistance to fluconazole is increasingly reported. A high proportion of ICU patients become colonized, but only 5% to 30% of them develop an invasive infection. Progressive colonization and major abdominal surgery are common risk factors, but invasive candidiasis is difficult to predict and early diagnosis remains a major challenge. Indeed, blood cultures are positive in a minority of cases and often late in the course of infection. New nonculture-based laboratory techniques may contribute to early diagnosis and management of invasive candidiasis. Both serologic (mannan, antimannan, and betaglucan) and molecular (Candida-specific PCR in blood and serum) have been applied as serial screening procedures in high-risk patients. However, although reasonably sensitive and specific, these techniques are largely investigational and their clinical usefulness remains to be established. Identification of patients susceptible to benefit from empirical antifungal treatment remains challenging, but it is mandatory to avoid antifungal overuse in critically ill patients. Growing evidence suggests that monitoring the dynamic of Candida colonization in surgical patients and prediction rules based on combined risk factors may be used to identify ICU patients at high risk of invasive candidiasis susceptible to benefit from prophylaxis or preemptive antifungal treatment.
PMCID: PMC3224461  PMID: 21906271
8.  Candidiasis (oropharyngeal) 
Clinical Evidence  2009;2009:1304.
Candida is a fungus present in the mouths of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad-spectrum antibiotics, and corticosteroid use. In most people, untreated candidiasis persists for months or years unless associated risk factors are treated or eliminated. In neonates, spontaneous cure of oropharyngeal candidiasis usually occurs after 3 to 8 weeks.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent and treat oropharyngeal candidiasis in: adults having treatment causing immunosuppression; infants and children; people with diabetes; people with dentures; and people with HIV infection? Which treatments reduce the risk of acquiring resistance to antifungal drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 46 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antifungals (absorbed or partially absorbed, and topical absorbed/partially absorbed/non-absorbed: e.g., amphotericin B, fluconazole, itraconazole, miconazole, and nystatin) used for intermittent or continuous prophylaxis or therapy, and denture hygiene.
Key Points
Opportunistic infection with the fungus Candida albicans causes painful red or white lesions of the oropharynx, which can affect taste, speech, and eating. Candida is present in the mouth of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad-spectrum antibiotics, corticosteroid use, haematinic deficiencies, and denture wear.
In people with immunosuppression following cancer treatment, absorbed (ketoconazole, itraconazole, or fluconazole) or partially absorbed antifungal drugs (miconazole, clotrimazole) prevent ) oropharyngeal candidiasis compared with placebo or non-absorbed antifungal drugs. We don't know whether antifungal treatment is effective in this group. Non-absorbed antifungal drugs (nystatin or amphotericin B) may be no more effective than placebo at preventing candidiasis.We don't know whether antifungal prophylaxis is effective in adults having tissue transplants, as few studies have been found.We don't know whether antifungals are effective in preventing or treating oropharyngeal candidiasis in people with diabetes mellitus.
Prophylaxis with fluconazole is more effective than oral nystatin or amphotericin B at preventing candidiasis in immunocompromised infants and children, while treatment with fluconazole and miconazole increases cure rates compared with nystatin in both immunocompromised and immunocompetent infants and children.
Antifungal drugs may increase clinical improvement or cure in people with oropharyngeal candidiasis caused by wearing dentures. We don't know whether denture hygiene or removing dentures at night reduces the risk of developing oropharyngeal candidiasis.
Daily or weekly prophylaxis with fluconazole or itraconazole reduces the incidence of candidiasis in people with HIV infection. Prophylaxis with nystatin may not be effective. Treatment with topical suspensions of itraconazole used in a swish-and-swallow mode, clotrimazole lozenges, and miconazole buccal slow-release tablets may be as effective as oral tablets at reducing symptoms of candidiasis in people with HIV infection.
Continuous prophylaxis with antifungal agents does not increase the risk of developing antifungal resistance compared with intermittent prophylaxis, and is more likely to reduce the number of attacks in people with HIV infection.
PMCID: PMC2907793  PMID: 19445752
Journal of clinical pathology  2009;63(4):337-340.
The significance of finding Candida species in heart blood cultures obtained at postmortem examination has never been studied. Therefore, we describe the findings of autopsy patients with postmortem candidemia and compare them to autopsy patients with antemortem candidemia.
Twenty-three patients with Candida species isolated from heart blood at autopsy were identified over a ten-year period. These patients were compared to 10 autopsy patients found during the same time period with antemortem blood cultures isolating Candida species, but not positive postmortem heart blood cultures. Ante- and postmortem records were reviewed.
All 23 patients with Candida species isolated from postmortem blood culture had one or more antemortem risk factors for disseminated candidiasis such as positive antemortem blood cultures, isolation of Candida from sterile internal sites, neutropenia, recent abdominal surgery, broadspectrum antibiotic administration or the use of central venous catheters or other invasive devices. Eight patients had histologic proof of invasive candidiasis in addition to the positive heart blood cultures. This group did not differ with respect to risk factors from 10 autopsy patients with disseminated candidiasis and antemortem blood cultures with Candida species. However, all the patients with antemortem candidemia had histologic evidence of disseminated candidiasis at autopsy.
Candidemia, when documented by heart blood culture performed at autopsy or by antemortem blood culture, is an insensitive, but highly specific indicator of disseminated candidiasis.
PMCID: PMC3086197  PMID: 19939858
Candida; disseminated candidiasis; candidemia; postmortem; autopsy
10.  Polymerase chain reaction-and RNA hybridization-based method for the investigation of deep-seated candidiasis 
To determine the usefulness of a polymerase chain reaction (PCR) and RNA hybridization method for the diagnosis of invasive candidiasis and to compare its sensitivity with blood cultures.
Blood cultures and a blood sample for PCR were taken from patients with suspected invasive candidiasis. A 105 base pair conserved segment within the rDNA of Candida species was amplified. The amplicon was detected by hybridization and gel electrophoresis.
Intensive care units of two tertiary care hospitals.
One hundred and eighteen patients 16 years of age or older with four more risk factors for invasive candidiasis were enrolled. Present or recent past treatment with broad spectrum antibiotics, cancer chemotherapy, immunosuppressive drugs, granulocytopenia or granulocytosis, intravascular catheterization, tracheal intubation, recent abdominal surgery and parenteral nutrition were considered risk factors.
Forty-three patients had invasive candidiasis. PCR detected infections in 28 and 26 patients (sensitivity 65.1% and 60.4%) by hybridization and gel electrophoresis, respectively. The sensitivity of blood cultures was 58.1%. Of 25 patients with positive blood cultures, 17 were positive by PCR with the hybridization method. Eleven patients with invasive candidiasis had negative blood cultures but were positive by PCR.
PCR, especially with a hybridization detection method, is more sensitive than blood culture for invasive candidiasis and may facilitate the diagnosis of nonfungemic disease.
PMCID: PMC3250902  PMID: 22346529
Candidiasis; DNA amplification; Polymerase chain reaction
11.  Detection of antibodies to Candida albicans germ tubes for diagnosis and therapeutic monitoring of invasive candidiasis in patients with hematologic malignancies. 
Journal of Clinical Microbiology  1997;35(12):3284-3287.
We prospectively investigated the ability of detection of antibodies to Candida albicans germ tubes (CAGT) to diagnose invasive candidiasis in 95 consecutive admissions of 73 patients with hematologic disorders undergoing intensive chemotherapy. The episodes were divided into three groups according to clinical and microbiological diagnosis. Group 1 comprised eight admissions of eight patients with invasive candidiasis. Group 2 comprised 42 admissions of 34 patients without evidence of invasive candidiasis. Group 3 comprised the remaining 45 admissions of 37 patients with febrile episodes which were not diagnosed by microbiological culture. Antibodies to CAGT were detected in 87.5% of group 1 patients. Detection of antibodies to CAGT in patients with Candida fungemia was delayed somewhat relative to the time the blood culture was positive, but antibodies to CAGT were detected earlier than a diagnosis was made in patients with deep-tissue candidiasis. Sera from 2 admissions in group 2 and 12 admissions in group 3 revealed antibodies to CAGT. At a titer of > or = 1:20, detection of antibodies to CAGT had a sensitivity of 87.5%, specificity of 95.2%, positive predictive value of 77.8%, and negative predictive value of 97.6%. Antibodies to CAGT were usually detected before beginning of empiric antifungal therapy. Titers of antibodies to CAGT were maintained in most patients who died but declined and eventually disappeared in the patients who survived. Since antibodies to CAGT were detected in all patients with tissue-proven invasive candidiasis but negative by blood culture, detection of antibodies to CAGT complemented blood cultures for diagnosis and therapeutic monitoring of patients with hematologic malignancies and invasive candidiasis.
PMCID: PMC230163  PMID: 9399535
12.  Validation and comparison of clinical prediction rules for invasive candidiasis in intensive care unit patients: a matched case-control study 
Critical Care  2011;15(4):R198.
Due to the increasing prevalence and severity of invasive candidiasis, investigators have developed clinical prediction rules to identify patients who may benefit from antifungal prophylaxis or early empiric therapy. The aims of this study were to validate and compare the Paphitou and Ostrosky-Zeichner clinical prediction rules in ICU patients in a 689-bed academic medical center.
We conducted a retrospective matched case-control study from May 2003 to June 2008 to evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each rule. Cases included adults with ICU stays of at least four days and invasive candidiasis matched to three controls by age, gender and ICU admission date. The clinical prediction rules were applied to cases and controls via retrospective chart review to evaluate the success of the rules in predicting invasive candidiasis. Paphitou's rule included diabetes, total parenteral nutrition (TPN) and dialysis with or without antibiotics. Ostrosky-Zeichner's rule included antibiotics or central venous catheter plus at least two of the following: surgery, immunosuppression, TPN, dialysis, corticosteroids and pancreatitis. Conditional logistic regression was performed to evaluate the rules. Discriminative power was evaluated by area under the receiver operating characteristic curve (AUC ROC).
A total of 352 patients were included (88 cases and 264 controls). The incidence of invasive candidiasis among adults with an ICU stay of at least four days was 2.3%. The prediction rules performed similarly, exhibiting low PPVs (0.041 to 0.054), high NPVs (0.983 to 0.990) and AUC ROCs (0.649 to 0.705). A new prediction rule (Nebraska Medical Center rule) was developed with PPVs, NPVs and AUC ROCs of 0.047, 0.994 and 0.770, respectively.
Based on low PPVs and high NPVs, the rules are most useful for identifying patients who are not likely to develop invasive candidiasis, potentially preventing unnecessary antifungal use, optimizing patient ICU care and facilitating the design of forthcoming antifungal clinical trials.
PMCID: PMC3387640  PMID: 21846332
candidiasis; clinical prediction rules; prophylaxis
13.  Nonvalue of antigen detection immunoassays for diagnosis of candidemia. 
Journal of Clinical Microbiology  1990;28(10):2320-2326.
We evaluated the Cand-Tec (Ramco Laboratories Inc., Houston, Tex.) and LA-Candida antigen detection system (Immuno-Mycologics Inc., Norman, Okla.) tests as possible rapid alternatives to blood cultures for the identification of patients with candidemia. Tests were performed on sera from (i) 33 patients with candidemia, (ii) 82 patients with fever and risk factors for invasive candidiasis, and (iii) 13 healthy controls. A total of 21 patients had no evidence of invasive candidiasis, as determined by clinical course, blood culture, and/or autopsy; results for 61 patients were indeterminate regarding the presence of invasive candidiasis, or else the patients had invasive candidiasis with organ involvement. By using a threshold positive Cand-Tec titer of greater than or equal to 1:4, the sensitivity in candidemic patients was 49%; the specificity was 43% (patients with true-negative results had neither candidemia nor other evidence of invasive candidiasis). Coexistent disseminated candidiasis in some candidemic patients may have accounted for some positive Cand-Tec tests and possible overestimation of the sensitivity of the test for candidemia. Cand-Tec test results were negative for healthy controls. All test results obtained by the LA-Candida antigen detection system assay were negative. Our findings indicate that neither of these assays reliably identifies patients with candidemia.
PMCID: PMC268169  PMID: 2229358
14.  Clinical factors associated with a Candida albicans Germ Tube Antibody positive test in Intensive Care Unit patients 
Poor outcomes of invasive candidiasis (IC) are associated with the difficulty in establishing the microbiological diagnosis at an early stage. New scores and laboratory tests have been developed in order to make an early therapeutic intervention in an attempt to reduce the high mortality associated with invasive fungal infections. Candida albicans IFA IgG has been recently commercialized for germ tube antibody detection (CAGTA). This test provides a rapid and simple diagnosis of IC (84.4% sensitivity and 94.7% specificity). The aim of this study is to identify the patients who could be benefited by the use of CAGTA test in critical care setting.
A prospective, cohort, observational multicentre study was carried out in six medical/surgical Intensive care units (ICU) of tertiary-care Spanish hospitals. Candida albicans Germ Tube Antibody test was performed twice a week if predetermined risk factors were present, and serologically demonstrated candidiasis was considered if the testing serum dilution was ≥ 1:160 in at least one sample and no other microbiological evidence of invasive candidiasis was found.
Fifty-three critically ill non-neutropenic patients (37.7% post surgery) were included. Twenty-two patients (41.5%) had CAGTA-positive results, none of them with positive blood culture for Candida. Neither corrected colonization index nor antifungal treatment had influence on CAGTA results. This finding could corroborate that the CAGTA may be an important biomarker to distinguish between colonization and infection in these patients. The presence of acute renal failure at the beginning of the study was more frequent in CAGTA-negative patients. Previous surgery was statistically more frequent in CAGTA-positive patients.
This study identified previous surgery as the principal clinical factor associated with CAGTA-positive results and emphasises the utility of this promising technique, which was not influenced by high Candida colonization or antifungal treatment. Our results suggest that detection of CAGTA may be important for the diagnosis of invasive candidiasis in surgical patients admitted in ICU.
PMCID: PMC3061907  PMID: 21388550
15.  Prospective observational multicenter study to define a diagnostic algorithm for biliary candidiasis 
World Journal of Gastroenterology : WJG  2014;20(34):12260-12268.
AIM: To develop an algorithm to improve the diagnosis and treatment of patients with biliary candidiasis.
METHODS: We performed a prospective study of 127 patients who underwent endoscopic retrograde cholangiopancreatography, for various biliary disorders, at 3 tertiary referral centers in Germany from July 2011 through July 2012 ( NCT01109550). Bile, buccal, and stool samples were collected. When indicated, endoscopic transpapillary bile duct biopsies were performed to clarify the etiology of bile duct strictures and to prove invasive fungal infections.
RESULTS: Candida species were detected in 38 of the 127 bile samples (29.9%). By multivariate analysis patients’ age and previous endoscopic sphincterotomy were independent risk factors for biliary candidiasis (P < 0.05). Patients with immunosuppression (P = 0.058) and recent long-term antibiotic therapy (> 7 d) (P = 0.089) tend to be at risk for biliary candidiasis. One patient was negative in mycological culture of bile fluid but invasive biliary candidiasis was diagnosed histologically. Of Candida subspecies detected, 36.7% were azole-resistant, such as C glabrata. Eight patients received anti-mycotic therapy, based on our algorithm. Of these, 3 had cancer with biliary tract involvement, 2 had secondary sclerosing cholangitis, 1 had retroperitoneal fibrosis, and 5 had septicemia. In all patients contamination was ruled out by smears of the endoscope channel.
CONCLUSION: Gastroenterologists should be aware of frequent candida colonization in patients with cholangitis and biliary disorders. Our suggested algorithm facilitates the further clinical management.
PMCID: PMC4161811  PMID: 25232260
Cholangitis; Biliary candidiasis; Invasive fungal infection; Biliary obstruction
16.  Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants 
Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist.
Our population PK model derived from 357 fluconazole plasma concentrations from 55 infants (23–40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient population’s pharmacokinetic response to fluconazole to predict fluconazole exposure (median, 10th and 90th percentile population variability range) after 3, 6 and 12 mg/kg dosing.
For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/day in the 1st 90 days after birth is needed to achieve an AUC of >400 mg*h/L and an AUC/MIC>50 for Candida species with MIC<8 µg/ml in ≥ 90% of <30 week gestation infants and 80% of 30–40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early prevention of candidiasis in 23–29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations ≥ 2 or 4 µg/ml, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with serum creatinine ≥ 1.3 mg/dl have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours.
A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis, twice weekly prophylaxis regimens can provide adequate exposure when unit specific MICs are taken into account.
PMCID: PMC2771384  PMID: 19593252
neonate; pharmacology; antifungal treatment
17.  Outcomes of Neonatal Candidiasis: The Impact of Delayed Initiation of Antifungal Therapy 
Objective/Methods. To determine the outcomes of invasive neonatal candidiasis before institution of routine antifungal prophylaxis, we conducted a retrospective review of cases of invasive candidiasis in newborns in a referral-based neonatal intensive care unit located in a single tertiary academic center between January 1998 and December 2002. Results. Sixty-three newborns with invasive neonatal candidiasis were identified. Overall mortality rate was 35%. Virtually every infant had a central venous catheter (CVC), required mechanical ventilation and previous administration of antibacterial agents. Delayed institution of antifungal therapy was associated with increased mortality. In addition, length of hospitalization, duration of prior antibacterial therapy, mechanical ventilation, and CVC use, as well as evidence of end-organ disease, were associated with an adverse outcome. Conclusions. Reliance on available laboratory tools in cases of invasive neonatal candidiasis can result in delayed diagnosis and increased mortality. A risk-factor-based approach to empirical treatment could be justified in this setting.
PMCID: PMC3216279  PMID: 22121380
18.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
Study design
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
19.  Incidence and Predictors of Invasive Candidiasis Associated with Candidemia in Children 
Mycoses  2011;54(2):146-153.
Risk factors for invasive candidiasis in children with candidemia are poorly defined.
We performed a retrospective cohort study of all children with candidemia at our tertiary children’s hospital from 2000 to 2006. Invasive candidiasis was diagnosed by review of the medical record and standardized EORTC/MSG criteria. A variety of risk factors for invasive candidiasis were explored.
Of 194 episodes of candidemia in the microbiology laboratory database, 180 clinical records were available. Evaluation for invasive candidiasis consisted of 174 (97%) echocardiograms; 167 (93%) dilated ophthalmologic examinations, 136 (76%) chest CT scans, and 108 (60%) abdominal ultrasounds (complete, hepatosplenic or renal). Of the 180, 15 (8%) patients were identified with invasive candidiasis (4 proven, 1 probable, 10 possible). Prematurity <32 weeks (P<0.01), an underlying immunocompromising disorder (P<0.01), and ≥2 days of candidemia (P=0.05) were significantly associated with invasive candidiasis.
Invasive candidiasis, especially proven or probable, in the setting of candidemia was not common in our hospital, but premature infants and immunocompromised children were at significantly higher risk. Based on our findings, extensive imaging and examination by an ophthalmologist was particularly low-yield for invasive candidiasis in immunocompetent children beyond infancy.
PMCID: PMC2888996  PMID: 19821906
Pediatric; Candidemia; Invasive; Risk Factors
20.  Chemokine Receptor Ccr1 Drives Neutrophil-Mediated Kidney Immunopathology and Mortality in Invasive Candidiasis 
PLoS Pathogens  2012;8(8):e1002865.
Invasive candidiasis is the 4th leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1lo to Ccr1high at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1+/+ and Ccr1−/− donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1+/+ recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1+/+ cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.
Author Summary
Invasive infection by the yeast Candida represents a significant cause of morbidity and mortality in patients in the intensive care unit. Neutrophils, which are recruited to sites of Candida infection by chemokines and their receptors, are important immune cells in host defense against invasive candidiasis. Consistent with that, lack of neutrophils is a well-established risk factor for adverse outcome after infection. In this study, we performed a broad survey of the chemokine system in a mouse model of invasive candidiasis with an aim to determine factors that regulate neutrophil trafficking to sites of infection. We used that survey to identify Ccr1 as a mediator of mortality in the model via excessive recruitment of neutrophils from the blood to the kidney that results in kidney tissue injury. Strikingly, the effect of Ccr1 on neutrophil accumulation in the kidney was not seen until the late phase of the infection, when the receptor was up-regulated on the neutrophil surface. Together these data demonstrate that neutrophils, besides their recognized protective roles in antifungal host defense, may also exert detrimental effects by causing uncontrolled tissue damage, and identify Ccr1 as a mediator of neutrophil tissue injury in a mouse model of invasive candidiasis.
PMCID: PMC3420964  PMID: 22916017
21.  Diagnosis of invasive candidiasis by enzyme-linked immunosorbent assay using the N-terminal fragment of Candida albicans hyphal wall protein 1 
BMC Microbiology  2007;7:35.
The diagnosis of invasive candidiasis is difficult because there are no specific clinical manifestations of the disease and colonization and infection are difficult to distinguish. In the last decade, much effort has been made to develop reliable tests for rapid diagnosis of invasive candidiasis, but none of them have found widespread clinical use.
Antibodies against a recombinant N-terminal fragment of the Candida albicans germ tube-specific antigen hyphal wall protein 1 (Hwp1) generated in Escherichia coli were detected by both immunoblotting and ELISA tests in a group of 36 hematological or Intensive Care Unit patients with invasive candidiasis and in a group of 45 control patients at high risk for the mycosis who did not have clinical or microbiological data to document invasive candidiasis. Results were compared with an immunofluorescence test to detect antibodies to C. albicans germ tubes (CAGT). The sensitivity, specificity, positive and negative predictive values of a diagnostic test based on the detection of antibodies against the N-terminal fragment of Hwp1 by immunoblotting were 27.8 %, 95.6 %, 83.3 % and 62.3 %, respectively. Detection of antibodies to the N-terminal fragment of Hwp1 by ELISA increased the sensitivity (88.9 %) and the negative predictive value (90.2 %) but slightly decreased the specificity (82.6 %) and positive predictive values (80 %). The kinetics of antibody response to the N-terminal fragment of Hwp1 by ELISA was very similar to that observed by detecting antibodies to CAGT.
An ELISA test to detect antibodies against a recombinant N-terminal fragment of the C. albicans germ tube cell wall antigen Hwp1 allows the diagnosis of invasive candidiasis with similar results to those obtained by detecting antibodies to CAGT but without the need of treating the sera to adsorb the antibodies against the cell wall surface of the blastospore.
PMCID: PMC1868733  PMID: 17448251
22.  Candidiasis (vulvovaginal) 
Clinical Evidence  2010;2010:0815.
Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of alternative or complementary treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of treating a male sexual partner to resolve symptoms and prevent recurrence in non-pregnant women with symptomatic acute vulvovaginal candidiasis? What are the effects of alternative or complementary treatments for symptomatic recurrent vulvovaginal candidiasis in non-pregnant women? What are the effects of treating a male sexual partner in non-pregnant women with symptomatic recurrent vulvovaginal candidiasis? What are the effects of treating asymptomatic non-pregnant women with a positive swab for candidiasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 61 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alternative or complementary treatments; douching; drug treatments; garlic; intravaginal preparations (boric acid, nystatin, imidazoles, tea tree oil); oral fluconazole; oral itraconazole; treating a male sexual partner; and yoghurt containing Lactobacillus acidophilus (oral or vaginal).
Key Points
Vulvovaginal candidiasis is characterised by vulval itching and abnormal "cheese-like" or watery vaginal discharge. Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics. Incidence increases with the onset of sexual activity, but associations with different types of contraceptives are unclear.Recurrent symptoms are common, but are caused by candidiasis in only one third of cases.
Intravaginal imidazoles reduce symptoms of acute vulvovaginal candidiasis in non-pregnant women. Intravaginal imidazoles (butoconazole, clotrimazole, miconazole) reduce symptoms compared with placebo and all seem to have similar efficacy compared with each other. RCTs suggest that single-dose regimens may be as effective as multiple-dose regimens.Intravaginal imidazoles and oral fluconazole or itraconazole seem equally effective in treating acute attacks.
Intravaginal nystatin reduces symptoms compared with placebo, but we don't know how it compares with intravaginal imidazoles or oral fluconazole or itraconazole.
The benefits of other intravaginal treatments, to treat acute attacks or prevent recurrence, remain unclear, and some may be associated with serious adverse effects. We found no RCT evidence assessing intravaginal boric acid or tea tree oil.We found no RCT evidence assessing garlic or yoghurt, used intravaginally or orally.We found no RCT evidence on efficacy of douching, but it is associated with serious adverse effects such as PID and infections, endometritis, and ectopic pregnancy. Oral fluconazole and itraconazole are likely to be beneficial in preventing recurrence of infection. Treating the woman's male sexual partner does not reduce symptoms or prevent recurrence in the woman.
PMCID: PMC2907618  PMID: 21718579
23.  Time to Initiation of Antifungal Therapy for Neonatal Candidiasis 
The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.
PMCID: PMC3716169  PMID: 23507285
24.  Antibiotic Use and Misuse in the Neonatal Intensive Care Unit 
Clinics in Perinatology  2011;39(1):61-68.
Neonatal sepsis causes significant morbidity and mortality, especially in preterm infants. Consequently, clinicians are compelled to treat with empirical antibiotics at the first signs of suspected sepsis. Unfortunately, both broad-spectrum antibiotics and prolonged treatment with empirical antibiotics are associated with adverse outcomes including invasive candidiasis, increased antimicrobial resistance, necrotizing enterocolitis, late-onset sepsis, and death. Most common neonatal pathogens are susceptible to narrow-spectrum antibiotics. The choice of antibiotic and duration of empirical treatment are strongly associated with center-based rather than with individual patient risk factors, implying that these choices are modifiable across centers. Thus, clinicians should aim to treat with short courses of narrow-spectrum antibiotics whenever possible, choosing the appropriate antibiotics and treatment duration to balance the risks of potentially untreated sepsis against the adverse effects of treatment in infants with sterile cultures.
PMCID: PMC3285418  PMID: 22341537
neonatal intensive care unit; empirical; antibiotic; sepsis; infection
25.  Comparison of enzyme immunoassay and gas-liquid chromatography for the rapid diagnosis of invasive candidiasis in cancer patients. 
Journal of Clinical Microbiology  1985;21(6):972-979.
Three proposed quantitative markers for candidiasis, arabinitol, mannose, and mannan in serum, are compared in 50 normal blood donors and 38 high-risk patients, 23 with and 15 without invasive candidiasis. Arabinitol concentrations in serum, the arabinitol/creatinine ratio, and mannose concentrations in serum were significantly greater in the 15 patients without candidiasis than in the normal blood donors (P less than 0.05). The sensitivities and specificities were 26 and 87% for arabinitol, 13 and 93% for the arabinitol/creatinine ratio, and 39 and 87% for mannose. On the other hand, mannan concentrations in serum were less than 1 ng/ml in normal blood donors and patients without candidiasis (P = 0.344), and the sensitivity and specificity were 65 and 100%, respectively. Of 23 patients with proven or probable candidiasis, 16 had mannan levels in serum greater than the mean + 2 standard deviations (0.46 ng/ml) for the 15 controls. In 16 patients with invasive candidiasis and positive blood cultures for the Candida spp., only 13 had elevated levels of at least one of the three markers. The arabinitol/creatinine ratio, the mannose level, and the mannan level became elevated an average of 4 days before, 1 day before, and on the same day that the blood cultures were drawn, respectively. Conversely, mannan was detected in the sera of six of seven patients with invasive candidiasis and negative blood cultures. We conclude that the best approach to diagnosing invasive candidiasis involves obtaining blood cultures and carrying out serial assays for mannan in serum.
PMCID: PMC271829  PMID: 3891776

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