Risk of Clostridioides difficile infection following different antibiotics: insights from multi-source medical data.

OBJECTIVE: Antibiotic utilization stands as the strongest modifiable determinant for Clostridioides difficile infection (CDI). However, previous studies have relied on aggregated antibiotic categories, leaving prescribers without detailed comparative risk information for individual antibiotics. The objective of this study was to estimate the risk of CDI comprehensively across specific antibiotics. METHODS: Two methodologies were integrated to access and rank the risk of CDI associated with individual antibiotics or classes. Initially, a network comparison was conducted by analysing data from randomized controlled trials (RCTs). Subsequently, a real-world disproportionality analysis using the Food and Drug Adverse Event Reporting System (FAERS) database complemented and enriched the findings from RCTs. RESULTS: The network comparison, encompassing 61 RCTs with 25,931 patients, revealed that exposure to cefepime [odds ratio (OR) 2.56, 95% confidence interval (CI) 1.20-5.44; P=0.02] and imipenem/cilastatin (OR 3.86, 95% CI 1.61-9.29; P=0.003) exhibited higher frequencies of CDI compared with piperacillin/tazobactam. No significant differences were observed between the carbapenems, albeit a trend indicating higher incidence of CDI with imipenem/cilastatin compared with meropenem (OR 3.89, 95% CI 0.94-16.09). In the FAERS disproportionality analysis, nearly all antibiotics displayed associations with CDI, and CDI risk signals often clustered within the majority of antibiotic classes. Among these, lincomycin demonstrated the strongest association (OR 112.17, 95% CI 51.68-243.43). Additionally, oral third-generation cephalosporins tended to exhibit higher CDI risk signals than other antibiotics. CONCLUSIONS: The findings unveiled substantial diversity in the risk of CDI, both within and between antibiotic classes, providing valuable guidance for clinicians in antibiotic prescription decisions and for initiatives aimed at antibiotic stewardship.

Neurological disorders following the use of tumor necrosis factor-α inhibitors in inflammatory bowel disease patients: a real-world pharmacovigilance analysis.

BACKGROUND: Tumor necrosis factor-α inhibitors (TNFis) are used for the treatment of inflammatory bowel disease (IBD). The aim of this study was to evaluate the association between neurological adverse events (AEs) and TNFi use. METHODS: Data of TNFis indicated for IBD were collected from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the marketed date to the second quarter of 2023. The reporting odds ratio (ROR) and a Bayesian confidence propagation neural network were used to identify signals. RESULTS: A total of 4,964 neurological AEs were reported in the IBD population. Infliximab had 3 signals, including demyelination [ROR (95% CI): 1.69 (1.33,2.15)], meningitis listeria [ROR (95% CI): 5.05 (3.52,7.25)], and optic neuritis [ROR (95% CI): 1.72 (1.3,2.26)]. The signals for adalimumab were gait disturbance [ROR (95% CI): 1.43 (1.32,1.56)] and muscular weakness [ROR (95% CI): 1.4 (1.27,1.55)]. A peripheral neuropathy signal was found for adalimumab [ROR (95% CI): 1.34 (1.18,1.53)] and certolizumab pegol [ROR (95% CI): 1.49 (1.07,2.08)]. However, there were no signals among neurological AEs for golimumab. CONCLUSION: Neurological signals were detected for TNFi use, indicating that the risk of neurological AEs requires additional attention in clinical use of TNFis.

Safety Profile of Selective Serotonin Reuptake Inhibitors in Real-World Settings: A Pharmacovigilance Study Based on FDA Adverse Event Reporting System.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed agents to treat depression. Considering the growth in antidepressant prescription rates, SSRI-induced adverse events (AEs) need to be comprehensively clarified. OBJECTIVE: This study was to investigate safety profiles and potential AEs associated with SSRIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: A retrospective pharmacovigilance analysis was conducted using the FAERS database, with Open Vigil 2.1 used for data extraction. The study included cases from the marketing date of each SSRI (ie, citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, and sertraline) to April 30, 2023. We employed the reporting odds ratio and Bayesian confidence propagation neural network as analytical tools to assess the association between SSRIs and AEs. The Medical Dictionary for Regulatory Activities was used to standardize the definition of AEs. AE classification was achieved using system organ classes (SOCs). RESULTS: Overall, 427 655 AE reports were identified for the 6 SSRIs, primarily associated with 25 SOCs, including psychiatric, nervous system, congenital, familial, genetic, cardiac, and reproductive disorders. Notably, sertraline (n = 967) and fluvoxamine (n = 169) exhibited the highest and lowest signal frequencies, respectively. All SSRIs had relatively strong signals related to congenital, psychiatric, and nervous disorders. CONCLUSIONS AND RELEVANCE: Most of our findings are consistent with those reported previously, but some AEs were not previously identified. However, AEs attributed to SSRIs remain ambiguous, warranting further validation. Applying data-mining methods to the FAERS database can provide additional insights that can assist in appropriately utilizing SSRIs.

Evaluation of the effect of managing oxycodone/acetaminophen as a psychotropic medicine: An interrupted time-series study.

Background: Oxycodone/acetaminophen has been reported for misuse for many times in China. To cope with that, Chinese national authorities jointly issued a policy, requiring that oxycodone/acetaminophen should be managed as a psychotropic medicine starting 1 September 2019. This paper aimed to evaluate the effect of this policy in medical institutions. Methods: We used interrupted time-series analysis to examine the immediate level and slope changes in the mean number of tablets prescribed, proportion of oxycodone/acetaminophen prescription exceeding 30 pills, days supplied per prescription and the proportion of days supplied exceeding 10 days with prescription data from 5 tertiary hospitals in Xi'an city between 1 January 2018 and 30 June 2021 (42 months). We divided the prescriptions into two groups, one for long-term drug users, and the other for short-term drug users. Results: In total, 12,491 prescriptions were included in the final study, with 8,941 and 3,550 prescriptions for the short-term and long-term drug users, respectively. Significant differences in the proportion of prescriptions issued by various departments, were observed between pre- and post-implementation of the policy for both short-term and long-term drug users (p < 0.001). For short-term drug users, the policy implementation was only associated with an immediate level decrease in proportion of prescriptions exceeding 30 tablets (-4.09%, p < 0.001). For long-term drug users, after the policy, the mean number of tablets prescribed and the mean proportion of prescriptions exceeding 30 tablets experienced a level decrease of 22.96 tablets (p < 0.001) and a level decrease of 41.13% (p < 0.001), respectively; the mean number of days supplied showed a significant level decrease (6.88 days per prescription) and slope increase (0.19 days per month), and the mean proportion of days supplied exceeding 10 days showed a significant level decrease (-10.51% per prescription) and a slope increase (0.27% per month). Conclusion: Implementation of stricter management for oxycodone/acetaminophen achieved its goal of reducing the risk of misuse in short-term drug users. For those long-term drug users, policy needed to be strengthened as the prescription exceeding 10 days was still at a high level after the intervention. Policies targeting patients with different drug demands are needed. Many other strategies can be implemented, including establishing specific guidelines/principles and conducting training programs.

Efficacy and Safety of Combination Antifungals as Empirical, Preemptive, and Targeted Therapies for Invasive Fungal Infections in Intensive-Care Units.

Purpose: To determine whether combinations of antifungal drugs are effective and safe for patients in intensive-care units. Methods: This study compared the efficacy and safety of caspofungin (CAS), voriconazole (VOR), amphotericin B liposome (L-AmB), CAS+VOR, and CAS+L-AmB as empirical, preemptive, and targeted therapies for invasive fungal infection (IFI). Results: Comparing the CAS, VOR, and CAS+VOR groups revealed that there were no differences in response rates between all therapy types, IFI-associated death within 90 days was less common in the CAS+VOR group (1.8%) than the VOR group (14.3%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For empirical or preemptive therapy, the CAS group had a better response rate (80.0%) than the CAS+VOR group (47.1%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For targeted therapy, no differences were found for efficacy and safety. There were no differences among the CAS, L-AmB, and CAS+L-AmB groups in efficacy and safety. Conclusion: Patients who received CAS monotherapy as an empirical or preemptive therapy could achieve good outcomes. Patients who received CAS+VOR or CAS+L-AmB achieved almost the same outcomes when compared with those who received CAS, VOR, and L-AmB monotherapy as targeted therapies, but those who received CAS+VOR had a lower IFI mortality rate than did those who received VOR monotherapy.

In vitro synergistic antifungal activities of caspofungin in combination with fluconazole or voriconazole against Candida species determined by the Etest method.

OBJECTIVES: Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. METHODS: In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). RESULTS: For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. CONCLUSION: A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation.

Latamoxef-induced coagulation disorders: Incidence and risk factors.

WHAT IS KNOWN AND OBJECTIVE: To observe the effect of latamoxef on coagulation function and to analyse its risk factors. METHODS: A retrospective cohort study was performed to compare patients receiving latamoxef versus those treated with ceftazidime. Baseline characteristics and coagulation parameters were recorded and analysed to explore whether treatment with latamoxef increased the risks of coagulation disorders and bleeding. RESULTS AND DISCUSSION: A total number of 162 patients receiving latamoxef and 93 patients receiving ceftazidime were included. Haemorrhagic events were similar between groups, but patients receiving latamoxef had a higher risk of coagulation disorders compared to those receiving ceftazidime. Multivariate analysis revealed that the exposure of antibiotics, especially the cumulative defined daily doses (DDDs), and the nutrition risk may be the predictors of coagulation disorders. WHAT IS NEW AND CONCLUSION: Latamoxef might induce coagulation disorders. Cumulative DDDs and the nutrition risk were linked with coagulation disorders.

Determination of tigecycline in human lung epithelial cells and polymorphonuclear neutrophils by liquid chromatography/tandem mass spectrometry and its application in a cellular pharmacokinetics study.

RATIONALE: In order to characterize the intracellular pharmacokinetic properties of tigecycline, we developed and fully validated a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantification of tigecycline in human lung epithelial (BEAS-2B) cells and polymorphonuclear neutrophils (PMNs). METHODS: Tetracycline was used as an internal standard and chromatographic separation was achieved on a C18 Hypersil Gold aQ column using two mobile phases, a solution of water (containing 0.1% formic acid) and acetonitrile. The flow rate was 0.4 mL/min for 5.0 min. Tigecycline drug uptake was evaluated by incubating the BEAS-2B cells and the PMNs for up to 3 h at tigecycline concentrations of 1 mg/L. RESULTS: The assay was linear over the tested concentration range of 0.01-2 mg/L for tigecycline in BEAS-2B cells and PMNs (r2 >0.99). The inter- and inter-day precisions (RSD, %) were <10.02% and the accuracies (%) were within the range of 85-115%. The uptake study showed that after incubation with tigecycline (1 mg/L) for 3 h at 37°C, the intracellular peak concentration of BEAS-2B cells was 14.44 ± 7.12 mg/L at 1 h, and 41.43 ± 25.66 mg/L in PMNs at 20 min. The mean intracellular concentrations fluctuated in the range of 0.8-14.44 mg/L in BEAS-2B cells and 10.14-41.43 mg/L in PMNs for 1 mg/L tigecycline exposure. CONCLUSIONS: Validated LC/MS/MS is a simple, rapid, and sensitive method for determining the intracellular concentration of tigecycline, and tigecycline has good penetrations both in human BEAS-2B cells and PMNs. The method can be efficiently used for future studies of the intracellular pharmacokinetics of tigecycline.

Impact of antibiotic prescription on the resistance of Klebsiella pneumoniae at a tertiary hospital in China, 2012-2019.

BACKGROUND: The incidence of Klebsiella pneumoniae (KP) infections is worrisome. Previous studies have shown that increased antibiotic treatment might affect the resistance profile of this organism. The objective of this study was to describe the resistance profile of KP strains and to correlate it with antibiotics consumption. METHODS: A retrospective observational analysis was performed to examine exposure to antibiotics and resistant profile, comparing the results of different measuring outcomes of resistance (the incidence and the percentage of resistant KP) during January 2012 to June 2019 by using the autoregressive integrated moving average and transfer function model. RESULTS: During the study period, the use of some third-generation cephalosporins and carbapenems continued to increase and a total of 5,519 KP isolates were collected. There were positive relationships between amikacin-resistant KP, ciprofloxacin-resistant KP, and corresponding antibiotic use in the transfer function models; both for the incidence rate and the resistant rate (time lag = 0) (P < .05). CONCLUSIONS: The present study confirms that the history of amikacin or ciprofloxacin use influences the susceptibility of these agents against KP with no delay. Similar results were obtained with different measuring outcomes of resistance.

Pharmacokinetic/pharmacodynamic adequacy of polymyxin B against extensively drug-resistant Gram-negative bacteria in critically ill, general ward and cystic fibrosis patient populations.

Dose-limiting nephrotoxicity is a significant side effect of polymyxin B treatment. Only limited clinical studies describe the pharmacodynamics of polymyxin B, with little guidance existing for treatment optimisation against multidrug-resistant Gram-negative bacteria. In this study, differences in the likelihood of achieving efficacious and toxic exposures of polymyxin B for critically ill, general ward and cystic fibrosis (CF) patients were evaluated. The following dosing regimens were tested: maintenance doses of 1, 1.25, 1.5 and 2 mg/kg every 12 h (q12h); and loading doses of 2 mg/kg followed by 1.25 mg/kg q12h and 2.5 mg/kg followed by 1.5 mg/kg q12h. Patient weight notably influenced exposure and the required patient dose. To achieve an optimised exposure with minimal toxicity risk, an empirical polymyxin B dose of 2 mg/kg q12h was required for critically ill patients weighing 50 kg, whereas doses of 1.25 mg/kg q12h and 1 mg/kg q12h were required for those weighing 75 kg and 100 kg, respectively. Conversely, 2 mg/kg q12h was required for general ward patients weighing 75 kg. For general ward and CF patients weighing 50 kg, the target exposure could not be achieved with any regimen. Furthermore, the likelihood of toxicity was always high for bacteria with minimum inhibitory concentrations (MICs) of ≥2 mg/L. These findings support the use of a loading dose to increase the achievement of polymyxin B target exposures. To improve efficacy, doses should be optimised according to the patient population.

Erythromycin relaxes BALB/c mouse airway smooth muscle.

AIMS: Bitter taste receptor (TAS2R) agonists have bronchodilatory potentials. Erythromycin is a ligand of TAS2R10, but its relaxant profile is unknown. This study was performed to understand the relaxant effects of erythromycin and its potential mechanism. MAIN METHODS: Airway resistance was tested by the whole body plethysmography in the ovalbumin-aluminum hydroxide induced asthma model mice. Tracheal ring segment myography was used to investigate the isometric tension of the smooth muscle. The cyclic adenosine monophosphate (cAMP) concentration was measured by enzyme immunoassay kit. Changes in the calcium influx in airway smooth muscle cells (ASMCs) were surveyed using a real-time confocal microscopy. KEY FINDINGS: Erythromycin significantly relieved airway hyperreactivity in asthma model mice. Erythromycin relaxed mouse tracheal segments precontracted with carbachol, KCl, 5-hydroxytryptamine and U46619, and further dilated the tracheal rings relaxed by isoprenaline or atropine. Epithelium removal, indomethacin or NS-398 partially reduced the relaxation. U73122, 2-APB, iberiotoxin or ouabain did not change the concentration-relaxation curves of erythromycin on tracheal segments. Erythromycin didn't elevate cAMP level. CaCl2-induced contraction in the K+-rich solution was impaired by erythromycin in the Ca2+-free solution. The intercellular Ca2+ level in the ASMCs was decreased by erythromycin, which was partly inhibited by Bay K8644 but not gallein. SIGNIFICANCE: Erythromycin had marked bronchodilatory effect. The relaxation might be related to the L-type voltage-dependent calcium channel, but not the gustducin-associated ßγ/phospholipase-Cß/inositol 1,4,5-tri-phosphate receptor/large conductance Ca2+-activated K+ channel pathway or a cAMP-dependent way.

Comparation of vancomycin penetration into cerebrospinal fluid in postoperative intracranial infection and community-acquired meningitis patients.

WHAT IS KNOWN AND OBJECTIVE: To compare the penetration of vancomycin into cerebrospinal fluid (CSF) in patients with postoperative intracranial infection and community-acquired meningitis, and to identify related factors influencing the penetration in these two diseases. METHODS: The concentrations of vancomycin in serum and CSF were determined by enzyme amplified immunoassay, and the CSF-to-serum ratios were calculated. The correlation between CSF-to-serum ratios of vancomycin and CSF elements was analyzed. RESULTS AND DISCUSSION: In postoperative intracranial infection patients and community-acquired meningitis patients, the vancomycin concentration in CSF was 1.90 ± 1.29 mg/L and 2.47 ± 1.15 mg/L, while the CSF-to-serum ratio was 0.19 ± 0.12 and 0.26 ± 0.12, respectively. There was a significant correlation between vancomycin serum concentration and bodyweight (P < 0.05). The CSF-to-serum ratio in postoperative intracranial infection patients was correlated to white blood cell count in CSF. However, in community-acquired meningitis patients, no relationship was seen with regards to CSF white blood cell count, protein or glucose. WHAT IS NEW AND CONCLUSION: Cerebrospinal fluid vancomycin penetration was similar in postoperative intracranial infection and community-acquired meningitis patients. The CSF-to-serum ratio was only correlated to CSF white blood cell count in postoperative intracranial infection patients.

Pharmacists' perception of pharmaceutical care in community pharmacy: a questionnaire survey in Northwest China.

The aim of this study was to explore the perceptions of community pharmacists towards the concept of pharmaceutical care, implementing frequencies of pharmaceutical care, and barriers to implementation of pharmaceutical care in China. A 38-item self-completion pre-tested questionnaire was administered to a quota sample of 130 pharmacists in community pharmacies in Xi'an, Shaanxi Province, northwest China in April 2008. Main outcome measures included understanding of pharmaceutical care; perceived frequency of pharmaceutical care activities; attitude towards pharmaceutical care; barriers to implementation of pharmaceutical care. A response rate of 77.7% (101/130) was achieved. The data were analysed descriptively. Factor analysis was used to explore potential barriers to the provision of pharmaceutical care. Respondents' understanding of the definition of pharmaceutical care was not entirely satisfactory: it was widely but incorrectly seen as a medication counselling service and many pharmacists appeared to misunderstand their role in the process. Respondents spent most of their work time performing prescription checks and providing patients with directions for drug administration, dosage, and precautions, but they tended to ignore health promotion within and outside of pharmacy settings. Factor analysis suggested four factors influencing the implementation of pharmaceutical care in the surveyed community pharmacies: lack of external conditions for developing or providing pharmaceutical care, lack of time and skills, absence of information and economic incentive, and lack of full support from other health professionals, with a cumulative variance of 64.7%. Cronbach's alpha for the four factors was 0.71, 0.72, 0.69 and 0.74, respectively. Although the respondent pharmacists had a certain degree of understanding of the definition, aim, function and use of pharmaceutical care, and carried out some activities currently, a range of barriers need to be overcome before comprehensive pharmaceutical care becomes a reality in China. These barriers could be overcome through participation in effective continuing educational programmes, availability of more resources, effective collaboration with other health professionals.