Liver, renal, genitourinary and diabetic ketoacidosis risks among new users of empagliflozin versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Post-authorization safety study based on multinational cohorts.

AIM: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: In this large multinational, observational, new-user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP-4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity-score deciles, were calculated. RESULTS: In total, 64 599 empagliflozin initiators and 203 315 DPP-4 inhibitor initiators were included. There was an increased risk [pooled adjusted incidence rate ratios (95% confidence interval)] of DKA [2.19 (1.74-2.76)] and decreased risks of ALI [0.77 (0.50-1.19) in patients without predisposing conditions of liver disease; 0.70 (0.56-0.88) in all patients] and AKI [0.54 (0.41-0.73)]. In the UK data, there was an increased risk of GI [males: 4.04 (3.46-4.71); females: 3.24 (2.81-3.74)] and decreased risks of CKD [0.53 (0.43-0.65)] and severe complications of UTI [0.51 (0.37-0.72)]. The results were generally consistent in subgroup and sensitivity analyses. CONCLUSIONS: Compared with DDP-4 inhibitor use, empagliflozin use was associated with increased risks of DKA and GI and decreased risks of ALI, AKI, CKD and severe complications of UTI. These associations are consistent with previous studies and known class effects of sodium-glucose cotransporter 2 inhibitors, including renoprotective effects and beneficial effects on alanine aminotransferase levels.

Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

Association of SGLT-2 inhibitors with bacterial urinary tract infection in type 2 diabetes.

OBJECTIVE: We aimed to investigate the factors associated with UTI in patients with T2D whether being treated with SGLT-2i or not. METHODS: Adult patients with T2D, whose urine culture results were available, were analyzed retrospectively. Urine culture was obtained from mid-flow urine. Antibacterial treatment was given to the patients with UTI, which was defined by positive urine cultures and/or clinical findings. We grouped the patients as follows: Group A, those treated with SGLT-2i; and Group B, those not treated with SGLT-2i. RESULTS: A total of 101 patients were included. Median age was 56 (45-67), 56.4% (n = 57) of the patients were female. Urine culture was positive in 54.9% (n = 28) and 16% (n = 8) of Group A (n = 51) and Group B (n = 50), respectively. Of those for whom urine culture was positive, Escherichia coli was isolated in 83.3% (n = 30), and both Escherichia coli and Klebsiella pneumoniae (K.pneumoniae) were isolated in 16.7% (n = 6). Klebsiella pneumoniae was isolated only from Group A. The need for and duration of hospitalization were higher in Group A (p < 0.001). UTI was detected in 60 patients. ROC analysis showed that a HbA1c of > 5.8% was associated with UTI with good accuracy (AUC: 0.835, p < 0.001). In multiple logistic regression analysis, SGLT-2i use and glucosuria were positive predictors for UTI (p = 0.004, Odds Ratio: 1984.013; and p = 0.028, and Odds Ratio: 12.480, respectively). CONCLUSION: Besides the association of HbA1c and BMI with UTI, SGLT-2i use and glucosuria predicted UTI. Urine culture is important with respect to the choice of antibacterial treatment, especially in those patients under SGLT-2i treatment. The effect of SGLT-2i on the development of UTI is independent of baseline BMI score or HbA1c.

Modified Zhibai Dihuang pill alleviated urinary tract infection induced by extended-spectrum ß-lactamase Escherichia coli in rats by regulating biofilm formation.

CONTEXT: Zhibai Dihuang pill (ZD), a traditional Chinese medicine nourishes Yin and reduces internal heat, is believed to have therapeutic effects on urinary tract infections (UTIs). OBJECTIVE: To explore the effects and mechanism of modified ZD (MZD) on UTI induced by extended-spectrum ß-lactamase (ESBLs) Escherichia coli. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were randomly divided into control, model (0.5 mL 1.5 × 108 CFU/mL ESBLs E. coli), MZD (20 g/kg MZD), LVFX (0.025 g/kg LVFX), and MZD + LVFX groups (20 g/kg MZD + 0.025 g/kg LVFX), n = 6. After 14 days of treatment, serum biochemical indicators, renal function indicators, bladder and renal histopathology, and urine bacterial counts in rats were determined. Additionally, the effects of MZD on ESBLs E. coli biofilm formation and related gene expression were analyzed. RESULTS: MZD significantly decreased the count of white blood cells (from 13.12 to 9.13), the proportion of neutrophils (from 43.53 to 23.18), C-reactive protein (from 13.21 to 9.71), serum creatinine (from 35.78 to 30.15), and urea nitrogen (from 12.56 to 10.15), relieved the inflammation and fibrosis of bladder and kidney tissues, and reduced the number of bacteria in urine (from 2174 to 559). In addition, MZD inhibited the formation of ESBLs E. coli biofilms (2.04-fold) and decreased the gene expressions of luxS, pfS and ompA (1.41-1.62-fold). DISCUSSION AND CONCLUSION: MZD treated ESBLs E. coli-induced UTI inhibited biofilm formation, providing a theoretical basis for the clinical application of MZD. Further study on the clinical effect of MZD may provide a novel therapy option for UTI.

Copper primes adaptation of uropathogenic Escherichia coli to superoxide stress by activating superoxide dismutases.

Copper and superoxide are used by the phagocytes to kill bacteria. Copper is a host effector encountered by uropathogenic Escherichia coli (UPEC) during urinary tract infection in a non-human primate model, and in humans. UPEC is exposed to higher levels of copper in the gut prior to entering the urinary tract. Effects of pre-exposure to copper on bacterial killing by superoxide has not been reported. We hypothesized that copper-replete E. coli is more sensitive to killing by superoxide in vitro, and in activated macrophages. We utilized wild-type UPEC strain CFT073, and its isogenic mutants lacking copper efflux systems, superoxide dismutases (SODs), regulators of a superoxide dismutase, and complemented mutants to address this question. Surprisingly, our results reveal that copper protects UPEC against killing by superoxide in vitro. This copper-dependent protection was amplified in the mutants lacking copper efflux systems. Increased levels of copper and manganese were detected in UPEC exposed to sublethal concentration of copper. Copper activated the transcription of sodA in a SoxR- and SoxS-dependent manner resulting in enhanced levels of SodA activity. Importantly, pre-exposure to copper increased the survival of UPEC within RAW264.7 and bone marrow-derived murine macrophages. Loss of SodA, but not SodB or SodC, in UPEC obliterated copper-dependent protection from superoxide in vitro, and from killing within macrophages. Collectively, our results suggest a model in which sublethal levels of copper trigger the activation of SodA and SodC through independent mechanisms that converge to promote the survival of UPEC from killing by superoxide. A major implication of our findings is that bacteria colonizing copper-rich milieus are primed for efficient detoxification of superoxide.

Association between contraceptive use and risk of lower urinary tract infection (LUTI): A case-control study.

AIM: The aim of this study was to analyze the association between widely used contraceptive methods and the manifestation of lower urinary tract infections (LUTI) in patients treated in gynecological practices in Germany. MATERIALS AND METHODS: This study was based on IQVIA Disease Analyzer database and includes a total of 133,638 females aged between 16 and 50 years who received an initial diagnosis of LUTI including cystitis (ICD-10: N39.0, N30.0) between January 2011 and December 2020 (index date). 1 : 1 matching of LUTI cases to non-LUTI controls was used to investigate the association between predefined criteria and LUTI. A greedy nearest neighbor propensity score method was used to balance cases and controls with respect to age, pregnancy, visit frequency during the observation period, and comorbidities including cancer, diabetes mellitus, and urolithiasis. Univariate logistic regression models were used to assess the association between contraceptive prescriptions and LUTI. RESULTS: The general use of any contraceptive method was negatively associated with subsequent LUTI. Injectable contraceptives and pills were negatively associated with LUTI manifestation. There was a significant negative association between monophasic preparations containing < 50 µg estrogen, triphasic preparations, and progestogen-only preparations and LUTI. By contrast, we found a significant positive association between emergency contraceptives and LUTI. CONCLUSION: The general application of birth control methods as well as the use of injectable contraceptives and oral contraceptives were negatively associated with LUTI manifestation. In contrast to other birth control methods, the intake of emergency contraception was positively associated with a manifestation of LUTI.

Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment.

OBJECTIVES: We conducted the first phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab in patients with high-grade non-muscle-invasive bladder cancer (HGNMIBC) who had persistent or recurrent disease after prior intravesical therapy with BCG. The primary endpoint was the safety of this combination. The secondary endpoint was clinical activity at three months following BCG treatment. METHODS: Eighteen patients were consented for the study, five of which were screen failures. Six doses of pembrolizumab were administered every 3 weeks over 16 weeks concurrently with six weekly doses of BCG beginning at week 7. Patient safety was evaluated from the time of consent through 30 days following pembrolizumab treatment. Clinical activity was determined using cystoscopy and biopsy of suspicious lesions. RESULTS: Treatment-related adverse events included one grade 4 adverse event (AEs) (adrenal insufficiency). There were nine grade 3 AEs (chest discomfort, pulmonary embolism, arthritis, wrist edema, injection site reaction, bilateral wrist pain, cardiomyopathy, hypokalemia, urinary tract infection). There were 49 grade 1 and 30 grade 2 AEs (88% of AEs). Eleven patients finished the treatment, and two patients died during the study. Of 13 patients treated, nine patients (69%) had no evidence of disease at 3 months following BCG treatment. CONCLUSIONS: We report for the first time that combining BCG and pembrolizumab in treating HGNMIBC is safe allowing complete treatment of most patients. A phase III trial has opened to test the efficacy of this combination in HGNMIBC (KEYNOTE-676).

Estimation of sodium-glucose cotransporter 2 inhibitor-related genital and urinary tract infections via electronic medical record-based common data model.

WHAT IS KNOWN AND OBJECTIVES: In Korea, the side effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been clearly reported, aside from voluntary reporting. We aimed to develop detection algorithms for SGLT2i-related genital tract infections (GTIs) and urinary tract infections (UTIs) via a common data model (CDM), an electronic medical record-based database for supporting multi-hospital clinical research. We estimated the occurrence of GTIs and UTIs and-by assessing the status of each step of the algorithm-we also aimed to determine how clinicians responded to the SGLT2i-related GTIs and UTIs. METHODS: We targeted all patients who were prescribed SGLT2i at Catholic University Seoul St. Mary's Hospital and Hallym University Dongtan Sacred Heart Hospital from January 2014 to August 2018. We developed algorithms for detection of SGLT2i-related GTIs or UTIs that divided patients into "most likely," "possibly" or "less likely" categories of GTIs or UTIs. The numbers of patients at each step were extracted. RESULTS AND DISCUSSION: A total of 4253 patients received their first prescription of SGLT2i. According to the algorithm used in this study, the proportions of "most likely GTI" and "possibly GTI" were 0.9% (37 out of 4253) and 19.4% (826 out of 4253 patients), respectively. Similarly, the proportions of "most likely UTI" and "possibly UTI" were 0.9% (38 out of 4253) and 20.2% (858 out of 4253 patients), respectively. Compared to the various existing prospective studies, both GTIs and UTIs showed lower occurrence among patients who met "most likely" criteria and higher occurrence among those who met "possibly" criteria. When a GTI or UTI occurred or was suspected, the overall rate of discontinuing SGLT2i was 51.8% (1721 out of 3323). Despite a confirmed or suspected GTI and an UTI, 62.8% (1460 out of 2323) and 14.2% (142 out of 1000) of patients continued to take SGLT2i, respectively. The discontinuation rate for suspected GTIs was significantly lower than that for suspected UTIs (37.2% vs. 85.8%, p < 0.001). WHAT IS NEW AND CONCLUSION: In this study, although the GTIs appeared to have a similar occurrence as UTIs, however, the discontinuation rate of SGLT2i for suspected GTIs was relatively lower. Our study is novel in that we identified how the physicians approached SGLT2i-related GTIs or UTIs at each step in a real-world clinical practice setting. Although we could estimate SGLT2i-related GTIs and UTIs via CDM, we were limited in our ability to accurately detect mild drug side effects via CDM, which lacked data for operational definition.

Hyperglucosuria induced by dapagliflozin augments bacterial colonization in the murine urinary tract.

AIM: To test the effects of dapagliflozin-induced hyperglucosuria on ascending bacterial urinary tract infection (UTI) in a mouse model. METHODS: Dapagliflozin or canagliflozin was used to induce hyperglucosuria in non-diabetic adult female mice prior to transurethral inoculation with uropathogenic Escherichia coli (UPEC) or Klebsiella pneumoniae. Glucose, bacterial load, cytokines, neutrophil mobilization and inflammation during acute and chronic UTI were determined. RESULTS: Significant increase in UPEC load was observed in the urinary tract of hyperglucosuric mice compared with controls. Dapagliflozin-treated mice developed bacteraemia resulting in UPEC colonization of the spleen and liver at a higher frequency than controls. Chronic UTI in hyperglucosuric mice resulted in an increased incidence of renal abscesses. Histopathological evaluation revealed only modest increases in tissue damage in the urinary bladders and kidneys of dapagliflozin-treated mice, despite a profound increase in bacterial load. There was poor neutrophil mobilization to the urine of hyperglucosuric mice. We also observed a delayed increase of IL-1ß in urine, and bladders, and IL-6 in urine of hyperglucosuric mice. Experimental inoculation with K. pneumoniae also revealed higher bacterial burden in the urinary bladder, spleen and liver from dapagliflozin-treated mice compared with controls. CONCLUSION: Collectively, our results indicate that dapagliflozin-induced hyperglucosuria in non-diabetic female mice leads to increased susceptibility to severe UTI, and bacteraemia of urinary tract origin.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study.

Background: Prior studies evaluating risk for severe urinary tract infections (UTIs) with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have reported conflicting findings. Objective: To assess whether patients initiating use of SGLT-2 inhibitors were at increased risk for severe UTI events compared with those initiating use of dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor (GLP-1) agonists. Design: Population-based cohort study. Setting: 2 large, U.S.-based databases of commercial claims (March 2013 to September 2015). Participants: Within each database, 2 cohorts were created and matched 1:1 on propensity score. Patients were aged 18 years or older, had type 2 diabetes mellitus, and were initiating use of SGLT-2 inhibitors versus DPP-4 inhibitors (cohort 1) or GLP-1 agonists (cohort 2). Measurements: The primary outcome was a severe UTI event, defined as a hospitalization for primary UTI, sepsis with UTI, or pyelonephritis; the secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios (HRs) were estimated in each propensity score-matched cohort, with adjustment for more than 90 baseline characteristics. Results: After 1:1 matching on propensity score, 123 752 patients were identified in cohort 1 and 111 978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events (incidence rate [IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group (IR, 1.77) (HR, 0.98 [95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events (IR, 2.15), compared with 87 events in the GLP-1 agonist group (IR, 2.96) (HR, 0.72 [CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs (cohort 1: HR, 0.96 [CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [CI, 0.84 to 0.99]). Limitation: Generalizability of the study findings may be limited to patients with commercial insurance. Conclusion: In a large cohort of patients seen in routine clinical practice, risk for severe and nonsevere UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications. Primary Funding Source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

Triple therapy with low-dose dapagliflozin plus saxagliptin versus dual therapy with each monocomponent, all added to metformin, in uncontrolled type 2 diabetes.

AIM: To evaluate the efficacy and safety of triple therapy with low-dose dapagliflozin plus saxagliptin added to metformin in uncontrolled type 2 diabetes. MATERIALS AND METHODS: This 24-week, double-blind trial (NCT02681094) randomized 883 patients (glycated haemoglobin [HbA1c] 7.5-10.0%) on metformin ≥1500 mg/d to add-on dapagliflozin 5 mg/d plus saxagliptin 5 mg/d or to add-on of either monocomponent. The primary endpoint was change in HbA1c from baseline. RESULTS: Baseline mean ± SD patient characteristics were: age 56.7 ± 10.5 years; HbA1c 8.2 ± 0.9%; and diabetes duration 7.6 ± 6.1 years. Triple therapy significantly decreased HbA1c versus dual therapy (-1.03% vs. -0.63% [dapagliflozin] vs. -0.69% [saxagliptin]; P < .0001). More patients achieved HbA1c <7.0% with triple versus dual therapy (41.6% vs. 21.8% [dapagliflozin; P < .0001] vs. 29.8% [saxagliptin; P = .0018]). Triple therapy significantly decreased fasting plasma glucose (-1.5 mmol/L vs. -1.1 mmol/L [dapagliflozin; P = .0135] vs. -0.7 mmol/L [saxagliptin; P < .0001]) and body weight (-2.0 kg vs. -0.4 kg [saxagliptin; P < .0001]), and ß-hydroxybutyrate levels were lower than with dapagliflozin plus metformin (mean difference -0.51; P = .0009). Urinary tract/genital infections and hypoglycaemia occurred in <5.0% and 5.8% of patients, respectively, with triple therapy. CONCLUSIONS: Triple therapy with once-daily dapagliflozin 5 mg, saxagliptin 5 mg and metformin significantly improved glycaemic control versus dual therapy with either agent added to metformin in uncontrolled type 2 diabetes, and was generally well tolerated.

Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population-based study of older women and men with diabetes.

AIMS: The objective of the study was to quantify the association between SGLT2 inhibitors and genital mycotic infection and between SGLT2 inhibitors and urinary tract infection (UTI) within 30 days of drug initiation among older women and men. MATERIALS AND METHODS: This was a retrospective cohort study using linked administrative databases of women and men with diabetes, aged 66 years or older, in Ontario, Canada. We compared the incidence of genital mycotic infection or UTI within 30 days between new users of an SGLT2 inhibitor and of a dipeptidyl-peptidase-4 (DPP4) inhibitor. RESULTS: We identified 21 444 incident users of SGLT2 inhibitor and 22 463 incident users of DPP4 inhibitor. Among SGLT2 inhibitor users, there were 8848 (41%) women and the mean age at index was 71.8 ± 5 (SD) years. After adjusting for propensity score, age, sex and recent UTI, there was a 2.47-fold increased risk of genital mycotic infection with incident use of SGLT2 inhibitors (adjusted hazard ratio (HR), 2.47; 95% confidence interval (CI), 2.08-2.92; P < 0.001) within 30 days compared to incident use of DPP4 inhibitors. For UTI, the adjusted HR was 0.89 (95% CI, 0.78-1.00; P = 0.05). CONCLUSIONS: Incident use of SGLT2 inhibitors among older women and men is associated with increased risk of genital mycotic infections within 30 days; there is no associated increased risk of UTI. These findings from a real-world setting provide evidence of the potential harms of SGLT2 inhibitors.

Clinical outcomes of botulinum toxin A management for neurogenic detrusor overactivity: meta-analysis.

The aim of this work was to evaluate the efficacy and safety of botulinum toxin A (BTX-A) treatment in patients with neurogenic detrusor overactivity. PUBMED, EMBASE, and Cochrane Library were identified on 13 May 2017 to identify relevant randomized controlled trials. All data obtained were analyzed using Stata 12.0. Five randomized controlled trials were included in this study. Compared to placebo, the BTX-A groups had significantly fewer urinary incontinence (UI) episodes per day and per week (BTX-A with 300 U for frequency of UI per day at week 2, mean difference (MD): -1.13, 95% confidence interval (CI): -1.89 to -0.37; 200 U; BTX-A with 300 U for frequency of UI per week at week 6, MD: -11.42, 95% CI: -13.91 to -8.93; BTX-A with 200 U for frequency of UI per week at week 6, MD: -10.72, 95% CI: -13.40 to -8.04), increased in maximum cystometric capacity at week 6 (BTX-A with 300 U, MD: 154.88, 95% CI: 133.92-175.84; BTX-A with 200 U, MD: 141.30, 95% CI: 121.28-161.33), decreased maximum detrusor pressure at week 6 (BTX-A with 300 U, MD: -31.72, 95% CI: -37.69 to -25.75; BTX-A with 200 U, MD: -33.47, 95% CI: -39.20 to -27.73). For adverse effects, BTX-A was often associated with more complications and urinary tract infections (BTX-A with 300 U: relative risk (RR):1.42, 95% CI: 1.15-1.76; BTX-A with 200 U: RR: 1.42, 95% CI: 1.11-1.82). This meta-analysis suggests that treatment with BTX-A is effective and safe for neurogenic detrusor overactivity, and recommends using BTX-A with 300 U or with 200 U, as suitable dosage.

Sodium-glucose cotransporter-2 inhibitors: an overview and perioperative implications.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a relatively new class of drugs used in the management of diabetes mellitus. This review will highlight key pharmacologic characteristics of this class of drugs; discuss their potential role in management of patients with cardiac disease; and raise several perioperative concerns for anesthesiologists caring for patients on SGLT-2 inhibitors. RECENT FINDINGS: Recent trials have shown a strong mortality benefit in diabetic patients on SGLT 2 inhibitors especially in patients with a high cardiovascular burden. In addition, there is a reduction in HbA1c levels, blood pressure, weight and readmissions secondary to heart failure in this patient population. However, these drugs have been also associated with an increased incidence of adverse events, such as euglycemic ketoacidosis, urinary tract infections, acute kidney injury and limb amputations. SUMMARY: SGLT 2 inhibitors are being increasingly prescribed secondary to their significant salutatory effect in patients with type II diabetes mellitus. Although there are no perioperative consensus guidelines for management of patients on SGLT2 inhibitors, they should be discontinued at least 24-48 h prior to major surgeries. Their overall management in the perioperative period should be carried out on a case-to-case basis using a multidisciplinary approach.

Prostatitis, other genitourinary infections and prostate cancer risk: Influence of non-steroidal anti-inflammatory drugs? Results from the EPICAP study.

Epidemiological studies have suggested that prostatitis may increase the risk of prostate cancer due to chronic inflammation. We studied the association between several genitourinary infections and the risk of prostate cancer based on data from the EPICAP study. EPICAP is a population-based case-control study conducted in the département of Hérault, France, between 2012 and 2014. A total of 819 incident cases and 879 controls have been face to face interviewed using a standardized questionnaire gathering information on known or suspected risk factors of prostate cancer, and personal history of genitourinary infections: prostatitis, urethritis, orchi-epididymitis, and acute pyelonephritis. Odds Ratios (OR) and their 95% confidence interval were estimated using multivariate unconditional logistic regression. Overall, 139 (18%) cases and 98 (12%) controls reported having at least one personal history of genitourinary infections (OR = 1.64 [1.23-2.20]). The risk increased with the number of infections (p-trend < 0.05). The association was specifically observed with personal history of chronic prostatitis and acute pyelonephritis (OR = 2.95 [1.26-6.92] and OR = 2.66 [1.29-5.51], respectively) and in men who did not use any non-steroidal anti-inflammatory drugs (OR = 2.00 [1.37-2.91]). Our results reinforce the hypothesis that chronic inflammation, generated by a personal history of genitourinary infections, may play a role in prostate carcinogenesis.

Inconsistency in the Definition of Urinary Tract Infection after Intravesical Botulinum Toxin A Injection: A Systematic Review.

PURPOSE: To more accurately examine the rate of urinary tract infection following onabotulinumtoxinA injection of the bladder we systematically reviewed the literature for definitions of urinary tract infection in studies of onabotulinumtoxinA injections. We assessed the studies for consistency with guideline statements defining urinary tract infections. MATERIALS AND METHODS: We systematically reviewed the literature by querying MEDLINE® and Embase®. We included original studies on adult patients with idiopathic overactive bladder and/or neurogenic detrusor overactivity who underwent cystoscopy with onabotulinumtoxinA injection and in whom urinary tract infection was a reported outcome. RESULTS: We identified 299 publications, of which 50 met study inclusion criteria. In 27 studies (54%) urinary tract infection diagnostic criteria were defined with a total of 10 definitions among these studies. None of the overactive bladder studies used a definition which met the EAU (European Association of Urology) criteria for urinary tract infection. Only 2 of the 10 studies on patients with neurogenic bladder used a urinary tract infection definition consistent with the NIDRR (National Institute on Disability and Rehabilitation Research) standards. CONCLUSIONS: Definitions of urinary tract infection are heterogeneous and frequently absent in the literature on onabotulinumtoxinA to treat overactive bladder and/or neurogenic bladder. Given the potential for post-procedure urinary symptoms in this setting, explicit criteria are imperative to establish the true urinary tract infection rate following treatment with onabotulinumtoxinA.

Association Between Urinary Tract Infections and Antipsychotic Drug Use in Older Adults.

Antipsychotic drugs are frequently prescribed to older adults, but they may be associated with serious adverse effects. The objective was to investigate the association between use of antipsychotics in older adults and the risk of urinary tract infections (UTIs).This study was designed as a cohort study.Data were obtained from the Clinical Practice Research Datalink from January 1, 2000, to September 29, 2016.Primary care patients 65 years or older in the United Kingdom with a first prescription for an oral antipsychotic were included in the study.Incidence of UTIs was calculated for periods with and without exposure to antipsychotic drugs in one cohort. Cox proportional hazard regression analysis with Andersen-Gill extension for recurrent events was used to calculate hazard ratios (HRs) with 95% confidence interval (CI).During the study period, 191,827 individuals with a first prescription for an oral antipsychotic drug were identified. Current use of antipsychotics was associated with an increased risk of UTI compared with past use (adjusted HR, 1.31; 95% CI, 1.28-1.34). This effect was strongest in the first 14 days of use (adjusted HR, 1.83; 95% CI, 1.73-1.95) and in individuals who used more than one antipsychotic drug concomitantly (adjusted HR, 1.64; 95% CI, 1.45-1.87). The risk was slightly higher for typical antipsychotics than for atypical antipsychotics. Stratification by sex showed that risk estimates were slightly higher in men than in women.Use of antipsychotics was associated with an increased risk of UTIs in both men and women, particularly in the first weeks after the start of treatment.

Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials.

AIM: To evaluate the safety and tolerability of dapagliflozin, a highly selective sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were pooled from 13 placebo-controlled trials of up to 24 weeks' duration (dapagliflozin, n = 2360; placebo, n = 2295). Larger placebo-/comparator-controlled pools of 21 (≤208 weeks; dapagliflozin, n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin, n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively. RESULTS: Over 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common renal AE was decreased creatinine clearance: 1.1% vs 0.7%). In the 21-study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval 0.010-0.089). In the 30-study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving dapagliflozin and control, respectively. CONCLUSION: The overall incidence rates of AEs and SAEs were similar in the dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.

Hospital-acquired fever in oriental medical hospitals.

BACKGROUND: Traditional Oriental medicine is used in many Asian countries and involves herbal medicines, acupuncture, moxibustion, and cupping. We investigated the incidence and causes of hospital-acquired fever (HAF) and the characteristics of febrile inpatients in Oriental medical hospitals (OMHs). METHODS: Patients hospitalized in two OMHs of a university medical institute in Seoul, Korea, were retrospectively reviewed from 2006 to 2013. Adult patients with HAF were enrolled. RESULTS: There were 560 cases of HAF (5.0%). Infection, non-infection, and unknown cause were noted in 331 cases (59.1%), 109 cases (19.5%), and 120 cases (21.4%) of HAF, respectively. Respiratory tract infection was the most common cause (51.2%) of infectious fever, followed by urinary tract infection. Drug fever due to herbal medicine was the most common cause of non-infectious fever (53.1%), followed by procedure-related fever caused by oriental medical procedures. The infection group had higher white blood cell count (WBC) (10,400/mm3 vs. 7000/mm3, p < 0.001) and more frequent history of antibiotic therapy (29.6% vs. 15.1%, p < 0.001). Multivariate analysis showed that older age (odds ratio (OR) 1.67, 95% confidence interval (C.I.) 1.08-2.56, p = 0.020), history of antibiotic therapy (OR 3.17, C.I. 1.85-5.41, p < 0.001), and WBC > 10,000/mm3 (OR 2.22, C.I. 1.85-3.32, p < 0.001) were associated with infection. CONCLUSIONS: Compared to previous studies on HAF in Western medicine, the incidence of HAF in OMHs was not high. However, Oriental medical treatment does play some role in HAF. Fever in patients with history of antibiotic therapy, or high WBC was more likely of infectious origin.

Is fast reversal and early surgery (within 24 h) in patients on warfarin medication with trochanteric hip fractures safe? A case-control study.

BACKGROUND: Hip fracture patients in general are elderly and they often have comorbidities that may necessitate anticoagulation treatment, such as warfarin. It has been emphasized that these patients benefit from surgery without delay to avoid complications and reduce mortality. This creates a challenge for patients on warfarin and especially for those with trochanteric or subtrochanteric hip fractures treated with intramedullary nailing, as this is associated with increased bleeding compared to other types of hip fractures and surgical methods. The aim of the study was to evaluate if early surgery (within 24 h) of trochanteric or subtrochanteric hip fractures using intramedullary nailing is safe in patients on warfarin treatment after fast reversal of the warfarin effect. METHODS: A retrospective case-control study including 198 patients: 99 warfarin patients and 99 patients without anticoagulants as a 1:1 ratio control group matched for age, gender and surgical implant. All patients were operated within 24 h with a cephalomedullary nail due to a trochanteric or subtrochanteric hip fracture. All patients on warfarin were reversed if necessary to INR ≤ 1.5 before surgery using vitamin K and/or four-factor prothrombin complex concentrate (PCC). Per- and postoperative data, transfusion rates, adverse events and mortality was compared. RESULTS: There were no significant differences in the calculated blood-loss, in-house adverse events or mortality (in-house, 30-day or 1-year) between the groups. There were no significant differences in the pre- or peroperative transfusions rates, but there was an increased rate of postoperative transfusions in the control group (p = 0.02). CONCLUSION: We found that surgical treatment with intramedullary nailing within 24 h of patients with trochanteric or subtrochanteric hip fractures on warfarin medication after reversing its effect to INR ≤ 1.5 using vitamin K and/or PCC is safe.