Tigecycline-Induced Hypoglycemia in Critically Ill Patients with Severe Infections: A Retrospective Cohort Study

Tigecycline-Induced Hypoglycemia in Critically Ill Patients with Severe Infections: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Tigecycline-Induced Hypoglycemia in Critically Ill Patients with Severe Infections: A Retrospective Cohort Study ziming Yuan, feng Li, zhihua Zhang, zhihao Tian, yan Huo, yan Chen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8717410/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Objective:‌This study assessed the association between tigecycline administration and blood glucose reduction in critically ill patients with severe infections, and identified related risk factors. ‌Methods:‌ Mixed-model repeated measures and generalized estimating equations analyzed blood glucose changes before and after tigecycline treatment. Multivariate linear regression and binary logistic regression identified factors associated with glucose reduction and hypoglycemia. ROC curve analysis evaluated hypoglycemia predictors. ‌Results:‌ Among 169 patients (mean age 64.2±15.8 years), daily blood glucose levels significantly decreased at three time points (6 am, 2 pm, 10 pm) following tigecycline administration, independent of other factors. Glucose reduction correlated significantly with minimum pre-treatment glucose levels, maximum 24-hour glucose decrease, and tigecycline therapy duration. Hypoglycemia occurred in 19 patients (11.2%), associated with higher 28-day mortality (OR=3.83), maximum 24-hour glucose decrease (OR=1.25), lower pre-treatment glucose (OR=0.67), and ICU admission (OR=4.84). The combined predictor (maximum 24-hour glucose decrease + admission type) achieved an AUC of 0.84 (95% CI: 0.75-0.93) with 0.79 sensitivity and 0.79 specificity. ‌Conclusion:‌ Tigecycline administration is associated with decreased blood glucose and may increase short-term mortality in critically ill patients with severe infections. Early monitoring and identification of hypoglycemia risk are recommended during tigecycline therapy. Tigecycline hypoglycemia critically ill patients severe infection Figures Figure 1 Figure 2 Highlight Declining blood glucose levels and hypoglycemia have been identified in critically ill patients with severe infections who are receiving tigecycline therapy. These conditions may further elevate short-term mortality risk. Additionally, the clinical use of certain indicators is recommended for early detection and alerting. Introduction Antimicrobial resistance is one of the most urgent global health concerns in the twenty-first century 1 . In intensive care units, infections stemming from multidrug-resistant (MDR) Gram-negative bacteria are particularly difficult to manage, presenting a major public health threat and significantly contributing to morbidity and mortality 2 . In addressing this challenge, ongoing efforts have focused on developing effective antibiotics against MDR bacteria, including β-lactam/β-lactamase inhibitor combinations, novel cephalosporins, tetracyclines, aminoglycosides, and quinolones 3 . Tigecycline is a novel 9-t-butylglycylamido derivative of minocycline that is mainly aimed at treating infections with methicillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci, extended-spectrum β-lactamase-producing gram-negative bacteria and Acinetobacter baumannii 4 . Tigecycline was initially approved by the US Food and Drug Administration in 2005 for the treatment of adults with complicated intra-abdominal infections (cIAIs) and complicated skin and skin structure infections (cSSSIs) 5 , 6 . In 2008, tigecycline also received FDA approval for the treatment of adult patients with community-acquired bacterial pneumonia 7 . However, with the escalating clinical utilization of tigecycline, an increasing number of adverse drug reactions (ADRs) have been documented. The most frequently reported treatment-related adverse effects include nausea, vomiting, pancreatitis, and hepatic function abnormalities 8 . Notably, hypoglycemia is documented in the prescribing information as an infrequent adverse event, occurring in fewer than 2% of cases 9 . The reported odds ratio (ROR) for hypoglycemia in patients treated with tigecycline-excluding those also receiving sulfonylureas or meglitinides-was 3.32 10 . Although the underlying mechanism is not yet fully elucidated, there is a possibility that the drug triggers excessive insulin secretion 11 . Most episodes of severe hypoglycemia resolve without causing apparent permanent injury 11 . However, previous studies indicate that critically ill patients experiencing severe hypoglycemia face a mortality risk twice as high as those without hypoglycemia 12 . Therefore, it is critical to promptly identify hypoglycemia and initiate targeted treatment. To date, there have been limited studies examining the risk factors for hypoglycemia in patients treated with tigecycline. In this study, we conducted a retrospective analysis of critically ill patients admitted to the intensive care unit (ICU) who received tigecycline therapy. The objectives were to determine the incidence of hypoglycemia and its prognostic implications, analyze the trend in blood glucose levels, identify associated risk factors, and explore potential predictors of hypoglycemia. Materials and methods Study design We conducted a retrospective cohort study in ICU in three tertiary hospitals in Shanghai, China. A retrospective cohort study included critically ill adult patients aged ≥ 18 years who were diagnosed with severe infections and received tigecycline therapy between January2024 and June 2025. The following exclusion criteria were applied: 1) treatment duration with tigecycline < 24 hours; 2) inadequate blood glucose monitoring data; or 3) pre-existing diabetes mellitus diagnosed prior to admission. Data collection at baseline At baseline, patient data were collected, encompassing the diagnosis upon admission, Acute Physiology and Chronic Health Evaluation (APACHE II) score, infecting microorganisms, comorbidities, and demographic characteristics (sex and age). The APACHE II score was determined based on the worst values recorded during the initial 24-hour period following admission. All other variables were extracted directly from medical records and routine laboratory testing. Data measurement in the follow-up In the subsequent follow-up period, we systematically recorded daily blood glucose levels, including the dosage and duration of tigecycline administration, alongside liver and renal function parameters. Daily blood glucose measurements were conducted three times daily (at 6:00 AM, 2:00 PM, and 10:00 PM) using a point-of-care electrochemical glucose meter (FreeStyle Optium, Abbott Diabetes Care Ltd.), performed by experienced nursing staff. Furthermore, follow-up assessments were extended until June 2026 to ascertain survival status at discharge and post-discharge. Survival data were collected through face-to-face interviews conducted in the hospital or via telephone interviews after discharge, both administered by experienced intensivists. Definitions of changes in the blood glucose In this study, hypoglycemia was operationally defined as a minimum blood glucose level of < 2.8 mmol/L following tigecycline administration, consistent with established criteria 13 . The change in blood glucose was quantified as the difference between the minimum blood glucose level observed prior to tigecycline administration and the lowest level recorded post-administration. Additionally, the maximum decrease in blood glucose within a 24-hour period was defined as the difference between the highest and lowest blood glucose levels recorded during the 24-hour window following tigecycline administration. Statistical analysis Characteristics of the patients are described as the means (standard deviations [SDs]) or medians (interquartile ranges [IQRs]) for continuous variables and frequencies (percentages) for categorical variables. Characteristics of patients with and without hypoglycemia were compared using Student’s t test or the nonparametric Mann-Whitney U test for continuous variables and the chi-square test for categorical variables. The variables with a P value < 0.2 in the univariate analysis were eligible for inclusion in multivariate analysis. First, mixed-model repeated measures analysis was employed to compare mean blood glucose levels before and after tigecycline administration. The two phases (before and after tigecycline administration) and daily blood glucose measurements (recorded at 6 am, 2 pm, and 10 pm) were incorporated as repeated factors in the model. Additional covariates and categorical variables included in the analysis were sex, age, comorbidities, prognosis, as well as the duration and dosage of tigecycline administration. Furthermore, to establish a more reliable assessment of blood glucose trends before and after tigecycline administration, patients with complete blood glucose monitoring data across sequential days-specifically, two days prior to administration, the day of administration, and two days following administration-were selected for analysis using generalized estimating equations. Secondly, a binary logistic regression model was utilized to identify risk factors associated with hypoglycemia. Multivariate linear regression analysis was conducted to assess factors correlated with reductions in blood glucose levels. To mitigate potential collinearity issues in the regression models, a backward stepwise regression approach was employed for variable selection. Specifically, variables that failed to achieve statistical significance in the multivariate analysis were systematically excluded from the final models. Additionally, the goodness-of-fit of the logistic regression model was evaluated using the Hosmer-Lemeshow test (P = 0.29). Multicollinearity among predictor variables in the models was assessed by calculating the variance inflation factor (VIF); variables exhibiting a VIF ≥ 5 were subsequently removed from the analysis. Finally, receiver operating characteristic (ROC) curves and their corresponding areas under the curve (AUCs) were computed to evaluate the predictive accuracy of identified factors for hypoglycemia. Third, overall survival analysis was performed using the Kaplan-Meier survival method, and the log-rank test was used to compare survival in patients with and without hypoglycemia. A two-tailed P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS statistics version 23.0 (IBM corporation, NY, USA). Results Incidence of hypoglycemia A cohort study encompassing 169 critically ill adult patients with severe infections who received tigecycline treatment was conducted. Among these patients, 19 (11.2%) developed hypoglycemia. Patients who experienced hypoglycemia exhibited a tendency toward relatively lower APACHE II scores. Prior to tigecycline administration, they demonstrated lower minimum blood glucose levels. Within 24 hours following tigecycline administration, these patients showed significantly reduced minimum blood glucose levels and a greater maximum decrease in blood glucose compared to baseline (Table 1 ). Table 1 Incidence of hypoglycemia in the cohort Total (n = 169) Non-hypoglycemia (n = 150) Hypoglycemia (n = 19) P value Age (years), mean (SD) 64.3 (15.8) 63.7 (15.6) 68.5 (16.9) 0.21 Sex, n (%) Male 105 (62.1) 96 (64.0) 9 (47.4) 0.16 Female 64 (37.9) 54 (36.0) 10 (52.6) APACHE II score, mean (SD) 26.4 (8.7) 26.9 (8.6) 22.5 (9.3) 0.04 Duration of tigecycline administration (hours), mean (SD) 277.7 (194.2) 278.7 (201.0) 279.5 (132.1) 0.86 Minimum blood glucose before tigecycline administration (mmol/L), mean (SD) 5.8 (1.5) 5.9 (1.5) 4.9 (1.9) 0.004 Minimum blood glucose after tigecycline administration (mmol/L), median (IQR) 5.1 (4.3-6.0) 5.2 (4.5–6.1) 2.5 (1.7–2.7) < 0.001 Time duration to the minimum blood glucose after tigecycline administration (hours), mean (SD) 146.4 (127.6) 145.2 (126.2) 156.3 (141.3) 0.72 Maximum decrease in blood glucose within 24 hours (mmol/L), median (IQR) 4.5 (2.5–8.1) 4.1 (2.4–7.4) 7.6 (5.0-13.7) 0.004 Death within 28 days after the admission, n (%) 35 (20.7) 26 (17.3) 9 (47.4) 0.002 Dosage of tigecycline, n (%) 0.25 50mg 129 (76.3) 112 (74.7) 17 (89.5) 100mg 40 (23.7) 38 (25.3) 2 (10.5) Routine laboratory testing at baseline, mean (SD) Total bilirubin (µmol/L) 20.9 (32.6) 20.1 (32.2) 26.5 (36.14) 0.43 Albumin (g/L) 32.2 (6.6) 32.6 (6.3) 28.9 (8.3) 0.02 Creatinine (µmoI/L) 97.9 (91.7) 96.8 (93.2) 107.2 (79.6) 0.64 Glutamic-pyruvic transaminase (u/L) 50.7 (88.1) 52.7 (92.9) 34.6 (25.7) 0.40 Glutamic oxalacetic transaminase(u/L) 50.2 (84.9) 52.2 (89.6) 34.6 (23.3) 0.40 Routine laboratory testing after tigecycline administration, mean (SD) Total bilirubin (µmol/L) 23.9 (43.0) 22.5 (43.1) 34.7 (40.9) 0.24 Albumin (g/L) 30.9 (5.4) 31.3 (5.4) 28.2 (5.1) 0.02 Creatinine (µmoI/L) 94.8 (100.7) 90.3 (99.5) 130.6 (106.2) 0.09 Glutamic-pyruvic transaminase (u/L) 46.4 (43.4) 47.4 (44.6) 38.4 (31.4) 0.41 Glutamic oxalacetic transaminase(u/L) 49.5 (75.7) 48.8 (76.7) 55.2 (69.1) 0.71 Underlying diseases, n (%) Hypertension 86 (50.9) 77 (51.3) 9 (47.4) 0.75 Renal dysfunction 9 (5.3) 7 (4.7) 2 (10.5) 0.60 Cancer 12 (7.1) 10 (6.7) 2 (10.5) 0.89 Cardiovascular diseases 16 (9.5) 13 (8.7) 3 (15.8) 0.56 Trend in blood glucose after tigecycline administration Following tigecycline administration, daily blood glucose levels exhibited a significant decline, irrespective of other confounding factors. Additionally, blood glucose measurements taken at three distinct time points demonstrated a circadian rhythm, with the lowest values observed at 6:00 AM (Table 2 ). Furthermore, a cohort of 119 patients with complete blood glucose monitoring data from sequential days before and after tigecycline administration was analyzed. After adjusting for the timing of measurements, blood glucose levels were found to have significantly decreased on the day of tigecycline administration, with a continued decline observed over the subsequent two days (Table 2 ). Table 2 Trend in blood glucose before and after tigecycline administration by mixed-model repeated measures and generalized estimating equations Coefficient 95% CI P value All patients (n = 169) Phase Before administration - 1.0 After administration -1.21 -1.51, -0.91 < 0.001 Measuring points of time 6am - 1.0 2pm 1.83 1.44, 2.23 < 0.001 10pm 2.03 1.65, 2.42 < 0.001 Patients with complete data (n = 119) Phase 2 days before administration - 1.0 - 1 day before administration -0.01 -0.35, 0.32 0.937 The day of administration -0.57 -0.96, -0.19 0.004 1 day after administration -0.94 -1.39, -0.49 0.001 2 days after administration -0.94 -1.38, -0.51 0.001 Measuring points of time 6am - 1.0 - 2pm 2.09 1.69, 2.50 0.001 10pm 2.33 1.98, 2.68 0.001 Tigecycline-induced hypoglycemia and blood glucose reduction risks Independent predictors of hypoglycemia were identified as a lower minimum blood glucose level prior to tigecycline administration (OR = 0.67, 95% CI [confidence interval]), a greater maximum decrease in blood glucose during the first 24 hours post-tigecycline administration (OR = 1.25), and admission to the ICU (OR = 4.84) (Table 3 ). Furthermore, patients who developed hypoglycemia exhibited significantly higher 28-day all-cause mortality rates (OR = 3.83). Additionally, multivariate analysis revealed that the magnitude of blood glucose reduction was positively associated with the baseline minimum blood glucose level before tigecycline administration, the maximum blood glucose decrease within 24 hours post-treatment, and the duration of tigecycline administration (in hours). Conversely, it demonstrated a negative correlation with male sex and the APACHE II score (Supplemental Digital Content-Table 1). Table 3 Risk factors for hypoglycemia after tigecycline administration by logistic regression OR value 95% CI P value Minimum blood glucose before tigecycline administration (mmol/L) 0.67 0.47, 0.96 0.031 Maximum decrease in blood glucose within 24 hours (mmol/L) after tigecycline administration 1.25 1.11, 1.41 < 0.001 Death within 28 days after the admission 3.83 1.22, 12.01 0.021 We subsequently employed individual risk factors and their combinations to construct ROC curves for predictive performance evaluation. Among the individual risk factors, the maximum blood glucose reduction within 24 hours post-tigecycline administration demonstrated the highest AUC value of 0.76. For factor combinations, the integration of maximum 24-hour blood glucose reduction and admission type yielded the optimal predictive model with an AUC of 0.84 (95% CI, 0.75–0.93) (Fig. 1 ; see Supplemental Digital Content, Table 2 ). Survival analysis In the study, all deaths occurring within 28 days took place in ICU, as detailed in Table 1 . Additionally, a total of 32 patients died after discharge from the hospital, comprising 3 patients with hypoglycemia and 29 without hypoglycemia. The overall mortality rates were calculated at 2.7 deaths per person-year for patients with hypoglycemia and 1.0 death per person-year for those without hypoglycemia. Subsequently, Kaplan-Meier survival curves were generated (Fig. 2 ). The median survival time for patients with hypoglycemia was 33 days, compared to 355 days for those without hypoglycemia (P = 0.019). Discussion The incidence of hypoglycemia among critically ill patients demonstrates significant variability across geographic regions, healthcare institutions, admission categories, and diagnostic criteria 14 . Despite inconsistencies in the diagnostic criteria for hypoglycemia across studies 15 – 17 , the Chinese diagnostic guidelines define hypoglycemia as blood glucose levels below 2.8 mmol/L (50 mg/dL) in non-diabetic patients 13 . In this study, we operationalized a hypoglycemic event as a blood glucose level falling below 2.8 mmol/L following tigecycline administration. The incidence of hypoglycemia in our cohort was 11.2%, which is higher than the range of 0.4% to 6.2% reported in previous studies 12 , 18 – 19 , likely due to differences in definitions and patient populations. Furthermore, our study focused on the outcome of hypoglycemia, so the difference between the minimum blood glucose levels before and after administration was considered as a measurement of the decrease in blood glucose. Therefore, our study suggested that there is a substantial risk of a reduction in blood glucose and even the development of hypoglycemia in critically ill patients with severe infections after tigecycline administration. We investigated the potential risk factors linked to declining blood glucose and hypoglycemia. Both the minimum blood glucose level prior to tigecycline administration and the maximum decrease in blood glucose within 24 hours following tigecycline administration were found to be associated with hypoglycemia and the magnitude of blood glucose reduction. Furthermore, the combination of the maximum decrease in blood glucose within 24 hours after tigecycline administration and the cause of ICU admission emerged as a significant predictor of hypoglycemia, demonstrating high sensitivity and specificity (79% each). Second, we observed substantial interindividual variability in the time to reach the minimum blood glucose level following tigecycline administration, with durations ranging from 16 hours to 460 hours post-administration. Notably, this variability was not significantly associated with baseline blood glucose levels prior to tigecycline treatment. Third, the duration of tigecycline therapy exhibited a correlation with the degree of blood glucose reduction. However, different dosing regimens (50 mg or 100 mg every 12 hours) did not demonstrate a significant impact on either the occurrence or time to onset of hypoglycemia. Furthermore, these dosing variations were not correlated with 28-day mortality or long-term mortality outcomes, suggesting that increasing the dose of tigecycline does not appear to elevate the risk of hypoglycemia or adversely affect prognosis. In a prior case report 20 , a patient developed symptoms of hypoglycemia following tigecycline administration, with the condition resolving 34 hours after discontinuation of the drug. Given that the half-life of tigecycline is approximately 27 hours per 100 mg dose, the duration of hypoglycemia aligns with the drug's pharmacokinetic profile 9 , 20 , thereby supporting a potential causal relationship between tigecycline and hypoglycemia. Additionally, other antibiotics, including cefditoren, ertapenem, and clarithromycin, have been documented to increase the risk of hypoglycemia 10 . In this study, no significant differences were observed between males and females in baseline blood glucose levels prior to tigecycline administration or in the incidence of hypoglycemia. However, females exhibited a significantly greater reduction in blood glucose and significantly lower post-administration blood glucose levels compared to males. Given the limited sample size of our study, further investigation with enhanced statistical power is warranted to validate these findings. Compared with neurological patients, general surgery patients exhibited a higher risk of hypoglycemia. The APACHE II score was relatively lower in this patient group, and the reduction in blood glucose levels demonstrated a negative correlation with the APACHE II score. Previous studies have indicated that patients with brain injury may experience abnormal elevations in blood glucose due to pituitary and hypothalamic dysfunction 21 , which could account for the relatively lower incidence of hypoglycemia observed in neurological patients. Furthermore, the incidence of hypoglycemia and the extent of blood glucose reduction were found to be independent of other factors, including liver and kidney function as well as underlying diseases. This finding provides a scientific rationale for the clinical management of hypoglycemia in these patient populations. In survival analysis, no significant difference was observed in APACHE II scores between patients who died within 28 days of ICU admission and those who survived, nor between those who died by the end of the follow-up period and those who survived. This suggests that disease severity was comparable across these patient groups, indicating that premature mortality was more likely attributable to declining blood glucose levels rather than disease severity per se. Furthermore, survival analysis revealed that 28-day mortality was significantly higher in patients experiencing hypoglycemia compared to those without hypoglycemia. However, cumulative mortality rates gradually converged between the two groups after one year of follow-up. Taken together with the significant correlation between hypoglycemia and mortality within the initial 28 days of ICU admission, these findings suggest that hypoglycemia exerts a substantial impact on short-term survival but has a relatively limited influence on long-term prognosis in these patients. ‌Limitations of the Study‌ Several limitations should be acknowledged in this study. First, the sample size was relatively limited, which may have resulted in wide confidence intervals for certain outcome indicators. However, it is important to note that tigecycline is predominantly used in patients with severe infections, inherently constraining the potential sample size for this study. Second, hypoglycemia is more frequently observed in diabetic patients undergoing hypoglycemic therapy 20 . Yet, this study included a very small number of diabetic patients, and these individuals were excluded from analysis. To better understand the impact of diabetes on hypoglycemia risk, future studies should actively recruit sufficient diabetic patients for comprehensive evaluation. Third, some patients received glucose supplementation following a decline in blood glucose levels, which may have effectively prevented the occurrence of hypoglycemic events. Due to the challenges in accurately quantifying glucose supplementation, this study likely underestimated the true incidence of hypoglycemia. Conclusion Our study has significant clinical implications. We observed that critically ill patients with severe infections exhibited a rapid decline in blood glucose levels following tigecycline administration, and that hypoglycemia in these patients was significantly associated with increased short-term mortality. Consequently, it is imperative to closely monitor blood glucose in patients undergoing tigecycline therapy. Certain predictors of blood glucose reduction and hypoglycemia, such as the minimum blood glucose level prior to tigecycline administration and the maximum decrease in blood glucose within 24 hours post-administration, can serve as valuable early warning indicators in clinical practice for the management of critically ill patients with severe infections. Declarations Authors contribution Yan Chen and Weifeng Huang conceived and designed the study. Ziming Yuan and Feng Li conducted the study and contributed to the acquisition of data. Zhihua Zhang ang Zhihao Tian performed the statistical analysis and interpretation of the data. Ziming Yuan and Feng Li prepared the manuscript. Yan Chen and Weifeng Huang critically revised the manuscript. All authors read the manuscript and approved the final manuscript. Funding This study was supported by Shanghai Municipal Health Commission (Project No. 202540042), Shanghai Xuhui District Medical Scientific Research Project (No. SHXH202414). Data Availability The datasets generated and/or analyzed during the current study are not publicly available due to privacy reasons. The corresponding author can be contacted for the availability of data. Ethics approval and consent to participate This study was approved by the Ethics Committee of Shanghai Xuhui Central Hospital, reference number 2025.41. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent will be obtained from all subjects. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Baran A, Kwiatkowska A, Potocki L. Antibiotics and bacterial resistance—a short story of an endless arms race. Int J Mol Sci. 2023;24(6):5777. 10.3390/ijms24065777 . Başaran SN, Öksüz L. Newly developed antibiotics against multidrug-resistant and carbapenem-resistant Gram-negative bacteria: action and resistance mechanisms. Arch Microbiol. 2025;207(5):110. 10.1007/s00203-025-04298-z . 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Review: traumatic brain injury and hyperglycemia, a potentially modifiable risk factor. Oncotarget. 2016;7(43):71052–61. 10.18632/oncotarget.11234 . Additional Declarations No competing interests reported. Supplementary Files supplementaryfiles.doc Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 17 Mar, 2026 Reviewers agreed at journal 12 Mar, 2026 Reviewers invited by journal 06 Mar, 2026 Editor invited by journal 10 Feb, 2026 Editor assigned by journal 03 Feb, 2026 Submission checks completed at journal 03 Feb, 2026 First submitted to journal 28 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8717410","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":601730604,"identity":"1e8b1d44-6111-4604-8cd7-486d9a9166c7","order_by":0,"name":"ziming Yuan","email":"","orcid":"","institution":"Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"ziming","middleName":"","lastName":"Yuan","suffix":""},{"id":601730605,"identity":"61a8aac3-8a3a-4861-ba00-2646ee69cfb6","order_by":1,"name":"feng Li","email":"","orcid":"","institution":"Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"feng","middleName":"","lastName":"Li","suffix":""},{"id":601730608,"identity":"a43f065e-c4f6-4e79-855b-1535d6a3c822","order_by":2,"name":"zhihua Zhang","email":"","orcid":"","institution":"Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"zhihua","middleName":"","lastName":"Zhang","suffix":""},{"id":601730611,"identity":"7e849882-00d2-4010-91a7-038cc6c22589","order_by":3,"name":"zhihao Tian","email":"","orcid":"","institution":"Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"zhihao","middleName":"","lastName":"Tian","suffix":""},{"id":601730612,"identity":"5a13f132-c932-45dd-af23-e70304129a56","order_by":4,"name":"yan Huo","email":"","orcid":"","institution":"Yangpu Hospital, School of Medicine, Tongji University","correspondingAuthor":false,"prefix":"","firstName":"yan","middleName":"","lastName":"Huo","suffix":""},{"id":601730613,"identity":"4a2468c0-312b-46de-aebe-ce6ce9b90719","order_by":5,"name":"yan Chen","email":"","orcid":"","institution":"Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"yan","middleName":"","lastName":"Chen","suffix":""},{"id":601730614,"identity":"df0e4145-001b-425c-8468-1786d1278883","order_by":6,"name":"weifeng Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYBACAyidACY/NoBIxsYDRGthnNnAIAGkGojXwswL1sLAgFeLufThgw9/VDDkGRw/e/i17Q6bOt32w0BbamyicWmx7EtLNpA4w1BscCYvzTr3TJqE2ZlEoJZjabkNuBx2hsdMwrDtf+KGAzlmxrlthyXMDgC1MDYcxqOF//uPxH8MiRvOvzEztgRpOf+QkBYeNoaDDUAtN3KMHzOCtNwgYItlD5uxZMMxhsSZN96YMfa2pUluuwG0JQGPX8x5mB9+/FHDkNh3Psf4w882G36z8+kPH3yoscGpBRmwScCZCUQoBwHmD0QqHAWjYBSMghEGAHIxZPm4lwBXAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University","correspondingAuthor":true,"prefix":"","firstName":"weifeng","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2026-01-28 06:53:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8717410/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8717410/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104471848,"identity":"db272514-c6ae-4cef-9d40-bac878bc61c8","added_by":"auto","created_at":"2026-03-12 07:28:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36072,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of receiver operating characteristic (ROC) using single and combined factors predictive of hypoglycemia.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8717410/v1/75199ea63a5675ca7398f294.png"},{"id":104471886,"identity":"7c978607-17ef-44a0-9fc9-5b3cb7a43293","added_by":"auto","created_at":"2026-03-12 07:28:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":18477,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of critically ill patients with and without hypoglycemia.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8717410/v1/c0f29221d1da233c7c8731b2.png"},{"id":104471987,"identity":"33fe59ce-b1fc-4e47-8080-8998199e8ad5","added_by":"auto","created_at":"2026-03-12 07:28:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1134826,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8717410/v1/b4408631-11b6-4cd9-a706-37b203535385.pdf"},{"id":104471964,"identity":"c19f01e9-07c5-48c3-9060-0109b1bd3572","added_by":"auto","created_at":"2026-03-12 07:28:27","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":27136,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfiles.doc","url":"https://assets-eu.researchsquare.com/files/rs-8717410/v1/fc88aa4564f9a69c600b368b.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Tigecycline-Induced Hypoglycemia in Critically Ill Patients with Severe Infections: A Retrospective Cohort Study","fulltext":[{"header":"Highlight","content":"\u003cp\u003eDeclining blood glucose levels and hypoglycemia have been identified in critically ill patients with severe infections who are receiving tigecycline therapy. These conditions may further elevate short-term mortality risk. Additionally, the clinical use of certain indicators is recommended for early detection and alerting.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAntimicrobial resistance is one of the most urgent global health concerns in the twenty-first century\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In intensive care units, infections stemming from multidrug-resistant (MDR) Gram-negative bacteria are particularly difficult to manage, presenting a major public health threat and significantly contributing to morbidity and mortality\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. In addressing this challenge, ongoing efforts have focused on developing effective antibiotics against MDR bacteria, including β-lactam/β-lactamase inhibitor combinations, novel cephalosporins, tetracyclines, aminoglycosides, and quinolones\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Tigecycline is a novel 9-t-butylglycylamido derivative of minocycline that is mainly aimed at treating infections with methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, vancomycin-resistant enterococci, extended-spectrum β-lactamase-producing gram-negative bacteria and \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Tigecycline was initially approved by the US Food and Drug Administration in 2005 for the treatment of adults with complicated intra-abdominal infections (cIAIs) and complicated skin and skin structure infections (cSSSIs)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In 2008, tigecycline also received FDA approval for the treatment of adult patients with community-acquired bacterial pneumonia\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, with the escalating clinical utilization of tigecycline, an increasing number of adverse drug reactions (ADRs) have been documented. The most frequently reported treatment-related adverse effects include nausea, vomiting, pancreatitis, and hepatic function abnormalities\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Notably, hypoglycemia is documented in the prescribing information as an infrequent adverse event, occurring in fewer than 2% of cases\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The reported odds ratio (ROR) for hypoglycemia in patients treated with tigecycline-excluding those also receiving sulfonylureas or meglitinides-was 3.32\u003csup\u003e10\u003c/sup\u003e. Although the underlying mechanism is not yet fully elucidated, there is a possibility that the drug triggers excessive insulin secretion\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMost episodes of severe hypoglycemia resolve without causing apparent permanent injury\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, previous studies indicate that critically ill patients experiencing severe hypoglycemia face a mortality risk twice as high as those without hypoglycemia\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTherefore, it is critical to promptly identify hypoglycemia and initiate targeted treatment. To date, there have been limited studies examining the risk factors for hypoglycemia in patients treated with tigecycline. In this study, we conducted a retrospective analysis of critically ill patients admitted to the intensive care unit (ICU) who received tigecycline therapy. The objectives were to determine the incidence of hypoglycemia and its prognostic implications, analyze the trend in blood glucose levels, identify associated risk factors, and explore potential predictors of hypoglycemia.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective cohort study in ICU in three tertiary hospitals in Shanghai, China. A retrospective cohort study included critically ill adult patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who were diagnosed with severe infections and received tigecycline therapy between January2024 and June 2025. The following exclusion criteria were applied: 1) treatment duration with tigecycline\u0026thinsp;\u0026lt;\u0026thinsp;24 hours; 2) inadequate blood glucose monitoring data; or 3) pre-existing diabetes mellitus diagnosed prior to admission.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection at baseline\u003c/h3\u003e\n\u003cp\u003eAt baseline, patient data were collected, encompassing the diagnosis upon admission, Acute Physiology and Chronic Health Evaluation (APACHE II) score, infecting microorganisms, comorbidities, and demographic characteristics (sex and age). The APACHE II score was determined based on the worst values recorded during the initial 24-hour period following admission. All other variables were extracted directly from medical records and routine laboratory testing.\u003c/p\u003e\n\u003ch3\u003eData measurement in the follow-up\u003c/h3\u003e\n\u003cp\u003eIn the subsequent follow-up period, we systematically recorded daily blood glucose levels, including the dosage and duration of tigecycline administration, alongside liver and renal function parameters. Daily blood glucose measurements were conducted three times daily (at 6:00 AM, 2:00 PM, and 10:00 PM) using a point-of-care electrochemical glucose meter (FreeStyle Optium, Abbott Diabetes Care Ltd.), performed by experienced nursing staff. Furthermore, follow-up assessments were extended until June 2026 to ascertain survival status at discharge and post-discharge. Survival data were collected through face-to-face interviews conducted in the hospital or via telephone interviews after discharge, both administered by experienced intensivists.\u003c/p\u003e\n\u003ch3\u003eDefinitions of changes in the blood glucose\u003c/h3\u003e\n\u003cp\u003eIn this study, hypoglycemia was operationally defined as a minimum blood glucose level of \u0026lt;\u0026thinsp;2.8 mmol/L following tigecycline administration, consistent with established criteria\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The change in blood glucose was quantified as the difference between the minimum blood glucose level observed prior to tigecycline administration and the lowest level recorded post-administration. Additionally, the maximum decrease in blood glucose within a 24-hour period was defined as the difference between the highest and lowest blood glucose levels recorded during the 24-hour window following tigecycline administration.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCharacteristics of the patients are described as the means (standard deviations [SDs]) or medians (interquartile ranges [IQRs]) for continuous variables and frequencies (percentages) for categorical variables. Characteristics of patients with and without hypoglycemia were compared using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e test or the nonparametric Mann-Whitney U test for continuous variables and the chi-square test for categorical variables. The variables with a \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in the univariate analysis were eligible for inclusion in multivariate analysis.\u003c/p\u003e \u003cp\u003eFirst, mixed-model repeated measures analysis was employed to compare mean blood glucose levels before and after tigecycline administration. The two phases (before and after tigecycline administration) and daily blood glucose measurements (recorded at 6 am, 2 pm, and 10 pm) were incorporated as repeated factors in the model. Additional covariates and categorical variables included in the analysis were sex, age, comorbidities, prognosis, as well as the duration and dosage of tigecycline administration. Furthermore, to establish a more reliable assessment of blood glucose trends before and after tigecycline administration, patients with complete blood glucose monitoring data across sequential days-specifically, two days prior to administration, the day of administration, and two days following administration-were selected for analysis using generalized estimating equations.\u003c/p\u003e \u003cp\u003eSecondly, a binary logistic regression model was utilized to identify risk factors associated with hypoglycemia. Multivariate linear regression analysis was conducted to assess factors correlated with reductions in blood glucose levels. To mitigate potential collinearity issues in the regression models, a backward stepwise regression approach was employed for variable selection. Specifically, variables that failed to achieve statistical significance in the multivariate analysis were systematically excluded from the final models. Additionally, the goodness-of-fit of the logistic regression model was evaluated using the Hosmer-Lemeshow test (P\u0026thinsp;=\u0026thinsp;0.29). Multicollinearity among predictor variables in the models was assessed by calculating the variance inflation factor (VIF); variables exhibiting a VIF\u0026thinsp;\u0026ge;\u0026thinsp;5 were subsequently removed from the analysis. Finally, receiver operating characteristic (ROC) curves and their corresponding areas under the curve (AUCs) were computed to evaluate the predictive accuracy of identified factors for hypoglycemia.\u003c/p\u003e \u003cp\u003eThird, overall survival analysis was performed using the Kaplan-Meier survival method, and the log-rank test was used to compare survival in patients with and without hypoglycemia. A two-tailed \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using SPSS statistics version 23.0 (IBM corporation, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eIncidence of hypoglycemia\u003c/h2\u003e \u003cp\u003eA cohort study encompassing 169 critically ill adult patients with severe infections who received tigecycline treatment was conducted. Among these patients, 19 (11.2%) developed hypoglycemia. Patients who experienced hypoglycemia exhibited a tendency toward relatively lower APACHE II scores. Prior to tigecycline administration, they demonstrated lower minimum blood glucose levels. Within 24 hours following tigecycline administration, these patients showed significantly reduced minimum blood glucose levels and a greater maximum decrease in blood glucose compared to baseline (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence of hypoglycemia in the cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;169)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-hypoglycemia (n\u0026thinsp;=\u0026thinsp;150)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoglycemia (n\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years), mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64.3 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.7 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e68.5 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e105 (62.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96 (64.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54 (36.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10 (52.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAPACHE II score, mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.4 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26.9 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.5 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDuration of tigecycline administration (hours), mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e277.7 (194.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e278.7 (201.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e279.5 (132.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMinimum blood glucose before tigecycline administration (mmol/L), mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.8 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.9 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.9 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMinimum blood glucose after tigecycline administration (mmol/L), median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.1 (4.3-6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.2 (4.5\u0026ndash;6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.5 (1.7\u0026ndash;2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime duration to the minimum blood glucose after tigecycline administration (hours), mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e146.4 (127.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e145.2 (126.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e156.3 (141.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaximum decrease in blood glucose within 24 hours (mmol/L), median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.5 (2.5\u0026ndash;8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.1 (2.4\u0026ndash;7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.6 (5.0-13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDeath within 28 days after the admission, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35 (20.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDosage of tigecycline, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129 (76.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e112 (74.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17 (89.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e100mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40 (23.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38 (25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRoutine laboratory testing at baseline, mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.9 (32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.1 (32.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26.5 (36.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.2 (6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32.6 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28.9 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (\u0026micro;moI/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e97.9 (91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96.8 (93.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e107.2 (79.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlutamic-pyruvic transaminase (u/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.7 (88.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.7 (92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34.6 (25.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlutamic oxalacetic transaminase(u/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.2 (84.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.2 (89.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34.6 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRoutine laboratory testing after tigecycline administration, mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.9 (43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.5 (43.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34.7 (40.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30.9 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.3 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28.2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (\u0026micro;moI/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e94.8 (100.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90.3 (99.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e130.6 (106.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlutamic-pyruvic transaminase (u/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46.4 (43.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47.4 (44.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38.4 (31.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlutamic oxalacetic transaminase(u/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49.5 (75.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.8 (76.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e55.2 (69.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnderlying diseases, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86 (50.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77 (51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTrend in blood glucose after tigecycline administration\u003c/h3\u003e\n\u003cp\u003eFollowing tigecycline administration, daily blood glucose levels exhibited a significant decline, irrespective of other confounding factors. Additionally, blood glucose measurements taken at three distinct time points demonstrated a circadian rhythm, with the lowest values observed at 6:00 AM (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, a cohort of 119 patients with complete blood glucose monitoring data from sequential days before and after tigecycline administration was analyzed. After adjusting for the timing of measurements, blood glucose levels were found to have significantly decreased on the day of tigecycline administration, with a continued decline observed over the subsequent two days (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTrend in blood glucose before and after tigecycline administration by mixed-model repeated measures and generalized estimating equations\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoefficient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;169)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfter administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.51, -0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMeasuring points of time\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6am\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2pm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.44, 2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10pm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.65, 2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatients with complete data (n\u0026thinsp;=\u0026thinsp;119)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhase\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 days before administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 day before administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.35, 0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.937\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe day of administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.96, -0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 day after administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.39, -0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 days after administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.38, -0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMeasuring points of time\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6am\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2pm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.69, 2.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10pm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.98, 2.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTigecycline-induced hypoglycemia and blood glucose reduction risks\u003c/h2\u003e \u003cp\u003eIndependent predictors of hypoglycemia were identified as a lower minimum blood glucose level prior to tigecycline administration (OR\u0026thinsp;=\u0026thinsp;0.67, 95% CI [confidence interval]), a greater maximum decrease in blood glucose during the first 24 hours post-tigecycline administration (OR\u0026thinsp;=\u0026thinsp;1.25), and admission to the ICU (OR\u0026thinsp;=\u0026thinsp;4.84) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, patients who developed hypoglycemia exhibited significantly higher 28-day all-cause mortality rates (OR\u0026thinsp;=\u0026thinsp;3.83). Additionally, multivariate analysis revealed that the magnitude of blood glucose reduction was positively associated with the baseline minimum blood glucose level before tigecycline administration, the maximum blood glucose decrease within 24 hours post-treatment, and the duration of tigecycline administration (in hours). Conversely, it demonstrated a negative correlation with male sex and the APACHE II score (Supplemental Digital Content-Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors for hypoglycemia after tigecycline administration by logistic regression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinimum blood glucose before tigecycline administration (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.47, 0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum decrease in blood glucose within 24 hours (mmol/L) after tigecycline administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.11, 1.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath within 28 days after the admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.22, 12.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe subsequently employed individual risk factors and their combinations to construct ROC curves for predictive performance evaluation. Among the individual risk factors, the maximum blood glucose reduction within 24 hours post-tigecycline administration demonstrated the highest AUC value of 0.76. For factor combinations, the integration of maximum 24-hour blood glucose reduction and admission type yielded the optimal predictive model with an AUC of 0.84 (95% CI, 0.75\u0026ndash;0.93) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; see Supplemental Digital Content, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSurvival analysis\u003c/h2\u003e \u003cp\u003eIn the study, all deaths occurring within 28 days took place in ICU, as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Additionally, a total of 32 patients died after discharge from the hospital, comprising 3 patients with hypoglycemia and 29 without hypoglycemia. The overall mortality rates were calculated at 2.7 deaths per person-year for patients with hypoglycemia and 1.0 death per person-year for those without hypoglycemia. Subsequently, Kaplan-Meier survival curves were generated (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median survival time for patients with hypoglycemia was 33 days, compared to 355 days for those without hypoglycemia (P\u0026thinsp;=\u0026thinsp;0.019).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe incidence of hypoglycemia among critically ill patients demonstrates significant variability across geographic regions, healthcare institutions, admission categories, and diagnostic criteria\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Despite inconsistencies in the diagnostic criteria for hypoglycemia across studies \u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, the Chinese diagnostic guidelines define hypoglycemia as blood glucose levels below 2.8 mmol/L (50 mg/dL) in non-diabetic patients \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. In this study, we operationalized a hypoglycemic event as a blood glucose level falling below 2.8 mmol/L following tigecycline administration. The incidence of hypoglycemia in our cohort was 11.2%, which is higher than the range of 0.4% to 6.2% reported in previous studies \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, likely due to differences in definitions and patient populations. Furthermore, our study focused on the outcome of hypoglycemia, so the difference between the minimum blood glucose levels before and after administration was considered as a measurement of the decrease in blood glucose. Therefore, our study suggested that there is a substantial risk of a reduction in blood glucose and even the development of hypoglycemia in critically ill patients with severe infections after tigecycline administration.\u003c/p\u003e \u003cp\u003eWe investigated the potential risk factors linked to declining blood glucose and hypoglycemia. Both the minimum blood glucose level prior to tigecycline administration and the maximum decrease in blood glucose within 24 hours following tigecycline administration were found to be associated with hypoglycemia and the magnitude of blood glucose reduction. Furthermore, the combination of the maximum decrease in blood glucose within 24 hours after tigecycline administration and the cause of ICU admission emerged as a significant predictor of hypoglycemia, demonstrating high sensitivity and specificity (79% each). Second, we observed substantial interindividual variability in the time to reach the minimum blood glucose level following tigecycline administration, with durations ranging from 16 hours to 460 hours post-administration. Notably, this variability was not significantly associated with baseline blood glucose levels prior to tigecycline treatment. Third, the duration of tigecycline therapy exhibited a correlation with the degree of blood glucose reduction. However, different dosing regimens (50 mg or 100 mg every 12 hours) did not demonstrate a significant impact on either the occurrence or time to onset of hypoglycemia. Furthermore, these dosing variations were not correlated with 28-day mortality or long-term mortality outcomes, suggesting that increasing the dose of tigecycline does not appear to elevate the risk of hypoglycemia or adversely affect prognosis. In a prior case report \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, a patient developed symptoms of hypoglycemia following tigecycline administration, with the condition resolving 34 hours after discontinuation of the drug. Given that the half-life of tigecycline is approximately 27 hours per 100 mg dose, the duration of hypoglycemia aligns with the drug's pharmacokinetic profile \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, thereby supporting a potential causal relationship between tigecycline and hypoglycemia. Additionally, other antibiotics, including cefditoren, ertapenem, and clarithromycin, have been documented to increase the risk of hypoglycemia \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, no significant differences were observed between males and females in baseline blood glucose levels prior to tigecycline administration or in the incidence of hypoglycemia. However, females exhibited a significantly greater reduction in blood glucose and significantly lower post-administration blood glucose levels compared to males. Given the limited sample size of our study, further investigation with enhanced statistical power is warranted to validate these findings. Compared with neurological patients, general surgery patients exhibited a higher risk of hypoglycemia. The APACHE II score was relatively lower in this patient group, and the reduction in blood glucose levels demonstrated a negative correlation with the APACHE II score. Previous studies have indicated that patients with brain injury may experience abnormal elevations in blood glucose due to pituitary and hypothalamic dysfunction \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, which could account for the relatively lower incidence of hypoglycemia observed in neurological patients. Furthermore, the incidence of hypoglycemia and the extent of blood glucose reduction were found to be independent of other factors, including liver and kidney function as well as underlying diseases. This finding provides a scientific rationale for the clinical management of hypoglycemia in these patient populations.\u003c/p\u003e \u003cp\u003eIn survival analysis, no significant difference was observed in APACHE II scores between patients who died within 28 days of ICU admission and those who survived, nor between those who died by the end of the follow-up period and those who survived. This suggests that disease severity was comparable across these patient groups, indicating that premature mortality was more likely attributable to declining blood glucose levels rather than disease severity per se. Furthermore, survival analysis revealed that 28-day mortality was significantly higher in patients experiencing hypoglycemia compared to those without hypoglycemia. However, cumulative mortality rates gradually converged between the two groups after one year of follow-up. Taken together with the significant correlation between hypoglycemia and mortality within the initial 28 days of ICU admission, these findings suggest that hypoglycemia exerts a substantial impact on short-term survival but has a relatively limited influence on long-term prognosis in these patients.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e\u0026zwnj;Limitations of the Study\u0026zwnj;\u003c/h2\u003e \u003cp\u003eSeveral limitations should be acknowledged in this study. First, the sample size was relatively limited, which may have resulted in wide confidence intervals for certain outcome indicators. However, it is important to note that tigecycline is predominantly used in patients with severe infections, inherently constraining the potential sample size for this study. Second, hypoglycemia is more frequently observed in diabetic patients undergoing hypoglycemic therapy \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Yet, this study included a very small number of diabetic patients, and these individuals were excluded from analysis. To better understand the impact of diabetes on hypoglycemia risk, future studies should actively recruit sufficient diabetic patients for comprehensive evaluation. Third, some patients received glucose supplementation following a decline in blood glucose levels, which may have effectively prevented the occurrence of hypoglycemic events. Due to the challenges in accurately quantifying glucose supplementation, this study likely underestimated the true incidence of hypoglycemia.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study has significant clinical implications. We observed that critically ill patients with severe infections exhibited a rapid decline in blood glucose levels following tigecycline administration, and that hypoglycemia in these patients was significantly associated with increased short-term mortality. Consequently, it is imperative to closely monitor blood glucose in patients undergoing tigecycline therapy. Certain predictors of blood glucose reduction and hypoglycemia, such as the minimum blood glucose level prior to tigecycline administration and the maximum decrease in blood glucose within 24 hours post-administration, can serve as valuable early warning indicators in clinical practice for the management of critically ill patients with severe infections.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYan Chen and Weifeng Huang conceived and designed the study. Ziming Yuan and Feng Li conducted the study and contributed to the acquisition of data. Zhihua Zhang ang Zhihao Tian performed the statistical analysis and interpretation of the data. Ziming Yuan and Feng Li prepared the manuscript. Yan Chen and Weifeng Huang critically revised the manuscript. All authors read the manuscript and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Shanghai Municipal Health Commission (Project No. 202540042), Shanghai Xuhui District Medical Scientific Research Project (No. SHXH202414).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to privacy reasons. The corresponding author can be contacted for the availability of data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Shanghai Xuhui Central Hospital, reference number 2025.41. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent will be obtained from all subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBaran A, Kwiatkowska A, Potocki L. Antibiotics and bacterial resistance\u0026mdash;a short story of an endless arms race. 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Oncotarget. 2016;7(43):71052\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.18632/oncotarget.11234\u003c/span\u003e\u003cspan address=\"10.18632/oncotarget.11234\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Tigecycline, hypoglycemia, critically ill patients, severe infection","lastPublishedDoi":"10.21203/rs.3.rs-8717410/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8717410/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjective:‌This study assessed the association between tigecycline administration and blood glucose reduction in critically ill patients with severe infections, and identified related risk factors.\u003c/p\u003e\n\u003cp\u003e‌Methods:‌ Mixed-model repeated measures and generalized estimating equations analyzed blood glucose changes before and after tigecycline treatment. Multivariate linear regression and binary logistic regression identified factors associated with glucose reduction and hypoglycemia. ROC curve analysis evaluated hypoglycemia predictors.\u003c/p\u003e\n\u003cp\u003e‌Results:‌ Among 169 patients (mean age 64.2±15.8 years), daily blood glucose levels significantly decreased at three time points (6 am, 2 pm, 10 pm) following tigecycline administration, independent of other factors. Glucose reduction correlated significantly with minimum pre-treatment glucose levels, maximum 24-hour glucose decrease, and tigecycline therapy duration. Hypoglycemia occurred in 19 patients (11.2%), associated with higher 28-day mortality (OR=3.83), maximum 24-hour glucose decrease (OR=1.25), lower pre-treatment glucose (OR=0.67), and ICU admission (OR=4.84). The combined predictor (maximum 24-hour glucose decrease + admission type) achieved an AUC of 0.84 (95% CI: 0.75-0.93) with 0.79 sensitivity and 0.79 specificity.\u003c/p\u003e\n\u003cp\u003e‌Conclusion:‌ Tigecycline administration is associated with decreased blood glucose and may increase short-term mortality in critically ill patients with severe infections. Early monitoring and identification of hypoglycemia risk are recommended during tigecycline therapy.\u003c/p\u003e","manuscriptTitle":"Tigecycline-Induced Hypoglycemia in Critically Ill Patients with Severe Infections: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-12 07:25:56","doi":"10.21203/rs.3.rs-8717410/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-18T03:38:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178679244770550821243007009921175568255","date":"2026-03-12T05:44:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T06:04:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-10T15:39:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-03T12:41:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-03T12:40:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pharmacology and Toxicology","date":"2026-01-28T06:44:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1eefb8f-2757-4f3c-a444-7c9f0d182c7b","owner":[],"postedDate":"March 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-12T07:25:57+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-12 07:25:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8717410","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8717410","identity":"rs-8717410","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}