Carbapenem-Resistant Klebsiella pneumoniae Associated with COVID-19.

Infections with carbapenem-resistant Enterobacteriaceae are emerging as an important challenge in healthcare settings. Currently, carbapenem-resistant Klebsiella pneumoniae (CRKP) are the species of CRE most commonly encountered in hospitals. CRKP is resistant to almost all available antimicrobial agents, and infections with CRKP have been associated with high rates of morbidity and mortality, particularly among persons with prolonged hospitalization exposed to invasive devices. We report nine patients hospitalized in an intensive care unit (ICU) with severe coronavirus disease 2019 (COVID-19) who developed invasive infections due to carbapenemase-producing Klebsiella pneumoniae (CP-Kp), KPC and OXA-48, strains that have not been previously identified in our hospital. Despite ceftazidime/avibactam therapy, five patients died. Coinfections can contribute to a poor prognosis for patients with COVID-19, especially for high-risk populations such as elderly patients. Therefore, it is crucial to establish a rigorous program of antibiotic administration in intensive care units.

Association between vildagliptin and risk of angioedema, foot ulcers, skin lesions, hepatic toxicity, and serious infections in patients with type 2 diabetes mellitus: A European multidatabase, noninterventional, postauthorization safety study.

OBJECTIVES: This noninterventional, multidatabase, analytical cohort study explored whether vildagliptin is associated with an increased risk of specific safety events of interest, namely angioedema, foot ulcers, or skin lesions, adverse hepatic events, or serious infections compared with other noninsulin antidiabetic drugs (NIADs) using real-world data from five European electronic healthcare databases. DESIGN: Patients with type 2 diabetes mellitus aged ≥18 years on NIAD treatment were included between January 2005 and June 2014. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest were estimated using negative binomial regression. PATIENTS: Approximately 2.8% of the included patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years. RESULTS: The adjusted IRRs (vildagliptin vs. other NIADs) were in the range of 0.87-3.71 (angioedema), 0.73-1.19 (foot ulcers), 0.37-1.18 (skin lesions), 0.24-1.14 (composite of foot ulcer or skin lesions), 0.29-0.55 (serious hepatic events), and 0.59-1.04 (serious infections), with no lower bound of the 95% CIs > 1. CONCLUSIONS: Overall, there was no increased risk of the events of interest in association with vildagliptin use compared with other NIADs.

Pancreatic safety of vildagliptin in patients with type 2 diabetes mellitus: A European, noninterventional, postauthorization safety study.

This cohort study assessed the pancreatic safety of vildagliptin versus other noninsulin antidiabetic drugs (NIADs) based on data from five European electronic health care databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated separately for acute pancreatitis and pancreatic cancer for vildagliptin (± other NIADs) compared with other NIADs using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin during the study, with an average follow-up time of 1.4 years. For acute pancreatitis, adjusted IRRs ranged between 0.89 andt 2.58 with all corresponding 95% CIs crossing 1. For pancreatic cancer adjusted IRRs ranged from 0.56 to 3.64, with the lower limit of 95% CIs >1 in some analyses. Post hoc sensitivity analyses taking latency time into account markedly lowered the risk estimates with corresponding 95% CIs crossing 1. Overall, the results do not suggest an increased pancreatitis risk with vildagliptin, while the observation for pancreatic cancer have to be interpreted carefully as this study was not designed to assess pancreatic cancer and rather be explained by certain underlying limitations including latency -time, chance findings and/or bias and confounding.

Factors that may Account for Cardiovascular Risk Reduction with a Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, in Young Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: In a meta-analysis, we observed a significant 37% relative risk reduction in prospectively adjudicated major adverse cardiac events [MACEs, comprising of non-fatal myocardial infarction, non-fatal stroke, cardiovascular (CV) death] with vildagliptin vs. comparators in younger (< 65 years) patients with type 2 diabetes mellitus (T2DM), while the risk was similar in older patients (≥ 65 years). We carried out an exploratory analysis to identify the patient characteristics and on-treatment effects that may have contributed to the different outcomes in the two age groups. METHODS: On-treatment differences (vildagliptin vs. comparators) for the change from baseline in CV risk factors were analyzed using an analysis of covariance model with the baseline value for each variable of interest, treatment and study as covariates. Additional adjustments for background antihypertensive and statin use were performed when analyzing changes in blood pressure and lipids, respectively. Baseline characteristics and patient demographics were analyzed using descriptive statistics. RESULTS: Patients aged < 65 years had shorter diabetes duration (4.4 vs. 8.2 years) and slightly higher glycated hemoglobin (HbA1c) at baseline (8.3% vs. 8.0%) than patients aged ≥ 65 years. More patients in the  ≥ 65 year age group had hypertension (73.1% vs. 51.3%), dyslipidemia (53.3% vs. 43.9%) and a history of CV events (32.2% vs. 12.9%). There were small, but statistically significant differences in the change in HbA1c and total cholesterol in favor of vildagliptin relative to comparators, which were similar in both age groups. Significant differences were observed in the reduction in systolic blood pressure (SBP) (- 0.52 mmHg; 95% CI - 0.97, - 0.07; p = 0.023), low-density lipoprotein (LDL cholesterol) (- 0.12 mmol/l; 95% CI - 0.19, - 0.04; p = 0.002) and weight (- 0.48 kg; 95% CI - 0.95, - 0.01; p < 0.047) in patients < 65 years, but not in patients ≥ 65 years. The incidence of hypoglycemic events was lower in patients treated with vildagliptin [2.1 and 3.5 per 100 subject years exposure (SYEs) in < 65 and ≥ 65 years, respectively] than with comparators (5.8 and 7.5 per 100 SYEs, respectively). CONCLUSION: Based on our findings, it can be hypothesized that the positive effects of vildagliptin on SBP, LDL cholesterol, hypoglycemia and weight observed in younger, but not in older patients could be associated with the lower risk of MACE in younger patients with T2DM. FUNDING: Novartis.

Cardiovascular safety of vildagliptin in patients with type 2 diabetes: A European multi-database, non-interventional post-authorization safety study.

The aim of this non-interventional, multi-database, analytical cohort study was to assess the cardiovascular (CV) safety of vildagliptin vs other non-insulin antidiabetic drugs (NIADs) using real-world data from 5 European electronic healthcare databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest (myocardial infarction [MI], acute coronary syndrome [ACS], stroke, congestive heart failure [CHF], individually and as a composite) were estimated using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years, resulting in a cumulative current vildagliptin exposure of 28 330 person-years. The adjusted IRRs (vildagliptin [±other NIADs] vs other NIADs) were in the range of 0.61 to 0.97 (MI), 0.55 to 1.60 (ACS), 0.02 to 0.77 (stroke), 0.49 to 1.03 (CHF), and 0.22 to 1.02 (composite CV outcomes). The IRRs and their 95% CIs were close to 1, demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs other NIADs in real-world conditions.

Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance.

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.