First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

[Application of detecting bronchoalveolar lavage fluid Aspergillus galactomannan antigen in the diagnosis of pulmonary aspergillosis].

OBJECTIVE: To prospectively evaluate the utility of detecting bronchoalveolar lavage fluid (BALF) Aspergillus galactomannan antigen (GM) in the diagnosis of pulmonary aspergillosis. METHODS: From August 2008 to April 2012, 121 patients suspected of pulmonary aspergillosis were recruited and classified into pulmonary aspergillosis group (n = 57) and non-pulmonary disease group (n = 64) according to the 2008 diagnostic criteria and classification of European Organization for Research and Treatment of Cancer/National Institute of Mycoses Study Group(EORTC/MSG). The absorbency (A) and I value of GM in the patients' serum and BALF were detected by enzyme-linked immunosorbent assay (ELISA). And their values were compared and analyzed. RESULTS: Twenty cases were confirmed by pathological examinations and 37 cases by clinical diagnosis in the pulmonary aspergillosis group. The mean rank of GM's I value in the serum and BALF samples was 88.21 and 86.49. And they significantly increased compared with the non-pulmonary aspergillosis group (36.77, 38.30) (P < 0.01). At a different serum GM threshold I = 0.5, 0.8, 1.0, the sensitivities were 0.842, 0.649 and 0.228; the specificities 0.906, 0.938, 0.929; the positive predictive values 0.889, 0.902, 0.984 and the negative predictive values 0.866, 0.750, 0.589 respectively. And at a different BALF GM threshold I = 0.5, 0.8, 1.0, the sensitivities were 0.930, 0.657, 0.561; the specificities 0.766, 0.922, 0.969; the positive predictive values 0.779, 0.884, 0.941 and the negative predictive values 0.925, 0.756, 0.713 respectively. CONCLUSION: The detection of GM in BALF may be employed for the clinical diagnosis of pulmonary aspergillosis.

[Keutel syndrome with tracheal stenosis as the major symptom: case report and literature review].

OBJECTIVE: To investigate the clinical characteristics, diagnosis and therapy of Keutel syndrome, and thereby to minimize the misdiagnosis. METHOD: Data of a case of Keutel syndrome diagnosed at the Provincial Hospital Affiliated to Shandong University were analyzed and related literature were reviewed. RESULT: An 8-month-26-day-old boy was presented with inspiratory and expiratory stridor and wheezing after movement on lung auscultation. His craniofacial appearance was characterized by midfacial hypoplasia with a broad depressed nasal bridge. The nose was small and flat. A grade 2-3/6 systolic murmur was heard between the second and third ribs at left edge of the sternum. The end phalanges of his fingers were thickened. Chest radiograph showed tracheobronchial cartilage calcification and tracheobronchial stenosis. Echocardiographic examination revealed the right pulmonary stenosis. With endoscopic surgery, antiobstructive and antibiotic therapy clinical symptoms were improved. Three weeks later he died of lung reinfection after he was discharged from our hospital. English literature search with "Keutel syndrome" as the key word at "PubMed" showed 22 articles covering 26 patients, and the clinical symptoms were hearing loss (91%), persistent respiratory symptoms (68%), recurrent otitis media/sinusitis (67%), growth development delay (52%) in turn, and signs were brachytelephalangism (100%), low nasal bridge (95%), midfacial hypoplasia (93%), cardiac murmur (69%), and auxiliary examinations showed abnormal cartilage calcification (100%), pulmonary arterial stenosis (72%), tracheobronchial stenosis (50%). CONCLUSION: The diagnosis of Keutel syndrome should be considered in patients with brachytelephalangism, abnormal cartilage calcification, peripheral pulmonary stenosis, and midfacial hypoplasia. Tracheal stenosis was main clinical manifestation in part of patients.