Prolonged vs short-term infusion of ß-lactam antibiotics for the treatment of febrile neutropenia: A systematic review and meta-analysis.

BACKGROUND: The optimisation of the use of ß-lactam antibiotics (BLA) via prolonged infusions in life-threatening complications such as febrile neutropenia (FN) is still controversial. This systematic review and meta-analysis aim to evaluate the efficacy of this strategy in onco-haematological patients with FN. METHODS: A systematic search was performed of PubMed, Web of Science, Cochrane, EMBASE, World Health Organization, and ClinicalTrials.gov, from database inception until December 2022. The search included randomised controlled trials (RCTs) and observational studies that compared prolonged vs short-term infusions of the same BLA. The primary outcome was all-cause mortality. Secondary outcomes were defervescence, requirement of vasoactive drugs, length of hospital stay and adverse events. Pooled risk ratios were calculated using random effects models. RESULTS: Five studies were included, comprising 691 episodes of FN, mainly in haematological patients. Prolonged infusion was not associated with a reduction in all-cause mortality (pRR 0.83; 95% confidence interval 0.47-1.48). Nor differences were found in secondary outcomes. CONCLUSIONS: The limited data available did not show significant differences in terms of all-cause mortality or significant secondary outcomes in patients with FN receiving BLA in prolonged vs. short-term infusion. High-quality RCTs are needed to determine whether there are subgroups of FN patients who would benefit from prolonged BLA infusion.

Contamination of health-care workers' hands with Escherichia coli and Klebsiella species after routine patient care: a prospective observational study.

OBJECTIVE: To compare the frequency of health-care worker (HCW) hand contamination by Escherichia coli versus Klebsiella species after patient care and to determine activities associated with contamination. METHODS: We conducted a prospective observational study at two tertiary-care centres. We observed HCWs caring for patients colonized/infected with E. coli or Klebsiella. HCW hands were cultured before room entry and after patient care. Contamination was defined as detecting E. coli or Klebsiella on HCW hands. Risk factors for contamination were analysed using logistic regression. Patient-to-HCW transmission was confirmed by pulsed-field gel electrophoresis (PFGE). RESULTS: We performed 466 HCW observations: 290 from patients with E. coli, 149 with Klebsiella, and 27 with both species. Eighty-seven per cent of observations (404/464) occurred in patients who had received chlorhexidine bathing within 2 days. HCW hand contamination rates were similar between E. coli (6.2%; 18/290) and Klebsiella (7.4%; 11/149) (p 0.6). High-risk activities independently associated with contamination were toilet assistance (OR 9.34; 95% CI 3.10-28.16), contact with moist secretions (OR 6.93; 95% CI 2.82-17.00), and hygiene/bed-bathing (OR 3.80; 95% CI 1.48-9.80). PFGE identified identical/closely related isolates in the patient and HCW hands in 100% (18/18) of E. coli and 54.5% (6/11) of Klebsiella observations. CONCLUSIONS: We did not find a difference in HCW hand contamination rates between E. coli and Klebsiella after patient care. Hand hygiene should be reinforced after high-risk activities. Discrepancies in matching patient and HCW hand isolates occurred more frequently for Klebsiella than for E. coli; differences in species-level transmission dynamics might exist.

No evidence of increased ocular involvement in candidemic patients initially treated with echinocandins.

Candins are commonly used as initial therapy in patients with candidemia and are known to diffuse poorly into ocular tissue. The aim of our multicenter study was to assess whether eye involvement was more common in patients initially treated with echinocandins. We performed a post hoc analysis of a prospective, multicenter, population-based candidemic surveillance program implemented in Spain during 2010-2011 (CANDIPOP project). Eye involvement was detected in 13 of 168 patients with candidemia (7.7%) who underwent ophthalmoscopy. Two patients had endophthalmitis, while the remaining patients had chorioretinitis. The frequency of ocular candidiasis was similar in patients receiving initial therapy with candins (3/56; 5.4%) or with other regimens (10/112; 8.9%). At multivariate analysis, risk conditions for eye involvement were dialysis after candidemia (OR, 19.4; 95% CI, 1.7-218.4) and involvement of organs other than the eye (OR, 5.4; 95% CI, 1.1-25.7). In conclusion, eye involvement was not found to be more frequent in patients receiving initial therapy with echinocandins than in patients receiving other drugs.

Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance.

OBJECTIVES: The clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration-time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients. METHODS: We included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3-7 days) and late (3-30 days) mortality. RESULTS: Rates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48-5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04-0.98; p 0.026). CONCLUSIONS: High fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found.

Evaluation of the possible influence of trailing and paradoxical effects on the clinical outcome of patients with candidemia.

OBJECTIVE: Paradoxical growth (PG) and trailing effect (TE) are frequently observed during antifungal susceptibility testing (AFST). These two phenomena interfere with the determination of the minimal inhibitory concentration (MIC). The aim of this study was to assess the clinical impact of TE and PG. METHODS: We analysed the frequency of TE and PG of 690 Candida isolates collected from a population-based study performed in Spain (CANDIPOP) and correlated the results with clinical outcome of the patients. RESULTS: Around 70% (484/690) of the isolates exhibited TE to azoles. Candida tropicalis showed the highest presence of TE (39/53 isolates exhibited residual growth >25% of control). No TE was seen in most of the isolates from the psilosis complex. PG was mainly associated with echinocandins. In patients treated with fluconazole within the first 48 hours after blood sampling (n = 221), the presence of TE to azoles tended to be associated with lower 30-day mortality (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.25-1.00) but not with clinical failure (OR 0.85, 95% CI 0.45-1.54). In the subgroup of 117 patients treated with echinocandins, the presence of PG was not associated with patient's response to antifungal treatment (OR for 30-day mortality 1.63, 95% CI 0.76-4.03; OR for clinical failure 1.17, 95% CI 0.53-2.70). CONCLUSIONS: TE or PG are widely expressed among Candida spp., although they do not seem to influence clinical outcome.

Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort.

We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17-0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41-1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia.

Propensity Score Analysis of the Role of Initial Antifungal Therapy in the Outcome of Candida glabrata Bloodstream Infections.

Candida glabrata isolates have reduced in vitro susceptibility to azoles, which raises concerns about the clinical effectiveness of fluconazole for treating bloodstream infection (BSI) by this Candida species. We aimed to evaluate whether the choice of initial antifungal treatment (fluconazole versus echinocandins or liposomal amphotericin B [L-AmB]-based regimens) has an impact on the outcome of C. glabrata BSI. We analyzed data from a prospective, multicenter, population-based surveillance program on candidemia conducted in 5 metropolitan areas of Spain (May 2010 to April 2011). Adult patients with an episode of C. glabrata BSI were included. The main outcomes were 14-day mortality and treatment failure (14-day mortality and/or persistent C. glabrata BSI for ≥48 h despite antifungal initiation). The impact of using fluconazole as initial antifungal treatment on the patients' prognosis was assessed by logistic regression analysis with the addition of a propensity score approach. A total of 94 patients with C. glabrata BSI were identified. Of these, 34 had received fluconazole and 35 had received an echinocandin/L-AmB-based regimen. Patients in the echinocandin/L-AmB group had poorer baseline clinical status than did those in the fluconazole group. Patients in the fluconazole group were more frequently (55.9% versus 28.6%) and much earlier (median time, 3 versus 7 days) switched to another antifungal regimen. Overall, 14-day mortality was 13% (9/69) and treatment failure 34.8% (24/69), with no significant differences between the groups. On multivariate analysis, after adjusting for baseline characteristics by propensity score, fluconazole use was not associated with an unfavorable evolution (adjusted odds ratio [OR] for 14-day mortality, 1.16, with 95% confidence interval [CI] of 0.22 to 6.17; adjusted OR for treatment failure, 0.83, with 95% CI of 0.27 to 2.61). In conclusion, initial fluconazole treatment was not associated with a poorer outcome than that obtained with echinocandins/L-AmB regimens in patients with C. glabrata BSI. (This study has been registered at ClinicalTrials.gov under registration no. NCT01236261.).

First recurrence of Clostridium difficile infection: clinical relevance, risk factors, and prognosis.

Therapy for recurrent Clostridium difficile-associated diarrhea (CDAD) is challenging. We evaluated the frequency, associated risk factors, and prognosis of first CDAD recurrences. Prospective cohort study of all consecutive cases of primary CDAD diagnosed in a university hospital from January 2006 to June 2013. Recurrent infection was defined as reappearance of symptoms within 8 weeks of the primary diagnosis, provided that CDAD symptoms had previously resolved and a new toxin test was positive. Predictors of a first episode of recurrent CDAD were determined by logistic regression analysis. In total, 502 patients (51.6 % men) with a mean age of 62.3 years (SD 18.5) had CDAD; 379 (76 %) were cured, 61 (12 %) had a first recurrence, 52 (10 %) died within 30 days of the CDAD diagnosis, nine (2 %) required colectomy, and one was lost to follow-up. Among the 61 patients with a first recurrence, 36 (59.3 %) were cured, 15 (23.7 %) had a second recurrence, nine (15.3 %) died, and one (1.7 %) required colectomy. On multivariate analysis, age older than 65 years (OR 2.04; 95 % CI, 1.14-3.68; P < 0.02) and enteral nutrition (OR, 3.62; 95%CI, 1.66-7.87; P < 0.01) were predictors of a first recurrence. A risk score was developed for first CDAD recurrence using the predictive factors and selected biological variables. In our CDAD cohort, 12 % of patients had a first recurrence of this disease, in which the prognosis was less favorable than that of the primary episode, as it heralded a higher risk of additional recurrences. Patient age and enteral nutrition were predictors of a first recurrence.

A simple prediction score for estimating the risk of candidaemia caused by fluconazole non-susceptible strains.

We aimed to develop a simple prediction score to identify fluconazole non-susceptible (Flu-NS) candidaemia using simple clinical criteria. A derivation cohort was extracted from the CANDIPOP study, a prospective, multicentre, population-based surveillance programme on candidaemia conducted in 29 hospitals in Spain from April 2010 to May 2011. The score was validated with an external, multicentre cohort of adults with candidaemia in six tertiary hospitals in three countries. The prediction score was based on three variables selected by a logistic regression model together with the severity of disease. In total, 617 and 297 cases of candidaemia were included in the derivation and validation cohorts, respectively; of these, 134 (21.7%) and 57 (19.2%) were caused by Flu-NS strains. Factors independently associated with Flu-NS were transplant recipient status (adjusted odds ratio (AOR) 2.13; 95% CI 1.01-4.55; p 0.047), hospitalization in a unit with a high prevalence (≥ 15%) of Flu-NS strains (7.53; 4.68-12.10; p < 0.001), and previous azole therapy for at least 3 days (2.04; 1.16-3.62; p 0.014). The area under the receiver operating characteristics curve (AUC) was 0.76 (0.72-0.81), and using 2 points as the Flu-NS prediction score cut-off gave a sensitivity of 82.1%, a specificity of 65.6%, and a negative predictive value of 93%. The AUC in the validation cohort was 0.72 (95% CI 0.65-0.79). Hence, the Flu-NS prediction score helped to exclude Flu-NS Candida strains. This could improve the selection of empirical treatments for candidaemia in the future.

Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.

INTRODUCTION: Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. METHODS AND ANALYSIS: A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. ETHICS AND DISSEMINATION: The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study. TRIAL REGISTRATION NUMBER: NCT01898338.

Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain.

A prospective, population-based surveillance on candidaemia was implemented in five metropolitan areas of Spain from May 2010 to April 2011. We aimed to describe the distribution and susceptibility pattern of Candida species, and to evaluate risk factors for mortality in patients with oncological (solid tumours) and haematological malignancies. Adults (≥ 16 years) with cancer were included in the present report. Impact of therapeutic strategies on 7- and 30-day mortality were analysed by logistic regression, adjusting for propensity score by inverse weighting probability of receiving early antifungal treatment and catheter removal. We included 238 (32.6%) patients (195 oncological, 43 haematological). Compared with oncological patients, haematological patients were more likely to have received chemotherapy (53.5% versus 17.4%, p < 0.001) or corticosteroids (41.9% versus 21%, p < 0.001), and have neutropenia (44.2% versus 1.5%, p < 0.001). Overall, 14.8% of patients developed breakthrough candidaemia. Non-albicans Candida species (71.1% versus 55.6%, p 0.056) and Candida tropicalis (22.2% versus 7.6%, p 0.011) were more frequent in haematological patients. Based on EUCAST breakpoints, 27.6% of Candida isolates were non-susceptible to fluconazole. Resistance to echinocandins was negligible. Mortality at 7 and 30 days was 12.2% and 31.5%, respectively, and did not differ significantly between the patient groups. Prompt antifungal therapy together with catheter removal (≤ 48 hours) was associated with lower mortality at 7 days (adjusted OR 0.05; 95% CI 0.01-0.42) and 30 days (adjusted OR 0.27; 95% CI 0.16-0.46). In conclusion, non-albicans species are emerging as the predominant isolates, particularly in haematological patients. Prompt, adequate antifungal treatment plus catheter removal may lead to a reduction in mortality.

Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain.

A prospective, multicentre, population-based surveillance programme for Candida bloodstream infections was implemented in five metropolitan areas of Spain to determine its incidence and the prevalence of antifungal resistance, and to identify predictors of death. Between May 2010 and April 2011, Candida isolates were centralized to a reference laboratory for species identification by DNA sequencing and for susceptibility testing by EUCAST reference procedure. Prognostic factors associated with early (0-7 days) and late (8-30 days) death were analysed using logistic regression modelling. We detected 773 episodes: annual incidence of 8.1 cases/100 000 inhabitants, 0.89/1000 admissions and 1.36/10 000 patient-days. Highest incidence was found in infants younger than 1 year (96.4/100 000 inhabitants). Candida albicans was the predominant species (45.4%), followed by Candida parapsilosis (24.9%), Candida glabrata (13.4%) and Candida tropicalis (7.7%). Overall, 79% of Candida isolates were susceptible to fluconazole. Cumulative mortality at 7 and 30 days after the first episode of candidaemia was 12.8% and 30.6%, respectively. Multivariate analysis showed that therapeutic measures within the first 48 h may improve early mortality: antifungal treatment (OR 0.51, 95% CI 0.27-0.95) and central venous catheter removal (OR 0.43, 95% CI 0.21-0.87). Predictors of late death included host factors (e.g. patients' comorbid status and signs of organ dysfunction), primary source (OR 1.63, 95% CI 1.03-2.61), and severe sepsis or septic shock (OR 1.77, 95% CI 1.05-3.00). In Spain, the proportion of Candida isolates non-susceptible to fluconazole is higher than in previous reports. Early mortality may be improved with strict adherence to guidelines.