Safety of empirical antibiotic therapy discontinuing for fever of unknown origin during high-risk neutropenia in children.

BACKGROUND: ECIL-2021 recommends discontinuing empirical antibiotic therapy (EAT) in febrile-neutropenic children after 72 h of treatment and at least 24-48 h of apyrexia in the case of fever of unknown origin (FUO). These guidelines are rarely applied to high-risk children's neutropenia. MATERIAL AND METHODS: We retrospectively included all consecutive FUO episodes occurring during profound neutropenia ≥ 10 days in children in our institution. We evaluated the safety of EAT discontinuation in patients for whom the ECIL guidelines were followed compared to those for whom they didn't. We used a combined criterion of mortality and intensive care unit admission at 30 days. We identified risk factors for recurrent fever after EAT discontinuation. RESULTS: Fifty-one FUO episodes occurred in 37 patients. EAT discontinuation followed ECIL guidelines in 19 (37 %) episodes. No deaths and-or transfers in ICU occurred in the ECIL group. The duration of EAT was shorter by nine days in the group following ECIL guidelines (p < 0.001). We observed 14 (27 %) episodes of recurrent fever. Mucositis was significantly associated with recurrent fever (p < 0.01). CONCLUSION: EAT discontinuation seems feasible and safe in FUO during prolonged febrile neutropenia in children. However, mucosal lesions should prompt thorough surveillance due to the risk of recurrent fever.

Early application of metagenomics next-generation sequencing may significantly reduce unnecessary consumption of antibiotics in patients with fever of unknown origin.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is a novel nucleic acid method for the detection of unknown and difficult pathogenic microorganisms, and its application in the etiological diagnosis of fever of unknown origin (FUO) is less reported. We aimed to comprehensively assess the value of mNGS in the etiologic diagnosis of FUO by the pathogen spectrum and diagnostic performance, and to investigate whether it is different in the time to diagnosis, length of hospitalization, antibiotic consumption and cost between FUO patients with and without early application of mNGS. METHODS: A total of 149 FUO inpatients underwent both mNGS and routine pathogen detection was retrospectively analyzed. The diagnostic performance of mNGS, culture and CMTs for the final clinical diagnosis was evaluated by using sensitivity, specificity, positive predictive value, negative predictive value and total conforming rate. Patients were furtherly divided into two groups: the earlier mNGS detection group (sampling time: 0 to 3 days of the admission) and the later mNGS detection group (sampling time: after 3 days of the admission). The length of hospital stay, time spent on diagnosis, cost and consumption of antibiotics were compared between the two groups. RESULTS: Compared with the conventional microbiological methods, mNGS detected much more species and had the higher negative predictive (67.6%) and total conforming rate (65.1%). Patients with mNGS sampled earlier had a significantly shorter time to diagnosis (6.05+/-6.23 vs. 10.5+/-6.4 days, P < 0.001) and days of hospital stay (13.7+/-20.0 vs. 30.3 +/-26.9, P < 0.001), as well as a significantly less consumption (13.3+/-7.8 vs. 19.5+/-8.0, P < 0.001) and cost (4543+/-7326 vs. 9873 +/- 9958 China Yuan [CNY], P = 0.001) of antibiotics compared with the patients sampled later. CONCLUSIONS: mNGS could significantly improve the detected pathogen spectrum, clinical conforming rate of pathogens while having good negative predictive value for ruling out infections. Early mNGS detection may shorten the diagnosis time and hospitalization days and reduce unnecessary consumption of antibiotics.

Do statins decrease vascular inflammation in patients at risk for large-vessel vasculitis? A retrospective observational study with FDG-PET/CT in polymyalgia rheumatica, giant cell arteritis and fever of unknown origin.

OBJECTIVES: [18F] Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) can detect the presence of large-vessel vasculitis (LVV) in patients with polymyalgia rheumatica (PMR), giant cell arteritis (GCA) and fever of unknown origin (FUO). The aim of this study was to evaluate whether statins could reduce FDG-PET/CT-assessed vascular inflammation in this group of patients. METHODS: Clinical, demographic, laboratory data, current pharmacological treatments, and cardiovascular risk factors of patients with PMR, GCA and FUO, who underwent FDG-PET/CT, were recorded. FDG uptake was measured at prespecified arterial sites with the mean standardised uptake value (SUV), and with a qualitative visual score, summed up to obtain a total vascular score (TVS). LVV was diagnosed if arterial FDG visual uptake was equal or higher of liver uptake. RESULTS: 129 patients were included (96 with PMR, 16 with GCA, 13 with both PMR and GCA, and 4 with FUO), of whom 75 (58.1%) showed LVV. Twenty out of 129 (15.5%) patients were taking statins. TVS was significantly lower in patients treated with statins (p=0.02), especially in the aorta (p=0.023) and femoral arteries (p=0.027). CONCLUSIONS: Our preliminary results suggest that statins may exert a potential protective role on vascular inflammation in patients with PMR and GCA. Statin use could spuriously decrease FDG uptake of the vessel walls.

Safety and risk of febrile recurrence after early antibiotic discontinuation in high-risk neutropenic patients with haematological malignancies: a multicentre observational study.

BACKGROUND: Early antibiotic discontinuation according to the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations is not systematically applied in high-risk neutropenic patients with haematological malignancies. METHODS: A retrospective multicentre observational study was conducted over 2 years to evaluate the safety of early antibiotic discontinuation for fever of unknown origin (FUO) during neutropenia after induction chemotherapy or HSCT, in comparison with a historical cohort. We used Cox proportional hazards models, censored on neutropenia resolution, to analyse factors associated with febrile recurrence. RESULTS: Among 147 included patients in the ECIL-4 cohort, mainly diagnosed with acute leukaemia (n = 104, 71%), antibiotics were discontinued during 170 post-chemotherapy neutropenic episodes. In comparison with the historical cohort of 178 episodes of neutropenia without antibiotic discontinuation, no significant differences were observed regarding febrile recurrences [71.2% (121/170) versus 71.3% (127/178), P = 0.97], admission in ICUs [6.5% (11/170) versus 11.2% (20/178), P = 0.17], septic shock [0.6% (1/170) versus 3.9% (7/178), P = 0.07] and 30 day mortality [1.4% (2/147) versus 2.7% (4/150), P = 0.084]. In the ECIL-4 cohort, the rate of bacteraemia in case of febrile recurrence was higher [27.1% (46/170) versus 11.8% (21/178), P < 0.01] and antibiotic consumption was significantly lower (15.5 versus 19.9 days, P < 0.001). After early antibiotic discontinuation according to ECIL-4 recommendations, enterocolitis was associated with febrile recurrence [HR = 2.31 (95% CI = 1.4-3.8), P < 0.001] and stage III-IV oral mucositis with bacteraemia [HR = 2.26 (95% CI = 1.22-4.2), P = 0.01]. CONCLUSIONS: After an FUO episode in high-risk neutropenia, compliance with ECIL-4 recommendations for early antibiotic discontinuation appears to be safe and mucosal damage was associated with febrile recurrence and bacteraemia. Prospective interventional studies are warranted to assess this strategy in high-risk neutropenic patients.

Second-trimester miscarriage caused by recurrent Klebsiella pneumoniae infection: a case report.

BACKGROUND: Klebsiella pneumoniae (K. pneumoniae) can cause hospital- and community-acquired pneumonia, and urinary tract, wound, and blood infections. As there are few reports on K. pneumoniae infections in pregnancy and no treatment guidelines, diagnosis and treatment are difficult. The diagnosis and treatment require a bacterial culture to confirm the diagnosis. Therefore, the condition is often exacerbated due to a lack of timely medication. CASE DESCRIPTION: We report a case of a pregnant woman with recurrent K. pneumoniae infection during pregnancy. The 40-year-old woman was admitted to hospital at 14 weeks gestation due to fever of unknown origin. She was treated with empiric antibiotics, and her fever resolved within 1 day. A blood culture showed K. pneumoniae infection. She was discharged after 11 days of treatment. However, 10 days later, she was re-hospitalized due to fever, and treated with cefoperazone sodium and sulbactam sodium. Her fever resolved within 1 day. A blood culture again showed K. pneumoniae infection. On day 5, she experienced chills and a miscarriage. Cervical secretions showed K. pneumoniae, and a placental examination revealed chorioamnionitis. The treatment was changed to meropenem, and the patient recovered within 2 weeks. CONCLUSIONS: When a fever of unknown origin occurs during pregnancy, one should be wary of K. pneumoniae recurrence or secondary infection, and use sensitive antibiotics early. When K. pneumoniae is cultivated, the course of treatment must be sufficient, and the source of infection must be actively searched to prevent secondary infections, such as kidney cysts, liver cysts, lung cysts, and community infections. Finding the cause and taking appropriate treatment can prevent the occurrence of adverse pregnancy and childbirth history.

Efficacy of Intravenous Itraconazole Versus Liposomal Amphotericin B as Empirical Antifungal Therapy in Hematological Malignancy with Persistent Fever and Neutropenia: Study Protocol for a Multicenter, Prospective, Randomized Non-inferiority Trial.

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

The clinical characteristics and outcomes of patients with fever of unknown origin caused by parasitic infection.

ABSTRACT: There are over 200 causes of fever of unknown origin (FUO), and although parasitic infection is an increasingly uncommon cause, a definitive diagnosis remains important to ensure rapid treatment and to prevent adverse sequelae through delay. Here, we studied the clinical features and outcomes of patients admitted with FUO and diagnosed with parasitic infection to improve our understanding of the features of parasitic FUO.Medical records of patients admitted to Peking Union Medical College Hospital between 2013 and 2019 with FUO and diagnosed with parasitic infection were reviewed. The clinical features and outcomes of patients for whom follow-up data were available were summarized.Six patients were admitted with FUO and diagnosed with parasitic infections (6/1013; 0.59%). Patients were more commonly middle-aged men and had a relatively long disease course. Most suffered from hyperpyrexia and other non-specific symptoms. Routine examinations were non-specific, and some patients had positive tumor markers, antinuclear antibodies, or positron emission tomography/computed tomography results. Diagnoses were confirmed by bone marrow smears, serum antibody testing, or feces examination. All 6 cases received anthelmintic treatments and recovered well.Parasitic infections must be screened for and actively excluded in FUO patients so that targeted therapy can be rapidly administered to ensure optimal outcomes.

Bone Marrow Sarcoidosis with Pancytopenia and Renal Failure Presenting as Fever of Unknown Origin: The Pivotal Role of 18F-FDG PET/CT in Lesion Detection.

We describe a case of fever of unknown origin (FUO), renal failure, and pancytopenia. Initially, lymph proliferative disorder was suspected; therefore, bone marrow biopsy and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) were performed. Bronchoscopy and lung biopsy were performed because of abnormal FDG uptake in both lung fields. Imaging data and laboratory and histological results confirmed sarcoidosis with bone marrow invasion. The patient was discharged after favorable response to corticosteroid therapy. Sarcoidosis may present as FUO without typical specific presentations in the skin or lungs. Combined 18F-FDP PET/CT helped identify the biopsy site and confirmed the sarcoidosis diagnosis.

Diagnostic Yield of Initial and Consecutive Blood Cultures in Children With Cancer and Febrile Neutropenia.

BACKGROUND: The timing and necessity of repeated blood cultures (BCs) in children with cancer and febrile neutropenia (FN) are unknown. We evaluated the diagnostic yield of BCs collected pre- and post-empiric FN antibiotics. METHODS: Data collected prospectively from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study were used. Diagnostic yield was calculated as the number of FN episodes with a true bloodstream infection (BSI) detected divided by the number of FN episodes that had a BC taken. RESULTS: A BSI was identified in 13% of 858 FN episodes. The diagnostic yield of pre-antibiotic BCs was higher than of post-antibiotic cultures (12.3% vs 4.4%, P < .001). Two-thirds of the post-antibiotic BSIs were associated with a new episode of fever or clinical instability, and only 2 new BSIs were identified after 48 hours of empiric antibiotics and persistent fever. A contaminated BC was identified more frequently in post-antibiotic cultures. CONCLUSIONS: In the absence of new fever or clinical instability, BCs beyond 48 hours of persistent fever have limited yield. Opportunity exists to optimize BC collection in this population and reduce the burden of unnecessary tests on patients, healthcare workers, and hospitals.

Fever Without an Apparent Source in Young Infants: A Multicenter Retrospective Evaluation of Adherence to the Dutch Guidelines.

BACKGROUND: The Dutch fever without an apparent source (FWS) guidelines were published to timely recognize and treat serious infections. We determined the adherence to the Dutch FWS guidelines and the percentage of serious infections in infants younger than 3 months of age. Second, we identified which clinical criteria, diagnostic tests, and management were associated with nonadherence to the guidelines. METHODS: A retrospective cohort study was performed in 2 Dutch teaching hospitals. We assessed the charts of all infants with FWS who presented at the emergency departments from September 30, 2017, to October 1, 2019. Diagnostic and therapeutic decisions were compared with the recommendations, as published in the Dutch guidelines. Infants were categorized into the nonadherence group in case 1 or more recommendations were not adhered to. RESULTS: Data on 231 infants were studied; 51.5% of the cases adhered to the Dutch guidelines and 16.0% suffered from a serious infection. The percentage of infants with a serious infection was higher in the adherence compared with the nonadherence group. We observed no relevant differences in clinical outcomes. Univariate regression analysis showed that an abnormal white blood cell count was associated with nonadherence (OR 0.4, P = 0.049). Not obtaining a urine and blood culture and not starting intravenous antibiotic treatment were the most frequent reasons for nonadherence to the guidelines. CONCLUSIONS: Our study indicates that there was nonadherence in a large proportion of FWS cases. The guidelines may need to be adjusted to increase adherence.

Subacute Thyroiditis: An Unusual Presentation of Fever of Unknown Origin Following Upper Respiratory Tract Infection.

BACKGROUND Fever of unknown origin (FUO) is a diagnosis that requires a demanding workup from physicians before confirming a diagnosis. Thyroid diseases are a rare cause of FUO. Subacute thyroiditis is an inflammatory disease that can lead to a wide spectrum of presentations. CASE REPORT We report a case of a previously healthy male who presented with persistent fever of 4 weeks following an upper respiratory tract infection associated with constitutional symptoms. His laboratory workup included complete blood counts (CBC), complete metabolic panel (blood urea and creatinine, liver function tests, and serum electrolytes), blood cultures, abdominal and pelvic ultrasound, and computed tomography abdomen and pelvis that were inconclusive. His thyroid function tests showed a hyperthyroid state and a thyroid scan confirmed a picture of thyroiditis. The patient was treated with Ibuprofen and then with prednisolone; he showed significant improvement over a few days and was discharged with treatment of tapering doses of prednisolone over 6 weeks. Two weeks after discharge the patient had a follow-up at an outpatient clinic and was found to be in good health with resolution of his symptoms. CONCLUSIONS Thyroid disorders are not a common cause of FUO, and even if the clinical assessment of the patient is not suggestive of thyroid disease, we should consider it a possible cause. and thyroid function test should be performed to exclude thyroid problems.

Pyrexia of unknown origin in HIV-negative adults from Himachal Pradesh (India): will you suspect disseminated histoplasmosis?

Histoplasmosis is usually clinically suspected only in people who reside in, are migrants from or are travelling to endemic areas such as North America. Immunocompetent patients with a low level of exposure typically have either subclinical or mild and self-limiting infection. The most common risk for the development of progressive disseminated form is HIV infection. We recently managed two patients with disseminated histoplasmosis, presenting with prolonged fever, significant weight loss, pallor and hepatosplenomegaly. Both were HIV-negative and lived in Himachal Pradesh (India), a region that was considered "Histoplasma-free" until recently.

Enterovirus, parechovirus, adenovirus and herpes virus type 6 viraemia in fever without source.

OBJECTIVES: To evaluate the potential associations between fever without a source (FWS) in children and detection of human enterovirus (HEV), human parechovirus (HPeV), adenovirus (AdV) and human herpesvirus type 6 (HHV-6) in the plasma; and to assess whether the detection of viruses in the plasma is associated with a reduced risk of serious bacterial infection (SBI) and antibiotic use. DESIGN AND SETTING: Between November 2015 and December 2017, this prospective, single-centre, diagnostic study tested the plasma of children <3 years old with FWS. Real-time (reverse-transcription) PCR for HEV, HPeV, AdV and HHV-6 was used in addition to the standardised institutional work-up. A control cohort was also tested for the presence of viruses in their blood. RESULTS: HEV, HPeV, AdV and HHV-6 were tested for in the plasma of 135 patients of median age 2.4 months old. At least one virus was detected in 47 of 135 (34.8%): HEV in 14.1%, HHV-6 in 11.1%, HPeV in 5.9% and AdV in 5.2%. There was no difference in antibiotic use between patients with or without virus detected, despite a relative risk of 0.2 for an SBI among patients with viraemia. Controls were less frequently viraemic than children with FWS (6.0% vs 34.8%; p<0.001). CONCLUSIONS: HEV, HPeV, AdV and HHV-6 are frequently detected in the plasma of children with FWS. Antibiotic use was similar between viraemic and non-viraemic patients despite a lower risk of SBI among patients with viraemia. Point-of-care viral PCR testing of plasma might reduce antibiotic use and possibly investigations and admission rates in patients with FWS. TRIAL REGISTRATION NUMBER: NCT03224026.

Possible clinical indications of ceftobiprole

Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of adult community-acquired pneumonia and non-ventilator associated hospital-acquired pneumonia. However, its microbiological and pharmacokinetic profile is very attractive as armamentarium for empirical monotherapy treatment in other infections too. Among these, the following scenarios could be considered complicated skin and soft tissue infections, moderate-severe diabetic foot infections without bone involvement, vascular-catheter-associated-bloodstream infections, and fever without apparent focus in the hospitalized patient without septic shock or profound immunosuppression

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Possible clinical indications of ceftobiprole.

Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of adult community-acquired pneumonia and non-ventilator associated hospital-acquired pneumonia. However, its microbiological and pharmacokinetic profile is very attractive as armamentarium for empirical monotherapy treatment in other infections too. Among these, the following scenarios could be considered complicated skin and soft tissue infections, moderate-severe diabetic foot infections without bone involvement, vascular-catheter-associated-bloodstream infections, and fever without apparent focus in the hospitalized patient without septic shock or profound immunosuppression.

Factors associated with treatment type of non-malarial febrile illnesses in under-fives at Kenyatta National Hospital in Nairobi, Kenya.

BACKGROUND: Non-malarial febrile illnesses comprise of almost half of all fever presenting morbidities, among under-five children in sub-Saharan Africa. Studies have reported cases of prescription of antimalarial medications to these febrile under-fives who were negative for malaria. The treatment of these children with antimalarial medications increases incidences of antimalarial drug resistance as well as further morbidities and mortalities, due to failure to treat the actual underlying causes of fever. AIM: To identify clinical and demographic factors associated with treatment type (malarial/non-malarial) of non-malarial febrile illnesses (NMFI) in children aged ≤5 at the Kenyatta National Hospital in Nairobi, Kenya. METHODS: A positivist epistemological approach, cross sectional descriptive study design was used. A structured questionnaire was used on a sample of 341 medical records of children aged ≤5 years to extract data on clinical examinations (recorded as yes or no), diagnostic test results, and demographic data on the child's sex and age. Descriptive and inferential analysis was applied to the data. RESULTS: Prescription of antimalarial drugs despite negative microscopy results was found in 44 (12.9%) of the children, with mortality reported in 48 (14.1%). Assessment of respiratory distress was 0.13 (0.03,0.58) times associated with less likelihood of prescribing an antimalarial in those with a negative microscopy. A male patient was 0.21 (0.05,0.89) times less likely to receive an intravenous antimalarial after a negative microscopy. Patients aged ˂1 with a negative microscopy result were more likely to receive an antimalarial than older children. CONCLUSION: There is a need to eliminate incorrect treatment of NMFI with antimalarial medication, while ensuring correct diagnosis and treatment of the specific illness occurs. This requires strengthening and adherence to diagnostic and treatment guidelines of febrile illnesses in under-fives, consequently reducing morbidities and mortalities associated with inadequate management of NMFIs.

Estimating the impact of deploying an electronic clinical decision support tool as part of a national practice improvement project.

OBJECTIVE: Estimate the impact on clinical practice of using a mobile device-based electronic clinical decision support (mECDS) tool within a national standardization project. MATERIALS AND METHODS: An mECDS tool (app) was released as part of a change package to provide febrile infant management guidance to clinicians. App usage was analyzed using 2 measures: metric hits per case (metric-related screen view count divided by site-reported febrile infant cases in each designated market area [DMA] monthly) and cumulative prior metric hits per site (DMA metric hits summed from study month 1 until the month preceding the index, divided by sites in the DMA). For each metric, a mixed logistic regression model was fit to model site performance as a function of app usage. RESULTS: An increase of 200 cumulative prior metric hits per site was associated with increased odds of adherence to 3 metrics: appropriate admission (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.18), appropriate length of stay (OR, 1.20; 95% CI, 1.12-1.28), and inappropriate chest x-ray (OR, 0.82; 95% CI, 0.75-0.91). Ten additional metric hits per case were also associated: OR were 1.18 (95% CI, 1.02-1.36), 1.36 (95% CI, 1.14-1.62), and 0.74 (95% CI, 0.62-0.89). DISCUSSION: mECDS tools are increasingly being implemented, but their impact on clinical practice is poorly described. To our knowledge, although ecologic in nature, this report is the first to link clinical practice to mECDS use on a national scale and outside of an electronic health record. CONCLUSIONS: mECDS use was associated with changes in adherence to targeted metrics. Future studies should seek to link mECDS usage more directly to clinical practice and assess other site-level factors.