Background Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population. Results Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, −5.3% [95% confidence interval {CI}, −11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, −3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. Conclusions Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. Clinical Trials Registration NCT02493764.
Background SAB is common, serious, and potentially lethal. Antibiotic options are limited, especially for MRSA. Ceftobiprole is an advanced-generation cephalosporin with bactericidal activity against Gram-positive (including MRSA) and Gram-negative pathogens, with efficacy and safety demonstrated in previous Phase 3 studies in acute bacterial skin infections and pneumonia. The present study evaluated ceftobiprole in patients with complicated SAB. Methods ERADICATE was a randomized (1:1), double-blind, multicenter, Phase 3, non-inferiority trial comparing ceftobiprole (BPR) vs daptomycin (DAP) ± optional aztreonam, for up to 42 days of treatment, in patients with complicated SAB (NCT03138733). The primary efficacy endpoint was overall clinical success 70 days post-randomization, adjudicated by a blinded independent Data Review Committee. Success required survival, no new SAB complications, symptom improvement, SAB clearance, and no receipt of other potentially effective antibiotics. The non-inferiority margin for the difference in success rates was -15% (BPR-DAP, 95% CI, 2-sided, lower bound). Safety was assessed through adverse events (AE) and laboratory data. Results Of 390 patients randomized, 387 (189 BPR, 198 DAP) were in the modified intent-to-treat (mITT) population who received study medication and had a positive baseline blood culture for S. aureus (94 MRSA). Median treatment duration was 21 days for both groups. Key baseline characteristics were balanced (Fig. 1). In the BPR group 69.8% experienced success, compared to 68.7% for DAP (adjusted difference 2.0%, 95% CI -7.1% to 11.1%, Fig. 2). There were no significant differences in mortality, microbiological eradication, or in key subgroup analyses (Fig. 3). The proportion of patients experiencing ≥1 AE was 63% for BPR and 59% for DAP. Treatment-related severe or serious AEs were infrequent. Gastrointestinal AEs, mostly mild nausea, were more frequent with BPR, consistent with data from previous Phase 3 studies. Conclusion Ceftobiprole is non-inferior to daptomycin for overall success in patients with complicated SAB. All-cause mortality, microbiological eradication rates and new SAB complications were similar between treatment groups. Both treatments were well tolerated. Disclosures Thomas L. Holland, MD, Aridis: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|Karius: Advisor/Consultant|Lysovant: Advisor/Consultant Sara E. Cosgrove, MD, Basilea: Advisor/Consultant|Debiopharma: Advisor/Consultant Sarah B. Doernberg, MD, MAS, Basilea: Advisor/Consultant|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Johnson and Johnson: Advisor/Consultant|NIH: Grant/Research Support|Regeneron: Grant/Research Support Maziar Assadi Gehr, MD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Marc Engelhardt, MD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Kamal Hamed, MD, Basilea Pharmaceutica: previous full time employee of Basilea Pharmaceutica International Ltd|Lysovant: full time employee of Lysovant Daniel Ionescu, MD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Mark Jones, PhD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Mikael Sauley, MSc, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Jennifer Smart, PhD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Harald Seifert, MD, Basilea Pharmaceutica: Advisor/Consultant|Debiopharm: Advisor/Consultant|Eumedica: Advisor/Consultant|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|Shionogi: Advisor/Consultant Timothy C. Jenkins, MD, Basilea: Clinical outcomes adjudication committee Vance G. Fowler, Jr, MD, MHS, Armata Valanbio Akagera Aridis Roche: Advisor/Consultant|BASILEA: Grant/Research Support|Basilea Novartis Debiopharm Genentech: Advisor/Consultant|MedImmune Bayer Janssen Contrafect Regeneron Destiny Amphliphi Integrated Bioth: Advisor/Consultant|NIH MedImmune Allergan Theravance Novartis Merck Contrafect Karius Genentech Regeneron Janssen: Grant/Research Support.
To confirm the diagnosis of myasthenia gravis (MG), in addition to clinical observation of the muscle weakness dynamics, pharmacological and functional tests, Computed tomography/Magnetic resonance imaging (CT/MRI) of the mediastinum, detection of antibodies to acetylcholine receptors (AChR) and to muscle specific tyrosine kinase (MuSK)/; electrophysiological tests are used: rhythmic nerve stimulation (RNS)/decrement test and electromyography of a single muscle fiber (single-fiber EMG (SF-EMG)/jitter). The aim of our study is to determine the possible relationship between the level of antibodies to AChR and the decrement test value, to verify a correlation between SF-EMG and the severity of MG seropositive to AChR. To evaluate the effectiveness of pathogenetic treatment and prediction of the duration of remission according to the results of the study. A total of 31 patients with myasthenia gravis seropositive to AChR were examined, among whom there were 19 (61.3%) women aged 19 to 74 years. The pattern of muscle weakness was evaluated by a score of the International Clinical Classification of Severity of Myasthenia gravis scale (MGFA). The presence of respiratory failure and its degree was assessed by spirography. The number of antibodies to AChR was determined using enzyme-linked immunosorbent assay (ELISA). The criteria for inclusion in the study were the confirmed diagnosis of seropositive myasthenia gravis with an AChR antibody level of more than 0.5 nmol/L. All patients underwent electrophysiological studies. Patients were examined three times: 1) at the time of visiting the doctor (in the hospital or on an outpatient basis); 2) in 16 and 3) in 24 weeks from the start of the study. Depending on the clinical condition of the patients the following treatment was prescribed: pyridostigmine, methylprednisolone, azathioprine. Statistical analyses were performed using the statistical computing environment R (R Core Team). In the dynamics of observation, a decrease in the level of antibodies to AChR and an improvement in the condition of patients according to the MGFA classification were generally observed but no correlation was found between the severity of MG and the level of antibodies to AChR during the first visit (Kruskal-Wallis test: H (4, N=31)=2.23 p=0.69); during the second visit (Kruskal-Wallis test: H (5, N=31)=9.44 p=0.09), as well as during the third visit (Kruskal-Wallis test: H (2, N=30)=2.74 p=0.25). A correlation was found between the concentration of antibodies to AChR and a thymectomy in the clinical history (Kruskal-Wallistest: H (1, N=7)=3.153752 p=0.07): over time, the level of antibodies decreased. Decrement test deviations were detected in 23 (74.2%) of the 31 patients, SF-EMG – in 20 (95%) of 21 patients. Abnormal jitter was recorded in 100% of cases with a generalized form of myasthenia gravis. During all three visits, a correlation was determined between the highest decrement test of symptomatic muscle and MG severity according to MGFA (r=0.39; p=0.042), (r=0.35; p=0.048), (r=0.41; p=0.039); and also between the jitter value and MG severity (r=0.54; p=0.032) (r=0.35; p=0.048), (r=0.61; p=0.034 respectively). Analysis of the contingency tables using the exact Fisher test provided information on the best method of treating patients. We consider that the most effective prognostic test that may affect the choice of further treatment is SF-EMG. However, due to the difficulties of using this method in routine practice, rhythmic nerve stimulation (RNS) test in clinically weak muscles should be recommended. It is not recommended to monitor antibodies to AChR in order to predict the course of the disease, it is better to use this test only for the diagnosis of seropositive myasthenia gravis.
A clinical and psychopathological examination of 120 COPD patients undergoing in-patient treatment was conducted on the basis of the Ivano-Frankivsk Regional Clinical Hospital. The aim of the work was to detect the prevalence and adequacy of diagnosis of systemic effects and concomitant diseases in patients with COPD. The article deals with the issue of depression in patients with chronic obstructive pulmonary disease (COPD). The results of clinical and psychopathological examination of 120 patients with stage II-IV COPD with the help of Hamilton's depression scale and Spilberger-Hanin anxiety scale are presented. Based on the analysis of the results of the study, anxiety and depression disorders were observed in patients with COPD: in patients with COPD II-III stage - severe mild depression was diagnosed, and in patients with COPD IV stage - moderate severity. In addition, the study suggests the need for appropriate medical or psychotherapeutic treatment.
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