Investigation of tazobactam/piperacillin– or meropenem–induced liver injury based on retrospective observational study and the FDA Adverse Event Reporting System

Investigation of tazobactam/piperacillin– or meropenem–induced liver injury based on retrospective observational study and the FDA Adverse Event Reporting System | 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 Article Investigation of tazobactam/piperacillin– or meropenem–induced liver injury based on retrospective observational study and the FDA Adverse Event Reporting System Chihiro Shiraishi, Hideo Kato, Toru Ogura, Takuya Iwamoto This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3607226/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Aug, 2024 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract Background Our objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury by performing a retrospective observational study and a study using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods In a retrospective observational study, data of patients hospitalized in Mie University Hospital between 2010 and 2022 who initiated treatment with tazobactam/piperacillin or meropenem in the intensive care unit were extracted. Liver injury was defined as an elevated alanine aminotransferase (ALT) grade based on the Common Terminology Criteria for Adverse Events. The FAERS database between 2013 and 2022 were used. Results In the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included administration period (odds ratio [OR] = 1.080, p = 0.005), sequential organ failure assessment score (OR = 1.133, p = 0.004), and ALT (OR = 1.042, p = 0.007). Male, age, the fourth–generation cephalosporin, carbapenem, β –lactam and β –lactamase inhibitor combination, and complication of sepsis were associated with liver injury ( p < 0.001). Conclusion The periodic monitoring of liver function is strongly recommended in patients receiving tazobactam/piperacillin or meropenem, particularly in those with multiple risk factors for liver injury. tazobactam/piperacillin meropenem liver injury intensive care unit Figures Figure 1 Figure 2 Figure 3 Introduction Nearly 20% of patients receiving antibiotics for at least 24 h experience adverse events 1 . It is estimated that antibiotics are prescribed 10 times more frequently in the intensive care unit (ICU) than in general wards, thus significantly increasing the risk of adverse events in ICU patients 1 , moreover, ICU patients face the risk of drug accumulation because of organ failure and sensitivity to drug reactions because of their unstable status, thus leading to diverse forms of toxicity including hepatotoxicity, neurological dysfunction, and acute kidney injury. Although the common causes of liver injury include hypoxic hepatitis, congestive hepatopathy, septic shock, and drug–induced liver injury 2 , liver injury in ICU patients is mainly caused by antibiotics 3 . Tazobactam/piperacillin (TZP), which is a combination of a β –lactam antibiotic and a β –lactamase inhibitor, and meropenem (MEM), which is a carbapenem, are commonly used as an empiric treatment in ICU patients with severe bacterial infections 4, 5 and are associated with a significantly increased incidence of liver injury 6 . However, the frequency of severe antibiotic–related hepatotoxicity is lower than that of antibiotic–related nephrotoxicity (liver injury vs. renal dysfunction: TZP, 5–6% vs. 9%; MEM, 4% vs. 21%) 7, 8 . Therefore, it remains difficult to assess the cause of TZP– or MEM–induced hepatotoxicity. Typology of the injury can be classified as hepatitis (mostly due to hepatocyte necrosis), cholestatic (bile duct damage or cholangiolitis) or mixed cholestasis/hepatitis injury 9 . The liver injury associated with TZP or MEM is probably hypersensitivity or allergy 9 , while the cholestatic hepatitis is probably immunological–mediated tissue damage 10 . First, a retrospective observational study was conducted to evaluate the risk factors for TZP– or MEM–induced liver injury in ICU patients with serious infection. Given that our study was a single–center retrospective observational study, propensity score matching (PSM) analyses were conducted to reduce the bias of patient background. Next, we conducted a sub–group analysis to detect the independent risk factor for liver injury of TZP and MEM. Finally, we investigated the association between liver injury and clinical profiles in patients receiving broad–spectrum antibiotics including TZP or MEM by using the database of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Results (i) Retrospective observational study Patient characteristics During the study period, 1,247 patients received TZP or MEM in the ICU. Figure 1 shows a flowchart of the patient selection process. The exclusion criteria were as follows: age < 15 years (n = 6), patients with a history of biliary tract or liver injury (n = 232), alanine aminotransferase (ALT) ≥ 40 U/L (n = 486), patients receiving TZP or MEM ≤ 3 days (n = 148), and no measurement of ALT or alkaline phosphatase (ALP) (n = 5). After conducting PSM analysis with age and estimated glomerular filtration rate, 204 patients were enrolled in this retrospective observational study. Table 1 provides a summary of the baseline characteristics of the patients. Liver injury occurred in of 43 (42%) patients receiving TZP and 43 (42%) patients receiving MEM. The median (interquartile range [IQR]) age, body weight, and administration period were 72.0 (65.0–80.0) years, 62.0 (51.6–72.8) kg, and 8.0 (6.0–13.0) days, respectively. No difference was observed in patient’s characteristics between TZP and MEM. Sources of infection and blood culture identification were shown in Supplementary Table S1 – S2. Table 1 Patient characteristics in the retrospective observational study All (n = 204) TZP (n = 102) MEM (n = 102) p –value n (%) n (%) n (%) Age * , years 72.0 [65.0–80.0] 72.0 [65.0–81.3] 71.5 [65.8–79.0] 0.967 Male 145 (71.1) 74 (72.5) 71 (69.6) 0.758 Body weight * , kg 62.0 [51.6–72.8] 63.1 [51.6–72.7] 59.7 [51.0–73.2] 0.530 BMI * , kg/m 2 23.6 [19.8–27.3] 24.2 [19.8–27.6] 23.3 [19.8–27.0] 0.473 Administration period * , day 8.0 [6.0–13.0] 8.0 [5.0–14.0] 7.0 [6.0–11.0] 0.390 Alcohol drinking history 53 (26.0) 28 (27.5) 25 (24.5) 1.000 SOFA score * 7.0 [5.0–10.8] 7.0 [5.0–11.0] 8.0 [5.0–10.0] 0.826 PSI * 5.0 [4.0–5.0] 5.0 [5.0–5.0] 4.0 [4.0–5.0] 0.068 Alb * , g/dL 2.8 [2.5–3.3] 2.8 [2.5–3.3] 2.8 [2.5–3.2] 0.962 ALP * , U/L 253.0 [186.0–355.0] 267.0 [186.0–409.0] 239.5 [183.0–310.7] 0.116 ALT * , U/L 21.5 [14.0–30.0] 20.5 [15.0–29.3] 22.5 [13.8–30.0] 0.641 ALBI score * –1.6 [–2.0– − 1.3] –1.6 [–2.0– − 1.3] –1.7 [–2.0– − 1.3] 0.404 FIB–4 score * 3.2 [2.1–7.0] 2.8 [2.0–5.7] 3.6 [2.2–7.5] 0.076 AST * , U/L 35.0 [23.0–52.0] 35.0 [21.8–51.3] 35.0 [24.8–52.3] 0.526 T–Bil * , mg/dL 0.9 [0.5–1.5] 1.0 [0.5–1.5] 0.9 [0.4–1.6] 0.392 BUN * , mg/dL 27.7 [17.8–43.9] 25.9 [18.3–46.6] 28.1 [16.8–42.3] 0.721 eGFR * , mL/min/1.73m 2 54.0 [28.0–87.5] 50.9 [26.6–86.2] 61.6 [28.8–91.2] 0.781 ECMO 19 (9.3) 11 (10.8) 8 (7.8) 0.631 HD 15 (7.4) 9 (8.8) 6 (5.9) 0.593 CHDF 45 (22.1) 22 (21.6) 23 (22.5) 1.000 CRP * , mg/dL 10.5 [5.8–17.7] 11.1 [6.1–17.5] 10.2 [4.6–19.3] 0.700 Eosinophil * , /µL 20.0 [0.0–110.0] 10.0 [0.0–102.5] 40.0 [0.0–115.0] 0.037 Dose per day * , g per day – 13.5 [9.0–13.5] 2.0 [1.5–3.0] – Dose/kg per day * , g/kg per day – 0.2 [0.1–0.2] 0.04 [0.02–0.05] – Macrolide 3 (1.5) 2 (2.0) 1 (1.0) 1.000 SXT 4 (2.0) 2 (2.0) 2 (2.0) 1.000 Carbamazepine 3 (1.5) 2 (2.0) 1 (1.0) 1.000 Valproic acid 3 (1.5) 3 (2.9) 0 (0.0) 0.246 Acetaminophen 40 (19.6) 21 (20.6) 19 (18.6) 1.000 Acetaminophen dose 500.0 [400.0–1000.0] 500.0 [400.0–1000.0] 400.0 [400.0–1000.0] 0.185 Amiodarone 8 (3.9) 5 (4.9) 3 (2.9) 0.721 Statin 7 (3.4) 7 (6.9) 0 (0.0) 0.014 Propofol 24 (11.8) 13 (12.7) 11 (10.8) 0.828 RIF 0 (0.0) 0 (0.0) 0 (0.0) 1.000 NSAIDs 18 (8.8) 9 (8.8) 9 (8.8) 1.000 Opioids 103 (50.5) 54 (52.9) 49 (48.0) 0.576 VAN 47 (23.0) 24 (23.5) 23 (22.5) 1.000 TEI 7 (3.4) 4 (3.9) 3 (3.0) 1.000 LIN 21 (10.3) 8 (7.8) 13 (12.7) 0.357 DAP 10 (4.9) 4 (3.9) 6 (5.9) 0.748 CAS 2 (1.0) 2 (2.0) 0 (0.0) 0.498 MFG 1 (0.5) 1 (1.0) 0 (0.0) 1.000 ALBI score = (log 10 T–Bil × 0.66) + (− 0.085 × Alb) 47 FIB–4 score = age × AST/ (platelet × (ALT) 1/2 48 eGFR [mL/min/1.73 m 2 ] = 194 × serum creatinine − 1.094 × age − 0.287 (×0.739 if female) 49 Alb, serum albumin; ALBI, albumin–bilirubin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CHDF, continuous hemodiafiltration; CAS, caspofungin; CRP, C–reactive protein; DAP, daptomycin; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FIB–4, Fibrosis–4; HD, hemodialysis; LIN, linezolid; MFG, micafungin; MEM, meropenem; NSAIDs, Non–Steroidal Anti–Inflammatory Drugs; PSI, pneumonia severity index; TEI, teicoplanin; RIF, rifampicin; SOFA, sequential organ failure assessment; SXT, sulfamethoxazole/trimethoprim; T–Bil, total bilirubin, VAN, vancomycin Chi–squared test or Mann–Whitney U test * Data are presented as median [interquartile range]. Liver injury Figure 2 shows the biochemical classification of liver injury based on the Roussel Uclaf Causality Assessment Method (RUCAM) (TZP; n = 43, MEM; n = 43). Among 86 patients developed liver injury, 50 (58%) developed classified as cholestasis. For TZP, 26 patients (61%) had cholestasis, 10 patients (23%) had hepatitis, and 7 patients (16%) mixed cholestasis/hepatitis; for MEM, 24 patients (56%) had cholestasis, 8 patients (19%) had hepatitis, and 11 patients (26%) had mixed cholestasis/hepatitis (Fig. 2 ). According to the RUCAM, the liver injury in this study was possible or probable induced by TZP or MEM: TZP 5.0 (4.0–6.0) and MEM 6.0 (5.0–7.0) (data not shown). Univariate and multiple logistic regression analysis for TZP or MEM Univariate logistic regression analysis determined that male, administration period, SOFA score, ALT, and AST were potential independent variables in liver injury. The final model using the stepwise forward selection method included administration period (odds ratio [OR] = 1.080, 95% confidence interval (CI) = 1.019–1.143, p = 0.005), sequential organ failure assessment (SOFA) score (OR = 1.133, 95% CI = 1.038–1.237, p = 0.004), and ALT (OR = 1.042, 95% CI = 1.011–1.073, p = 0.007) (adjusted coefficient of determination = 0.116, p < 0.001; Table 2 ). Administration period was significantly longer with increasing grade of liver injury (grade 0, 6.5 [5.0–10.3] days; grade 1, 9.0 [6.8–13.3] days; grade 2, 10.5 [7.0–14.0] days; grade ≥ 3, 11.0 [6.3–17.5] days; p = 0.003) (data not shown). Table 2 Univariable and multiple logistic regression analysis of TZP or MEM in the retrospective observational study TZP or MEM (n = 204) univariable analysis multiple analysis OR [95% CI] p –value OR [95% CI] p –value Age, years 0.982 [0.963–1.002] 0.077 Male 1.991 [1.046–3.792] 0.033 Body weight, kg 1.017 [1.001–1.035] 0.051 BMI, kg/m 2 1.029 [0.983–1.078] 0.206 Administration period, day 1.088 [1.030–1.149] 0.001 1.080 [1.019–1.143] 0.005 Alcohol drinking history 0.678 [0.352–1.308] 0.244 SOFA score 1.088 [1.012–1.169] 0.021 1.133 [1.038–1.237] 0.004 PSI 0.764 [0.581–1.004] 0.254 Alb, g/dL 1.036 [0.186–5.782] 0.968 ALP, U/L 0.300 [0.035–2.560] 0.265 ALT, U/L 1.041 [1.011–1.071] 0.005 1.042 [1.011–1.073] 0.007 ALBI score 1.244 [0.688–2.250] 0.469 FIB–4 score 1.000 [0.973–1.028] 0.974 AST, U/L 1.012 [1.000–1.024] 0.048 T–Bil, mg/dL 1.051 [0.960–1.150] 0.273 BUN, mg/dL 0.738 [0.142–3.839] 0.717 eGFR, mL/min/1.73m 2 1.006 [1.000–1.012] 0.089 CRP, mg/dL 1.014 [0.982–1.047] 0.391 Eosinophil, /µL 0.998 [0.996–1.001] 0.110 Dose per day, g per day 1.020 [0.968–1.075] 0.458 Dose/kg per day, g/kg per day 0.698 [0.045–10.730] 0.796 Co–administered drugs 1.045 [0.538–2.027] 0.897 Acetaminophen dose, mg per day 1.000 [0.998–1.001] 0.502 MEM 0.961 [0.552–1.673] 0.887 Adjusted coefficient of determination = 0.116 ( p < 0.001) ALBI score = (log 10 T–Bil × 0.66) + (− 0.085 × Alb) 47 FIB–4 score = age × AST/ (platelet × (ALT) 1/2 48 eGFR [mL/min/1.73 m 2 ] = 194 × serum creatinine − 1.094 × age − 0.287 (×0.739 if female) 49 Variables with p < 0.05 were included in the multivariate model. By using the stepwise forward selection method, potential independent variables were further examined to construct the final model. Alb, serum albumin; ALBI, albumin–bilirubin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CI, confidence interval; CRP, C–reactive protein; eGFR, estimated glomerular filtration rate; FIB–4, Fibrosis–4; MEM, meropenem; OR, odds ratio; PSI, pneumonia severity index; SOFA, sequential organ failure assessment; T–Bil, total bilirubin; TZP, tazobactam/piperacillin Sub – group analysis for TZP The univariate logistic regression analysis demonstrated that administration period, SOFA score, ALT, Fibrosis–4 (FIB–4) score, and aspartate aminotransferase (AST) were selected as potential independent variables in liver injury. By using the stepwise forward selection method, the final model included administration period (OR = 1.078, 95% CI = 1.001–1.165, p = 0.049) and SOFA score (OR = 1.136, 95% CI = 1.013–1.275, p = 0.030) (adjusted coefficient of determination = 0.158, p < 0.001; Table 3 ). When the interaction term was introduced, no significant interactions were found between the independent variables. The cut–off values and area under the receiver operating characteristic curve (AUC) of administration period and SOFA score were six days (AUC, 0.69; p = 0.003) and six points (AUC, 0.66; p = 0.003), respectively. The administration period increased as the grade of liver injury increased (grade 0, 6.0 [4.5–12.0] days; grade 1, 9.5 [6.0–14.0] days; grade 2, 12.5 [7.5–15.3] days; grade ≥ 3, 18.0 [18.0–20.0] days; p = 0.004) (data not shown). Table 3 Univariable and multiple logistic regression analysis divided TZP and MEM in the retrospective observational study TZP (n = 102) MEM (n = 102) univariable analysis multiple analysis univariable analysis multiple analysis OR [95% CI] p –value OR [95% CI] p –value OR [95% CI] p –value OR [95% CI] p –value Age, years 0.995 [0.968–1.023] 0.705 0.969 [0.940–0.998] 0.029 Male 1.244 [0.513–3.017] 0.629 3.527 [1.348–9.228] 0.007 3.854 [1.427–10.406] 0.001 Body weight, kg 1.009 [0.989–1.029] 0.382 1.023 [0.996–1.049] 0.084 BMI, kg/m 2 1.023 [0.963–1.086] 0.453 1.022 [0.954–1.094] 0.533 Administration period, day 1.108 [1.020–1.190] 0.008 1.078 [1.001–1.165] 0.049 1.082 [0.996–1.158] 0.035 1.082 [1.003–1.168] 0.020 Alcohol drinking history 0.761 [0.561–1.304] 0.559 0.589 [0.228–1.525] 0.274 SOFA score 1.165 [1.042–1.302] 0.005 1.136 [1.013–1.275] 0.030 1.027 [0.932–1.132] 0.585 PSI 0.904 [0.589–1.387] 0.643 0.661 [0.452–0.965] 0.052 Alb, g/dL 0.625 [0.290–1.347] 0.223 1.843 [0.783–4.341] 0.154 ALP, U/L 1.000 [0.999–1.001] 0.952 0.998 [0.993–1.003] 0.479 ALT, U/L 1.081 [1.033–1.132] 0.010 1.011 [0.971–1.053] 0.590 ALBI score 2.107 [0.897–4.948] 0.076 0.654 [0.267–1.600] 0.349 FIB–4 score 1.100 [1.006–1.100] 0.022 0.988 [0.955–1.022] 0.449 AST, U/L 1.018 [1.001–1.035] 0.025 1.001 [0.985–1.017] 0.882 T–Bil, mg/dL 1.093 [0.958–1.247] 0.138 0.987 [0.845–1.152] 0.866 BUN, mg/dL 1.007 [0.992–1.022] 0.993 0.985 [0.966–1.003] 0.080 eGFR, mL/min/1.73m 2 1.002 [0.993–1.011] 0.670 1.010 [1.001–1.021] 0.032 CRP, mg/dL 0.996 [0.945–1.049] 0.874 1.022 [0.980–1.066] 0.303 Eosinophil, /µL 0.997 [0.992–1.001] 0.055 1.000 [0.997–1.003] 0.828 Dose per day, g per day 1.073 [0.958–1.202] 0.215 1.340 [0.887–2.024] 0.156 Dose/kg per day, g/kg per day 0.942 [0.015–57.814] 0.977 1.690 [0.129–22.089] 0.689 Co–administered drugs 1.338 [0.563–3.177] 0.510 0.635 [0.218–1.853] 0.399 Acetaminophen dose, mg per day 0.998 [0.995–1.002] 0.280 1.000 [0.998–1.001] 0.845 TZP; adjusted coefficient of determination = 0.158 ( p < 0.001) MEM; adjusted coefficient of determination = 0.092 ( p = 0.002) ALBI score = (log 10 T–Bil × 0.66) + (− 0.085× Alb) 47 FIB–4 score = age × AST/ (platelet × (ALT) 1/2 48 eGFR [mL/min/1.73 m 2 ] = 194 × serum creatinine − 1.094 × age − 0.287 (×0.739 if female) 49 Variables with p < 0.05 were included in the multivariate model. Using the stepwise forward selection method, potential independent variables were further examined to construct the final model. Alb, serum albumin; ALBI, albumin–bilirubin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CI, confidence interval; CRP, C–reactive protein; eGFR, estimated glomerular filtration rate; FIB–4, Fibrosis–4; MEM, meropenem; OR, odds ratio; PSI, pneumonia severity index; SOFA, sequential organ failure assessment; T–Bil, total bilirubin; TZP, tazobactam/piperacillin Sub – group analysis for MEM The univariate logistic regression analysis demonstrated that age, male, administration period, and eGFR were selected as potential independent variables in liver injury. By using the stepwise forward selection method, the final model included male (OR = 3.854, 95% CI = 1.427–10.406, p = 0.001) and administration period (OR = 1.082, 95% CI = 1.003–1.168, p = 0.020) (adjusted coefficient of determination = 0.092, p = 0.002; Table 3 ). When the interaction term was introduced, no significant interactions were found between the independent variables. The cut–off value and AUC of administration period was six days (AUC, 0.69; p = 0.001). Similar to TZP, administration period was significantly longer in patients with severe liver injury (grade 0, 6.0 [5.0–9.0] days; grade 1, 11.0 [7.0–12.0] days; grade 2, 7.5 [6.3–14.5] days; grade ≥ 3, 11.0 [7.0–15.8] days; p = 0.002) (data not shown). Comparison of patient background by sex in patients receiving MEM Supplementary Table S3 shows the comparison of patient background by sex in patients receiving MEM. Body weight, alcohol drinking history, pneumonia severity index (PSI), vancomycin, and linezolid were significantly higher in male than in female (male vs. female: body weight; 61.7 kg vs. 48.7 kg, p < 0.001; alcohol drinking history, 34% vs. 3%, p < 0.001; PSI, 5.0 vs. 4.0, p = 0.005; vancomycin, 28% vs. 10%, p = 0.032; linezolid, 17% vs. 3%, p = 0.049). (ii) FAERS database study Total of 195,893 reports were extracted from the FAERS database. Figure 3 shows a flowchart of the patient. These reports include the fourth–generation cephalosporin (n = 10,758), carbapenem (n = 22,165), β –lactam and β –lactamase inhibitor combination (n = 28,427), and quinolone (n = 151,936). The number of reports attributed to the development of drug–induced liver injury were 1,159 (11%). Table 4 shows the patient characteristics between the liver and non–liver injury groups. The reporting odds ratio (ROR) and 95% CI for the above variables were as follows: male (ROR = 1.237, 95% CI = 1.090–1.405, p = 0.001), age (ROR = 0.988, 95% CI = 0.986–0.991, p < 0.001), the fourth–generation cephalosporin (ROR = 1.400, 95% CI = 1.124–1.743, p = 0.003), carbapenem (ROR = 1.845, 95% CI = 1.592–2.138, p < 0.001), β –lactam and β –lactamase inhibitor combination (ROR = 1.383, 95% CI = 1.194–1.603, p < 0.001), and complication of sepsis (ROR = 1.705, 95% CI = 1.126–2.582, p = 0.012). Table 4 Demographic and clinical characteristics and risk analysis of liver injury in the study using FAERS database. Variables Liver injury (n = 1,159) Non–liver injury (n = 194,734) ROR [95% CI] p –value n (%) n (%) Sex Female 465 (40.1) 93,521 (48.0) Male 494 (42.6) 80,296 (41.2) 1.237 [1.090–1.405] 0.001 Unknown 200 (17.3) 20,917 (10.7) Age * , years 54.0 [36.8–67.0] 61.0 [45.0–72.0] 0.989 [0.986–0.992] < 0.001 Unknown 223 (19.2) 47,914 (24.6) The fourth–generation cephalosporin 87 (7.5) 10,671 (5.5) 1.400 [1.124–1.743] 0.003 FEP 87 (7.5) 10,671 (5.5) 1.400 [1.124–1.743] 0.003 Carbapenem 220 (19.0) 21,945 (11.3) 1.845 [1.592–2.138] < 0.001 DOR 6 (0.5) 867 (0.4) 1.164 [0.520–2.603] 0.712 BIPM 10 (0.9) 199 (0.1) 8.508 [4.496–16.100] < 0.001 MEM 208 (17.9) 21,116 (10.8) 1.798 [1.547–2.091] < 0.001 β –lactam and β –lactamase inhibitor combination 220 (19.0) 28,207 (14.5) 1.383 [1.194–1.603] < 0.001 C/T 0 (0.0) 927 (0.5) – – TZP 220 (19.0) 27,333 (14.0) 1.435 [1.238–1.663] < 0.001 Quinolone 849 (73.3) 151,087 (77.6) 0.791 [0.694–0.901] < 0.001 GRNX 6 (0.5) 345 (0.2) 2.932 [1.305–6.585] 0.009 STFX 5 (0.4) 171 (0.1) 4.930 [2.022–12.018] < 0.001 CIP 335 (28.9) 73,282 (37.6) 0.674 [0.593–0.765] < 0.001 TFLX 5 (0.4) 158 (0.1) 5.336 [2.186–13.021] < 0.001 MXF 175 (15.1) 17,979 (9.2) 1.748 [1.488–2.055] < 0.001 LVX 371 (32.0) 69,443 (35.7) 0.849 [0.751–0.961] 0.010 Sepsis 23 (2.0) 2,285 (1.2) 1.705 [1.126–2.582] 0.012 BIPM, biapenem; CI, confidence interval; CIP, ciprofloxacin; C/T, ceftolozane–tazobactam; DOR, doripenem; FAERS, FDA Adverse Event Reporting System; FEP, cefepime; GRNX, garenoxacin; LVX, levofloxacin; MEM, meropenem; MXF, moxifloxacin; ROR, reporting odds ratio; STFX, sitafloxacin; TFLX, tosufloxacin; TZP, tazobactam/piperacillin *Data are presented as median [interquartile range]. Discussion The retrospective observational study revealed that the occurrence rate of liver injury increased in association with the administration period of TZP or MEM. An administration period of more than six days increased the incidence of liver injury. The administration period was prolonged in patients receiving TZP or MEM and corresponded with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade of liver injury. These findings suggest that early antibiotic change reduces the development of liver injury. In the FAERS database study, sepsis was one of the risk factors on liver injury. In addition, the results revealed that an elevated SOFA score increased the incidence of liver injury in patients receiving TZP. The cut–off value for the SOFA score for the occurrence of liver injury was estimated to be six points. These findings indicated that the baseline condition contributed to the TZP–induced liver injury. Furthermore, MEM–induced liver injury was significantly higher in males; this finding is consistent with the FAERS database study. Antibiotics are one of the common causes of drug–induced liver injury 11, 12 . The liver receives most of its blood supply (approximately 70%) from the intestine via portal circulation and is constantly exposed to gut–derived factors including bacterial products and inflammatory cytokines. Therefore, reducing bacterial density, eliminating target harmful bacteria, inhibiting secondary bacterial proliferation, and reducing bacterial translocation by the liver are considered the pharmacological mechanisms of drug–induced liver injury. Antibiotic therapy aims to eliminate pathogenic bacteria; however, this microbial clearance also reduces beneficial commensal bacteria, and this situation has important pathological implications for the liver 13, 14 . The risk of drug–induced liver injury caused by microbiota dysbiosis has been recognized a multifactorial process. Antibiotics directly affect the structure and diversity of gut microbiota, which alters metabolites. The depletion of probiotics after antibiotics interference can reduce the efficacy of hepatoprotective agents and leads to the development of liver injury 15 . Lactobacillus and Bifidobacterium spp., which play significant roles in regulating intestinal flora balance, reduce oxidative stress and inflammation and improve liver pathological changes 16 . By contrast, it has been reported that cefoxitin significantly reduces gut microbiota diversity and increases the levels of pathogenic bacteria such as Firmicutes , Tendericutes , and Vibrio , which cause damage to the intestinal barrier 16 . In other words, the sufficient decreases in beneficial intestinal bacteria such as Lactobacillus spp. and Bifidobacterium spp. and the sufficient increase in pathogenic bacteria, including Enterococcus spp., can aggravate the progression of liver injury 17, 18 . Therefore, a follow–up liver function test is essential during the administration of antibiotics that affect intestinal microorganisms and their metabolic activities. TZP– or MEM–associated cholestasis was seen in many patients in this retrospective observational study. Cholestatic injury accounts for approximately 30% of drug–induced liver injuries 19 . Most cases are mild and manageable and occasionally leads to vanishing bile duct syndrome 20 . Cholestatic hepatitis caused by carbapenems is probably immunoallergic and resembles the rare and clinically apparent liver injury that has been linked to penicillin and cephalosporins. In a Spanish cohort, patients older than 55 years were significantly more likely to develop a cholestatic or mixed liver injury. Given that the median age of this study population is 71.5 years, older age may have contributed to the development of liver injury 21 . The recommended treatment length is described in the guidelines of the Infectious Diseases Society of America: five to seven days for infections caused by coagulase – negative staphylococci , seven to fourteen days for enterococci and Gram – negative organisms , and two to six weeks for S. aureus 22 . In the current study, administration for more than six days was associated with the development of liver injury. In clinical settings, a three–day incubation period is sufficient to reveal the result of a blood culture test 23 . Therefore, antimicrobial de–escalation is a treatment strategy in early adequate antimicrobial therapy. A previous study revealed that de–escalation is not associated with adverse consequences compared with treatment with broad–spectrum antibiotics (mortality or clinical failure) 24 . Clinicians should consider switching from TZP or MEM to other antibiotics within six days. By contrast, the careful monitoring of liver function is needed for patients who require the prolonged administration of TZP or MEM. A reduction in the length of antibiotic administration is a potentially viable strategy to minimize the consequences of antibiotic overuse in critical care, including antibiotic resistance, adverse effects, clostridium difficile colitis, and costs 25 . Bacterial resistance decreases the chance of early adequate therapy 26 and are associated with mortality 27, 28 . The SOFA score is a well–known and simple scoring system and a valid tool for predicting sepsis in critical care units. A SOFA score > 2 points at baseline represents organ dysfunction or cellular damage 29 . In addition, sepsis is defined as a life–threatening organ dysfunction caused by the dysregulated response of the host to infection. Acetaminophen–induced liver injury also reported that a SOFA score > 7 points predict organ failure 30 . Therefore, special attention should be paid for monitoring liver injury in patients with a SOFA score > 6 points. Heavy drinkers are likely to develop alcoholic hepatitis, which is associated with impaired liver function due to a severe inflammatory response 31, 32, 33, 34 . It was reported that men tend to consume more alcohol and experience alcohol–induced physical impairment compared with women 35 . Notably, alcohol history has been found to be substantially present in men in our study population (Supplementary Table S3), thus suggesting that men are at a high risk of liver injury. It has been reported that amoxicillin–induced liver injury is also more frequent in men than in women 36 . The elevation of ALT from baseline may be positively associated with drug–induced liver injury. This finding was consistent with previous studies 37, 38 . A positive correlation between ALT levels and hepatocyte necrosis also existed in an animal study 39 . Oxidative stress, which causes necrosis, is removed by Kupffer cells in the liver 40 , thus suggesting that Kupffer cell function and the number of Kupffer cells may be involved in the development of drug–induced liver injury 37 . However, it is unclear whether TZP– or MEM–induced liver injuries occur in similar phenomena. Therefore, the mechanism of TZP– or MEM–induced liver injury needs further research. There are several limitations of this study. First, we extracted reports of liver injury that occurred during the administration of broad–spectrum antibiotics by using the term “drug–induced liver injury”, which was derived from Medical Dictionary for Regulatory Activities (MedDRA) terminology; however, the causal relationship between events, medications, and severity of liver injury remains uncertain. Second, information on the concomitant use of drugs that potentially interact with TZP or MEM was lacking in the FAERS database. Third, given that the FAERS database did not include clinical laboratory data such as serum creatinine level and alanine aminotransferase, we could not evaluate renal and liver functions as risk factors of antibiotics–induced liver injury. Fourth, this was a single–center retrospective observational study; thus, it was difficult to avoid the influence of unknown confounding factors. Fifth, among the carbapenem group, only two patients received doripenem and one patient received biapenem. Most patients were administered MEM; therefore, we extracted only patients receiving MEM. In the future, further study is needed to clarify the differences in carbapenem–treated patients. Finally, since critically ill patients were received numerous medications and often experienced the change of drug dosing and medication regimens, it is difficult to exclude the patients who used additional drugs other than TZP or MEM. Conclusions Our study was the first to demonstrate that a prolonged administration period (more than six days) could increase the risk of liver injury in patients receiving TZP or MEM. In addition, an elevated SOFA score (more than six points) in TZP and male in MEM were also identified as risk factors of liver injury. On the basis of these findings, a periodical monitoring of liver function is recommended in patients receiving TZP or MEM, particularly in those with multiple risk factors for the development of liver injury. The findings of this study provide useful information for the appropriate use of TZP or MEM. Materials and Methods Retrospective observational study Data from patients receiving TZP or MEM in the ICU of Mie University Hospital from January 2010 to March 2022 were analyzed. The exclusion criteria were age < 15 years, patients with a history of biliary tract or liver injury, baseline ALT ≥ 40 U/L, administration period of TZP or MEM ≤ 3 days, and no measurement of ALT or ALP. A retrospective observational study was performed to obtain the following demographic data: sex; age; height; body weight; body mass index; daily dose and treatment duration of MEM and TZP; baseline clinical laboratory data (serum albumin [Alb], ALP, ALT, albumin–bilirubin [ALBI] grade, FIB–4 score, AST, total bilirubin [T–Bil], blood urea nitrogen, serum creatinine [SCr], eGFR, C–reactive protein, and eosinophil); and medical records of extracorporeal membrane oxygenation, hemodialysis, and continuous hemodiafiltration. The SOFA score and PSI were extracted for the evaluation of infection severity 41, 42 . As the mortality rate is directly related to the degree of organ dysfunction, it is evident that it must also be related to the SOFA score for each organ system 43 . PSI scoring system is one of the most widely used scoring tools to evaluate the condition and prognosis of community acquired pneumonia patients 44 . We collected information on concomitant systematically administered medications that could cause drug–induced liver injury (macrolide, sulfamethoxazole/trimethoprim, carbamazepine, valproic acid, acetaminophen, amiodarone, statin, propofol, rifampicin, non–steroidal anti–inflammatory drugs, and opioids) 45, 46 , other antibiotics and antifungal drugs. Acetaminophen dose was also extracted. The ALBI score and FIB–4 score were calculated using the following formula: ALBI score = (log 10 T–Bil × 0.66) + (− 0.085 × Alb) 47 , FIB–4 score = age × AST/ (platelet × (ALT) 1/2 48 . The eGFR was calculated using the prediction equation for Japanese patients: eGFR (mL/min/1.73 m 2 ) = 194 × SCr − 1.094 × age − 0.287 (×0.739 if female) 49 . PSM analysis Age and eGFR were considered potential confounders in patients receiving TZP or MEM, and these were adjusted using PSM analysis. Propensity scores were calculated using bivariate logistic regression by using a 1:1 case–control match with a caliper value of 0.1 (one–to–one nearest–neighbor matching). The standardized difference (10% or 0.1) was used to compare the distribution of all paired covariates between groups. Liver injury evaluation Liver injury was defined as an elevation of ALT grade on the basis of the CTCAE version 4.0 (Supplementary Table S4) after the initiation of TZP or MEM therapy 50 . The possibility of TZP– or MEM–induced liver injury was evaluated using the RUCAM (0 or less indicate that the drug is “excluded” as a cause; 1 to 2 that it is “unlikely”; 3 to 5 “possible”; 6 to 8 “probable”; and greater than 8, “highly probable”) 50 . The total score consists of points for 8 separate factors in 7 categories that help define the “signature” of the drug induced liver injury. These factors are: ( 1 ) time to onset (+ 1 or + 2); ( 2 ) course (–2, 0, + 1, +2 or + 3); ( 3 ) risk factors (2 scores: 0 or + 1 each); ( 4 ) concomitant drugs (0, − 1, − 2 or − 3); ( 5 ) nondrug causes of liver injury (–3, − 2, 0, + 1, or + 2); ( 6 ) previous information on the hepatotoxicity of the drug (0, + 1, or + 2); and ( 7 ) response to rechallenge (–2, 0, + 1, or + 3). The individual points range from − 3 to + 3 and the total possible score ranges from − 9 to + 14. Liver injury was classified biochemically as being hepatitis, cholestatic, mixed cholestasis/hepatitis, and other by using R value, which was defined as ALT/upper limit of normal (ULN) divided by ALP/ULN: hepatitis, ALT > 2 ULN and ALP ≤ ULN or R ≥ 5; cholestatic, ALT ≤ ULN and ALP > 2 ULN or R ≤ 2; mixed, ALT > 2 ULN, ALP > ULN, and 2 < R < 5 51 . FAERS database study The FAERS database generated from post–marketing spontaneous pharmacovigilance databases was used for this study. The FAERS database includes ˃ 1.4 million cases of adverse events reported worldwide after January 2004 and consists of seven data tables: patient demographic and administrative information, drug and biologic information, adverse events, patient outcomes, report sources, start end dates of drug therapy, and indications for use/diagnosis 52 . The source of the databases complies with the guidelines set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the databases adhere to the ICH–standardized adverse event information guidelines 53 . For the current study, adverse event reports were downloaded from the website of the US Food and Drug Association (FDA) ( https://www.fda.gov/ ; accessed on January 22, 2023). Reports with the same case number were identified as duplicate reports, and the most recent reports were used, as recommended by the FDA 54 . Data were extracted from the FAERS database between January 2013 and September 2022. We collected reports of the following antibiotics, which have broad–spectrum use in empiric therapy in the ICU 55 : the fourth–generation cephalosporin (cefepime), carbapenem (doripenem, biapenem, and MEM), β –lactam and β –lactamase inhibitor combination (tazobactam/ceftolozane and TZP), and quinolone (garenoxacin, sitafloxacin, ciprofloxacin, tosufloxacin, moxifloxacin, and levofloxacin). The collected data included the case number, drug name, adverse event name, start date of administration, end date of administration, date of development of the adverse event, sex, age, and medical history of sepsis (10040054), which were derived from MedDRA terminology. The sample code was provided in Supplementary Script S5. Adverse events detection Adverse events were coded according to preferred terms (drug–induced liver injury; 10072268) derived from MedDRA terminology. Event reports were identified using the standardized MedDRA query (version 26.0). Reports with development of liver injury during antibiotics administration were classified as “liver injury group” and other reports as “non– liver injury group.” Statistical analyses Statistical analyses were performed using R software version 4.1.3 (R Core Team, 2022) 56 and JMP Pro 16 statistical package (SAS Institute, Cary, NC, USA). Categorical data were summarized as numbers (%) and analyzed using the chi–squared test. Continuous data were summarized as medians (IQR) and analyzed using the Mann–Whitney U test. Statistical significance was defined as a two–tailed p –value < 0.05. (i) Retrospective observational study Univariable and multiple logistic regression analyses were performed to identify the independent variables for the TZP– or MEM–induced liver injury. Variables with p –value < 0.05 were included in the multivariate model. By using the stepwise forward selection method, potential independent variables were further examined to construct the final model. A multiple logistic regression analysis was used to determine the multiple regression equation for TZP– or MEM–induced liver injury. We verified these interactions by focusing on each significant independent variable. Clinical characteristics were compared and stratified by independent variables as needed. When multicollinearity was present, we selected an independent variable on the basis of its clinical relevance by sensitivity analyses. The cut–off values of continuous variables for the development of TZP– or MEM–induced liver injury was determined by using the receiver operating characteristic curve method. Missing values were handled without correction. (ii) FAERS database study The association between clinical profiles and antibiotics–induced liver injury was evaluated using ROR with a 95% CI. A statistically significant ROR was formally defined as a lower limit of the 95% CI exceeding 1.0. Ethics approval This study was conducted in accordance with the Declaration of Helsinki and its amendments after obtaining approval from the Clinical Research Ethics Review Committee of Mie University Hospital (No. H2022–107). The requirement for patient consent was waived by the board owing to the retrospective nature of the study. Patents This section is not mandatory but may be added if there are patents resulting from the work reported in this manuscript. Declarations Acknowledgments We would like to thank Editage (www.editage.com) for the English language editing. Author Contributions Conceptualization, H.K. and C.S.; methodology, H.K. and C.S.; software, C.S.; validation, H.K., and T.I.; formal analysis, H.K. and C.S.; investigation, C.S.; resources, C.S.; data curation, C.S. and H.K.; writing–original draft preparation, H.K. and C.S.; writing–review and editing, H.K. and C.S. and T.O.; visualization, H.K. and C.S.; supervision, H.K. and T.I.; project administration, H.K.; funding acquisition, H.K. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Data Availability Statement Data that support the findings of this manuscript are available upon request from the corresponding author. Conflicts of Interest The authors declare no conflicts of interest. Supplementary Information The following supporting information can be downloaded at: www.mdpi.com/xxx/s1,Supplementary Table S1, Sources of infection; Supplementary Table S2, Blood culture identification; Supplementary Table S3, Comparison of patient background by sex (MEM, retrospective observational study); Supplementary Table S4, Common Terminology Criteria for Adverse Events: elevation of alanine aminotransferase; Supplementary Script S5, R scripts Disclaimer/Publisher’s Note The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References Tamma, P.D., Avdic, E., Li, D.X., Dzintars, K. & Cosgrove, S.E. Association of adverse events with antibiotic use in hospitalized patients. 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Supplementary Files ScirepAppendix.doc Cite Share Download PDF Status: Published Journal Publication published 06 Aug, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 27 Jan, 2024 Reviews received at journal 20 Jan, 2024 Reviewers agreed at journal 05 Jan, 2024 Reviewers agreed at journal 22 Nov, 2023 Reviewers invited by journal 22 Nov, 2023 Editor assigned by journal 22 Nov, 2023 Editor invited by journal 15 Nov, 2023 Submission checks completed at journal 15 Nov, 2023 First submitted to journal 13 Nov, 2023 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-3607226","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":249679137,"identity":"8ea1effe-301b-4d4e-883b-2952be86b50b","order_by":0,"name":"Chihiro Shiraishi","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chihiro","middleName":"","lastName":"Shiraishi","suffix":""},{"id":249679138,"identity":"466de263-55c1-4201-b16a-c96e62fe3fee","order_by":1,"name":"Hideo Kato","email":"data:image/png;base64,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","orcid":"","institution":"Mie University Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hideo","middleName":"","lastName":"Kato","suffix":""},{"id":249679140,"identity":"9cc1e8ab-d652-4151-b181-951c45ad5546","order_by":2,"name":"Toru Ogura","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Toru","middleName":"","lastName":"Ogura","suffix":""},{"id":249679141,"identity":"1b504994-1ca6-43db-9742-4b93287bb3e1","order_by":3,"name":"Takuya Iwamoto","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Iwamoto","suffix":""}],"badges":[],"createdAt":"2023-11-13 22:59:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3607226/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3607226/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-69279-6","type":"published","date":"2024-08-06T15:57:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":46674415,"identity":"1d8d77ea-e314-4d9e-9ad6-575a18c3b556","added_by":"auto","created_at":"2023-11-17 19:03:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92414,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of patient selection in the retrospective observational study.\u003c/p\u003e\n\u003cp\u003eALT, alanine aminotransferase; ALP, alkaline phosphatase; FAS, full analysis set; ICU, intensive care unit; MEM, meropenem; TZP, tazobactam/piperacillin\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3607226/v1/6d4ab47b63479637ca0bb7af.png"},{"id":46674413,"identity":"e2eef437-b576-4c1b-a554-46c15c913c54","added_by":"auto","created_at":"2023-11-17 19:03:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12555,"visible":true,"origin":"","legend":"\u003cp\u003eClassification of liver injury using the RUCAM of TZP (A). Classification of liver injury using the RUCAM of MEM (B).\u003c/p\u003e\n\u003cp\u003eThe x axis represents the classification of liver injury; cholestasis, hepatitis, mixed, and other. The yaxis represents the number of the patients.\u003c/p\u003e\n\u003cp\u003eRUCAM, Roussel Uclaf Causality Assessment Method; MEM, meropenem; TZP, tazobactam/piperacillin\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3607226/v1/c25b925f9a8ac671fcedd1af.png"},{"id":46674412,"identity":"b23045b2-11cf-40a0-ad98-e09336b99279","added_by":"auto","created_at":"2023-11-17 19:03:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34461,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the process for data collection in the study using FAERS database. BIPM, biapenem; CIP, ciprofloxacin; C/T, ceftolozane–tazobactam; DOR, doripenem; FAERS, FDA Adverse Event Reporting System; FEP, cefepime; GRNX, garenoxacin; LVF, levofloxacin; MEM, meropenem; MXF, moxifloxacin; STFX, sitafloxacin; TFLX, tosufloxacin; TZP, tazobactam/piperacillin\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3607226/v1/3fc38694e199b60b6b69bb80.png"},{"id":62298940,"identity":"a4d66f6d-39f9-4da9-a8b5-4080c373de73","added_by":"auto","created_at":"2024-08-12 16:17:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1288036,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3607226/v1/4e930ffd-f311-4ab9-9058-eb98c7042f01.pdf"},{"id":46674414,"identity":"c2de4b3d-439d-4340-acf0-2d3eb64be0eb","added_by":"auto","created_at":"2023-11-17 19:03:49","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":166912,"visible":true,"origin":"","legend":"","description":"","filename":"ScirepAppendix.doc","url":"https://assets-eu.researchsquare.com/files/rs-3607226/v1/42b506513761137d4c693a9e.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Investigation of tazobactam/piperacillin– or meropenem–induced liver injury based on retrospective observational study and the FDA Adverse Event Reporting System","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eNearly 20% of patients receiving antibiotics for at least 24 h experience adverse events \u003csup\u003e1\u003c/sup\u003e. It is estimated that antibiotics are prescribed 10 times more frequently in the intensive care unit (ICU) than in general wards, thus significantly increasing the risk of adverse events in ICU patients \u003csup\u003e1\u003c/sup\u003e, moreover, ICU patients face the risk of drug accumulation because of organ failure and sensitivity to drug reactions because of their unstable status, thus leading to diverse forms of toxicity including hepatotoxicity, neurological dysfunction, and acute kidney injury.\u003c/p\u003e \u003cp\u003eAlthough the common causes of liver injury include hypoxic hepatitis, congestive hepatopathy, septic shock, and drug\u0026ndash;induced liver injury \u003csup\u003e2\u003c/sup\u003e, liver injury in ICU patients is mainly caused by antibiotics \u003csup\u003e3\u003c/sup\u003e. Tazobactam/piperacillin (TZP), which is a combination of a \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactam antibiotic and a \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactamase inhibitor, and meropenem (MEM), which is a carbapenem, are commonly used as an empiric treatment in ICU patients with severe bacterial infections \u003csup\u003e4, 5\u003c/sup\u003e and are associated with a significantly increased incidence of liver injury \u003csup\u003e6\u003c/sup\u003e. However, the frequency of severe antibiotic\u0026ndash;related hepatotoxicity is lower than that of antibiotic\u0026ndash;related nephrotoxicity (liver injury vs. renal dysfunction: TZP, 5\u0026ndash;6% vs. 9%; MEM, 4% vs. 21%) \u003csup\u003e7, 8\u003c/sup\u003e. Therefore, it remains difficult to assess the cause of TZP\u0026ndash; or MEM\u0026ndash;induced hepatotoxicity. Typology of the injury can be classified as hepatitis (mostly due to hepatocyte necrosis), cholestatic (bile duct damage or cholangiolitis) or mixed cholestasis/hepatitis injury \u003csup\u003e9\u003c/sup\u003e. The liver injury associated with TZP or MEM is probably hypersensitivity or allergy \u003csup\u003e9\u003c/sup\u003e, while the cholestatic hepatitis is probably immunological\u0026ndash;mediated tissue damage \u003csup\u003e10\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFirst, a retrospective observational study was conducted to evaluate the risk factors for TZP\u0026ndash; or MEM\u0026ndash;induced liver injury in ICU patients with serious infection. Given that our study was a single\u0026ndash;center retrospective observational study, propensity score matching (PSM) analyses were conducted to reduce the bias of patient background. Next, we conducted a sub\u0026ndash;group analysis to detect the independent risk factor for liver injury of TZP and MEM. Finally, we investigated the association between liver injury and clinical profiles in patients receiving broad\u0026ndash;spectrum antibiotics including TZP or MEM by using the database of the US Food and Drug Administration Adverse Event Reporting System (FAERS).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e(i) Retrospective observational study\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eDuring the study period, 1,247 patients received TZP or MEM in the ICU. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows a flowchart of the patient selection process. The exclusion criteria were as follows: age\u0026thinsp;\u0026lt;\u0026thinsp;15 years (n\u0026thinsp;=\u0026thinsp;6), patients with a history of biliary tract or liver injury (n\u0026thinsp;=\u0026thinsp;232), alanine aminotransferase (ALT)\u0026thinsp;\u0026ge;\u0026thinsp;40 U/L (n\u0026thinsp;=\u0026thinsp;486), patients receiving TZP or MEM\u0026thinsp;\u0026le;\u0026thinsp;3 days (n\u0026thinsp;=\u0026thinsp;148), and no measurement of ALT or alkaline phosphatase (ALP) (n\u0026thinsp;=\u0026thinsp;5). After conducting PSM analysis with age and estimated glomerular filtration rate, 204 patients were enrolled in this retrospective observational study. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides a summary of the baseline characteristics of the patients. Liver injury occurred in of 43 (42%) patients receiving TZP and 43 (42%) patients receiving MEM. The median (interquartile range [IQR]) age, body weight, and administration period were 72.0 (65.0\u0026ndash;80.0) years, 62.0 (51.6\u0026ndash;72.8) kg, and 8.0 (6.0\u0026ndash;13.0) days, respectively. No difference was observed in patient\u0026rsquo;s characteristics between TZP and MEM. Sources of infection and blood culture identification were shown in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u0026ndash; S2.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\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\u003ePatient characteristics in the retrospective observational study\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=\"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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;204)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTZP (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMEM (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003csup\u003e*\u003c/sup\u003e, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.0 [65.0\u0026ndash;80.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e72.0 [65.0\u0026ndash;81.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e71.5 [65.8\u0026ndash;79.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.967\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145 (71.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e74 (72.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e71 (69.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight\u003csup\u003e*\u003c/sup\u003e, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.0 [51.6\u0026ndash;72.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.1 [51.6\u0026ndash;72.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e59.7 [51.0\u0026ndash;73.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.530\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003csup\u003e*\u003c/sup\u003e, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.6 [19.8\u0026ndash;27.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.2 [19.8\u0026ndash;27.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.3 [19.8\u0026ndash;27.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.473\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdministration period\u003csup\u003e*\u003c/sup\u003e, day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.0 [6.0\u0026ndash;13.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.0 [5.0\u0026ndash;14.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.0 [6.0\u0026ndash;11.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.390\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol drinking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (26.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA score\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.0 [5.0\u0026ndash;10.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.0 [5.0\u0026ndash;11.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.0 [5.0\u0026ndash;10.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.826\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSI\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.0 [4.0\u0026ndash;5.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0 [5.0\u0026ndash;5.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 [4.0\u0026ndash;5.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlb\u003csup\u003e*\u003c/sup\u003e, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.8 [2.5\u0026ndash;3.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.8 [2.5\u0026ndash;3.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.8 [2.5\u0026ndash;3.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.962\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP\u003csup\u003e*\u003c/sup\u003e, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e253.0 [186.0\u0026ndash;355.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e267.0 [186.0\u0026ndash;409.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e239.5 [183.0\u0026ndash;310.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.116\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003csup\u003e*\u003c/sup\u003e, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.5 [14.0\u0026ndash;30.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.5 [15.0\u0026ndash;29.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.5 [13.8\u0026ndash;30.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.641\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALBI score\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;1.6 [\u0026ndash;2.0\u0026ndash; \u0026minus;\u0026thinsp;1.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;1.6 [\u0026ndash;2.0\u0026ndash; \u0026minus;\u0026thinsp;1.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;1.7 [\u0026ndash;2.0\u0026ndash; \u0026minus;\u0026thinsp;1.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.404\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIB\u0026ndash;4 score\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.2 [2.1\u0026ndash;7.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.8 [2.0\u0026ndash;5.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.6 [2.2\u0026ndash;7.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003csup\u003e*\u003c/sup\u003e, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.0 [23.0\u0026ndash;52.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35.0 [21.8\u0026ndash;51.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35.0 [24.8\u0026ndash;52.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.526\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u0026ndash;Bil\u003csup\u003e*\u003c/sup\u003e, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9 [0.5\u0026ndash;1.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0 [0.5\u0026ndash;1.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9 [0.4\u0026ndash;1.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.392\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN\u003csup\u003e*\u003c/sup\u003e, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.7 [17.8\u0026ndash;43.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25.9 [18.3\u0026ndash;46.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28.1 [16.8\u0026ndash;42.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.721\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u003csup\u003e*\u003c/sup\u003e, mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.0 [28.0\u0026ndash;87.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.9 [26.6\u0026ndash;86.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e61.6 [28.8\u0026ndash;91.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECMO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.631\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.593\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (22.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22 (21.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003csup\u003e*\u003c/sup\u003e, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.5 [5.8\u0026ndash;17.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1 [6.1\u0026ndash;17.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.2 [4.6\u0026ndash;19.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.700\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophil\u003csup\u003e*\u003c/sup\u003e, /\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.0 [0.0\u0026ndash;110.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0 [0.0\u0026ndash;102.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.0 [0.0\u0026ndash;115.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose per day\u003csup\u003e*\u003c/sup\u003e, g per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.5 [9.0\u0026ndash;13.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0 [1.5\u0026ndash;3.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose/kg per day\u003csup\u003e*\u003c/sup\u003e, g/kg per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.2 [0.1\u0026ndash;0.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.04 [0.02\u0026ndash;0.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacrolide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSXT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbamazepine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValproic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcetaminophen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (20.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19 (18.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcetaminophen dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e500.0 [400.0\u0026ndash;1000.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e500.0 [400.0\u0026ndash;1000.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e400.0 [400.0\u0026ndash;1000.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.185\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmiodarone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.721\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePropofol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.828\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRIF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSAIDs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103 (50.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54 (52.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49 (48.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.576\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVAN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (23.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTEI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLIN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13 (12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.748\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.498\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMFG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eALBI score = (log\u003csub\u003e10\u003c/sub\u003e T\u0026ndash;Bil \u0026times; 0.66) + (\u0026minus;\u0026thinsp;0.085 \u0026times; Alb) \u003csup\u003e47\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eFIB\u0026ndash;4 score\u0026thinsp;=\u0026thinsp;age \u0026times; AST/ (platelet \u0026times; (ALT)\u003csup\u003e1/2 48\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eeGFR [mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e]\u0026thinsp;=\u0026thinsp;194 \u0026times; serum creatinine\u003csup\u003e\u0026minus;\u0026thinsp;1.094\u003c/sup\u003e \u0026times; age\u003csup\u003e\u0026minus;\u0026thinsp;0.287\u003c/sup\u003e (\u0026times;0.739 if female) \u003csup\u003e49\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAlb, serum albumin; ALBI, albumin\u0026ndash;bilirubin; ALP, alkaline phosphatase; ALT, alanine aminotransferase;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CHDF, continuous hemodiafiltration; CAS, caspofungin; CRP, C\u0026ndash;reactive protein; DAP, daptomycin; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FIB\u0026ndash;4, Fibrosis\u0026ndash;4; HD, hemodialysis; LIN, linezolid; MFG, micafungin; MEM, meropenem; NSAIDs, Non\u0026ndash;Steroidal Anti\u0026ndash;Inflammatory Drugs; PSI, pneumonia severity index; TEI, teicoplanin; RIF, rifampicin; SOFA, sequential organ failure assessment; SXT, sulfamethoxazole/trimethoprim; T\u0026ndash;Bil, total bilirubin, VAN, vancomycin\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eChi\u0026ndash;squared test or Mann\u0026ndash;Whitney U test\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003eData are presented as median [interquartile range].\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eLiver injury\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the biochemical classification of liver injury based on the Roussel Uclaf Causality Assessment Method (RUCAM) (TZP; n\u0026thinsp;=\u0026thinsp;43, MEM; n\u0026thinsp;=\u0026thinsp;43). Among 86 patients developed liver injury, 50 (58%) developed classified as cholestasis. For TZP, 26 patients (61%) had cholestasis, 10 patients (23%) had hepatitis, and 7 patients (16%) mixed cholestasis/hepatitis; for MEM, 24 patients (56%) had cholestasis, 8 patients (19%) had hepatitis, and 11 patients (26%) had mixed cholestasis/hepatitis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). According to the RUCAM, the liver injury in this study was possible or probable induced by TZP or MEM: TZP 5.0 (4.0\u0026ndash;6.0) and MEM 6.0 (5.0\u0026ndash;7.0) (data not shown).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate and multiple logistic regression analysis for TZP or MEM\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eUnivariate logistic regression analysis determined that male, administration period, SOFA score, ALT, and AST were potential independent variables in liver injury. The final model using the stepwise forward selection method included administration period (odds ratio [OR]\u0026thinsp;=\u0026thinsp;1.080, 95% confidence interval (CI)\u0026thinsp;=\u0026thinsp;1.019\u0026ndash;1.143, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), sequential organ failure assessment (SOFA) score (OR\u0026thinsp;=\u0026thinsp;1.133, 95% CI\u0026thinsp;=\u0026thinsp;1.038\u0026ndash;1.237, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), and ALT (OR\u0026thinsp;=\u0026thinsp;1.042, 95% CI\u0026thinsp;=\u0026thinsp;1.011\u0026ndash;1.073, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) (adjusted coefficient of determination\u0026thinsp;=\u0026thinsp;0.116, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Administration period was significantly longer with increasing grade of liver injury (grade 0, 6.5 [5.0\u0026ndash;10.3] days; grade 1, 9.0 [6.8\u0026ndash;13.3] days; grade 2, 10.5 [7.0\u0026ndash;14.0] days; grade\u0026thinsp;\u0026ge;\u0026thinsp;3, 11.0 [6.3\u0026ndash;17.5] days; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) (data not shown).\u003c/p\u003e \u003c/div\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\u003eUnivariable and multiple logistic regression analysis of TZP or MEM in the retrospective observational study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eTZP or MEM (n\u0026thinsp;=\u0026thinsp;204)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eunivariable analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c7\" namest=\"c4\"\u003e \u003cp\u003emultiple analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR [95% CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR [95% CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.982 [0.963\u0026ndash;1.002]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.991 [1.046\u0026ndash;3.792]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.017 [1.001\u0026ndash;1.035]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.029 [0.983\u0026ndash;1.078]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdministration period, day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.088 [1.030\u0026ndash;1.149]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.080 [1.019\u0026ndash;1.143]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol drinking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.678 [0.352\u0026ndash;1.308]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.088 [1.012\u0026ndash;1.169]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.133 [1.038\u0026ndash;1.237]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.764 [0.581\u0026ndash;1.004]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlb, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.036 [0.186\u0026ndash;5.782]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.300 [0.035\u0026ndash;2.560]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.041 [1.011\u0026ndash;1.071]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.042 [1.011\u0026ndash;1.073]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALBI score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.244 [0.688\u0026ndash;2.250]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIB\u0026ndash;4 score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000 [0.973\u0026ndash;1.028]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.012 [1.000\u0026ndash;1.024]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u0026ndash;Bil, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.051 [0.960\u0026ndash;1.150]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.273\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.738 [0.142\u0026ndash;3.839]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.717\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR, mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.006 [1.000\u0026ndash;1.012]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.014 [0.982\u0026ndash;1.047]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.391\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophil, /\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.998 [0.996\u0026ndash;1.001]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose per day, g per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.020 [0.968\u0026ndash;1.075]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.458\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose/kg per day, g/kg per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.698 [0.045\u0026ndash;10.730]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.796\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo\u0026ndash;administered drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.045 [0.538\u0026ndash;2.027]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.897\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcetaminophen dose, mg per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000 [0.998\u0026ndash;1.001]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.502\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMEM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.961 [0.552\u0026ndash;1.673]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.887\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAdjusted coefficient of determination\u0026thinsp;=\u0026thinsp;0.116 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eALBI score = (log\u003csub\u003e10\u003c/sub\u003e T\u0026ndash;Bil \u0026times; 0.66) + (\u0026minus;\u0026thinsp;0.085 \u0026times; Alb) \u003csup\u003e47\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eFIB\u0026ndash;4 score\u0026thinsp;=\u0026thinsp;age \u0026times; AST/ (platelet \u0026times; (ALT)\u003csup\u003e1/2 48\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eeGFR [mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e]\u0026thinsp;=\u0026thinsp;194 \u0026times; serum creatinine\u003csup\u003e\u0026minus;\u0026thinsp;1.094\u003c/sup\u003e \u0026times; age\u003csup\u003e\u0026minus;\u0026thinsp;0.287\u003c/sup\u003e (\u0026times;0.739 if female) \u003csup\u003e49\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eVariables with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were included in the multivariate model.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eBy using the stepwise forward selection method, potential independent variables were further examined to construct the final model.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAlb, serum albumin; ALBI, albumin\u0026ndash;bilirubin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CI, confidence interval; CRP, C\u0026ndash;reactive protein; eGFR, estimated glomerular filtration rate; FIB\u0026ndash;4, Fibrosis\u0026ndash;4; MEM, meropenem; OR, odds ratio; PSI, pneumonia severity index; SOFA, sequential organ failure assessment; T\u0026ndash;Bil, total bilirubin; TZP, tazobactam/piperacillin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSub\u003c/b\u003e\u0026ndash;\u003cb\u003egroup analysis for TZP\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe univariate logistic regression analysis demonstrated that administration period, SOFA score, ALT, Fibrosis\u0026ndash;4 (FIB\u0026ndash;4) score, and aspartate aminotransferase (AST) were selected as potential independent variables in liver injury. By using the stepwise forward selection method, the final model included administration period (OR\u0026thinsp;=\u0026thinsp;1.078, 95% CI\u0026thinsp;=\u0026thinsp;1.001\u0026ndash;1.165, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049) and SOFA score (OR\u0026thinsp;=\u0026thinsp;1.136, 95% CI\u0026thinsp;=\u0026thinsp;1.013\u0026ndash;1.275, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030) (adjusted coefficient of determination\u0026thinsp;=\u0026thinsp;0.158, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). When the interaction term was introduced, no significant interactions were found between the independent variables. The cut\u0026ndash;off values and area under the receiver operating characteristic curve (AUC) of administration period and SOFA score were six days (AUC, 0.69; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) and six points (AUC, 0.66; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), respectively. The administration period increased as the grade of liver injury increased (grade 0, 6.0 [4.5\u0026ndash;12.0] days; grade 1, 9.5 [6.0\u0026ndash;14.0] days; grade 2, 12.5 [7.5\u0026ndash;15.3] days; grade\u0026thinsp;\u0026ge;\u0026thinsp;3, 18.0 [18.0\u0026ndash;20.0] days; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) (data not shown).\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\u003eUnivariable and multiple logistic regression analysis divided TZP and MEM in the retrospective observational study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eTZP (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c10\" namest=\"c7\"\u003e \u003cp\u003eMEM (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eunivariable analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003emultiple analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eunivariable analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003emultiple analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR [95% CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR [95% CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR [95% CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOR [95% CI]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.995 [0.968\u0026ndash;1.023]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.705\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.969 [0.940\u0026ndash;0.998]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.244 [0.513\u0026ndash;3.017]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.527 [1.348\u0026ndash;9.228]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.854 [1.427\u0026ndash;10.406]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.009 [0.989\u0026ndash;1.029]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.023 [0.996\u0026ndash;1.049]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.023 [0.963\u0026ndash;1.086]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.453\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.022 [0.954\u0026ndash;1.094]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.533\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdministration period, day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.108 [1.020\u0026ndash;1.190]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.078 [1.001\u0026ndash;1.165]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.082 [0.996\u0026ndash;1.158]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.082 [1.003\u0026ndash;1.168]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol drinking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.761 [0.561\u0026ndash;1.304]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.559\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.589 [0.228\u0026ndash;1.525]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.165 [1.042\u0026ndash;1.302]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.136 [1.013\u0026ndash;1.275]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.027 [0.932\u0026ndash;1.132]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.904 [0.589\u0026ndash;1.387]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.643\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.661 [0.452\u0026ndash;0.965]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlb, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.625 [0.290\u0026ndash;1.347]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.843 [0.783\u0026ndash;4.341]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000 [0.999\u0026ndash;1.001]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.952\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.998 [0.993\u0026ndash;1.003]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.479\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.081 [1.033\u0026ndash;1.132]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.011 [0.971\u0026ndash;1.053]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALBI score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.107 [0.897\u0026ndash;4.948]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.654 [0.267\u0026ndash;1.600]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIB\u0026ndash;4 score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.100 [1.006\u0026ndash;1.100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.988 [0.955\u0026ndash;1.022]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST, U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.018 [1.001\u0026ndash;1.035]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.001 [0.985\u0026ndash;1.017]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.882\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u0026ndash;Bil, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.093 [0.958\u0026ndash;1.247]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.987 [0.845\u0026ndash;1.152]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.007 [0.992\u0026ndash;1.022]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.985 [0.966\u0026ndash;1.003]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR, mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.002 [0.993\u0026ndash;1.011]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.670\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.010 [1.001\u0026ndash;1.021]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.996 [0.945\u0026ndash;1.049]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.022 [0.980\u0026ndash;1.066]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.303\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophil, /\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.997 [0.992\u0026ndash;1.001]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.000 [0.997\u0026ndash;1.003]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.828\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose per day, g per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.073 [0.958\u0026ndash;1.202]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.340 [0.887\u0026ndash;2.024]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose/kg per day, g/kg per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.942 [0.015\u0026ndash;57.814]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.977\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.690 [0.129\u0026ndash;22.089]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.689\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo\u0026ndash;administered drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.338 [0.563\u0026ndash;3.177]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.635 [0.218\u0026ndash;1.853]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcetaminophen dose, mg per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.998 [0.995\u0026ndash;1.002]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.000 [0.998\u0026ndash;1.001]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.845\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eTZP; adjusted coefficient of determination\u0026thinsp;=\u0026thinsp;0.158 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eMEM; adjusted coefficient of determination\u0026thinsp;=\u0026thinsp;0.092 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eALBI score = (log\u003csub\u003e10\u003c/sub\u003e T\u0026ndash;Bil \u0026times; 0.66) + (\u0026minus;\u0026thinsp;0.085\u0026times; Alb) \u003csup\u003e47\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eFIB\u0026ndash;4 score\u0026thinsp;=\u0026thinsp;age \u0026times; AST/ (platelet \u0026times; (ALT)\u003csup\u003e1/2 48\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eeGFR [mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e]\u0026thinsp;=\u0026thinsp;194 \u0026times; serum creatinine\u003csup\u003e\u0026minus;\u0026thinsp;1.094\u003c/sup\u003e \u0026times; age\u003csup\u003e\u0026minus;\u0026thinsp;0.287\u003c/sup\u003e (\u0026times;0.739 if female) \u003csup\u003e49\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eVariables with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were included in the multivariate model. Using the stepwise forward selection method, potential independent variables were further\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eexamined to construct the final model.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eAlb, serum albumin; ALBI, albumin\u0026ndash;bilirubin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eBUN, blood urea nitrogen; CI, confidence interval; CRP, C\u0026ndash;reactive protein; eGFR, estimated glomerular filtration rate; FIB\u0026ndash;4, Fibrosis\u0026ndash;4; MEM, meropenem;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eOR, odds ratio; PSI, pneumonia severity index; SOFA, sequential organ failure assessment; T\u0026ndash;Bil, total bilirubin; TZP, tazobactam/piperacillin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSub\u003c/b\u003e\u0026ndash;\u003cb\u003egroup analysis for MEM\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe univariate logistic regression analysis demonstrated that age, male, administration period, and eGFR were selected as potential independent variables in liver injury. By using the stepwise forward selection method, the final model included male (OR\u0026thinsp;=\u0026thinsp;3.854, 95% CI\u0026thinsp;=\u0026thinsp;1.427\u0026ndash;10.406, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and administration period (OR\u0026thinsp;=\u0026thinsp;1.082, 95% CI\u0026thinsp;=\u0026thinsp;1.003\u0026ndash;1.168, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) (adjusted coefficient of determination\u0026thinsp;=\u0026thinsp;0.092, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). When the interaction term was introduced, no significant interactions were found between the independent variables. The cut\u0026ndash;off value and AUC of administration period was six days (AUC, 0.69; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Similar to TZP, administration period was significantly longer in patients with severe liver injury (grade 0, 6.0 [5.0\u0026ndash;9.0] days; grade 1, 11.0 [7.0\u0026ndash;12.0] days; grade 2, 7.5 [6.3\u0026ndash;14.5] days; grade\u0026thinsp;\u0026ge;\u0026thinsp;3, 11.0 [7.0\u0026ndash;15.8] days; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (data not shown).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eComparison of patient background by sex in patients receiving MEM\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSupplementary Table S3 shows the comparison of patient background by sex in patients receiving MEM. Body weight, alcohol drinking history, pneumonia severity index (PSI), vancomycin, and linezolid were significantly higher in male than in female (male vs. female: body weight; 61.7 kg vs. 48.7 kg, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; alcohol drinking history, 34% vs. 3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; PSI, 5.0 vs. 4.0, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005; vancomycin, 28% vs. 10%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032; linezolid, 17% vs. 3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e(ii) FAERS database study\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eTotal of 195,893 reports were extracted from the FAERS database. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows a flowchart of the patient. These reports include the fourth\u0026ndash;generation cephalosporin (n\u0026thinsp;=\u0026thinsp;10,758), carbapenem (n\u0026thinsp;=\u0026thinsp;22,165), \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactam and \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactamase inhibitor combination (n\u0026thinsp;=\u0026thinsp;28,427), and quinolone (n\u0026thinsp;=\u0026thinsp;151,936). The number of reports attributed to the development of drug\u0026ndash;induced liver injury were 1,159 (11%). Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the patient characteristics between the liver and non\u0026ndash;liver injury groups. The reporting odds ratio (ROR) and 95% CI for the above variables were as follows: male (ROR\u0026thinsp;=\u0026thinsp;1.237, 95% CI\u0026thinsp;=\u0026thinsp;1.090\u0026ndash;1.405, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), age (ROR\u0026thinsp;=\u0026thinsp;0.988, 95% CI\u0026thinsp;=\u0026thinsp;0.986\u0026ndash;0.991, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), the fourth\u0026ndash;generation cephalosporin (ROR\u0026thinsp;=\u0026thinsp;1.400, 95% CI\u0026thinsp;=\u0026thinsp;1.124\u0026ndash;1.743, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), carbapenem (ROR\u0026thinsp;=\u0026thinsp;1.845, 95% CI\u0026thinsp;=\u0026thinsp;1.592\u0026ndash;2.138, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactam and \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactamase inhibitor combination (ROR\u0026thinsp;=\u0026thinsp;1.383, 95% CI\u0026thinsp;=\u0026thinsp;1.194\u0026ndash;1.603, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and complication of sepsis (ROR\u0026thinsp;=\u0026thinsp;1.705, 95% CI\u0026thinsp;=\u0026thinsp;1.126\u0026ndash;2.582, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics and risk analysis of liver injury in the study using FAERS database.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver injury\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,159)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eNon\u0026ndash;liver injury\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;194,734)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eROR [95% CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e465 (40.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e93,521 (48.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e494 (42.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e80,296 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.237 [1.090\u0026ndash;1.405]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e200 (17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e20,917 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003csup\u003e*\u003c/sup\u003e, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e54.0 [36.8\u0026ndash;67.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e61.0 [45.0\u0026ndash;72.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.989 [0.986\u0026ndash;0.992]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e223 (19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e47,914 (24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe fourth\u0026ndash;generation cephalosporin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e87 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e10,671 (5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.400 [1.124\u0026ndash;1.743]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e87 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e10,671 (5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.400 [1.124\u0026ndash;1.743]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e220 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e21,945 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.845 [1.592\u0026ndash;2.138]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eDOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e6 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e867 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.164 [0.520\u0026ndash;2.603]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.712\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBIPM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e10 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e199 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.508 [4.496\u0026ndash;16.100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eMEM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e208 (17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e21,116 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.798 [1.547\u0026ndash;2.091]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactam and \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactamase inhibitor combination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e220 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e28,207 (14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.383 [1.194\u0026ndash;1.603]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eC/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e927 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTZP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e220 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e27,333 (14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.435 [1.238\u0026ndash;1.663]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eQuinolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e849 (73.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e151,087 (77.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.791 [0.694\u0026ndash;0.901]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eGRNX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e6 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e345 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.932 [1.305\u0026ndash;6.585]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSTFX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e171 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.930 [2.022\u0026ndash;12.018]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eCIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e335 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e73,282 (37.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.674 [0.593\u0026ndash;0.765]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eTFLX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e158 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.336 [2.186\u0026ndash;13.021]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eMXF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e175 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e17,979 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.748 [1.488\u0026ndash;2.055]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eLVX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e371 (32.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e69,443 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.849 [0.751\u0026ndash;0.961]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e23 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2,285 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.705 [1.126\u0026ndash;2.582]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eBIPM, biapenem; CI, confidence interval; CIP, ciprofloxacin; C/T, ceftolozane\u0026ndash;tazobactam; DOR, doripenem;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eFAERS, FDA Adverse Event Reporting System; FEP, cefepime; GRNX, garenoxacin; LVX, levofloxacin; MEM, meropenem;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eMXF, moxifloxacin; ROR, reporting odds ratio; STFX, sitafloxacin; TFLX, tosufloxacin; TZP, tazobactam/piperacillin\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*Data are presented as median [interquartile range].\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe retrospective observational study revealed that the occurrence rate of liver injury increased in association with the administration period of TZP or MEM. An administration period of more than six days increased the incidence of liver injury. The administration period was prolonged in patients receiving TZP or MEM and corresponded with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade of liver injury. These findings suggest that early antibiotic change reduces the development of liver injury. In the FAERS database study, sepsis was one of the risk factors on liver injury. In addition, the results revealed that an elevated SOFA score increased the incidence of liver injury in patients receiving TZP. The cut\u0026ndash;off value for the SOFA score for the occurrence of liver injury was estimated to be six points. These findings indicated that the baseline condition contributed to the TZP\u0026ndash;induced liver injury. Furthermore, MEM\u0026ndash;induced liver injury was significantly higher in males; this finding is consistent with the FAERS database study.\u003c/p\u003e\u003cp\u003eAntibiotics are one of the common causes of drug\u0026ndash;induced liver injury \u003csup\u003e11, 12\u003c/sup\u003e. The liver receives most of its blood supply (approximately 70%) from the intestine via portal circulation and is constantly exposed to gut\u0026ndash;derived factors including bacterial products and inflammatory cytokines. Therefore, reducing bacterial density, eliminating target harmful bacteria, inhibiting secondary bacterial proliferation, and reducing bacterial translocation by the liver are considered the pharmacological mechanisms of drug\u0026ndash;induced liver injury.\u003c/p\u003e\u003cp\u003eAntibiotic therapy aims to eliminate pathogenic bacteria; however, this microbial clearance also reduces beneficial commensal bacteria, and this situation has important pathological implications for the liver \u003csup\u003e13, 14\u003c/sup\u003e. The risk of drug\u0026ndash;induced liver injury caused by microbiota dysbiosis has been recognized a multifactorial process. Antibiotics directly affect the structure and diversity of gut microbiota, which alters metabolites. The depletion of probiotics after antibiotics interference can reduce the efficacy of hepatoprotective agents and leads to the development of liver injury \u003csup\u003e15\u003c/sup\u003e. \u003cem\u003eLactobacillus\u003c/em\u003e and \u003cem\u003eBifidobacterium\u003c/em\u003e spp., which play significant roles in regulating intestinal flora balance, reduce oxidative stress and inflammation and improve liver pathological changes \u003csup\u003e16\u003c/sup\u003e. By contrast, it has been reported that cefoxitin significantly reduces gut microbiota diversity and increases the levels of pathogenic bacteria such as \u003cem\u003eFirmicutes\u003c/em\u003e, \u003cem\u003eTendericutes\u003c/em\u003e, and \u003cem\u003eVibrio\u003c/em\u003e, which cause damage to the intestinal barrier \u003csup\u003e16\u003c/sup\u003e. In other words, the sufficient decreases in beneficial intestinal bacteria such as \u003cem\u003eLactobacillus\u003c/em\u003e spp. and \u003cem\u003eBifidobacterium\u003c/em\u003e spp. and the sufficient increase in pathogenic bacteria, including \u003cem\u003eEnterococcus\u003c/em\u003e spp., can aggravate the progression of liver injury \u003csup\u003e17, 18\u003c/sup\u003e. Therefore, a follow\u0026ndash;up liver function test is essential during the administration of antibiotics that affect intestinal microorganisms and their metabolic activities.\u003c/p\u003e\u003cp\u003eTZP\u0026ndash; or MEM\u0026ndash;associated cholestasis was seen in many patients in this retrospective observational study. Cholestatic injury accounts for approximately 30% of drug\u0026ndash;induced liver injuries \u003csup\u003e19\u003c/sup\u003e. Most cases are mild and manageable and occasionally leads to vanishing bile duct syndrome \u003csup\u003e20\u003c/sup\u003e. Cholestatic hepatitis caused by carbapenems is probably immunoallergic and resembles the rare and clinically apparent liver injury that has been linked to penicillin and cephalosporins. In a Spanish cohort, patients older than 55 years were significantly more likely to develop a cholestatic or mixed liver injury. Given that the median age of this study population is 71.5 years, older age may have contributed to the development of liver injury \u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe recommended treatment length is described in the guidelines of the Infectious Diseases Society of America: five to seven days for infections caused by \u003cem\u003ecoagulase\u003c/em\u003e\u0026ndash;\u003cem\u003enegative staphylococci\u003c/em\u003e, seven to fourteen days for \u003cem\u003eenterococci\u003c/em\u003e and \u003cem\u003eGram\u003c/em\u003e\u0026ndash;\u003cem\u003enegative organisms\u003c/em\u003e, and two to six weeks for \u003cem\u003eS. aureus\u003c/em\u003e\u003csup\u003e22\u003c/sup\u003e. In the current study, administration for more than six days was associated with the development of liver injury. In clinical settings, a three\u0026ndash;day incubation period is sufficient to reveal the result of a blood culture test \u003csup\u003e23\u003c/sup\u003e. Therefore, antimicrobial de\u0026ndash;escalation is a treatment strategy in early adequate antimicrobial therapy. A previous study revealed that de\u0026ndash;escalation is not associated with adverse consequences compared with treatment with broad\u0026ndash;spectrum antibiotics (mortality or clinical failure) \u003csup\u003e24\u003c/sup\u003e. Clinicians should consider switching from TZP or MEM to other antibiotics within six days. By contrast, the careful monitoring of liver function is needed for patients who require the prolonged administration of TZP or MEM. A reduction in the length of antibiotic administration is a potentially viable strategy to minimize the consequences of antibiotic overuse in critical care, including antibiotic resistance, adverse effects, clostridium difficile colitis, and costs \u003csup\u003e25\u003c/sup\u003e. Bacterial resistance decreases the chance of early adequate therapy \u003csup\u003e26\u003c/sup\u003e and are associated with mortality \u003csup\u003e27, 28\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e The SOFA score is a well\u0026ndash;known and simple scoring system and a valid tool for predicting sepsis in critical care units. A SOFA score\u0026thinsp;\u0026gt;\u0026thinsp;2 points at baseline represents organ dysfunction or cellular damage \u003csup\u003e29\u003c/sup\u003e. In addition, sepsis is defined as a life\u0026ndash;threatening organ dysfunction caused by the dysregulated response of the host to infection. Acetaminophen\u0026ndash;induced liver injury also reported that a SOFA score\u0026thinsp;\u0026gt;\u0026thinsp;7 points predict organ failure \u003csup\u003e30\u003c/sup\u003e. Therefore, special attention should be paid for monitoring liver injury in patients with a SOFA score\u0026thinsp;\u0026gt;\u0026thinsp;6 points.\u003c/p\u003e\u003cp\u003eHeavy drinkers are likely to develop alcoholic hepatitis, which is associated with impaired liver function due to a severe inflammatory response \u003csup\u003e31, 32, 33, 34\u003c/sup\u003e. It was reported that men tend to consume more alcohol and experience alcohol\u0026ndash;induced physical impairment compared with women \u003csup\u003e35\u003c/sup\u003e. Notably, alcohol history has been found to be substantially present in men in our study population (Supplementary Table S3), thus suggesting that men are at a high risk of liver injury. It has been reported that amoxicillin\u0026ndash;induced liver injury is also more frequent in men than in women \u003csup\u003e36\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe elevation of ALT from baseline may be positively associated with drug\u0026ndash;induced liver injury. This finding was consistent with previous studies \u003csup\u003e37, 38\u003c/sup\u003e. A positive correlation between ALT levels and hepatocyte necrosis also existed in an animal study \u003csup\u003e39\u003c/sup\u003e. Oxidative stress, which causes necrosis, is removed by Kupffer cells in the liver \u003csup\u003e40\u003c/sup\u003e, thus suggesting that Kupffer cell function and the number of Kupffer cells may be involved in the development of drug\u0026ndash;induced liver injury \u003csup\u003e37\u003c/sup\u003e. However, it is unclear whether TZP\u0026ndash; or MEM\u0026ndash;induced liver injuries occur in similar phenomena. Therefore, the mechanism of TZP\u0026ndash; or MEM\u0026ndash;induced liver injury needs further research.\u003c/p\u003e\u003cp\u003eThere are several limitations of this study. First, we extracted reports of liver injury that occurred during the administration of broad\u0026ndash;spectrum antibiotics by using the term \u0026ldquo;drug\u0026ndash;induced liver injury\u0026rdquo;, which was derived from Medical Dictionary for Regulatory Activities (MedDRA) terminology; however, the causal relationship between events, medications, and severity of liver injury remains uncertain. Second, information on the concomitant use of drugs that potentially interact with TZP or MEM was lacking in the FAERS database. Third, given that the FAERS database did not include clinical laboratory data such as serum creatinine level and alanine aminotransferase, we could not evaluate renal and liver functions as risk factors of antibiotics\u0026ndash;induced liver injury. Fourth, this was a single\u0026ndash;center retrospective observational study; thus, it was difficult to avoid the influence of unknown confounding factors. Fifth, among the carbapenem group, only two patients received doripenem and one patient received biapenem. Most patients were administered MEM; therefore, we extracted only patients receiving MEM. In the future, further study is needed to clarify the differences in carbapenem\u0026ndash;treated patients. Finally, since critically ill patients were received numerous medications and often experienced the change of drug dosing and medication regimens, it is difficult to exclude the patients who used additional drugs other than TZP or MEM.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eOur study was the first to demonstrate that a prolonged administration period (more than six days) could increase the risk of liver injury in patients receiving TZP or MEM. In addition, an elevated SOFA score (more than six points) in TZP and male in MEM were also identified as risk factors of liver injury. On the basis of these findings, a periodical monitoring of liver function is recommended in patients receiving TZP or MEM, particularly in those with multiple risk factors for the development of liver injury. The findings of this study provide useful information for the appropriate use of TZP or MEM.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRetrospective observational study\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eData from patients receiving TZP or MEM in the ICU of Mie University Hospital from January 2010 to March 2022 were analyzed. The exclusion criteria were age\u0026thinsp;\u0026lt;\u0026thinsp;15 years, patients with a history of biliary tract or liver injury, baseline ALT\u0026thinsp;\u0026ge;\u0026thinsp;40 U/L, administration period of TZP or MEM\u0026thinsp;\u0026le;\u0026thinsp;3 days, and no measurement of ALT or ALP. A retrospective observational study was performed to obtain the following demographic data: sex; age; height; body weight; body mass index; daily dose and treatment duration of MEM and TZP; baseline clinical laboratory data (serum albumin [Alb], ALP, ALT, albumin\u0026ndash;bilirubin [ALBI] grade, FIB\u0026ndash;4 score, AST, total bilirubin [T\u0026ndash;Bil], blood urea nitrogen, serum creatinine [SCr], eGFR, C\u0026ndash;reactive protein, and eosinophil); and medical records of extracorporeal membrane oxygenation, hemodialysis, and continuous hemodiafiltration. The SOFA score and PSI were extracted for the evaluation of infection severity \u003csup\u003e41, 42\u003c/sup\u003e. As the mortality rate is directly related to the degree of organ dysfunction, it is evident that it must also be related to the SOFA score for each organ system \u003csup\u003e43\u003c/sup\u003e. PSI scoring system is one of the most widely used scoring tools to evaluate the condition and prognosis of community acquired pneumonia patients \u003csup\u003e44\u003c/sup\u003e. We collected information on concomitant systematically administered medications that could cause drug\u0026ndash;induced liver injury (macrolide, sulfamethoxazole/trimethoprim, carbamazepine, valproic acid, acetaminophen, amiodarone, statin, propofol, rifampicin, non\u0026ndash;steroidal anti\u0026ndash;inflammatory drugs, and opioids) \u003csup\u003e45, 46\u003c/sup\u003e, other antibiotics and antifungal drugs. Acetaminophen dose was also extracted. The ALBI score and FIB\u0026ndash;4 score were calculated using the following formula: ALBI score = (log\u003csub\u003e10\u003c/sub\u003e T\u0026ndash;Bil \u0026times; 0.66) + (\u0026minus;\u0026thinsp;0.085 \u0026times; Alb) \u003csup\u003e47\u003c/sup\u003e, FIB\u0026ndash;4 score\u0026thinsp;=\u0026thinsp;age \u0026times; AST/ (platelet \u0026times; (ALT)\u003csup\u003e1/2 48\u003c/sup\u003e. The eGFR was calculated using the prediction equation for Japanese patients: eGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u0026thinsp;=\u0026thinsp;194 \u0026times; SCr\u003csup\u003e\u0026minus;\u0026thinsp;1.094\u003c/sup\u003e \u0026times; age\u003csup\u003e\u0026minus;\u0026thinsp;0.287\u003c/sup\u003e (\u0026times;0.739 if female) \u003csup\u003e49\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePSM analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAge and eGFR were considered potential confounders in patients receiving TZP or MEM, and these were adjusted using PSM analysis. Propensity scores were calculated using bivariate logistic regression by using a 1:1 case\u0026ndash;control match with a caliper value of 0.1 (one\u0026ndash;to\u0026ndash;one nearest\u0026ndash;neighbor matching). The standardized difference (10% or 0.1) was used to compare the distribution of all paired covariates between groups.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLiver injury evaluation\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eLiver injury was defined as an elevation of ALT grade on the basis of the CTCAE version 4.0 (Supplementary Table S4) after the initiation of TZP or MEM therapy \u003csup\u003e50\u003c/sup\u003e. The possibility of TZP\u0026ndash; or MEM\u0026ndash;induced liver injury was evaluated using the RUCAM (0 or less indicate that the drug is \u0026ldquo;excluded\u0026rdquo; as a cause; 1 to 2 that it is \u0026ldquo;unlikely\u0026rdquo;; 3 to 5 \u0026ldquo;possible\u0026rdquo;; 6 to 8 \u0026ldquo;probable\u0026rdquo;; and greater than 8, \u0026ldquo;highly probable\u0026rdquo;) \u003csup\u003e50\u003c/sup\u003e. The total score consists of points for 8 separate factors in 7 categories that help define the \u0026ldquo;signature\u0026rdquo; of the drug induced liver injury. These factors are: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) time to onset (+\u0026thinsp;1 or +\u0026thinsp;2); (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) course (\u0026ndash;2, 0, +\u0026thinsp;1, +2 or +\u0026thinsp;3); (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) risk factors (2 scores: 0 or +\u0026thinsp;1 each); (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) concomitant drugs (0, \u0026minus;\u0026thinsp;1, \u0026minus;\u0026thinsp;2 or \u0026minus;\u0026thinsp;3); (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) nondrug causes of liver injury (\u0026ndash;3, \u0026minus;\u0026thinsp;2, 0, +\u0026thinsp;1, or +\u0026thinsp;2); (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) previous information on the hepatotoxicity of the drug (0, +\u0026thinsp;1, or +\u0026thinsp;2); and (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) response to rechallenge (\u0026ndash;2, 0, +\u0026thinsp;1, or +\u0026thinsp;3). The individual points range from \u0026minus;\u0026thinsp;3 to +\u0026thinsp;3 and the total possible score ranges from \u0026minus;\u0026thinsp;9 to +\u0026thinsp;14. Liver injury was classified biochemically as being hepatitis, cholestatic, mixed cholestasis/hepatitis, and other by using R value, which was defined as ALT/upper limit of normal (ULN) divided by ALP/ULN: hepatitis, ALT\u0026thinsp;\u0026gt;\u0026thinsp;2 ULN and ALP\u0026thinsp;\u0026le;\u0026thinsp;ULN or R\u0026thinsp;\u0026ge;\u0026thinsp;5; cholestatic, ALT\u0026thinsp;\u0026le;\u0026thinsp;ULN and ALP\u0026thinsp;\u0026gt;\u0026thinsp;2 ULN or R\u0026thinsp;\u0026le;\u0026thinsp;2; mixed, ALT\u0026thinsp;\u0026gt;\u0026thinsp;2 ULN, ALP\u0026thinsp;\u0026gt;\u0026thinsp;ULN, and 2\u0026thinsp;\u0026lt;\u0026thinsp;R\u0026thinsp;\u0026lt;\u0026thinsp;5 \u003csup\u003e51\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eFAERS database study\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe FAERS database generated from post\u0026ndash;marketing spontaneous pharmacovigilance databases was used for this study. The FAERS database includes ˃ 1.4\u0026nbsp;million cases of adverse events reported worldwide after January 2004 and consists of seven data tables: patient demographic and administrative information, drug and biologic information, adverse events, patient outcomes, report sources, start end dates of drug therapy, and indications for use/diagnosis \u003csup\u003e52\u003c/sup\u003e. The source of the databases complies with the guidelines set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the databases adhere to the ICH\u0026ndash;standardized adverse event information guidelines \u003csup\u003e53\u003c/sup\u003e. For the current study, adverse event reports were downloaded from the website of the US Food and Drug Association (FDA) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; accessed on January 22, 2023). Reports with the same case number were identified as duplicate reports, and the most recent reports were used, as recommended by the FDA \u003csup\u003e54\u003c/sup\u003e. Data were extracted from the FAERS database between January 2013 and September 2022. We collected reports of the following antibiotics, which have broad\u0026ndash;spectrum use in empiric therapy in the ICU \u003csup\u003e55\u003c/sup\u003e: the fourth\u0026ndash;generation cephalosporin (cefepime), carbapenem (doripenem, biapenem, and MEM), \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactam and \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactamase inhibitor combination (tazobactam/ceftolozane and TZP), and quinolone (garenoxacin, sitafloxacin, ciprofloxacin, tosufloxacin, moxifloxacin, and levofloxacin). The collected data included the case number, drug name, adverse event name, start date of administration, end date of administration, date of development of the adverse event, sex, age, and medical history of sepsis (10040054), which were derived from MedDRA terminology. The sample code was provided in Supplementary Script S5.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events detection\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAdverse events were coded according to preferred terms (drug\u0026ndash;induced liver injury; 10072268) derived from MedDRA terminology. Event reports were identified using the standardized MedDRA query (version 26.0). Reports with development of liver injury during antibiotics administration were classified as \u0026ldquo;liver injury group\u0026rdquo; and other reports as \u0026ldquo;non\u0026ndash; liver injury group.\u0026rdquo;\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eStatistical analyses were performed using R software version 4.1.3 (R Core Team, 2022) \u003csup\u003e56\u003c/sup\u003e and JMP Pro 16 statistical package (SAS Institute, Cary, NC, USA). Categorical data were summarized as numbers (%) and analyzed using the chi\u0026ndash;squared test. Continuous data were summarized as medians (IQR) and analyzed using the Mann\u0026ndash;Whitney U test. Statistical significance was defined as a two\u0026ndash;tailed \u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e(i) Retrospective observational study\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eUnivariable and multiple logistic regression analyses were performed to identify the independent variables for the TZP\u0026ndash; or MEM\u0026ndash;induced liver injury. Variables with \u003cem\u003ep\u003c/em\u003e\u0026ndash;value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were included in the multivariate model. By using the stepwise forward selection method, potential independent variables were further examined to construct the final model. A multiple logistic regression analysis was used to determine the multiple regression equation for TZP\u0026ndash; or MEM\u0026ndash;induced liver injury. We verified these interactions by focusing on each significant independent variable. Clinical characteristics were compared and stratified by independent variables as needed. When multicollinearity was present, we selected an independent variable on the basis of its clinical relevance by sensitivity analyses. The cut\u0026ndash;off values of continuous variables for the development of TZP\u0026ndash; or MEM\u0026ndash;induced liver injury was determined by using the receiver operating characteristic curve method. Missing values were handled without correction.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e(ii) FAERS database study\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe association between clinical profiles and antibiotics\u0026ndash;induced liver injury was evaluated using ROR with a 95% CI. A statistically significant ROR was formally defined as a lower limit of the 95% CI exceeding 1.0.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki and its amendments after obtaining approval from the Clinical Research Ethics Review Committee of Mie University Hospital (No. H2022\u0026ndash;107). The requirement for patient consent was waived by the board owing to the retrospective nature of the study.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003ePatents\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis section is not mandatory but may be added if there are patents resulting from the work reported in this manuscript.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for the English language editing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, H.K. and C.S.; methodology, H.K. and C.S.; software, C.S.; validation, H.K., and T.I.; formal analysis, H.K. and C.S.; investigation, C.S.; resources, C.S.; data curation, C.S. and H.K.; writing\u0026ndash;original draft preparation, H.K. and C.S.; writing\u0026ndash;review and editing, H.K. and C.S. and T.O.; visualization, H.K. and C.S.; supervision, H.K. and T.I.; project administration, H.K.; funding acquisition, H.K. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData that support the findings of this manuscript are available upon request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following supporting information can be downloaded at: www.mdpi.com/xxx/s1,Supplementary Table S1, Sources of infection;\u0026nbsp;Supplementary Table S2,\u0026nbsp;Blood culture identification; Supplementary Table S3, Comparison of patient background by sex (MEM, retrospective observational study); Supplementary Table S4, Common Terminology Criteria for Adverse Events: elevation of alanine aminotransferase; Supplementary Script S5,\u0026nbsp;R scripts\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDisclaimer/Publisher\u0026rsquo;s Note\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTamma, P.D., Avdic, E., Li, D.X., Dzintars, K. \u0026amp; Cosgrove, S.E. 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Available at: https://www.R-project.org/ [Last accessed on December 19, 2022]\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"tazobactam/piperacillin, meropenem, liver injury, intensive care unit","lastPublishedDoi":"10.21203/rs.3.rs-3607226/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3607226/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOur objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury by performing a retrospective observational study and a study using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn a retrospective observational study, data of patients hospitalized in Mie University Hospital between 2010 and 2022 who initiated treatment with tazobactam/piperacillin or meropenem in the intensive care unit were extracted. Liver injury was defined as an elevated alanine aminotransferase (ALT) grade based on the Common Terminology Criteria for Adverse Events. The FAERS database between 2013 and 2022 were used.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included administration period (odds ratio [OR]\u0026thinsp;=\u0026thinsp;1.080, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), sequential organ failure assessment score (OR\u0026thinsp;=\u0026thinsp;1.133, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), and ALT (OR\u0026thinsp;=\u0026thinsp;1.042, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007). Male, age, the fourth\u0026ndash;generation cephalosporin, carbapenem, \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactam and \u003cem\u003eβ\u003c/em\u003e\u0026ndash;lactamase inhibitor combination, and complication of sepsis were associated with liver injury (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe periodic monitoring of liver function is strongly recommended in patients receiving tazobactam/piperacillin or meropenem, particularly in those with multiple risk factors for liver injury.\u003c/p\u003e","manuscriptTitle":"Investigation of tazobactam/piperacillin– or meropenem–induced liver injury based on retrospective observational study and the FDA Adverse Event Reporting System","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-17 19:03:45","doi":"10.21203/rs.3.rs-3607226/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-27T11:44:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-21T03:40:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6c51e067-2b02-49bb-a790-9bb5ae275222_SNPRID","date":"2024-01-05T08:43:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"0214c2f2-9d13-4300-9d15-b7a83b4e8d0b","date":"2023-11-22T10:17:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-11-22T08:19:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-11-22T08:18:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-11-15T14:53:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-11-15T14:46:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-11-13T22:44:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0d18b2d5-fad6-450a-91fa-94c0556381b3","owner":[],"postedDate":"November 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T16:11:04+00:00","versionOfRecord":{"articleIdentity":"rs-3607226","link":"https://doi.org/10.1038/s41598-024-69279-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-08-06 15:57:05","publishedOnDateReadable":"August 6th, 2024"},"versionCreatedAt":"2023-11-17 19:03:45","video":"","vorDoi":"10.1038/s41598-024-69279-6","vorDoiUrl":"https://doi.org/10.1038/s41598-024-69279-6","workflowStages":[]},"version":"v1","identity":"rs-3607226","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3607226","identity":"rs-3607226","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}