Assessment of the Role of 1,3-ß-d-Glucan Testing for the Diagnosis of Invasive Fungal Infections in Adults.

Detection of 1,3-ß-d-glucan (BDG) in serum has been evaluated for its inclusion as a mycological criterion of invasive fungal infections (IFI) according to EORTC and Mycoses Study Group (MSG) definitions. BDG testing may be useful for the diagnosis of both invasive aspergillosis and invasive candidiasis, when interpreted in conjunction with other clinical/radiological signs and microbiological markers of IFI. However, its performance and utility vary according to patient population (hematologic cancer patients, solid-organ transplant recipients, intensive care unit patients) and pretest likelihood of IFI. The objectives of this article are to provide a systematic review of the performance of BDG testing and to assess recommendations for its use and interpretation in different clinical settings.

CSF lactate for accurate diagnosis of community-acquired bacterial meningitis.

CSF lactate measurement is recommended when nosocomial meningitis is suspected, but its value in community-acquired bacterial meningitis is controversial. We evaluated the diagnostic performance of lactate and other CSF parameters in a prospective cohort of adult patients with acute meningitis. Diagnostic accuracy of lactate and other CSF parameters in patients with microbiologically documented episodes was assessed by receiver operating characteristic (ROC) curves. The cut-offs with the best diagnostic performance were determined. Forty-five of 61 patients (74%) had a documented bacterial (n = 18; S. pneumoniae, 11; N. meningitidis, 5; other, 2) or viral (n = 27 enterovirus, 21; VZV, 3; other, 3) etiology. CSF parameters were significantly different in bacterial vs. viral meningitis, respectively (p < 0.001 for all comparisons): white cell count (median 1333 vs. 143/mm(3)), proteins (median 4115 vs. 829 mg/l), CSF/blood glucose ratio (median 0.1 vs. 0.52), lactate (median 13 vs. 2.3 mmol/l). ROC curve analysis showed that CSF lactate had the highest accuracy for discriminating bacterial from viral meningitis, with a cutoff set at 3.5 mmol/l providing 100% sensitivity, specificity, PPV, NPV, and efficiency. CSF lactate had the best accuracy for discriminating bacterial from viral meningitis and should be included in the initial diagnostic workup of this condition.

[Antimicrobial agents and renal elimination: towards individual dosage adjustment?]. / Agents anti-infectieux et fonction réna!e: vers des posologies sur mesure ?

The efficacy and safety of anti-infective treatments are associated with the drug blood concentration profile, which is directly correlated with a dosing adjustment to the individual patient's condition. Dosing adjustments to the renal function recommended in reference books are often imprecise and infrequently applied in clinical practice. The recent generalisation of the KDOQI (Kidney Disease Outcome Quality Initiative) staging of chronically impaired renal function represents an opportunity to review and refine the dosing recommendations in patients with renal insufficiency. The literature has been reviewed and compared to a predictive model of the fraction of drug cleared by the kidney based on the Dettli's principle. Revised drug dosing recommendations integrating these predictive parameters are proposed.

The dark side of SARS-CoV-2 rapid antigen testing: screening asymptomatic patients.

Several reports showed SARS-CoV-2 rapid antigen tests (RATs) performances among COVID-19 symptomatic subjects in outpatient settings during periods of highest incidence of infections and high rates of hospital admissions, but few data are present for asymptomatic patients. We investigated the role of RATs in an emergency department, as a novel screening tool before admission for COVID-19 asymptomatic patients. A total of 116 patients were screened on admission in a 250-bed community hospital in Morges, Switzerland. RAT detected 2/7 RT-PCR-positive patients and delivered two false-positive results. These data suggest the non-fiability of RATs screening in this clinical scenario.

Nosocomial influenza in south-western Swiss hospitals during two seasonal epidemics: an observational study.

BACKGROUND: In Switzerland each year, influenza leads to between 112,000 and 275,000 medical consultations. Data on nosocomial influenza infection are limited. AIM: To describe nosocomial cases of seasonal influenza in south-western Switzerland. METHODS: This study was conducted during two seasonal influenza epidemics from 2016 to 2018 in 27 acute care public hospitals in south-western Switzerland. During these two time-periods, every patient hospitalized for >72 h who was positively screened by reverse transcription-polymerase chain reaction or antigen detection for influenza was included in the survey. Characteristics of patients included age, sex, and comorbidities. Included patients were followed up until discharge or death. Complications and administration of antineuraminidases and/or antibiotics were registered. FINDINGS: The median influenza vaccine coverage of healthcare workers was 40%. In all, 836 patients were included (98% with type A influenza virus in 2016-2017; 77% with type B virus in 2017-2018). Most patients (81%) had an unknown vaccine status. Overall, the incidence of nosocomial influenza was 0.5 per 100 admissions (0.35 per 1000 patient-days). The most frequent comorbidities were diabetes (20%), chronic respiratory diseases (19%), and malnutrition (17%). Fever (77%) and cough (66%) were the most frequent symptoms. Seventy-one percent of patients received antineuraminidases, 28% received antibiotics. Infectious complications such as pneumonia were reported in 9%. Overall, the all-cause mortality was 6%. CONCLUSION: The occurrence of nosocomial influenza underlines the importance of vaccinating patients and healthcare workers, rapidly recognizing community- or hospital-acquired cases, and applying adequate additional measures to prevent dissemination, including the timely administration of antineuraminidases to avoid antibiotic use (and misuse).

High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function.

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.

Multiplex blood PCR in combination with blood cultures for improvement of microbiological documentation of infection in febrile neutropenia.

The frequent lack of microbiological documentation of infection by blood cultures (BC) has a major impact on clinical management of febrile neutropenic patients, especially in cases of unexplained persistent fever. We assessed the diagnostic utility of the LightCycler SeptiFast test (SF), a multiplex blood PCR, in febrile neutropenia. Blood for BC and SF was drawn at the onset of fever and every 3 days of persistent fever. SF results were compared with those of BC, clinical documentation of infection, and standard clinical, radiological, and microbiological criteria for invasive fungal infections (IFI). A total of 141 febrile neutropenic episodes in 86 hematological patients were studied: 44 (31%) microbiologically and 49 (35%) clinically documented infections and 48 (34%) unexplained fevers. At the onset of fever, BC detected 44 microorganisms in 35/141 (25%) episodes. Together, BC and SF identified 78 microorganisms in 61/141 (43%) episodes (P = 0.002 versus BC or SF alone): 12 were detected by BC and SF, 32 by BC only, and 34 by SF only. In 19/52 (37%) episodes of persistent fever, SF detected 28 new microorganisms (7 Gram-positive bacterial species, 15 Gram-negative bacterial species, and 6 fungal species [89% with a clinically documented site of infection]) whereas BC detected only 4 pathogens (8%) (P = 0.001). While BC did not detect fungi, SF identified 5 Candida spp. and 1 Aspergillus sp. in 5/7 probable or possible cases of IFI. Using SeptiFast PCR combined with blood cultures improves microbiological documentation in febrile neutropenia, especially when fever persists and invasive fungal infection is suspected. Technical adjustments may enhance the efficiency of this new molecular tool in this specific setting.

Validation and clinical application of a multiplex high performance liquid chromatography - tandem mass spectrometry assay for the monitoring of plasma concentrations of 12 antibiotics in patients with severe bacterial infections.

OBJECTIVE: Unpredictable pharmacokinetics of antibiotics in patients with life-threatening bacterial infections is associated with drug under- or overdosing. Therapeutic drug monitoring (TDM) may guide dosing adjustment aimed at maximizing antibacterial efficacy and minimizing toxicity. Rapid and accurate analytical methods are key for real-time TDM. Our objective was to develop a robust high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) for multiplex quantification of plasma concentrations of 12 antibiotics: imipenem/cilastatin, meropenem, ertapenem, cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam, amoxicillin, flucloxacillin, rifampicin, daptomycin. METHODS: A single extraction procedure consisting in methanol plasma protein precipitation and H2O dilution was used for all analytes. After chromatographic separation on an Acquity UPLC HSS-T3 2.1 × 50 mm, 1.8 µm (Waters®) column, quantification was performed by electro-spray ionisation-triple quadrupole mass spectrometry with selected reaction monitoring detection. Antibiotics were divided in two pools of calibration according to the frequency of analyses requests in the hospital routine antibiotic TDM program. Stable isotopically-labelled analogues were used as internal standards. A single analytical run lasted less than 9 min. RESULTS: The method was validated based on FDA recommendations, including assessment of extraction yield (96-113.8%), matrix effects, and analytical recovery (86.3-99.6%). The method was sensitive (lower limits of quantification 0.02-0.5 µg/mL), accurate (intra/inter-assay bias -11.3 to +12.7%) and precise (intra/inter-assay CVs 2.1-11.5%) over the clinically relevant plasma concentration ranges (upper limits of quantification 20-160 µg/mL). The application of the TDM assay was illustrated with clinical cases that highlight the impact on patients' management of an analytical assay providing information with short turn-around time on antibiotic plasma concentration. CONCLUSION: This simple, robust high-throughput multiplex HPLC-MS/MS assay for simultaneous quantification of plasma concentrations of 12 daily used antibiotics is optimally suited for clinically efficient real-time TDM.

Reassessment of recommended imipenem doses in febrile neutropenic patients with hematological malignancies.

Imipenem plasma concentrations were analyzed in 57 febrile neutropenic patients using the NONMEM program. The recommended 2-g/day regimen achieved coverage of the most common bacteria (MIC(90) = 1 mg/liter) during the whole dosing interval in only 53% of patients. This goal was achieved in 90% of patients with 3 g/day.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

[Empirical antibiotic therapy for febrile neutropenia]. / Antibiothérapie empirique lors de neutropénie fébrile.

Immediate broad-spectrum empirical antibacterial therapy is the key of management in febrile neutropenic patients. These patients can be stratified according to the risk of complications with the clinical MASCC score. Patients at low risk of complications can be efficaciously treated with oral antibiotics (e.g. fluoroquinolone and beta-lactam), provided that compliance and drug absorption are adequate. Early discharge is possible if clinical, logistic, and social criteria are fulfilled. Intravenous antibiotic therapy with broad-spectrum beta-lactam antibiotics in the hospital remains the standard in high-risk patients. The empirical addition of an aminoglycoside and/or a glycopeptide is recommended if the local incidence of infections due to beta-lactam resistant pathogens is high or in critically ill septic patients.

Accuracy of Sensititre YeastOne echinocandins epidemiological cut-off values for identification of FKS mutant Candida albicans and Candida glabrata: a ten year national survey of the Fungal Infection Network of Switzerland (FUNGINOS).

OBJECTIVES: Echinocandins represent the first-line treatment of candidaemia. Acquired echinocandin resistance is mainly observed among Candida albicans and Candida glabrata and is associated with FKS hotspot mutations. The commercial Sensititre YeastOne™ (SYO) kit is widely used for antifungal susceptibility testing, but interpretive clinical breakpoints are not well defined. We determined echinocandins epidemiological cut-off values (ECV) for C. albicans/glabrata tested by SYO and assessed their ability to identify FKS mutants in a national survey of candidaemia. METHODS: Bloodstream isolates of C. albicans and C. glabrata were collected in 25 Swiss hospitals from 2004 to 2013 and tested by SYO. FKS hotspot sequencing was performed for isolates with an MIC≥ECV for any echinocandin. RESULTS: In all, 1277 C. albicans and 347 C. glabrata were included. ECV 97.5% of caspofungin, anidulafungin and micafungin were 0.12, 0.06 and 0.03 µg/mL for C. albicans, and 0.25, 0.12 and 0.03 µg/mL for C. glabrata, respectively. FKS hotspot sequencing was performed for 70 isolates. No mutation was found in the 52 'limit wild-type' isolates (MIC=ECV for at least one echinocandin). Among the 18 'non-wild-type' isolates (MIC>ECV for at least one echinocandin), FKS mutations were recovered in the only two isolates with MIC>ECV for all three echinocandins, but not in those exhibiting a 'non-wild-type' phenotype for only one or two echinocandins. CONCLUSION: This 10-year nationwide survey showed that the rate of echinocandin resistance among C. albicans and C. glabrata remains low in Switzerland despite increased echinocandin use. SYO-ECV could discriminate FKS mutants from wild-type isolates tested by SYO in this population.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy.

BACKGROUND: Mannose-binding lectin (MBL) is a serum lectin involved in innate immune response. Low serum MBL concentration may constitute a risk factor for infection in patients receiving myelosuppressive chemotherapy. METHODS: We conducted a prospective, observational study that assessed MBL concentration as a risk factor for infection in patients with hematological malignancy who were hospitalized to undergo at least 1 chemotherapy cycle. MBL deficiency was defined using an algorithm that considered the serum MBL concentration and the MBL genotype. The primary end point was the ratio of duration of febrile neutropenia to the duration of neutropenia. Secondary end points included the incidence of severe infection (e.g., sepsis, pneumonia, bacteremia, and invasive fungal infection). Logistic regression analysis was conducted, and Fisher's exact test was used to analyze binary outcomes, and Kaplan-Meier estimates and log rank tests were used for time-to-event variables. RESULTS: We analyzed 255 patients who received 569 cycles of chemotherapy. The median duration of neutropenia per cycle was 7 days (interquartile range, 0-13 days). Sixty-two patients (24%) were found to have MBL deficiency. Febrile neutropenia occurred at least once in 200 patients. No difference in the primary outcome was seen. The incidence of severe infection was higher among MBL-deficient patients than among non-MBL-deficient patients (1.96 vs. 1.34 cases per 100 days for analysis of all patients [P=.008] and 1.85 vs. 0.94 cases per 100 days excluding patients with acute leukemia [P<.001]). CONCLUSIONS: MBL deficiency does not predispose adults with hematological cancer to more-frequent or more-prolonged febrile episodes during myelosuppressive chemotherapy, but MBL-deficient patients have a greater number of severe infections and experience their first severe infection earlier, compared with nondeficient patients.

[Anterior segment necrosis in multidrug-resistant Fusarium keratomycosis: a case study]. / Nécrose du segment antérieur sur kératomycose à Fusarium polyrésistant. A propos d'un cas.

Keratomycosis is a rare sight-threatening infection of the cornea, with greater morbidity than bacterial keratitis. Predisposing factors in its pathogenesis are corneal trauma, mostly of plant origin, and overuse of topical corticosteroids, associated or not with antibiotics. We report a case of a 71-year-old man who developed Fusarium (lichenicola or solani) keratitis, 15 days after beginning topical therapy with a corticosteroid and antibiotic. Despite aggressive antifungal therapy with fluconazole, he required a penetrating keratoplasty for impending corneal perforation, and finally, even after systemic use of itraconazole and topical use of amphotericin B, the infection progressed and an evisceration was required. In the evisceration material, a multidrug-resistant Fusarium lichenicola or solani, was found, partially sensitive to voriconazole only.

[Utility of procalcitonin for the diagnosis and the follow-up of infections in febrile neutropenic patients]. / Utilité de la procalcitonine dans le diagnostic et le suivi des infections chez les patients neutropéniques fébriles.

Procalcitonin is a marker of severe bacterial infections in non-neutropenic patients. The goal of this review is to assess its utility in the management of neutropenic patients. A delayed treatment of infection in this setting results in severe morbidity and high mortality. As traditional diagnostic tools often fail to exclude infection when fever occurs, all these patients receive empirical antimicrobial therapies during long periods of time. Present knowledge suggests that procalcitonin may contribute to identify patients in whom 1) antibiotics could be stopped in the absence of bacterial infection, 2) investigations and adjustments of the antimicrobial therapy for persistent fever are needed. The use of procalcitonin for the management of febrile neutropenic patients should be studied prospectively.

Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy.

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Hemostatic activation under anticoagulant treatment: a comparison of unfractionated heparin vs. nadroparin in the treatment of proximal deep vein thrombosis.

BACKGROUND: Multiple clinical trials have been performed to compare standard heparin with low molecular weight heparin in the therapy of deep vein thrombosis, but little is known about the time course of the markers of hemostatic system during the treatment with these two heparin regimens. METHODS: Twenty patients with proximal deep vein thrombosis confirmed by duplex ultrasound and phlebography were randomly assigned to either unfractionated heparin (UH) given as an intravenous bolus of 80 U/kg followed by a constant infusion of 18 U/kg/h, or nadroparin 185 AXa IU/kg once daily subcutaneously. Oral anticoagulants were started at day 4. Markers of hemostatic activation (F1+2, FPA, TAT, D-dimer) were measured daily for 4 days. Primary endpoints were the time course of these markers; secondary endpoints consisted in the evaluation of thromboembolic and hemorrhagic complications by clinical outcome and Marder score. RESULTS: Treatment with UH resulted in a rapid achievement of therapeutic heparin levels. UH reduced markers of fibrin formation and fibrinolysis more rapidly than nadroparin (p < 0.05). Within the nadroparin group activation of prothrombotic markers four hours after the subcutaneous injection (peak level) was significantly lower when compared with the time prior to injection (trough level). Secondary endpoints showed no significant difference between the two groups. CONCLUSION: Continuous intravenous perfusion of UH administered on a basis of a weight-adjusted nomogram controlled markers of the hemostatic system more rapidly than once-daily subcutaneously administered weight-adjusted nadroparin.