Predictive value of fecal calprotectin and lactoferrin levels for negative outcomes in Clostridioides difficile infection.

PURPOSE: We investigated the role of fecal calprotectin (FC) and lactoferrin (FL) as predictive biomarkers in Clostridioides difficile infection (CDI). METHODS: We assembled a prospective cohort including all patients with a laboratory-confirmed CDI diagnosis between January and December 2017. FL and FC levels were measured at diagnosis by commercial ELISA and EIA kits. We investigated the diagnostic accuracy of FC and FL to predict CDI recurrence and severity (study outcomes) and explored optimal cut-off values in addition to those proposed by the manufacturers (200 µg/g and 7.2 µg/mL, respectively). RESULTS: We included 170 CDI cases (152 first episodes and 18 recurrences). The rates of recurrence (first episodes only) and severity (entire cohort) were 9.2% (14/152) and 46.5% (79/170). Both FL and FC levels were significantly higher in patients who developed study outcomes. Optimal cut-off values for FC and FL to predict CDI recurrence were 1052 µg/g and 6.0 µg/mL. The optimal cut-off value for FC yielded higher specificity (60.9%) and positive predictive value (PPV) (16.9%) than that proposed by the manufacturer. Regarding CDI severity, the optimal cut-off value for FC (439 µg/g) also provided higher specificity (43.9%) and PPV (54.1%) than that of the manufacturer, whereas the optimal cut-off value for FL (4.6 µg/mL) resulted in an improvement of PPV (57.5%). CONCLUSION: By modifying the thresholds for assay positivity, the measurement of FC and FL at diagnosis is useful to predict recurrence and severity in CDI. Adding these biomarkers to current clinical scores may help to individualize CDI management.

Evaluation of the effectiveness and safety of oral vancomycin versus placebo in the prevention of recurrence of Clostridioides difficile infection in patients under systemic antibiotic therapy: a phase III, randomised, double-blind clinical trial.

INTRODUCTION: Clostridioides difficile infection (CDI) is the most prevalent cause of nosocomial bacterial diarrhoea and it is strongly associated with antibiotic use. The recurrence of CDI is a growing medical problem. Data from real-life studies and one open label randomised clinical trial (RCT) suggest that secondary prophylaxis with oral vancomycin (SPV) during subsequent courses of systemic antibiotics is a promising approach for reducing the risk of CDI recurrence. Our aim is to confirm the role of SPV through a double-blind RCT. METHODS AND ANALYSIS: We will perform a phase III, multicentre, placebo-controlled RCT (PREVAN trial) in a 2:1 ratio in favour of SPV (experimental treatment), in four tertiary care hospitals in Spain. Adult patients (≥18 years) with a previous history of CDI in the previous 180 days and with requirement for hospitalisation and systemic antibiotic therapy will be randomly allocated to receive either 125 mg of oral vancomycin or placebo every 6 hours for 10 days. Patients will be followed for 60 days after the end of treatment to verify a reduction in the rate of CDI recurrence in the experimental group. We assume a recurrence rate of 5% in the experimental group versus 25% in the placebo group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 104 subjects will be required in total (68 assigned to the SPV group and 34 to the placebo group). ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethic Committee for Research with medicinal products of the University Hospital '12 de Octubre' (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), which is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders. TRIAL REGISTRATION NUMBER: NCT05320068.

Efficacy and safety of oral fosfomycin for asymptomatic bacteriuria in kidney transplant recipients: Results from a Spanish multicenter cohort.

Current guidelines recommend against systematic screening or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of post-transplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR]: 1.1 - 10.5). Most episodes (96.4% [132/137]) were caused by gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended-spectrum ß-lactamase-producing Enterobacterales [20.4%] and carbapenem-resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [95%CI]: 31.9 - 48.9) for the whole cohort and 42.3% (95%CI: 31.2 - 54.0) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR]: 2.42; 95%CI: 1.11 - 5.29; P-value = 0.027) and use of fosfomycin as salvage therapy (OR: 8.31; 95%CI: 1.67 - 41.35; P-value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse event were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens.

Analysis of the factors predicting clinical response to tocilizumab therapy in patients with severe COVID-19.

BACKGROUND: Controversy remains about the efficacy of tocilizumab (TCZ) for the treatment of severe COVID-19. We aimed to analyze the profile of TCZ-respondent patients. METHODS: We retrospectively analyzed a cohort of patients with severe COVID-19 who received off-label TCZ after recommendation by a local committee and were admitted to the University Hospital "12 de Octubre" until May 2020. The primary end point was a significant clinical improvement (SCI) on day 14 after administration of TCZ. Factors independently related to SCI were analyzed by multivariate logistic regression models. RESULTS: Of 428 (63.3%) patients treated with TCZ, 271 (63.3%) experienced SCI. After adjustment for factors related to unfavorable outcomes, TCZ administration within the first 48 hours from admission (odds ratio [OR]: 1.98, 95% confidence Interval [95% CI]: 1.1-3.55; P = 0.02) and ALT levels >100 UI/L at day 0 (OR: 3.28; 95% CI: 1.3-8.1; P = 0.01) were independently related to SCI. The rate of SCI significantly decreased according to the time of TCZ administration: 70.2% in the first 48 hours from admission, 58.5% on days 3-7, and 45.1% after day 7 (P = 0.03 and P = 0.001, respectively). CONCLUSION: TCZ improves the prognosis of patients with COVID-19 the most if treatment starts within the first 48 hours after admission.

Combination therapy with tocilizumab and corticosteroids for aged patients with severe COVID-19 pneumonia: A single-center retrospective study.

BACKGROUND: The role of combination immunomodulatory therapy with systemic corticosteroids and tocilizumab (TCZ) for aged patients with COVID-19-associated cytokine release syndrome remains unclear. METHODS: A retrospective single-center study was conducted on consecutive patients aged ≥65 years who developed severe COVID-19 between 03 March and 01 May 2020 and were treated with corticosteroids at various doses (methylprednisolone 0.5mg/kg/12h to 250mg/24h), either alone (CS group) or associated with intravenous tocilizumab (400-600mg, one to three doses) (CS-TCZ group). The primary outcome was all-cause mortality by day +14, whereas secondary outcomes included mortality by day +28 and clinical improvement (discharge and/or a ≥2 point decrease on a 6-point ordinal scale) by day +14. Propensity score (PS)-based adjustment and inverse probability of treatment weights (IPTW) were applied. RESULTS: Totals of 181 and 80 patients were included in the CS and CS-TCZ groups, respectively. All-cause 14-day mortality was lower in the CS-TCZ group, both in the PS-adjusted (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.17-0.68; P=0.002) and IPTW-weighted models (odds ratio [OR]: 0.38; 95% CI: 0.21-0.68; P=0.001). This protective effect was also observed for 28-day mortality (PS-adjusted HR: 0.38; 95% CI: 0.21-0.72; P=0.003). Clinical improvement by day +14 was higher in the CS-TCZ group with IPTW analysis only (OR: 2.26; 95% CI: 1.49-3.41; P<0.001). The occurrence of secondary infection was similar between both groups. CONCLUSIONS: The combination of corticosteroids and TCZ was associated with better outcomes among patients aged ≥65 years with severe COVID-19.

Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: A single-centre retrospective comparative study.

OBJECTIVES: A subgroup of patients with SARS-CoV-2 infection was thought to have developed cytokine release syndrome and were treated with tocilizumab; however, a significant percentage of patients evolved. This study aimed to determine the usefulness of anakinra as a rescue treatment for patients with tocilizumab-refractory COVID-19 disease. METHODS: A prospective cohort of patients with COVID-19 pneumonia who received anakinra as salvage therapy after failure of tocilizumab were compared (1:1) with selected controls in a historical cohort of patients treated with tocilizumab. Cases and controls were matched by age, comorbidities, pulse oximetry oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio at baseline, and time elapsed since the initiation of treatment with tocilizumab. The primary outcome was the improvement in clinical status measured by a 6-point ordinal scale, from baseline to day 21. RESULTS: The study included 20 cases and 20 controls (mean age 65.3 ± 12.8 years, 65% males). No differences were found in the clinical improvement rates at 7, 14 and 21 days of follow-up. The in-hospital mortality rate for patients receiving anakinra was 55% vs. 45% in the control group (P = 0.527). CONCLUSIONS: Treatment with anakinra was not useful in improving the prognosis of patients with tocilizumab-refractory severe COVID-19.

Tocilizumab for the treatment of adult patients with severe COVID-19 pneumonia: A single-center cohort study.

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients-Results of a Spanish multicenter cohort.

Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram-negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended-spectrum ß-lactamase-producing Enterobacteriaceae [14%] or carbapenem-resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5-2) was administered for a median of 7 days (IQR: 3-10). Clinical cure (remission of UTI-attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow-up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98-112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.

Toxin B PCR Amplification Cycle Threshold Adds Little to Clinical Variables for Predicting Outcomes in Clostridium difficile Infection: a Retrospective Cohort Study.

The objective of the present study was to evaluate the value of the PCR cycle threshold (CT ) for predicting the recurrence/severity of infection compared to that of toxin detection plus clinical variables. First episodes of Clostridium difficile infection (CDI) diagnosed during 2015 at our institution were included. Samples were tested for glutamate dehydrogenase (GDH) and toxin A/B by use of a single enzyme immunoassay (EIA). The Xpert C. difficile PCR assay was performed on GDH-positive samples. Medical data were reviewed by investigators blinded to diagnostic results for comparison of patients with and without recurrence or a poor outcome (severe/severe-complicated CDI episodes and all-cause death). We generated two sets of predictive models by incorporating the presence of a positive toxin EIA ("EIA-including model") or the optimal PCR CT cutoff value ("PCR-including model") into the clinical variables. Among 227 episodes of CDI included in the study, the rates of recurrence and poor outcome were 15.8% and 30.8%, respectively. The mean PCR CT was lower for episodes with recurrence (24.00 ± 3.28 versus 26.02 ± 4.54; P = 0.002) or a poor outcome (24.9 ± 4.24 versus 26.05 ± 4.47; P = 0.07). The optimal cutoff value for recurrence was 25.65 (sensitivity, 77.8% [95% confidence interval {CI}, 60.9 to 89.9]; and specificity, 46.6% [95% CI, 39.4 to 53.9]). The area under the receiver operator characteristics curve (auROC) for the "PCR-including model" was similar to that for the "EIA-including model" (0.785 versus 0.775, respectively). The optimal PCR CT value for poor outcome was 27.55 (sensitivity, 78.6% [95% CI, 67.1 to 87.5]; and specificity, 35.7% [95% CI, 28.2 to 43.7]). The auROC of the "PCR-including model" was again similar to that of the "EIA-including model" (0.804 versus 0.801). Despite the inverse correlation between PCR CT and the risk of CDI recurrence/severity, this determination does not meaningfully increase the predictive value of clinical variables plus toxin EIA.

Impact on mortality of adherence to evidence-based interventions in patients with catheter-related bloodstream infection due to methicillin-sensitive Staphylococcus aureus.

BACKGROUND: Recent studies have demonstrated improved survival when the management of Staphylococcus aureus bloodstream infection (BSI) is compliant with evidence-based therapeutic interventions. Whether this effect extends to low-risk sources, such as catheter-related BSI, remains unclear. METHODS: We retrospectively included 225 episodes of methicillin-sensitive S. aureus catheter-related BSI diagnosed in our centre during two non-consecutive periods: 2002-2004 (first period (101 episodes)) and 2009-2013 (second period (124 episodes)). We evaluated the adherence (percentage of compliance = (no. of interventions performed/no. of interventions recommended) × 100) to the following bundle: early catheter removal (≤72 hours), early initiation of appropriate antibiotic therapy, adequate sampling of follow-up blood cultures, transthoracic echocardiography (TTE) during hospitalization and adequate duration of therapy. RESULTS: Patients in the second period had a higher burden of comorbidities and more severe underlying conditions. All-cause 30-day mortality was 9.3%, with a significant difference between the first and second periods (13.9% versus 5.6%; p value = .035). Bundle adherence was significantly higher in the second period, particularly for follow-up blood cultures (26.7% versus 48.4%; p value = .001), performance of TTE (45.5% versus 84.7%; p value < .001) and appropriate duration of therapy (34.7% versus 50.0%; p value = .022). Bundle adherence ≥ 55% was associated with lower 30-day mortality (hazard ratio: 0.31; 95% confidence interval: 0.13-0.76). This effect remained significant across propensity score-based models adjusted for septic shock, study period and underlying conditions. CONCLUSIONS: There was a survival benefit in adhering to a bundle of evidence-based interventions in the specific setting of catheter-related BSI due to methicillin-sensitive S. aureus.

T2Candida MR as a predictor of outcome in patients with suspected invasive candidiasis starting empirical antifungal treatment: a prospective pilot study.

Objectives: We assessed the potential role of T2Candida MR (T2MR) and serological biomarkers [ß-d-glucan (BDG) or Candida albicans germ tube antibodies (CAGTA)], alone or in combination with standard cultures, for identifying patients with suspected invasive candidiasis (IC), who may benefit from maintaining antifungal therapy. Methods: Prospective observational multicentre study including all adult patients receiving empirical antifungal therapy for suspected IC, from January to June 2017. CAGTA, BDG and T2MR were determined at baseline and at +2 and +4 days after enrolment. Primary endpoint was the diagnostic value of CAGTA, BDG and T2MR, alone or in combination with standard culture, to predict diagnosis of IC and/or mortality in the first 7 days after starting antifungal therapy (poor outcome). Results: Overall, 14/49 patients (28.6%) had a poor outcome (7 died within the first 7 days of antifungal therapy, whereas 7 ended with a diagnosis of IC). CAGTA [3/14 (21.4%) versus 8/35 (22.9%), P = 1] and BDG [8/14 (57.1%) versus 17/35 (48.6%), P = 0.75] results were similar in poor- and good-outcome patients. Conversely, a positive T2MR was associated with a higher risk of poor outcome [5/14 (35.7%) versus 0/35 (0.0%) P = 0.0001]. Specificity and positive predictive value of a positive T2MR for predicting poor outcome were both 100%, with a negative predictive value of 79.6%. After testing the combinations of biomarkers/standard cultures and T2MR/standard cultures, the combination of T2MR/standard cultures showed a high capacity to discriminate patients with poor outcome from those with good clinical evolution. Conclusions: T2MR may be of significant utility to identify patients who may benefit from maintaining antifungal therapy.

T2MR contributes to the very early diagnosis of complicated candidaemia. A prospective study.

Objectives: Diagnosis of complicated candidaemia represents a challenge for clinicians since early clinical manifestations may be non-specific and difficult to identify, thus precluding an appropriate treatment. Patients and methods: This was a multicentre prospective study for predicting complicated episodes in patients with bloodstream infection caused by Candida species, while assessing the value of follow-up blood cultures (BCs) and the persistence of positive results for T2Candida MR (T2MR) and blood ß-d-glucan (BDG) tests. Immediately after the first positive BC yielding Candida species, samples were obtained on days 0, +2, +4, +7 and +14, to simultaneously perform follow-up BC, T2MR and BDG. An episode of candidaemia was defined as 'complicated' when (i) it caused septic metastasis; and/or (ii) it was the cause of the patient's death. Results: From January to June 2017, 30 patients were enrolled in the study. Of these, nine (30%) had complicated candidaemia. Values of persistently positive samples for the prediction of complicated episodes for BCs, T2MR and BDG, respectively, were as follows: sensitivity (44.4%, 100%, 100%); specificity (76.1%, 76.1%, 38.9%); positive predictive value (PPV) (44.4%, 64.2%, 40.9%) and negative predictive value (NPV) (76.1%, 100%, 100%). In multivariate analysis, having a positive T2MR within the first 5 days was associated with an almost 37-fold higher risk of developing complicated candidaemia. Conclusions: The T2MR test performed in patients with proven candidaemia may be a better marker of complicated infection than follow-up BCs or BDG. It is possible that this test may change current clinical practice, influencing the length and type of antifungal therapy in this population.

Comparison of Predictors and Mortality Between Bloodstream Infections Caused by ESBL-Producing Escherichia coli and ESBL-Producing Klebsiella pneumoniae.

OBJECTIVETo compare the epidemiology, clinical characteristics, and mortality of patients with bloodstream infections (BSI) caused by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) versus ESBL-producing Klebsiella pneumoniae (ESBL-KP) and to examine the differences in clinical characteristics and outcome between BSIs caused by isolates with CTX-M versus other ESBL genotypesMETHODSAs part of the INCREMENT project, 33 tertiary hospitals in 12 countries retrospectively collected data on adult patients diagnosed with ESBL-EC BSI or ESBL-KP BSI between 2004 and 2013. Risk factors for ESBL-EC versus ESBL-KP BSI and for 30-day mortality were examined by bivariate analysis followed by multivariable logistic regression.RESULTSThe study included 909 patients: 687 with ESBL-EC BSI and 222 with ESBL-KP BSI. ESBL genotype by polymerase chain reaction amplification of 286 isolates was available. ESBL-KP BSI was associated with intensive care unit admission, cardiovascular and neurological comorbidities, length of stay to bacteremia >14 days from admission, and a nonurinary source. Overall, 30-day mortality was significantly higher in patients with ESBL-KP BSI than ESBL-EC BSI (33.7% vs 17.4%; odds ratio, 1.64; P=.016). CTX-M was the most prevalent ESBL subtype identified (218 of 286 polymerase chain reaction-tested isolates, 76%). No differences in clinical characteristics or in mortality between CTX-M and non-CTX-M ESBLs were detected.CONCLUSIONSClinical characteristics and risk of mortality differ significantly between ESBL-EC and ESBL-KP BSI. Therefore, all ESBL-producing Enterobacteriaceae should not be considered a homogeneous group. No differences in outcomes between genotypes were detected.CLINICAL TRIALS IDENTIFIERClinicalTrials.gov. Identifier: NCT01764490.Infect Control Hosp Epidemiol 2018;39:660-667.

Post-transplant hypocomplementemia: A novel marker of cardiovascular risk in kidney transplant recipients?

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is a leading cause of mortality after kidney transplantation (KT). The potential role of the complement system in the pathogenesis of post-transplant CVD remains unexplored. METHODS: Serum complement (C3 and C4) levels were measured at baseline and post-transplant months 1 and 6 in 447 kT recipients. The study outcome was post-transplant atherothrombotic event (PAE), a composite of acute coronary syndrome, critical peripheral arterial disease, stroke and/or transient ischemic attack. RESULTS: After a median follow-up of 4.2 years, 48 PAEs occurred in 43 patients (cumulative incidence: 9.6%; incidence rate: 2.6 events per 100 transplant-years). No differences were found in C3 and C4 levels at baseline or month 1 between patients with or without PAE. However, C3 levels at month 6 were significantly lower in patients developing PAE beyond that point (i.e., late PAE) (96.9 ±â€¯22.3 vs. 109.6 ±â€¯24.0 mg/dL; p = 0.013). The presence of C3 hypocomplementemia at month 6 was associated with a lower PAE-free survival (p = 0.002). After adjusting for conventional CVD risk factors and acute graft rejection, C3 hypocomplementemia at month 6 remained as an independent risk factor for late PAE in all the exploratory models (minimum hazard ratio: 3.24; p = 0.011). With respect to a model exclusively based on clinical variables, the inclusion of C3 levels at month 6 improved predictive capacity (areas under ROC curves: 0.788 and 0.812, respectively). CONCLUSIONS: Post-transplant monitoring of serum C3 levels might be useful to identify KT recipients at increased risk of CVD.

Herpes zoster in kidney transplant recipients: protective effect of anti-cytomegalovirus prophylaxis and natural killer cell count. A single-center cohort study.

Despite its impact on quality of life and potential for complications, specific risk and protective factors for herpes zoster (HZ) after kidney transplantation (KT) remain to be clarified. We included 444 patients undergoing KT between November 2008 and March 2013. Peripheral blood lymphocyte subpopulations were measured at baseline and months 1 and 6. The risk factors for early (first post-transplant year) and late HZ (years 1-5) were separately assessed. We observed 35 episodes of post-transplant HZ after a median follow-up of 48.3 months (incidence rate: 0.057 per 1000 transplant-days). Median interval from transplantation was 18.3 months. Six patients (17.1%) developed disseminated infection. Postherpetic neuralgia occurred in 10 cases (28.6%). The receipt of anti-cytomegalovirus (CMV) prophylaxis with (val)ganciclovir decreased the risk of early HZ [adjusted hazard ratio (aHR): 0.08; 95% CI: 0.01-1.13; P-value = 0.062], whereas the natural killer (NK) cell at month 6 was protective for the occurrence of late HZ [aHR (per 10-cells/µl increase): 0.94; 95% CI: 0.88-1.00; P-value = 0.054]. In conclusion, two easily ascertainable factors (whether the patient is receiving anti-CMV prophylaxis and the NK cell count at month 6) might be potentially useful to tailor preventive strategies according to individual susceptibility to post-transplant HZ.

Serum sCD30: A promising biomarker for predicting the risk of bacterial infection after kidney transplantation.

BACKGROUND: The transmembrane glycoprotein CD30 contributes to regulate the balance between Th1 and Th2 responses. Previous studies have reported conflicting results on the utility of its soluble form (sCD30) to predict post-transplant infection. METHODS: Serum sCD30 was measured by a commercial ELISA assay at baseline and post-transplant months 1, 3, and 6 in 100 kidney transplant (KT) recipients (279 monitoring points). The impact of sCD30 levels on the incidence of overall, bacterial and opportunistic infection during the first 12 months after transplantation was assessed by Cox regression. RESULTS: There were no differences in serum sCD30 according to the occurrence of overall or opportunistic infection. However, sCD30 levels were higher in patients with bacterial infection compared to those without at baseline (P=.038) and months 1 (P<.0001), 3 (P=.043), and 6 after transplantation (P=.006). Patients with baseline sCD30 levels ≥13.5 ng/mL had lower 12-month bacterial infection-free survival (35.0% vs 80.0%; P<.0001). After adjusting for potential confounders, baseline sCD30 levels ≥13.5 ng/mL remained as an independent risk factor for bacterial infection (adjusted hazard ratio [aHR]: 4.65; 95% confidence interval [CI]: 2.05-10.53; <.001). Analogously, sCD30 levels ≥6.0 ng/mL at month 1 acted as a risk factor for subsequent bacterial infection (aHR: 5.29; 95% CI: 1.11-25.14; P=.036). CONCLUSION: Higher serum sCD30 levels were associated with an increased risk of bacterial infection after KT. We hypothesize that this biomarker reflects a Th2 -polarized T-cell response, which exerts a detrimental effect on the immunity against bacterial pathogens.

Development and validation of the INCREMENT-ESBL predictive score for mortality in patients with bloodstream infections due to extended-spectrum-ß-lactamase-producing Enterobacteriaceae.

Background: Bloodstream infections (BSIs) due to ESBL-producing Enterobacteriaceae (ESBL-E) are frequent yet outcome prediction rules for clinical use have not been developed. The objective was to define and validate a predictive risk score for 30 day mortality. Methods: A multinational retrospective cohort study including consecutive episodes of BSI due to ESBL-E was performed; cases were randomly assigned to a derivation cohort (DC) or a validation cohort (VC). The main outcome variable was all-cause 30 day mortality. A predictive score was developed using logistic regression coefficients for the DC, then tested in the VC. Results: The DC and VC included 622 and 328 episodes, respectively. The final multivariate logistic regression model for mortality in the DC included age >50 years (OR = 2.63; 95% CI: 1.18-5.85; 3 points), infection due to Klebsiella spp. (OR = 2.08; 95% CI: 1.21-3.58; 2 points), source other than urinary tract (OR = 3.6; 95% CI: 2.02-6.44; 3 points), fatal underlying disease (OR = 3.91; 95% CI: 2.24-6.80; 4 points), Pitt score >3 (OR = 3.04; 95 CI: 1.69-5.47; 3 points), severe sepsis or septic shock at presentation (OR = 4.8; 95% CI: 2.72-8.46; 4 points) and inappropriate early targeted therapy (OR = 2.47; 95% CI: 1.58-4.63; 2 points). The score showed an area under the receiver operating curve (AUROC) of 0.85 in the DC and 0.82 in the VC. Mortality rates for patients with scores of < 11 and ≥11 were 5.6% and 45.9%, respectively, in the DC, and 5.4% and 34.8% in the VC. Conclusions: We developed and validated an easy-to-collect predictive scoring model for all-cause 30 day mortality useful for identifying patients at high and low risk of mortality.

A Multinational, Preregistered Cohort Study of ß-Lactam/ß-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae.

The spread of extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether ß-lactam/ß-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.).

Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational pre-registered cohort study.

OBJECTIVES: Data about the efficacy of ertapenem for the treatment of bloodstream infections (BSI) due to ESBL-producing Enterobacteriaceae (ESBL-E) are limited. We compared the clinical efficacy of ertapenem and other carbapenems in monomicrobial BSI due to ESBL-E. METHODS: A multinational retrospective cohort study (INCREMENT project) was performed (ClinicalTrials.gov identifier: NCT01764490). Patients given monotherapy with ertapenem or other carbapenems were compared. Empirical and targeted therapies were analysed. Propensity scores were used to control for confounding; sensitivity analyses were performed in subgroups. The outcome variables were cure/improvement rate at day 14 and all-cause 30 day mortality. RESULTS: The empirical therapy cohort (ETC) and the targeted therapy cohort (TTC) included 195 and 509 patients, respectively. Cure/improvement rates were 90.6% with ertapenem and 75.5% with other carbapenems (P = 0.06) in the ETC and 89.8% and 82.6% (P = 0.02) in the TTC, respectively; 30 day mortality rates were 3.1% and 23.3% (P = 0.01) in the ETC and 9.3% and 17.1% (P = 0.01) in the TTC, respectively. Adjusted ORs (95% CI) for cure/improvement with empirical and targeted ertapenem were 1.87 (0.24-20.08; P = 0.58) and 1.04 (0.44-2.50; P = 0.92), respectively. For the propensity-matched cohorts it was 1.18 (0.43-3.29; P = 0.74). Regarding 30 day mortality, the adjusted HR (95% CI) for targeted ertapenem was 0.93 (0.43-2.03; P = 0.86) and for the propensity-matched cohorts it was 1.05 (0.46-2.44; P = 0.90). Sensitivity analyses were consistent except for patients with severe sepsis/septic shock, which showed a non-significant trend favouring other carbapenems. CONCLUSIONS: Ertapenem appears as effective as other carbapenems for empirical and targeted therapy of BSI due to ESBL-E, but further studies are needed for patients with severe sepsis/septic shock.