Human microRNA sequencing and cytomegalovirus infection risk after kidney transplantation.

Cytomegalovirus (CMV)-seropositive kidney transplant recipients (KTRs) with detectable CMV-specific cell-mediated immunity according to the QuantiFERON-CMV assay (QTF-CMV) are expected to have adequate immune protection. Nevertheless, a proportion of patients still develop CMV infection. Human microRNAs (hsa-miRNAs) are promising biomarkers owing to their high stability and easy detection. We performed whole blood miRNA sequencing in samples coincident with the first reactive QTF-CMV after transplantation or cessation of antiviral prophylaxis to investigate hsa-miRNAs differentially expressed according to the occurrence of CMV infection. One-year incidence of CMV viremia was 55.0% (median interval from miRNA sequencing sampling of 29 days). After qPCR validation, we found that hsa-miR-125a-5p was downregulated in KTRs developing CMV viremia within the next 90 days (ΔCt: 7.9 ± 0.9 versus 7.3 ± 1.0; P = .011). This difference was more evident among KTRs preemptively managed (8.2 ± 0.9 versus 6.9 ± 0.8; P < .001), with an area under the receiver operating characteristic curve of 0.865. Functional enrichment analysis identified hsa-miR-125a-5p targets involved in cell cycle regulation and apoptosis, including the BAK1 gene, which was significantly downregulated in KTRs developing CMV viremia. In conclusion, hsa-miR-125a-5p may serve as biomarker to identify CMV-seropositive KTRs at risk of CMV reactivation despite detectable CMV-CMI.

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.

Efficacy and safety of a preventive strategy against tuberculosis in liver transplantation recipients including the treatment of latent infection with moxifloxacin.

BACKGROUND: Preventive management of tuberculosis in liver transplantation (LT) is challenging due to difficulties in detecting and treating latent tuberculosis infection (LTBI). The aim of this study was to analyze the safety and efficacy of a screening strategy for LTBI with the inclusion of moxifloxacin as treatment. METHODS: We performed a retrospective single-center study of all LTs performed between 2016 and 2019 with a minimum 4-year follow-up and a standardized protocol for the evaluation of LTBI. RESULTS: Pretransplant LTBI screening was performed in 191/218 (87.6%) patients, and LTBI was diagnosed in 27.2% of them. Treatment for LTBI was administered to 71.2% of the patients and included moxifloxacin in 75.6% of the cases. After a median follow-up of 1628 days, no cases of active tuberculosis occurred among moxifloxacin-treated patients. The incidence of Clostridioides difficile (0.46 vs. 0.38 episodes/1000 transplant-days; p =  .8) and multidrug-resistant gram-negative bacilli infection (0 vs. 0.7 episodes per 1000 transplant-days; p =  .08) were not significantly higher in comparison to patients who did not receive moxifloxacin. CONCLUSION: A preventive strategy based on systematic LTBI screening and moxifloxacin treatment before LT in positive cases appears safe and effective in preventing the development of tuberculosis in LT recipients. However, our findings are limited by a small sample size; thus, larger studies are required to validate our observations.

Novel intervention based on an individualized bundle of care to decrease infection in kidney transplant recipients.

BACKGROUND: Infection remains a relevant complication after kidney transplantation (KT). A well-established strategy in modern medicine is the application of bundles of evidence-based practice in clinical settings. The objective of this study is to explore the application of a personalized bundle of measures aimed to reduce the incidence of infection in the first 12 months after KT. METHODS: A single-center prospective cohort of 148 patients undergoing KT between February 2018 and September 2019 that received an individualized infection prevention strategy was compared to a preintervention cohort (n = 159). The bundle comprised a review of the patient's immunization history, infection risk by country of origin, screening for latent tuberculosis infection (LTBI), antimicrobial prophylaxis, and immunological assessment. Individualized recommendations were accordingly provided at a scheduled visit at day +30 after transplantation. RESULTS: The intervention cohort showed a higher compliance rate with the recommended vaccine schedule, screening for geographically restricted infections and LTBI, and intravenous immunoglobulin and vitamin D supplementation (p values <.001). The 1-year incidence rate of infection was lower in the intervention cohort (42.6% vs. 57.9%; p value = .037), as was the rate of infection-related hospitalization (17.6% vs. 32.1%; p value = .003) and the incidence of severe bacterial infection. There were no differences in graft rejection or mortality rates between groups. CONCLUSIONS: A multifaceted intervention, including a bundle of evidence-based practices, enhanced compliance with recommended preventive measures and was correlated with a reduction in the 12-month incidence of infection after KT.

Natural history and prognostic factors of candidemia in kidney transplant recipients: A retrospective, multinational study.

BACKGROUND: The natural history of candidemia in kidney transplant recipients (KTR) remains poorly understood. This study aimed to evaluate mortality, prognostic factors and overall graft loss after candidemia in KTRs. METHODS: This is a retrospective multicentre study enrolling all KTRs ≥15 years old with candidemia diagnosed at hospitals in Brazil, Spain and Italy from 2010 to 2020. Primary endpoints were mortality rates at 14 and 30 days. Secondary endpoints were prognostic factors of 14-day mortality and overall graft loss. RESULTS: We enrolled 93 KTRs of which 75 were from Brazil. The mean time interval from transplantation to the onset of candidemia was 45.2 ± 61.5 months. 42% of all patients were on haemodialysis, 31.3% had an episode of sepsis and 39% underwent surgery within 30 days before fungemia. European patients were more likely to receive echinocandin (32 vs. 72%, p < .001). 22.7% of Brazilian patients did not receive any antifungal before death. All-cause mortality at 14 days was higher in Brazil (41.3 vs. 11.1%, p = .016). Candida colonisation (OR 6.91 [95% CI: 1.08-44.3], p = .042) and hypotension (OR 4.87 [95% CI: 1.62-14.66], p = .005) were associated with 14-day mortality. Echinocandin treatment had a protective effect (OR 0.19 [95% CI: 0.05-0.73], p = .015). Graft loss at 90 days occurred in 48% of patients (70.7 in Brazil vs. 22.2% in Europe, p < .01). CONCLUSIONS: Candidemia in KTR is usually documented late after engraftment in patients requiring HD, surgical procedures and dysbiosis secondary to antibiotic use. Mortality was higher in Brazil. Echinocandin therapy was associated with improved survival.

Post-transplant dynamics and clinical significance of CMV-specific neutralizing antibodies in kidney transplant recipients treated with T-cell-depleting agents.

We measured cytomegalovirus (CMV)-specific antibodies that neutralize epithelial cell infection (CMV-AbNEIs) in 101 CMV-seropositive kidney transplant recipients (KTRs) at baseline and post-transplant months 3 and 6. All the patients received antithymocyte globulin and 3-month valganciclovir prophylaxis. There were no significant differences in pre-transplant AbNEIs titers between KTRs that developed or did not develop any-level CMV infection or the composite of high-level infection and/or disease. One-year CMV infection-free survival was comparable between KTRs with or without pre-transplant CMV-AbNEIs. No differences were observed by months 3 and 6 either. We observed no protective role for CMV-AbNEIs among CMV-seropositive KTRs undergoing T-cell-depleting induction.

Nirmatrelvir/ritonavir for the treatment of immunocompromised adult patients with early-stage symptomatic COVID-19: A real-life experience.

Regardless of vaccination status, progression to severe coronavirus disease 2019 (COVID-19) is still a relevant cause of morbidity among immunocompromised patients. Despite the proven efficacy of nirmatrelvir/ritonavir (NMV/r), concerns remain regarding the potential for drug-to-drug interactions (DDIs) and the safety in this at-risk population. We aimed to evaluate the clinical outcomes of immunocompromised patients treated with NMV/r, as well as the occurrence of DDIs and treatment-emergent adverse events (TEAEs). This retrospective observational study included all the patients with some form of immunosuppression and laboratory-confirmed COVID-19 that received NMV/r at our center from April to August 2022. The main outcome was worsening of the clinical status (increase of ≥1 point from baseline in a validated clinical progression scale) by Days +7 and +28 after the initiation of therapy. Safety outcomes included the rates of any TEAE and potentially severe DDIs. We included 110 patients. Main causes of immunosuppression were hematological malignancy (58.2%) (mainly multiple myeloma [22.7%] and non-Hodgkin lymphoma [13.6%]), active chemotherapy (30.0%) and hematopoietic stem cell transplantation (14.5%). Clinical worsening by Days +7 and +28 was observed in four (3.6%) and five patients (4.5%), respectively. Only one patient had a positive SARS-CoV-2 polymerase chain reaction test at Day +28. At least one potentially severe DDI was observed in 56.4% of the patients. The rate of attributable TEAEs was 10.9%, although only two patients (1.8%) required premature discontinuation of NMV/r. Early initiation of NMV/r therapy should be considered in immunocompromised patients with COVID-19, with particular attention to interacting medications.

Comparison of intracellular cytokine staining versus an ELISA-based assay to assess CMV-specific cell-mediated immunity in high-risk kidney transplant recipients.

The best method for monitoring cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) among high-risk kidney transplant (KT) recipients remains uncertain. We assessed CMV-CMI by intracellular cytokine staining (ICS) by flow cytometry and a commercial interferon (IFN)-γ release assay (QuantiFERON®-CMV [QTF-CMV]) at posttransplant months 3, 4, and 5 in 53 CMV-seropositive KT recipients that had received induction therapy with antithymocyte globulin (ATG) and a 3-month course of valganciclovir prophylaxis. The discriminative capacity (areas under receiver operating characteristics curve [auROCs]) and diagnostic accuracy to predict immune protection against CMV infection from the discontinuation of prophylaxis to month 12 were compared between both methods. There was significant although moderate correlations between CMV-specific IFN-γ-producing CD8+ T-cell counts enumerated by ICS and IFN-γ levels by QTF-CMV at months 3 (rho: 0.493; p = 0.005) and 4 (rho: 0.440; p = 0.077). The auROCs for CMV-specific CD4+ and CD8+ T-cells by ICS were nonsignificantly higher than that of QTF-CMV (0.696 and 0.733 vs. 0.678; p = 0.900 and 0.692, respectively). The optimal cut-off of ≥0.395 CMV-specific CD8+ T-cells yielded a sensitivity of 86.4%, specificity of 54.6%, positive predictive value of 79.2% and negative predictive value of 66.7% to predict protection. The corresponding estimates for QTF-CMV (IFN-γ levels ≥0.2 IU/mL) were 78.9%, 37.5%, 75.0%, and 42.9%, respectively. The enumeration of CMV-specific IFN-γ-producing CD8+ T-cells at the time of cessation of prophylaxis performed slightly better than the QTF-CMV assay to predict immune protection in seropositive KT recipients previously treated with ATG.

Production of OXA-48 carbapenemase acts as an independent risk factor for poor outcome in Klebsiella pneumoniae infection.

PURPOSE: To know whether the production of OXA-48 carbapenemase exerts an independent impact on the outcome of Klebsiella pneumoniae infection, once adjusted by clinical syndrome and baseline risk factors. METHODS: We performed a case-cohort study including 117 infectious episodes due to OXA-48-producing K. pneumoniae (OXA-48-Kp) and 117 episodes due to non-OXA-48-producing strains (non-OXA-48-Kp). Both groups were matched (1:1 ratio) by clinical syndrome (source of infection, preceding invasive procedures and indwelling devices, and associated bacteremia) and hospitalization ward at infection onset. Multivariate Cox regression was used to investigate the association between OXA-48-Kp infection and clinical cure by day 14 (primary outcome) and 30-day all-cause mortality (secondary outcome). RESULTS: Both study groups were well balanced regarding underlying conditions and comorbidity burden. Sepsis or septic shock were more frequent in OXA-48-Kp cases than non-OXA-48-Kp controls (41 [35.0%] vs. 17 [14.5%]; P-value < 0.0001). Clinical cure by day 14 was less commonly achieved in OXA-48-Kp cases (49 [41.9%] vs. 95 [81.2%]; P-value < 0.001), whereas 30-day all-cause mortality was higher (33 [28.2%] vs. 18 [15.4%]; P-value = 0.018). Multivariate analysis confirmed that OXA-48-Kp infection was independently associated with the lack of 14-day clinical cure (adjusted hazard ratio [aHR]: 0.45; 95% confidential interval [95%CI]: 0.29-0.70; P-value < 0.0001). A non-significant association was observed for 30-day all-cause mortality (aHR: 1.65; 95%CI: 0.92-2.94; P-value = 0.093). CONCLUSION: Our matched analysis suggests that the production of OXA-48 carbapenemase acts as an independent risk factor for poor outcome in K. pneumoniae infection as compared to episodes due to non-carbapenemase-producing strains.

Previous use of statins does not improve the outcome of bloodstream infection after kidney transplantation.

Previous studies have suggested that exposure to statins confers a protective effect in bloodstream infection (BSI) due to the anti-inflammatory and immunomodulatory properties attributed to these lipid-lowering drugs. Scarce evidence is available for the solid organ transplant population. Therefore, we compared the time to clinical cure (primary outcome) and the time to fever resolution, new requirement of intensive care unit admission or renal replacement therapy, and 30-day all-cause mortality (secondary outcomes) between kidney transplant (KT) recipients with post-transplant BSI that were receiving or not statin therapy for at least the previous 30 days. We included 80 KT recipients that developed 109 BSI episodes (43 [39.4%] and 66 [60.6%] episodes within the statin and non-statin groups, respectively). The median interval since the initial prescription to BSI was 512 days (interquartile range [IQR]: 172-1388). Most episodes were of urinary source and due to Enterobacterales. There were no differences in the median time to clinical cure in the statin and non-statin groups (3.4 [IQR: 3-6.8] versus 4 [IQR: 2-6] days; p-value = .112). The lack of effect was confirmed by multiple linear regression analysis adjusted for confounding factors (standardized ß coefficient = 0.040; p-value = .709). No significant differences were observed for any of the secondary outcomes either. Vital signs and laboratory values at BSI onset and after 72-96 h were similar in both groups. In conclusion, previous statin therapy had no apparent protective effect on the outcome of post-transplant BSI among KT recipients.

Lung abscess and empyema in a heart transplant recipient from Thailand.

The case discussed involves a 69-year-old Thai woman who underwent orthotopic heart transplantation 9 months before this event. She presented with fever without localizing signs or symptoms. However, her chest images revealed mass-like consolidation in the left upper lobe. Blood culture and lung tissue identified Rhodococcus equi. She was successfully treated with a combination of antimicrobial therapy, optimization of immunosuppressants, and surgical resection.

Fluconazole versus micafungin for initial antifungal prophylaxis against Candida in pancreas transplant recipients: A comparative study of two consecutive periods.

BACKGROUND: Invasive fungal infection, particularly intraabdominal candidiasis, exerts a negative impact on the outcome of pancreas transplant recipients (PTRs). Optimal antifungal prophylaxis in this context remains unclear. METHODS: We performed a single-centre retrospective study to compare the incidence of invasive candidiasis during the first 6 post-transplant months in a cohort of 218 PTRs over two periods in which different agents for antifungal prophylaxis were used: fluconazole (Fluco-Px) from March 1995 to June 2012, and micafungin followed by fluconazole (Mica-Px) from July 2012 to December 2018. RESULTS: A total of 152 and 66 PTRs received Fluco-Px and Mica-Px. Mean age was 39.7 ± 7.8 years, 56.4% (123/218) were males, and 85.3% (186/218) underwent simultaneous pancreas-kidney transplantation. Invasive candidiasis occurred in 21.7% (33/152) of PTRs under Fluco-Px compared to 24.2% (16/66) of those under Mica-Px (p-value = .681). Median time from transplantation to infection was 8 days (interquartile range [IQR]: 6-16) under Fluco-Px versus 6.5 (IQR: 3.3-15.8) under Mica-Px (p-value = .623). Non-albicans Candida species comprised 27.5% (11/40) and 25.0% (4/16) of episodes under Fluco-Px and Mica-Px respectively (p-value = .849). Surgical site infection was the most common form in both groups (82.5% [33/40] and 87.5% [14/16]; p-value = .954). Multivariable analysis identified cold ischaemia time of the pancreas and kidney grafts, surgical reintervention and insulin requirement after transplantation as risks factor for invasive candidiasis. CONCLUSION: This retrospective study did not reveal a significant benefit from the initial use of micafungin-based antifungal prophylaxis over fluconazole among PTRs in terms of invasive candidiasis.

Eradication of Staphylococcus aureus Post-Sternotomy Mediastinitis Following the Implementation of Universal Preoperative Nasal Decontamination With Mupirocin: An Interrupted Time-Series Analysis.

BACKGROUND: Although presurgical nasal decontamination with mupirocin (NDM) has been advocated as a measure for preventing postsurgical mediastinitis (PSM) due to Staphylococcus aureus, this strategy is not universally recommended due to lack of robust supporting evidence. We aimed to evaluate the role of preoperative NDM in the annual incidence of S. aureus PSM at our institution. METHODS: An interrupted time-series analysis, with an autoregressive error model, was applied to our single-center cohort by comparing preintervention (1990-2003) and postintervention (2005-2018) periods. Logistic regression was performed to analyze risk factors for S. aureus PSM. RESULTS: 12 236 sternotomy procedures were analyzed (6370 [52.1%] and 5866 [47.9%] in the pre- and postintervention periods, respectively). The mean annual percentage adherence to NDM estimated over the postintervention period was 90.2%. Only 4 of 127 total cases of S. aureus PSM occurred during the 14-year postintervention period (0.68/1000 sternotomies vs 19.31/1000 in the preintervention period; P < .0001). Interrupted time-series analysis demonstrated a statistically significant annual reduction in S. aureus PSM of -9.85 cases per 1000 sternotomies (-13.17 to -6.5; P < .0001) in 2005, with a decreasing trend maintained over the following 5 years and an estimated relative reduction of 84.8% (95% confidence interval [CI], 89.25-74.09%). Chronic obstructive pulmonary disease was the single independent risk factor for S. aureus PSM (odds ratio, 3.7; 95% CI, 1.72-7.93) and was equally distributed in patients undergoing sternotomy during pre- or postintervention periods. CONCLUSIONS: Our experience suggests the implementation of preoperative NDM significantly reduces the incidence of S. aureus PSM.

Cytomegalovirus Exposure and the Risk of Overall Infection After Kidney Transplantation: A Cohort Study on the Indirect Effects Attributable to Viral Replication.

Previous reports hypothesized that cytomegalovirus (CMV) may predispose to non-CMV infection after kidney transplantation (KT). We analysed the incidence of non-CMV infection (overall, bacterial and opportunistic) in 291 KT recipients according to the previous development of any level or high-level (≥1,000 IU/ml) CMV viremia. Exposure to CMV replication was assessed throughout fixed intervals covering first the 30, 90, 180 and 360 post-transplant days (cumulative exposure) and non-overlapping preceding periods (recent exposure). Adjusted Cox models were constructed for each landmark analysis. Overall, 67.7 and 50.5% patients experienced non-CMV and CMV infection, respectively. Patients with cumulative CMV exposure had higher incidence of non-CMV infection beyond days 30 (p-value = 0.002) and 90 (p-value = 0.068), although these associations did not remain after multivariable adjustment. No significant associations were observed for the remaining landmark models (including those based on high-level viremia or recent CMV exposure), or when bacterial and opportunistic infection were separately analysed. There were no differences in viral kinetics (peak CMV viremia and area under curve of CMV viral load) either. Our findings do not support the existence of an independent association between previous CMV exposure and the overall risk of post-transplant infection, although results might be affected by power limitations.

CMV infection, valganciclovir exposure, and the risk of BK viremia and associated nephropathy after kidney transplantation: Is there a link?

BACKGROUND: Immunomodulatory effects attributable to cytomegalovirus (CMV) would predispose to BK polyomavirus (BKPyV) infection after kidney transplantation (KT), although available evidence is conflicting. It has been suggested that (val)ganciclovir therapy may increase the risk of BKPyV viremia and BKPyV-associated nephropathy (BKPyVAN) as a result of drug-induced T-cell impairment. METHODS: We investigated whether CMV replication and/or (val)ganciclovir exposure (either as prophylaxis or treatment) were associated with the development of BKPyV viremia or BKPyVAN in a prospective cohort of 399 KT recipients. CMV infection (any level or high-level viremia and area under the curve of DNAemia) and (val)ganciclovir exposure (any duration of therapy and cumulative days of treatment) during the first post-transplant year were explored through separate landmark survival analyses. RESULTS: Cumulative incidence of BKPyV viremia and BKPyVAN after a median follow-up of 551 days was 23.1% and 2.5%, respectively. One-year rates of CMV infection and (val)ganciclovir therapy were 47.4% and 54.1%, respectively. No differences were observed in BKPyV viremia- or BKPyVAN-free survival according to previous CMV infection or (val)ganciclovir exposure in any of the landmark analyses. Adjusted Cox models confirmed this lack of association. CONCLUSION: Our findings do not confirm the existence of a relevant impact of CMV infection or (val)ganciclovir therapy on the risk of post-transplant BKPyV events.

Monitoring of CMV-specific cell-mediated immunity with a commercial ELISA-based interferon-γ release assay in kidney transplant recipients treated with antithymocyte globulin.

Monitoring for cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) may be useful for individualizing valganciclovir (VGCV) prophylaxis after kidney transplantation (KT). We performed a commercial ELISA-based interferon (IFN)-γ release assay (QTF-CMV) from posttransplant months 2-5 (362 points) in 120 CMV-seropositive KT recipients that received antithymocyte globulin as induction therapy and VGCV prophylaxis (median of 92 days). Forty-seven patients (39.3%) had CMV infection after discontinuation of prophylaxis. The QTF-CMV assay was reactive, nonreactive, and indeterminate in 264 (72.9%), 90 (24.9%), and 8 points (2.2%). The QTF-CMV assay at prophylaxis discontinuation exhibited suboptimal accuracy for predicting protective CMV-CMI (sensitivity: 77.4%; specificity: 34.3%; positive predictive value [PPV]: 64.1%; negative predictive value [NPV]: 50.0%), with no differences in 1-year CMV infection rates between patients with negative (nonreactive or indeterminate) or reactive results (45.8% vs 36.1%; P = .244). Specificity and PPV to predict protective CMV-CMI improved by elevating the IFN-γ cutoff value to 1.13 IU/mL (65.7% and 71.4%) and 7.0 IU/mL (85.7% and 76.2%), although NPVs decreased. The QTF-CMV assay as per manufacturer's interpretative criteria performed poorly to predict protection from CMV infection following discontinuation of VGCV prophylaxis among ATG-treated CMV-seropositive KT recipients. This performance is slightly improved by modifying the IFN-γ positivity threshold.

Impact of duration of antibiotic therapy in central venous catheter-related bloodstream infection due to Gram-negative bacilli.

BACKGROUND: A progressive increase in the incidence of catheter-related bloodstream infection (CRBSI) due to Gram-negative bacilli (GNB) has been reported. Current guidelines recommend antibiotic treatment for at least 7-14 days, although the supporting evidence is limited. METHODS: We performed a retrospective single-centre study including all patients with a definite diagnosis of GNB CRBSI from January 2012 to October 2018 in which the central venous catheter (CVC) was removed. The occurrence of therapeutic failure [clinical failure (persistence of symptoms and laboratory signs of infection), microbiological failure (persistent bacteraemia or relapse) and/or all-cause 30 day mortality] was compared between episodes receiving short [≤7 days (SC)] or long courses [>7 days (LC)] of appropriate antibiotic therapy following CVC removal. RESULTS: We included 54 GNB CRBSI episodes with an overall rate of therapeutic failure of 27.8% (15/54). Episodes receiving SC therapy were more frequently due to MDR GNB [60.9% (14/23) versus 34.5% (10/29); P = 0.058] and had higher Pitt scores [median (IQR) 1 (0-4) versus 0 (0-2); P = 0.086]. There were no significant differences in the rate of therapeutic failure between episodes treated with SC or LC therapy [30.4% (7/23) versus 27.6% (8/29); OR 1.15; 95% CI 0.34-3.83; P = 0.822]. The use of SCs was not associated with increased odds of therapeutic failure in any of the exploratory models performed. CONCLUSIONS: The administration of appropriate antibiotic therapy for ≤7 days may be as safe and effective as longer courses in episodes of GNB CRBSI once the CVC has been removed.

Therapeutic drug monitoring and adverse events of delayed-release posaconazole tablets in patients with chronic pulmonary aspergillosis.

BACKGROUND: Posaconazole delayed-release tablets offer better bioavailability than the liquid suspension, but no post-marketing data are available in immunocompetent hosts such as those with chronic pulmonary aspergillosis (CPA). OBJECTIVES: To explore the pharmacokinetics and adverse event (AE) profile of posaconazole tablets in patients with CPA. METHODS: Patients started on posaconazole tablets at the National Aspergillosis Centre (NAC), Manchester, UK between February 2014 and October 2015 were identified from the NAC database and analysed retrospectively. The medical records were reviewed for factors that could affect posaconazole serum levels and the development of AEs. RESULTS: Seventy-two patients were included; 50 (69%) were male and the mean age was 48.5 ±âŸ12 years. Therapeutic levels (≥1 mg/L) were achieved in 90% of cases on 200 mg versus 90% of cases on 300 mg daily (P = not significant). Based on multivariate analysis, female sex (P = 0.041), a 100 mg daily dose (P < 0.001), asthma (P = 0.01) and bronchiectasis (P = 0.001) were associated with subtherapeutic levels. Forty-nine (68%) patients developed AEs, mainly fatigue (37%), dyspnoea (18%) and nausea (12%). AEs were present on 115/196 (59%) occasions on 300 mg/day and on 45/115 (39%) occasions on 200 mg/day (P < 0.01). The mean level was 1.81 ±âŸ0.96 mg/L for patients reporting no AEs and 1.90 ±âŸ1.11 mg/L for those reporting AEs (P = not significant). Factors associated with AEs of grade ≥2 were a daily dose of 300 versus 200 mg (P = 0.001) and asthma (P = 0.008). CONCLUSIONS: A lower-than-recommended posaconazole tablet dose achieved therapeutic levels in most patients and was better tolerated. Males were more likely to achieve a therapeutic level. Underlying conditions affected the degree and frequency of AEs.