Clinical Outcomes of Third-Generation Cephalosporins, Carbapenems, and Piperacillin-Tazobactam in the Treatment of AmpC- Associated Enterobacterales Species Sepsis

Clinical Outcomes of Third-Generation Cephalosporins, Carbapenems, and Piperacillin-Tazobactam in the Treatment of AmpC- Associated Enterobacterales Species Sepsis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Outcomes of Third-Generation Cephalosporins, Carbapenems, and Piperacillin-Tazobactam in the Treatment of AmpC- Associated Enterobacterales Species Sepsis Mohammad Gharbeyah, Razan Rabi, Ahmad Al Bishawi, Mamon W. Swaileh, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7651779/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background AmpC-producing Enterobacterales are associated with resistance to many β-lactam antibiotics, and the optimal treatment approach remains challenging. The primary aim is to describe real-world outcomes of hospitalised patients with AmpC-associated Enterobacterales infections treated with different antibiotics. Methods This was a retrospective cohort study, including hospitalised patients with confirmed infections based on clinical evaluation and laboratory confirmation caused by AmpC-producing Enterobacterales. Patients received definitive therapy using 3GCss, piperacillin-tazobactam, or carbapenems, based on final culture results showing full susceptibility to the administered antibiotics. Results Patients were categorised into 3GCs, piperacillin-tazobactam, and carbapenem treatment groups. Significant baseline differences were observed; the carbapenem group included patients with higher rates of shock (32.4%) and mechanical ventilation (26.5%), compared to lower rates in the 3GCs group (shock 7%, mechanical ventilation 17%). After adjustment for potential confounders, Clinical failure rates were 17% for the 3GCs group, 32% for the piperacillin-tazobactam group, and 41% for the carbapenem group. The 28-day mortality (7%) and overall mortality (12%) were lowest in the 3GC group, followed by the piperacillin-tazobactam group (14.7% 28-day mortality). Conclusion In this real-world cohort, mortality and clinical failure appeared lower among patients with AmpC-associated Enterobacterales infections who received third-generation cephalosporins or piperacillin-tazobactam compared with carbapenems. These findings suggest that third-generation cephalosporins and piperacillin-tazobactam might be reasonable options in selected, less critically ill patients, but larger prospective studies are needed to better define their role, as these results are exploratory. AmpC β-lactamase Enterobacterales third-generation cephalosporins piperacillin-tazobactam carbapenems Figures Figure 1 Figure 2 Highlights • Third-generation cephalosporins showed low mortality in AmpC-associated infections. • Piperacillin-tazobactam had comparable outcomes to third-generation cephalosporins. • Carbapenem-treated patients had higher illness severity and mortality. • Clinical failure rates were lowest with third-generation cephalosporins. • Definitive, susceptibility-guided therapy may reduce the need for carbapenems. 1. Introduction Many Gram-negative bacilli, such as Enterobacter species, have a natural chromosomal gene for expressing AmpC β-lactamases within their genome. In the absence of beta-lactams, these bacterial species express AmpC β-lactamase enzymes at a low level, which are responsible for the hydrolysis of penicillin G, penicillin A, and first-generation cephalosporins. They are still sensitive to other members of the β-lactam family of antibiotics. [ 1 – 3 ]. Usually, the production of β-lactamase is suppressed at baseline; in the presence of cell wall fragments generated by certain β-lactam antibiotics, the production can increase anywhere between 10 and 100 times. [ 4 ]. The overproduction of AmpC results from two main mechanisms: induction of AmpC transcription upon exposure to β-lactam antibiotics or dysregulation because of point mutations in AmpC regulatory mechanisms. By their overexpression, these enzymes can hydrolyse all penicillins and third-generation cephalosporins (3GCs), e.g., cefuroxime, cefotaxime, ceftriaxone, ceftazidime, and aztreonam, thus conferring resistance against these agents as well as their combinations. However, this resistance does not extend to cefepime, a fourth-generation cephalosporin, or carbapenems. [ 2 , 5 ]. Beta-lactam antibiotics are AmpC inducers, however, these antibiotics do not have the same ability to induce AmpC expression. The potent inducers, such as amoxicillin, clavulanate, cefazolin, and imipenem, enhance AmpC production, whereas third-generation cephalosporin and piperacillin-tazobactam are much weaker inducers. Due to this risk of AmpC overproduction, some studies recommended against the use of third-generation cephalosporins for these species. Guidelines from the Infectious Diseases Society of America (IDSA) have recognised both cefepime and carbapenems as standard treatments for infections caused by AmpC-producing organisms because of their stability against hydrolysis by AmpC [ 6 , 7 ]. Recent literature has had conflicting evidence regarding the efficacy of third-generation cephalosporin and piperacillin-tazobactam in managing these species, considering these agents are not potent inducers of AmpC. For example, in a retrospective study, the rate of treatment failure in bloodstream infections (BSI) treated with third-generation cephalosporins (with or without other antibiotics) was comparable to that of control antibiotic regimens, which were fluoroquinolones, piperacillin, carbapenems, and others. [ 8 ]. In contrast, a large cohort study by Maillard et al. studied severe infections caused by wild-type AmpC β-lactamase-producing Enterobacterales, the effect of third-generation cephalosporins or piperacillin with cefepime or carbapenems, showed no significant difference in 30-day mortality, but treatment with third-generation cephalosporins or piperacillin was associated with the increased emergence of AmpC-overproducing strains, and a subsequently higher rate of treatment failure. [ 7 ]. The study aimed to evaluate the risk of clinical failure with third-generation cephalosporins or piperacillin-tazobactam compared to carbapenems in treating Enterobacter species-associated infections. The secondary objective was to assess the incidence of mortality and associated risk factors during therapy and the associated risk factors. 2. Method This retrospective cohort included all hospitalised patients at An-Najah National University Hospital (NNUH) in Palestine with a confirmed infection based on clinical assessment and positive culture identifying AmpC-associated Enterobacterales, that were fully susceptible to third-generation cephalosporins, and carbapenems, and received one of the following antibiotics: either a third-generation cephalosporin, piperacillin-tazobactam, or a carbapenem, delineating that the antibiotic was started after final culture. Exclusion criteria were: age less than 18, antibiotic course less than 3 days, and death within 48 hours after culture results. The patients were categorised based on treatment into the cephalosporin or piperacillin-tazobactam group and the carbapenem group. To avoid duplication, only the first qualifying infection episode per patient during the study period was included in the analysis. Repeat isolates or infections from the same patient were excluded. 2.1 Data collection and variables Data were collected from hospital records retrospectively. Variables include; Patients’ demographics as age, sex, and body mass index (BMI). Clinical severity : ICU admission, use of vasopressors, and mechanical ventilation. Comorbidities : hypertension, diabetes, cardiovascular diseases, and malignancy. Hospitalisation course surgery at admission, any surgical procedure during hospitalisation, renal replacement therapy, infection at admission, catheter during hospitalisation (Foley catheters, central lines). Infection characteristics : Site of infection (bloodstream, pneumonia, urine, skin/soft tissue), bacterial species (Enterobacter species; Citrobacter, Klebsiella aerogenes and others), the presence of non-enterobacter species, and previous hospitalisation in the past 12 months. Treatment characteristics : Empiric and definitive antibiotic therapy (cefepime, carbapenem, 3GCs or piperacillin-tazobactam). In the study, the third-generation cephalosporins used were ceftriaxone, ceftazidime, and cefotaxime. For this study, patients were classified according to the definitive antibiotic therapy, which we defined as the antibiotic regimen initiated after final culture and susceptibility results were available and continued for at least 3 consecutive days. Empiric therapy, defined as the initial antibiotic administered before culture results, was recorded separately but not used to determine treatment group assignment. Patients were therefore categorised into the third-generation cephalosporin, piperacillin-tazobactam, or carbapenem groups based on the definitive regimen they received. Regarding carbapenems, meropenem was predominantly used, while only a very small number of cases (fewer than five) had ertapenem or imipenem-cilastatin. Outcomes clinical success or failure, recurrence of AmpC-associated species infection of the same type or new type, time between new and previous infection, a culture of cephalosporin resistance AmpC Enterobacteriales, death within 28 days of infection, overall death, duration of hospitalisation, duration from first AmpC-E culture and death/discharge. 2.2 Definitions AmpC Enterobacterales species included Enterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii . Chromosomally-mediated AmpC production refers to the natural production of the AmpC enzyme by certain bacteria, encoded in their chromosome, which can break down beta-lactam antibiotics and lead to antibiotic resistance, usually without resistance to all beta-lactams. As there was no phenotypic confirmation or molecular/genetic testing, we referred to it as AmpC-associated Enterobacterales rather than confirmed AmpC producers. Treatment failure is defined as the persistence of an AmpC-associated bacterial species despite appropriate antibiotic therapy or the development of a new infection caused by the same bacterial species after completing the antibiotic course. This can include a recurrent infection at the same site or a new infection at a different site, along with either confirmed infection deterioration, such as worsening inflammatory markers or clinical status, or the need for modification of the antibiotic regimen by the attending physicians, that leads to switching to other broader antibiotics, or adjustments to the current treatment plan, also include if death occurred. Worsening inflammatory markers” referred specifically to a documented rise in leukocyte count or C-reactive protein compared with baseline values. “Clinical deterioration” was defined as physician-documented worsening of sepsis signs, including fever, hemodynamic instability, or increased oxygen/ventilation requirement. As this was a retrospective study, outcome assessment was not blinded; however, we sought to minimise subjectivity by using objective laboratory values and physician-recorded decisions rather than independent investigator interpretation. Ventilator-associated pneumonia (VAP) is defined as pneumonia that occurs after 48 hours of mechanical ventilation (MV). Hospital-acquired pneumonia is defined as pneumonia that occurs after 48 hours of hospitalisation. Bacteria identification and susceptibility were according to the VITEK® 2 Compact system (bioMérieux, Marcy l’Etoile, France). VITEK® 2 GN cards were used for identifying Gram-negative bacteria based on their biochemical characteristics. Antibiotic susceptibility was determined using the VITEK® 2 AST-N222 cards, which assess bacterial resistance to a panel of antibiotics, including amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, minocycline, pefloxacin, piperacillin, piperacillin/tazobactam, rifampicin, ticarcillin, ticarcillin/clavulanic acid, and tobramycin. The AmpC detection was assumed based on species and not tested phenotypically/genotypically. Patients with isolates confirmed to be fully susceptible to the administered antibiotic were included. Susceptibility was not assumed based on other β-lactam results. 2.3 Statistical analysis Data were illustrated as percentages and mean ± standard deviation (SD) or median (interquartile range) according to normality testing. The association between variables (AmpC- associated organisms, antibiotics used) with baseline characteristics, and outcomes was calculated using the independent T-test and Mann-Whitney U-test for numerical variables, while chi-square and exact Fisher's for categorical variables. The comparisons between the study groups were adjusted for confounders (Other antibiotics used, other organisms, age, and comorbidities) Logistic regression was used for binary comparisons; we limited the multivariable model to five clinically relevant predictors (based on literature) to reduce overfitting: age (number of comorbid conditions) [ 7 , 9 ], comorbidity burden (umber of comorbid conditions) [ 8 , 10 ], baseline severity (shock at presentation and mechanical ventilation) [ 11 , 12 ], and prior antibiotic exposure (antibiotic in previous 3 months: yes/no) [ 4 , 6 ]. Event-per-variable (EPV) for multivariable models with a target EPV ≥ 10. For k = 5 predictors, the target is 50 outcome events; given the observed event rates in our cohort, this would require roughly 171–260 patients, depending on the outcome. Our cohort (N = 109) did not meet this threshold, so multivariable results are presented as exploratory. Because treatment selection was strongly related to severity (e.g., shock/ICU devices), and the cohort comprised three treatment groups, we did not perform propensity score matching or weighting, which risk model instability and loss of effective sample size in this setting. Instead, we report standardized mean differences for baseline covariates by treatment group to characterize residual imbalance and interpret adjusted associations cautiously rather than as causal effects. The significance level was set at P ≤ 0.05. IBM SPSS version 24 was used. 3. Results A total of 109 patients were included in the study, categorised into three antibiotic treatment groups: third-generation cephalosporins (3GCs, n = 43), carbapenems (n = 34), and piperacillin-tazobactam (n = 32). The mean age of 54.9 ± 19 years. Patients were distributed across age categories as follows: 60 years (49.5%), with the carbapenem group having the highest proportion of patients aged > 60 years. Of the cohort, 38 (35%) patients were female. (Table 1 ) The most common comorbidities were hypertension (41%) and diabetes (39.4%). Malignancy occurred in 45.9% of the patients and was more frequent in solid tumours than in haematological malignancies. The most frequent pathogen was Enterobacter cloacae (78.9%). The cause of sepsis varied among the groups, with the most common being respiratory infections (22.9%), followed by urinary (13.8%) and bloodstream (11.9%) infections. Sepsis was the leading cause of hospital admission (28.4%). Most of the patients were admitted to the general wards (61.5%), though admission to the ICU was highest among the carbapenem-treated (58.8%). (Table 1 ) Table 1 Patient demographics, comorbidities, infectious organisms, and clinical characteristics across antibiotic treatment groups Variables Total (n = 109) 3GCs (n = 43) Piperacillin tazobactam (n = 32) Carbapenem (n = 34) Demographics, n (%) Age group 60 years 54 (49.5) 20 (46.5) 14 (43.8) 20 (58.8) Comorbidities, n (%) Hypertension 45 (41) 15 (36.6) 15 (44) 15 (44) Diabetes 43 (39.4) 16 (39) 11 (32.4) 16 (47) Cardiovascular diseases 39 (35.8) 16 (39) 9 (26.5) 14 (41) Chronic kidney disease 20 (18) 8 (19.5) 5 (14.7) 7 (20.6) End-stage renal disease 11 (10) 6 (14.6) 2 (5.9) 3 (8.8) Chronic liver disease 11 (10) 5 (12) 3 (8.8) 3 (8.8) Malignancy 50 ( 45.9) 20 (48.8) 17 (50) 13 (38) Solid 33 (30) 13 (31.7) 13 (38) 7 (20.6) Hematological 16 (14.7) 7 (17) 3 (8.8) 6 (17.6) Smoker, n (%) 32 (29.4) 11 (26.8) 10 (29.4) 11 (32.4) Organisms E cloacae 86 (78.9) 31 (75.6) 28 (82.4) 27 (79.4) E aerogenes 2 (1.8) 1 (2.4) - 1 (2.9) Citrobacter freundii 17 (15.6) 8 (19.5) 4 (11.8) 5 (14.7) Other Enterobacterales * 4 (3.7) 1 (2.4) 2 (5.9) 1 (2.9) Source of sepsis Respiratory 25 (22.9) 3 (7) 12 (35) 10 (29.4) Urinary 15 (13.8) 6 (14.6) 6 (17.6) 3 (8.8) Blood 13 (11.9) 7 (17) 3 (8.8) 3 (8.8) Other 10 (9) 5 (12) 3 (8.8) 2 (5.9) Cause of admission, n (%) Respiratory failure 6 (5.5) 2 (4.9) 1 (2.9) 3 (8.8) Sepsis 31 (28.4) 8 (19.5) 10 (29.4) 13 (38) chemotherapy 7 (6.4) 4 (9.8) 1 (2.9) 2 (5.9) Elective surgery 7 (6.4) 5 (12) 1 (2.9) 1 (2.9) Location Ward 67 (61.5) 28 (68) 25 (73.5) 14 (41) ICU 42 (38.5) 13 (31.7) 9 (26.5) 20 (58.8) 3GCs; third-generation cephalosporins, SD; standard deviation, ICU; intensive care unit * Other Enterobacterales included Enterobacter asburiae, and Enterobacter cancerogenus. In the total population (n = 109), shock was observed in 21% of patients, with 39.4% having respiratory failure. Mechanical ventilation was required in 20% of cases, and 47.7% of patients had undergone surgical intervention. 68.8% had an invasive device, with 18% having a central line and 24.8% having a Foley catheter. A comparative analysis of clinical status and treatment-related characteristics among the antibiotic groups revealed several significant differences. Shock occurred more frequently in the carbapenem group (32.4%, P = 0.006), compared to only 7% of the third-generation cephalosporin group. Similarly, the need for mechanical ventilation occurred more frequently in the carbapenem group (26.5%, P = 0.02) than in the cephalosporin cohort (17%). Regarding the use of invasive devices, the cohorts were also significantly different. The proportion of patients with central lines was significantly less in the third-generation cephalosporin group (9.8%, P = 0.009), while 23.5% of patients who received carbapenems had central lines. The same significant difference was seen with Foley catheter use, in which the patients receiving carbapenems demonstrated a significantly higher incidence (44%, P = 0.01) than the third-generation cephalosporin patients (9.8%). Significant differences were also seen between groups concerning prior antibiotic use. (58.8%, P = 0.028) compared to 36.6% in the 3rd-generation cephalosporin group and 32.4% in the piperacillin-tazobactam group. (Table 2 ) Table 2 Baseline Clinical Status and Antibiotic Use Across Treatment Groups Variables Total (n = 109) 3GCs (n = 43) Carbapenem (n = 34) P-value (3GCs vs Carbapenem) Piperacillin tazobactam (n = 32) P-value (Carbapenem vs Piperacillin tazobactam) P-value (3GCs vs Piperacillin tazobactam) Baseline status Shock 23 (21) 3 (7) 11 (32.4) 0.006 9 (26.5) 0.59 0.02 Respiratory failure 43 (39.4) 12 (29) 17 (50) 0.3 14 (41) 0.46 0.23 Mechanically ventilated 22 (20) 7 (17) 9 (26.5) 0.9 6 (17.6) 0.34 0.9 Surgical intervention 52 (47.7) 19 (46) 19 (55.9) 0.41 14 (41) 0.23 0.65 Presence of MDR organism 34 (31) 10 (24.4) 13 (38) 0.19 11 (32.4) 0.6 0.45 Presence of invasive devices 75 (68.8) 22 (53.7) 28 (82.4) 0.009 25 (73.5) 0.38 0.08 Central line 20 (18) 4 (9.8) 8 (23.5) 0.9 8 (23.5) 0.08 0.07 Foleys 27 (24.8) 4 (9.8) 15 (44) 0.1 8 (23.5) 0.01 0.07 ETT 9 (8.3) 5 (12) 2 (5.9) 0.9 2 (5.9) 0.4 0.5 Hospitalization past year 77 (70.6) 31 (75.6) 25 (73.5) 0.8 21 (61.8) 0.3 0.96 Antibiotic in the prior 3 months 46 (42) 15 (36.6) 20 (58.8) 0.055 11 (32.4) 0.028 0.7 Empiric antibiotic : Cephalosporin 32 (29.4) 28 (68) 3 (8.8) - 1 (2.9) - - Piperacillin tazobactam 35 (32) 3 (7) 6 (17.6) - 26 (76.5) - - Carbapenem 27 (24.8) 2 (4.9) 22 (64.7) - 3 (8.8) - - Co-Antibiotic Aminoglycoside 24 (22) 13 (31.7) 4 (11.8) 0.3 7 (20.6) 0.052 0.4 Tigecycline 7 (6.4) 3 (7) 4 (11.8) 0.05 0 (0) 0.5 0.13 Fluoroquinolone 26 (23.9) 10 (24.4) 9 (26.5) 0.3 7 (20.6) 0.9 0.21 Penicillin 1 (0.9) 1 (2.4) 0 (0) - 0 (0) 0.4 0.4 Colistin 7 (6.4) 0 (0) 7 (20.6) 0.007 0 (0) 0.002 - Source control 53 (48.6) 17 (41.5) 21 (61.8) 0.08 15 (44.1) 0.15 0.8 3GCs; third-generation cephalosporins, E; enterobacter, MDR; multidrug-resistant organism, ETT; endotracheal tube Table 3 shows the summary of clinical outcomes of the different antibiotic treatment groups. The clinical failure rate was 29.4%, with a significantly lower rate in the third-generation cephalosporin group compared to carbapenems (17% vs 41%, respectively, with p-value = 0.02). Mortality varied between groups; the 28-day mortality was lowest in the cephalosporin group (7%) and significantly higher in the carbapenem group (38%, p-value = 0.001). Overall mortality similarly had the highest rate in the carbapenem group (47%, P-value = 0.02) compared to cephalosporins (12%) and piperacillin-tazobactam (20.6%). 12.8% of patients needed ventilation, which was significantly lower in the cephalosporin group compared to carbapenems (p-value = 0.048). Similarly, shock was less frequent in the cephalosporins (9.8%) compared to the carbapenems (35%). Acute renal failure was observed in 14.7% of patients without statistically significant differences among the groups. Table 3 Clinical outcomes across antibiotic treatment groups. Outcome Total (n = 109) 3GCs (n = 43) P-value* 1 Carbapenem (n = 34) P-value* 2 Piperacillin tazobactam (n = 32) P-value* 3 Clinical failure 32 (29.4) 7 (17) 0.02 14 (41) 0.45 11 (32.4) 0.12 28-day death 21 (19) 3 (7) 0.001 13 (38) 0.03 5 (14.7) 0.3 Overall death 28 (25.7) 5 (12) 0.001 16 (47) 0.02 7 (20.6) 0.32 Duration of hospitalisation, Mean ± SD 23 ± 27.7 19.8 ± 28 0.15 29.7 ± 32 0.2 21 ± 21.8 0.8 Need for ventilation 14 (12.8) 3 (7) 0.048 8 (23.5) 0.1 3 (8.8) 0.8 Shock 20 (18) 4 (9.8) 0.007 12 (35) 0.02 4 (11.8) 0.8 Acute kidney injury 16 (14.7) 3 (7) 0.048 8 (23.5) 0.34 5 (14.7) 0.3 Time from infection to death/discharge, Mean ± SD 10.9 ± 34 3.8 ± 16 0.055 16 ± 33 0.85 47 ± 8 0.23 * 1 Compared to carbapenem * 2 Compared to piperacillin tazobactam * 3 Compared to cephalosporins 3GCs; third-generation cephalosporins, SD; standard deviation A multivariate analysis was conducted to adjust for potential confounding variables, as shown in Fig. 2. Compared with carbapenems, third-generation cephalosporins (3GCs) were associated with a significantly lower risk of overall mortality (OR 0.13, 95% CI 0.03–0.62, P = 0.01), 28-day mortality (OR 0.17, 95% CI 0.03–0.89, P = 0.04), and clinical failure (OR 0.26, 95% CI 0.07–0.96, P = 0.04). Piperacillin–tazobactam was also associated with reduced risk of overall mortality (OR 0.23, 95% CI 0.06–0.84, P = 0.03) and clinical failure (OR 0.32, 95% CI 0.10–0.99, P = 0.049) compared with carbapenems. For post-sepsis shock, both 3GCs (OR 0.28, 95% CI 0.08–0.94, P = 0.04) and piperacillin–tazobactam (OR 0.34, 95% CI 0.10–1.11, P = 0.07) showed trends toward lower risk, although the latter did not reach statistical significance. The occurrence of acute kidney injury was not significantly different between groups (3GCs: OR 0.87, 95% CI 0.20–3.82; piperacillin–tazobactam: OR 1.12, 95% CI 0.25–5.07). (Figs. 1 and 2) Figure 1 Forest plots of multivariate analysis for clinical outcomes across antibiotic treatment groups with cephalosporins Figure 2 Forest plots of multivariate analysis for clinical outcomes for carbapenem versus piperacillin tazobactam. Baseline imbalances were further quantified using standardized mean differences (SMDs), presented in Supplementary Table S1 . Large imbalances were observed between carbapenem- and cephalosporin-treated patients (notably for age, shock, and Foley catheter use), while cephalosporin and piperacillin–tazobactam groups were more comparable, with only moderate imbalance in shock and invasive device use. To be noted that an SMD > 0.1 indicates a potentially meaningful imbalance between groups. Large imbalances were observed particularly between carbapenem- and cephalosporin-treated patients (age, shock, Foley catheter use), while cephalosporin and piperacillin–tazobactam groups were more comparable. 4. Discussion Managing AmpC-producing Enterobacterales with third-generation cephalosporins (3GCs) and piperacillin-tazobactam is yet debatable, particularly in terms of concerns about AmpC overproduction and treatment failure. Historically, carbapenems have been the preferred agents, as they proved stability against AmpC-producing strains. However, recently, there is growing evidence toward using other agents and making carbapenem unnecessary in all cases, especially in less severe infections and in the absence of resistance. In this study, Definitive, susceptibility-guided therapy with third-generation cephalosporins or piperacillin–tazobactam was associated with lower crude and adjusted odds of adverse outcomes than carbapenems; however, patients selected for carbapenems had greater baseline severity, and residual confounding and limited power preclude causal inference. Prospective, adequately powered studies are warranted. For third-generation cephalosporins and piperacillin, the clinical failure rates were 17% and 32%, respectively. Though piperacillin-tazobactam showed a higher rate of failure than 3GCs, this difference was not statistically significant (OR 3.7, 95% CI 0.8–16). The 28-day mortality and overall mortality were lowest in the 3GCs group (7% and 12%, respectively), followed by piperacillin-tazobactam (15% and 21%)—with 28-day mortality OR 9.1 (95% CI 0.4–204) and overall mortality OR 3.7 (95% CI 0.22–7.6)—and highest in the carbapenem group (38% and 47%), where 28-day mortality had an OR of 1.5 (95% CI 0.41–5.4) and overall mortality was significantly higher (OR 7, 95% CI 1.43–35). This is similar to the findings in Derrick et al.’s study, where they found that 3GCs had no worse outcome, as the rates of overall treatment failure when compared to non-third-generation cephalosporin antibiotic therapy [ 8 ]. This equivalence also applied to in-hospital mortality, readmission, and reinfection, and the emergence of resistance was infrequent, observed only in the non-3GCs group among patients with repeat cultures, suggesting that when susceptibility is confirmed, 3GCs can still be an effective option. In contrast, Carrié et al showed that piperacillin-tazobactam was better than 3GCs in treating pneumonia among ICU patients with AmpC-producing organisms, especially when early source control and clinical stability were achieved early [ 11 ]. It is important to note that in our study, the patients were less critically ill, and antibiotic was started after susceptibility testing; both 3GCs and piperacillin-tazobactam performed well. Even piperacillin-tazobactam has previously been debated about its efficacy against AmpC-producing organisms [ 6 , 7 , 12 ]. In the MERINO trial, it was found that there was no significant difference between piperacillin-tazobactam and meropenem in mortality outcome, but piperacillin-tazobactam was associated with significantly higher microbiological failure [ 6 ]. On the other hand, many studies support our finding that piperacillin-tazobactam in certain settings is a suitable option with comparable outcomes to meropenem. In Tan et al, they found that empiric piperacillin-tazobactam was not associated with increased 30-day mortality versus carbapenems [ 9 ]. Likewise, McKamey et al and Mounier et al reported no clear advantage for carbapenems over piperacillin-tazobactam in similar infection profiles [ 10 , 13 ]. Notably, the study’s small sample size limits the precision and sstability of more complex methods, such as propensity score weighting/matching across three treatment arms. Accordingly, our findings should be interpreted as associations within a susceptibility-guided treatment context, not causal effects. Larger multicenter datasets are needed to support robust PS or target-trial-style analyses. Morover, the adjusted effect estimates, although statistically significant in some models, were imprecise with wide confidence intervals. These findings should therefore be interpreted cautiously and considered hypothesis-generating rather than definitive The relatively better outcomes with 3GCs in our cohort may be related to patient selection. According to our results, patients who received carbapenems had the highest rates of ICU admission (58.8%), shock (32.4%), need for mechanical ventilation (26.5%), and invasive device use, including central lines (23.5%) and Foley catheters (44%). In contrast, the third-generation cephalosporin group had much lower rates of ICU admission (31.7%), shock (7%), and mechanical ventilation (17%). These findings indicate that patients treated with carbapenems were more critically ill at baseline, and the worse outcomes may reflect their underlying condition rather than antibiotic failure. Though we performed multivariate analysis to adjust for confounders such as ICU status, comorbidities, prior antibiotic use, and infection severity, after adjusting for these differences, both 3GCs and piperacillin-tazobactam remained significantly associated with lower risk of treatment failure and mortality compared to carbapenems, raising a question of whether a true benefit beyond patient characteristics, or it is still due to a residual confounding, particularly given the small sample size. Additionally, we must point out that the other studies included a broader range of AmpC-E species than our studies, which included Serratia spp., Citrobacter spp., Providencia spp., and Morganella spp. [ 6 , 7 ], Or included different infection sites (e.g., pneumonia in Maillard et al. and Pilmis et al., or different sites in Peters et al) [ 4 , 7 ]. In this study, the clinical failure rates were lower than observed in the literature: 17% for 3GCs, 32% for piperacillin-tazobactam. For instance, Peters et al. observed treatment failure rates around 34% for both ceftriaxone and antipseudomonal beta-lactams. [ 4 ]. Mounier et al. observed a 29.4% clinical failure rate in critically ill patients. [ 10 ]. Herrmann et al. found only 21% early treatment response (equal to 79% failure) with piperacillin-tazobactam and 48.8% response (51.2% failure) with carbapenems. [ 12 ]. This may be affected partially due to the baseline characteristics of patients and susceptibility-based therapy. This study had many limitations. First, it was a retrospective study conducted at a single centre, which naturally introduces risks of selection bias and missing data. Because it was based on medical records, some clinical parameters, such as SOFA or APACHE scores, could not be calculated, as certain necessary parameters were not documented, including blood gas results, particularly for ICU patients, or other modified scores. Instead, we relied on available indicators of severity such as ICU admission, shock, vasopressor use, and mechanical ventilation, which may not fully capture overall illness severity.. Also, adjustment for common confounders was attempted, the possibility of residual confounding remains, exaggerating the outcome differences. Secondly, the sample size was small, especially when stratified by antibiotic groups. This may have limited the power of our statistical models and increased the chance of type II errors. Third, most patients did not have a follow-up culture, so the microbiological outcome could not be assessed. These findings also have important implications for antimicrobial stewardship. Avoiding carbapenems when appropriate may help decrease the use of carbapenem-resistant organisms such as carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa . This supports the use of carbapenem-sparing strategies as part of stewardship programs. However, clinical judgment remains the most important. In critically ill patients, carbapenems may still be the most appropriate option. Especially in countries like ours with high rates of multidrug-resistant organisms, individualised treatment decisions should be emphasised rather than a one fixed approach. Moreover, that AmpC production was not confirmed by phenotypic or molecular testing; classification was based on species known to harbour inducible chromosomal AmpC. Therefore, results should be interpreted as applying to “AmpC-associated Enterobacterales,”. The study is underpowered for fully adjusted multivariable modelling. The observed EPV for overall mortality (5.6), 28-day mortality (4.2), and clinical failure (6.4) were all below conventional thresholds (≥ 10) for five predictors, increasing the risk of model instability and overfitting. Adjusted findings should therefore be interpreted with caution and considered hypothesis-generating. Clinicians clearly tended to administer carbapenems to the sickest patients, as reflected in the higher frequency of shock, invasive devices, and ICU admission. Although we adjusted for prespecified covariates, residual confounding remains likely. To characterize baseline imbalance more transparently, we calculated standardized mean differences (SMDs), which confirmed large differences between carbapenem- and cephalosporin-treated patients, particularly for age, shock, and Foley catheter use (Supplementary Table X). In contrast, cephalosporin and piperacillin–tazobactam groups were more balanced, though some moderate differences remained. 4.1 Conclusion In conclusion, while there is a debate and conflicting results regarding resistance emergence with 3GCs and piperacillin-tazobactam, this study observed lower mortality and clinical failure with these agents compared to carbapenems. These findings are consistent with several other reports suggesting that non-carbapenem regimens may have comparable outcomes in selected patients.However, patients receiving carbapenems had greater baseline illness severity, and the possibility of residual confounding cannot be excluded. Given the single-centre design and limited sample size, these results should be interpreted as associations rather than causal effects. Based on these limitations, the results should be interpreted as exploratory associations rather than evidence of causal effects. Larger, prospective, multicenter studies are needed to validate these findings and to define the optimal role of carbapenem-sparing strategies in AmpC-producing Enterobacterales infections.. Abbreviations Acute kidney injury (AKI) Acute Physiology and Chronic Health Evaluation (APACHE) AmpC β-lactamase (AmpC) AmpC-associated Enterobacterales (AmpC-E) Body mass index (BMI) Bloodstream infection (BSI) Carbapenem-resistant Enterobacterales (CRE) Confidence interval (CI) C-reactive protein (CRP) Endotracheal tube (ETT) Intensive care unit (ICU) Infectious Diseases Society of America (IDSA) Institutional Review Board (IRB) Mechanical ventilation (MV) Multidrug-resistant (MDR) Odds ratio (OR) Propensity score (PS) Sequential Organ Failure Assessment (SOFA) Standard deviation (SD) Standardized mean difference (SMD) Third-generation cephalosporins (3GCs) Ventilator-associated pneumonia (VAP) Declarations 5.1 Ethics approval This study was approved by the Institutional Review Board (IRB) of An-Najah National University. 5.2 Consent to participate Informed consent was waived due to the retrospective nature of the study. 5.3 Availability of data and materials The datasets used during the current study are available from the corresponding author on reasonable request. 5.4 Competing interests The authors declare that they have no competing interests. 5.5Funding No external funding was received for this study. 5.6 Declaration of AI Use The authors declare that generative artificial intelligence (AI) and AI-assisted technologies were used solely to improve the readability and language of the manuscript. 5.7 Declaration of Helsinki for human-subject research This study was conducted in compliance with the World Medical Association Declaration of Helsinki. 6. Acknowledgement The authors would like to thank the microbiology departments at An-Najah National University Hospital for their support in data collection. 7. Author Contributions: MG and AAB contributed to supervision and conceptualization of the study. RR contributed to conceptualization, data collection, data analysis, and writing the original draft. MWS, GO, and JA were involved in data collection, manuscript revision, and provided final approval. AS contributed to conceptualization and critically revised the manuscript for final approval. All authors read and approved the final manuscript. References Theuretzbacher U. Resistance drives antibacterial drug development. Current Opinion in Pharmacology. 2011;11:433–8. https://doi.org/10.1016/j.coph.2011.07.008. Mizrahi A, Delerue T, Morel H, Le Monnier A, Carbonnelle E, Pilmis B, et al. Infections caused by naturally AmpC-producing Enterobacteriaceae: Can we use third-generation cephalosporins? A narrative review. Int J Antimicrob Agents. 2020;55:105834. https://doi.org/10.1016/j.ijantimicag.2019.10.015. Jacoby GA. AmpC β-Lactamases. Clinical Microbiology Reviews. 2009;22:161–82. https://doi.org/10.1128/cmr.00036-08. Peters DM, Winter JB, Droege CA, Ernst NE, Liao S. Comparison of Ceftriaxone and Antipseudomonal β-Lactam Antibiotics Utilized for Potential AmpC β-Lactamase-Producing Organisms. Hosp Pharm. 2021;56:560–8. https://doi.org/10.1177/0018578720931463. Kohlmann R, Bähr T, Gatermann SG. Species-specific mutation rates for ampC derepression in Enterobacterales with chromosomally encoded inducible AmpC β-lactamase. Journal of Antimicrobial Chemotherapy. 2018;73:1530–6. https://doi.org/10.1093/jac/dky084. Stewart AG, Paterson DL, Young B, Lye DC, Davis JS, Schneider K, et al. Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase–Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2). Open Forum Infectious Diseases. 2021;8:ofab387. https://doi.org/10.1093/ofid/ofab387. Maillard A, Delory T, Bernier J, Villa A, Chaibi K, Escaut L, et al. Effectiveness of third-generation cephalosporins or piperacillin compared with cefepime or carbapenems for severe infections caused by wild-type AmpC β-lactamase-producing Enterobacterales: A multi-centre retrospective propensity-weighted study. Int J Antimicrob Agents. 2023;62:106809. https://doi.org/10.1016/j.ijantimicag.2023.106809. Derrick C, Bookstaver PB, Lu ZK, Bland CM, King ST, Stover KR, et al. Multicenter, Observational Cohort Study Evaluating Third-Generation Cephalosporin Therapy for Bloodstream Infections Secondary to Enterobacter, Serratia, and Citrobacter Species. Antibiotics (Basel). 2020;9:254. https://doi.org/10.3390/antibiotics9050254. Tan SH, Ng TM, Chew KL, Yong J, Wu JE, Yap MY, et al. Outcomes of treating AmpC-producing Enterobacterales bacteraemia with carbapenems vs. non-carbapenems. Int J Antimicrob Agents. 2020;55:105860. https://doi.org/10.1016/j.ijantimicag.2019.105860. Mounier R, Le Guen R, Woerther P-L, Nacher M, Bonnefon C, Mongardon N, et al. Clinical outcome of wild-type AmpC-producing Enterobacterales infection in critically ill patients treated with β-lactams: a prospective multicenter study. Ann Intensive Care. 2022;12:107. https://doi.org/10.1186/s13613-022-01079-5. Carrié C, Bardonneau G, Petit L, Ouattara A, Gruson D, Pereira B, et al. Piperacillin-tazobactam should be preferred to third-generation cephalosporins to treat wild-type inducible AmpC-producing Enterobacterales in critically ill patients with hospital or ventilator-acquired pneumonia. J Crit Care. 2020;56:6–11. https://doi.org/10.1016/j.jcrc.2019.11.005. Herrmann L, Kimmig A, Rödel J, Hagel S, Rose N, Pletz MW, et al. Early Treatment Outcomes for Bloodstream Infections Caused by Potential AmpC Beta-Lactamase-Producing Enterobacterales with Focus on Piperacillin/Tazobactam: A Retrospective Cohort Study. Antibiotics (Basel). 2021;10:665. https://doi.org/10.3390/antibiotics10060665. McKamey L, Venugopalan V, Cherabuddi K, Borgert S, Voils S, Shah K, et al. Assessing antimicrobial stewardship initiatives: Clinical evaluation of cefepime or piperacillin/tazobactam in patients with bloodstream infections secondary to AmpC-producing organisms. Int J Antimicrob Agents. 2018;52:719–23. https://doi.org/10.1016/j.ijantimicag.2018.08.007. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":1021671,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of multivariate analysis for clinical outcomes across antibiotic treatment groups with cephalosporins\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7651779/v1/e8b0102459aee176a4c7461b.png"},{"id":94917226,"identity":"f6766d8d-36c7-4ebd-8263-87b93bfb36a0","added_by":"auto","created_at":"2025-11-01 11:53:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3008611,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of multivariate analysis for clinical outcomes for carbapenem versus piperacillin tazobactam.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7651779/v1/e1523525e60751eade332005.png"},{"id":96455720,"identity":"48deef45-3a91-447b-ae85-17f167c49ca3","added_by":"auto","created_at":"2025-11-21 10:04:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3795563,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7651779/v1/3776b557-247a-4cbd-adb4-61ea17240c5a.pdf"},{"id":94917174,"identity":"13608951-8c5a-4d6d-8e19-158d9f478139","added_by":"auto","created_at":"2025-11-01 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lowest with third-generation cephalosporins.\u003c/p\u003e\u003cp\u003e\u0026bull; Definitive, susceptibility-guided therapy may reduce the need for carbapenems.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eMany Gram-negative bacilli, such as Enterobacter species, have a natural chromosomal gene for expressing AmpC β-lactamases within their genome. In the absence of beta-lactams, these bacterial species express AmpC β-lactamase enzymes at a low level, which are responsible for the hydrolysis of penicillin G, penicillin A, and first-generation cephalosporins. They are still sensitive to other members of the β-lactam family of antibiotics. [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eUsually, the production of β-lactamase is suppressed at baseline; in the presence of cell wall fragments generated by certain β-lactam antibiotics, the production can increase anywhere between 10 and 100 times. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The overproduction of AmpC results from two main mechanisms: induction of AmpC transcription upon exposure to β-lactam antibiotics or dysregulation because of point mutations in AmpC regulatory mechanisms. By their overexpression, these enzymes can hydrolyse all penicillins and third-generation cephalosporins (3GCs), e.g., cefuroxime, cefotaxime, ceftriaxone, ceftazidime, and aztreonam, thus conferring resistance against these agents as well as their combinations. However, this resistance does not extend to cefepime, a fourth-generation cephalosporin, or carbapenems. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBeta-lactam antibiotics are AmpC inducers, however, these antibiotics do not have the same ability to induce AmpC expression. The potent inducers, such as amoxicillin, clavulanate, cefazolin, and imipenem, enhance AmpC production, whereas third-generation cephalosporin and piperacillin-tazobactam are much weaker inducers. Due to this risk of AmpC overproduction, some studies recommended against the use of third-generation cephalosporins for these species. Guidelines from the Infectious Diseases Society of America (IDSA) have recognised both cefepime and carbapenems as standard treatments for infections caused by AmpC-producing organisms because of their stability against hydrolysis by AmpC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent literature has had conflicting evidence regarding the efficacy of third-generation cephalosporin and piperacillin-tazobactam in managing these species, considering these agents are not potent inducers of AmpC. For example, in a retrospective study, the rate of treatment failure in bloodstream infections (BSI) treated with third-generation cephalosporins (with or without other antibiotics) was comparable to that of control antibiotic regimens, which were fluoroquinolones, piperacillin, carbapenems, and others. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In contrast, a large cohort study by Maillard et al. studied severe infections caused by wild-type AmpC β-lactamase-producing Enterobacterales, the effect of third-generation cephalosporins or piperacillin with cefepime or carbapenems, showed no significant difference in 30-day mortality, but treatment with third-generation cephalosporins or piperacillin was associated with the increased emergence of AmpC-overproducing strains, and a subsequently higher rate of treatment failure. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe study aimed to evaluate the risk of clinical failure with third-generation cephalosporins or piperacillin-tazobactam compared to carbapenems in treating Enterobacter species-associated infections. The secondary objective was to assess the incidence of mortality and associated risk factors during therapy and the associated risk factors.\u003c/p\u003e"},{"header":"2. Method","content":"\u003cp\u003eThis retrospective cohort included all hospitalised patients at An-Najah National University Hospital (NNUH) in Palestine with a confirmed infection based on clinical assessment and positive culture identifying AmpC-associated Enterobacterales, that were fully susceptible to third-generation cephalosporins, and carbapenems, and received one of the following antibiotics: either a third-generation cephalosporin, piperacillin-tazobactam, or a carbapenem, delineating that the antibiotic was started after final culture. Exclusion criteria were: age less than 18, antibiotic course less than 3 days, and death within 48 hours after culture results. The patients were categorised based on treatment into the cephalosporin or piperacillin-tazobactam group and the carbapenem group. To avoid duplication, only the first qualifying infection episode per patient during the study period was included in the analysis. Repeat isolates or infections from the same patient were excluded.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data collection and variables\u003c/h2\u003e\u003cp\u003eData were collected from hospital records retrospectively. Variables include;\u003c/p\u003e\u003cp\u003e\u003cb\u003ePatients\u0026rsquo; demographics\u003c/b\u003e as age, sex, and body mass index (BMI).\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical severity\u003c/b\u003e: ICU admission, use of vasopressors, and mechanical ventilation. \u003cb\u003eComorbidities\u003c/b\u003e: hypertension, diabetes, cardiovascular diseases, and malignancy.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eHospitalisation course\u003c/strong\u003e\u003cp\u003esurgery at admission, any surgical procedure during hospitalisation, renal replacement therapy, infection at admission, catheter during hospitalisation (Foley catheters, central lines).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eInfection characteristics\u003c/b\u003e: Site of infection (bloodstream, pneumonia, urine, skin/soft tissue), bacterial species (Enterobacter species; \u003cem\u003eCitrobacter, Klebsiella aerogenes\u003c/em\u003e and others), the presence of non-enterobacter species, and previous hospitalisation in the past 12 months. \u003cb\u003eTreatment characteristics\u003c/b\u003e: Empiric and definitive antibiotic therapy (cefepime, carbapenem, 3GCs or piperacillin-tazobactam). In the study, the third-generation cephalosporins used were ceftriaxone, ceftazidime, and cefotaxime. For this study, patients were classified according to the definitive antibiotic therapy, which we defined as the antibiotic regimen initiated after final culture and susceptibility results were available and continued for at least 3 consecutive days. Empiric therapy, defined as the initial antibiotic administered before culture results, was recorded separately but not used to determine treatment group assignment. Patients were therefore categorised into the third-generation cephalosporin, piperacillin-tazobactam, or carbapenem groups based on the definitive regimen they received. Regarding carbapenems, meropenem was predominantly used, while only a very small number of cases (fewer than five) had ertapenem or imipenem-cilastatin.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003cp\u003eclinical success or failure, recurrence of AmpC-associated species infection of the same type or new type, time between new and previous infection, a culture of cephalosporin resistance AmpC Enterobacteriales, death within 28 days of infection, overall death, duration of hospitalisation, duration from first AmpC-E culture and death/discharge.\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Definitions\u003c/h2\u003e\u003cp\u003eAmpC Enterobacterales species included \u003cem\u003eEnterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii\u003c/em\u003e. Chromosomally-mediated AmpC production refers to the natural production of the AmpC enzyme by certain bacteria, encoded in their chromosome, which can break down beta-lactam antibiotics and lead to antibiotic resistance, usually without resistance to all beta-lactams. As there was no phenotypic confirmation or molecular/genetic testing, we referred to it as AmpC-associated Enterobacterales rather than confirmed AmpC producers.\u003c/p\u003e\u003cp\u003eTreatment failure is defined as the persistence of an AmpC-associated bacterial species despite appropriate antibiotic therapy or the development of a new infection caused by the same bacterial species after completing the antibiotic course. This can include a recurrent infection at the same site or a new infection at a different site, along with either confirmed infection deterioration, such as worsening inflammatory markers or clinical status, or the need for modification of the antibiotic regimen by the attending physicians, that leads to switching to other broader antibiotics, or adjustments to the current treatment plan, also include if death occurred.\u003c/p\u003e\u003cp\u003eWorsening inflammatory markers\u0026rdquo; referred specifically to a documented rise in leukocyte count or C-reactive protein compared with baseline values. \u0026ldquo;Clinical deterioration\u0026rdquo; was defined as physician-documented worsening of sepsis signs, including fever, hemodynamic instability, or increased oxygen/ventilation requirement.\u003c/p\u003e\u003cp\u003eAs this was a retrospective study, outcome assessment was not blinded; however, we sought to minimise subjectivity by using objective laboratory values and physician-recorded decisions rather than independent investigator interpretation.\u003c/p\u003e\u003cp\u003eVentilator-associated pneumonia (VAP) is defined as pneumonia that occurs after 48 hours of mechanical ventilation (MV). Hospital-acquired pneumonia is defined as pneumonia that occurs after 48 hours of hospitalisation.\u003c/p\u003e\u003cp\u003eBacteria identification and susceptibility were according to the VITEK\u0026reg; 2 Compact system (bioM\u0026eacute;rieux, Marcy l\u0026rsquo;Etoile, France). VITEK\u0026reg; 2 GN cards were used for identifying Gram-negative bacteria based on their biochemical characteristics. Antibiotic susceptibility was determined using the VITEK\u0026reg; 2 AST-N222 cards, which assess bacterial resistance to a panel of antibiotics, including amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, minocycline, pefloxacin, piperacillin, piperacillin/tazobactam, rifampicin, ticarcillin, ticarcillin/clavulanic acid, and tobramycin. The AmpC detection was assumed based on species and not tested phenotypically/genotypically. Patients with isolates confirmed to be fully susceptible to the administered antibiotic were included. Susceptibility was not assumed based on other β-lactam results.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e\u003cp\u003eData were illustrated as percentages and mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (interquartile range) according to normality testing. The association between variables (AmpC- associated organisms, antibiotics used) with baseline characteristics, and outcomes was calculated using the independent T-test and Mann-Whitney U-test for numerical variables, while chi-square and exact Fisher's for categorical variables. The comparisons between the study groups were adjusted for confounders (Other antibiotics used, other organisms, age, and comorbidities) Logistic regression was used for binary comparisons; we limited the multivariable model to five clinically relevant predictors (based on literature) to reduce overfitting: age (number of comorbid conditions) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], comorbidity burden (umber of comorbid conditions) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], baseline severity (shock at presentation and mechanical ventilation) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and prior antibiotic exposure (antibiotic in previous 3 months: yes/no) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Event-per-variable (EPV) for multivariable models with a target EPV\u0026thinsp;\u0026ge;\u0026thinsp;10. For k\u0026thinsp;=\u0026thinsp;5 predictors, the target is 50 outcome events; given the observed event rates in our cohort, this would require roughly 171\u0026ndash;260 patients, depending on the outcome. Our cohort (N\u0026thinsp;=\u0026thinsp;109) did not meet this threshold, so multivariable results are presented as exploratory.\u003c/p\u003e\u003cp\u003eBecause treatment selection was strongly related to severity (e.g., shock/ICU devices), and the cohort comprised three treatment groups, we did not perform propensity score matching or weighting, which risk model instability and loss of effective sample size in this setting. Instead, we report standardized mean differences for baseline covariates by treatment group to characterize residual imbalance and interpret adjusted associations cautiously rather than as causal effects.\u003c/p\u003e\u003cp\u003eThe significance level was set at P\u0026thinsp;\u0026le;\u0026thinsp;0.05. IBM SPSS version 24 was used.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eA total of 109 patients were included in the study, categorised into three antibiotic treatment groups: third-generation cephalosporins (3GCs, n\u0026thinsp;=\u0026thinsp;43), carbapenems (n\u0026thinsp;=\u0026thinsp;34), and piperacillin-tazobactam (n\u0026thinsp;=\u0026thinsp;32). The mean age of 54.9\u0026thinsp;\u0026plusmn;\u0026thinsp;19 years. Patients were distributed across age categories as follows: \u0026lt;40 years (19.3%), 40\u0026ndash;60 years (31.2%), and \u0026gt;\u0026thinsp;60 years (49.5%), with the carbapenem group having the highest proportion of patients aged\u0026thinsp;\u0026gt;\u0026thinsp;60 years. Of the cohort, 38 (35%) patients were female. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThe most common comorbidities were hypertension (41%) and diabetes (39.4%). Malignancy occurred in 45.9% of the patients and was more frequent in solid tumours than in haematological malignancies. The most frequent pathogen was \u003cem\u003eEnterobacter cloacae\u003c/em\u003e (78.9%). The cause of sepsis varied among the groups, with the most common being respiratory infections (22.9%), followed by urinary (13.8%) and bloodstream (11.9%) infections. Sepsis was the leading cause of hospital admission (28.4%). Most of the patients were admitted to the general wards (61.5%), though admission to the ICU was highest among the carbapenem-treated (58.8%). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient demographics, comorbidities, infectious organisms, and clinical characteristics across antibiotic treatment groups\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=\"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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3GCs\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePiperacillin tazobactam (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCarbapenem\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDemographics, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;40 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (19.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (23.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (21.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e40\u0026ndash;60 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (31.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (30.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (29.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;60 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e54 (49.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (46.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 (43.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20 (58.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidities, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (36.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 (44)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (39.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (47)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiovascular diseases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (35.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14 (41)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic kidney disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (19.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnd-stage renal disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic liver disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalignancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50 ( 45.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (48.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 (50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSolid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33 (30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (31.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHematological\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (17.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoker, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (26.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOrganisms\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eE cloacae\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86 (78.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31 (75.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 (82.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27 (79.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eE aerogenes\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eCitrobacter freundii\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (19.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther Enterobacterales *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSource of sepsis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (22.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (29.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (13.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (17.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (11.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCause of admission, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (5.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (8.8)\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\" colname=\"c2\"\u003e\u003cp\u003e31 (28.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (19.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003echemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (6.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElective surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (6.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLocation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWard\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67 (61.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25 (73.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14 (41)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICU\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42 (38.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (31.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20 (58.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003e3GCs; third-generation cephalosporins, SD; standard deviation, ICU; intensive care unit\u003c/h3\u003e\n\u003cp\u003e* Other Enterobacterales included \u003cem\u003eEnterobacter asburiae, and Enterobacter cancerogenus.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn the total population (n\u0026thinsp;=\u0026thinsp;109), shock was observed in 21% of patients, with 39.4% having respiratory failure. Mechanical ventilation was required in 20% of cases, and 47.7% of patients had undergone surgical intervention. 68.8% had an invasive device, with 18% having a central line and 24.8% having a Foley catheter.\u003c/p\u003e\u003cp\u003eA comparative analysis of clinical status and treatment-related characteristics among the antibiotic groups revealed several significant differences. Shock occurred more frequently in the carbapenem group (32.4%, P\u0026thinsp;=\u0026thinsp;0.006), compared to only 7% of the third-generation cephalosporin group. Similarly, the need for mechanical ventilation occurred more frequently in the carbapenem group (26.5%, P\u0026thinsp;=\u0026thinsp;0.02) than in the cephalosporin cohort (17%). Regarding the use of invasive devices, the cohorts were also significantly different. The proportion of patients with central lines was significantly less in the third-generation cephalosporin group (9.8%, P\u0026thinsp;=\u0026thinsp;0.009), while 23.5% of patients who received carbapenems had central lines. The same significant difference was seen with Foley catheter use, in which the patients receiving carbapenems demonstrated a significantly higher incidence (44%, P\u0026thinsp;=\u0026thinsp;0.01) than the third-generation cephalosporin patients (9.8%). Significant differences were also seen between groups concerning prior antibiotic use. (58.8%, P\u0026thinsp;=\u0026thinsp;0.028) compared to 36.6% in the 3rd-generation cephalosporin group and 32.4% in the piperacillin-tazobactam group. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline Clinical Status and Antibiotic Use Across Treatment Groups\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3GCs\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarbapenem\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value (3GCs vs Carbapenem)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePiperacillin tazobactam (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eP-value (Carbapenem vs Piperacillin tazobactam)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003cp\u003e(3GCs vs Piperacillin tazobactam)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline status\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eShock\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (39.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 (50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14 (41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanically ventilated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 (17.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSurgical intervention\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52 (47.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19 (46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19 (55.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14 (41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePresence of MDR organism\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (24.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePresence of invasive devices\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75 (68.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (53.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 (82.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25 (73.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCentral line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFoleys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (24.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eETT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (8.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization past year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 (70.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31 (75.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25 (73.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e21 (61.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAntibiotic in the prior 3 months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46 (42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (36.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 (58.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.055\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEmpiric antibiotic\u003c/b\u003e:\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCephalosporin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePiperacillin tazobactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35 (32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (17.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e26 (76.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\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\" colname=\"c2\"\u003e\u003cp\u003e27 (24.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22 (64.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCo-Antibiotic\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAminoglycoside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (31.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.052\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTigecycline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (6.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFluoroquinolone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (23.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (24.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePenicillin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eColistin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (6.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSource control\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53 (48.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (41.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21 (61.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15 (44.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003e3GCs; third-generation cephalosporins, E; enterobacter, MDR; multidrug-resistant organism, ETT; endotracheal tube\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the summary of clinical outcomes of the different antibiotic treatment groups. The clinical failure rate was 29.4%, with a significantly lower rate in the third-generation cephalosporin group compared to carbapenems (17% vs 41%, respectively, with p-value\u0026thinsp;=\u0026thinsp;0.02). Mortality varied between groups; the 28-day mortality was lowest in the cephalosporin group (7%) and significantly higher in the carbapenem group (38%, p-value\u0026thinsp;=\u0026thinsp;0.001). Overall mortality similarly had the highest rate in the carbapenem group (47%, P-value\u0026thinsp;=\u0026thinsp;0.02) compared to cephalosporins (12%) and piperacillin-tazobactam (20.6%). 12.8% of patients needed ventilation, which was significantly lower in the cephalosporin group compared to carbapenems (p-value\u0026thinsp;=\u0026thinsp;0.048). Similarly, shock was less frequent in the cephalosporins (9.8%) compared to the carbapenems (35%). Acute renal failure was observed in 14.7% of patients without statistically significant differences among the groups.\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\u003eClinical outcomes across antibiotic treatment groups.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\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=\"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\u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3GCs\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value*\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCarbapenem\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eP-value*\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePiperacillin tazobactam (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP-value*\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14 (41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28-day death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverall death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (25.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of hospitalisation, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23\u0026thinsp;\u0026plusmn;\u0026thinsp;27.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e29.7\u0026thinsp;\u0026plusmn;\u0026thinsp;32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e21\u0026thinsp;\u0026plusmn;\u0026thinsp;21.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeed for ventilation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eShock\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 (35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute kidney injury\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime from infection to death/discharge, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.9\u0026thinsp;\u0026plusmn;\u0026thinsp;34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.055\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cb\u003e*\u003c/b\u003e\u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e Compared to carbapenem\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cb\u003e*\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e Compared to piperacillin tazobactam\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cb\u003e*\u003c/b\u003e\u003csup\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sup\u003e Compared to cephalosporins\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003e3GCs; third-generation cephalosporins, SD; standard deviation\u003c/h3\u003e\n\u003cp\u003eA multivariate analysis was conducted to adjust for potential confounding variables, as shown in Fig.\u0026nbsp;2. Compared with carbapenems, third-generation cephalosporins (3GCs) were associated with a significantly lower risk of overall mortality (OR 0.13, 95% CI 0.03\u0026ndash;0.62, P\u0026thinsp;=\u0026thinsp;0.01), 28-day mortality (OR 0.17, 95% CI 0.03\u0026ndash;0.89, P\u0026thinsp;=\u0026thinsp;0.04), and clinical failure (OR 0.26, 95% CI 0.07\u0026ndash;0.96, P\u0026thinsp;=\u0026thinsp;0.04). Piperacillin\u0026ndash;tazobactam was also associated with reduced risk of overall mortality (OR 0.23, 95% CI 0.06\u0026ndash;0.84, P\u0026thinsp;=\u0026thinsp;0.03) and clinical failure (OR 0.32, 95% CI 0.10\u0026ndash;0.99, P\u0026thinsp;=\u0026thinsp;0.049) compared with carbapenems. For post-sepsis shock, both 3GCs (OR 0.28, 95% CI 0.08\u0026ndash;0.94, P\u0026thinsp;=\u0026thinsp;0.04) and piperacillin\u0026ndash;tazobactam (OR 0.34, 95% CI 0.10\u0026ndash;1.11, P\u0026thinsp;=\u0026thinsp;0.07) showed trends toward lower risk, although the latter did not reach statistical significance. The occurrence of acute kidney injury was not significantly different between groups (3GCs: OR 0.87, 95% CI 0.20\u0026ndash;3.82; piperacillin\u0026ndash;tazobactam: OR 1.12, 95% CI 0.25\u0026ndash;5.07). (Figs.\u0026nbsp;1 and 2)\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e\u003cp\u003eForest plots of multivariate analysis for clinical outcomes across antibiotic treatment groups with cephalosporins\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e\u003cp\u003eForest plots of multivariate analysis for clinical outcomes for carbapenem versus piperacillin tazobactam.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eBaseline imbalances were further quantified using standardized mean differences (SMDs), presented in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Large imbalances were observed between carbapenem- and cephalosporin-treated patients (notably for age, shock, and Foley catheter use), while cephalosporin and piperacillin\u0026ndash;tazobactam groups were more comparable, with only moderate imbalance in shock and invasive device use. To be noted that an SMD\u0026thinsp;\u0026gt;\u0026thinsp;0.1 indicates a potentially meaningful imbalance between groups. Large imbalances were observed particularly between carbapenem- and cephalosporin-treated patients (age, shock, Foley catheter use), while cephalosporin and piperacillin\u0026ndash;tazobactam groups were more comparable.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eManaging AmpC-producing Enterobacterales with third-generation cephalosporins (3GCs) and piperacillin-tazobactam is yet debatable, particularly in terms of concerns about AmpC overproduction and treatment failure. Historically, carbapenems have been the preferred agents, as they proved stability against AmpC-producing strains. However, recently, there is growing evidence toward using other agents and making carbapenem unnecessary in all cases, especially in less severe infections and in the absence of resistance.\u003c/p\u003e\u003cp\u003eIn this study, Definitive, susceptibility-guided therapy with third-generation cephalosporins or piperacillin\u0026ndash;tazobactam was associated with lower crude and adjusted odds of adverse outcomes than carbapenems; however, patients selected for carbapenems had greater baseline severity, and residual confounding and limited power preclude causal inference. Prospective, adequately powered studies are warranted. For third-generation cephalosporins and piperacillin, the clinical failure rates were 17% and 32%, respectively. Though piperacillin-tazobactam showed a higher rate of failure than 3GCs, this difference was not statistically significant (OR 3.7, 95% CI 0.8\u0026ndash;16). The 28-day mortality and overall mortality were lowest in the 3GCs group (7% and 12%, respectively), followed by piperacillin-tazobactam (15% and 21%)\u0026mdash;with 28-day mortality OR 9.1 (95% CI 0.4\u0026ndash;204) and overall mortality OR 3.7 (95% CI 0.22\u0026ndash;7.6)\u0026mdash;and highest in the carbapenem group (38% and 47%), where 28-day mortality had an OR of 1.5 (95% CI 0.41\u0026ndash;5.4) and overall mortality was significantly higher (OR 7, 95% CI 1.43\u0026ndash;35). This is similar to the findings in Derrick et al.\u0026rsquo;s study, where they found that 3GCs had no worse outcome, as the rates of overall treatment failure when compared to non-third-generation cephalosporin antibiotic therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This equivalence also applied to in-hospital mortality, readmission, and reinfection, and the emergence of resistance was infrequent, observed only in the non-3GCs group among patients with repeat cultures, suggesting that when susceptibility is confirmed, 3GCs can still be an effective option. In contrast, Carri\u0026eacute; et al showed that piperacillin-tazobactam was better than 3GCs in treating pneumonia among ICU patients with AmpC-producing organisms, especially when early source control and clinical stability were achieved early [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. It is important to note that in our study, the patients were less critically ill, and antibiotic was started after susceptibility testing; both 3GCs and piperacillin-tazobactam performed well. Even piperacillin-tazobactam has previously been debated about its efficacy against AmpC-producing organisms [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In the MERINO trial, it was found that there was no significant difference between piperacillin-tazobactam and meropenem in mortality outcome, but piperacillin-tazobactam was associated with significantly higher microbiological failure [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. On the other hand, many studies support our finding that piperacillin-tazobactam in certain settings is a suitable option with comparable outcomes to meropenem. In Tan et al, they found that empiric piperacillin-tazobactam was not associated with increased 30-day mortality versus carbapenems [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Likewise, McKamey et al and Mounier et al reported no clear advantage for carbapenems over piperacillin-tazobactam in similar infection profiles [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Notably, the study\u0026rsquo;s small sample size limits the precision and sstability of more complex methods, such as propensity score weighting/matching across three treatment arms. Accordingly, our findings should be interpreted as associations within a susceptibility-guided treatment context, not causal effects. Larger multicenter datasets are needed to support robust PS or target-trial-style analyses. Morover, the adjusted effect estimates, although statistically significant in some models, were imprecise with wide confidence intervals. These findings should therefore be interpreted cautiously and considered hypothesis-generating rather than definitive\u003c/p\u003e\u003cp\u003eThe relatively better outcomes with 3GCs in our cohort may be related to patient selection. According to our results, patients who received carbapenems had the highest rates of ICU admission (58.8%), shock (32.4%), need for mechanical ventilation (26.5%), and invasive device use, including central lines (23.5%) and Foley catheters (44%). In contrast, the third-generation cephalosporin group had much lower rates of ICU admission (31.7%), shock (7%), and mechanical ventilation (17%). These findings indicate that patients treated with carbapenems were more critically ill at baseline, and the worse outcomes may reflect their underlying condition rather than antibiotic failure. Though we performed multivariate analysis to adjust for confounders such as ICU status, comorbidities, prior antibiotic use, and infection severity, after adjusting for these differences, both 3GCs and piperacillin-tazobactam remained significantly associated with lower risk of treatment failure and mortality compared to carbapenems, raising a question of whether a true benefit beyond patient characteristics, or it is still due to a residual confounding, particularly given the small sample size. Additionally, we must point out that the other studies included a broader range of AmpC-E species than our studies, which included Serratia spp., Citrobacter spp., Providencia spp., and Morganella spp. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], Or included different infection sites (e.g., pneumonia in Maillard et al. and Pilmis et al., or different sites in Peters et al) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, the clinical failure rates were lower than observed in the literature: 17% for 3GCs, 32% for piperacillin-tazobactam. For instance, Peters et al. observed treatment failure rates around 34% for both ceftriaxone and antipseudomonal beta-lactams. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Mounier et al. observed a 29.4% clinical failure rate in critically ill patients. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Herrmann et al. found only 21% early treatment response (equal to 79% failure) with piperacillin-tazobactam and 48.8% response (51.2% failure) with carbapenems. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This may be affected partially due to the baseline characteristics of patients and susceptibility-based therapy.\u003c/p\u003e\u003cp\u003eThis study had many limitations. First, it was a retrospective study conducted at a single centre, which naturally introduces risks of selection bias and missing data. Because it was based on medical records, some clinical parameters, such as SOFA or APACHE scores, could not be calculated, as certain necessary parameters were not documented, including blood gas results, particularly for ICU patients, or other modified scores. Instead, we relied on available indicators of severity such as ICU admission, shock, vasopressor use, and mechanical ventilation, which may not fully capture overall illness severity.. Also, adjustment for common confounders was attempted, the possibility of residual confounding remains, exaggerating the outcome differences.\u003c/p\u003e\u003cp\u003eSecondly, the sample size was small, especially when stratified by antibiotic groups. This may have limited the power of our statistical models and increased the chance of type II errors. Third, most patients did not have a follow-up culture, so the microbiological outcome could not be assessed. These findings also have important implications for antimicrobial stewardship. Avoiding carbapenems when appropriate may help decrease the use of carbapenem-resistant organisms such as carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e. This supports the use of carbapenem-sparing strategies as part of stewardship programs. However, clinical judgment remains the most important. In critically ill patients, carbapenems may still be the most appropriate option. Especially in countries like ours with high rates of multidrug-resistant organisms, individualised treatment decisions should be emphasised rather than a one fixed approach. Moreover, that AmpC production was not confirmed by phenotypic or molecular testing; classification was based on species known to harbour inducible chromosomal AmpC. Therefore, results should be interpreted as applying to \u0026ldquo;AmpC-associated Enterobacterales,\u0026rdquo;.\u003c/p\u003e\u003cp\u003eThe study is underpowered for fully adjusted multivariable modelling. The observed EPV for overall mortality (5.6), 28-day mortality (4.2), and clinical failure (6.4) were all below conventional thresholds (\u0026ge;\u0026thinsp;10) for five predictors, increasing the risk of model instability and overfitting. Adjusted findings should therefore be interpreted with caution and considered hypothesis-generating.\u003c/p\u003e\u003cp\u003eClinicians clearly tended to administer carbapenems to the sickest patients, as reflected in the higher frequency of shock, invasive devices, and ICU admission. Although we adjusted for prespecified covariates, residual confounding remains likely. To characterize baseline imbalance more transparently, we calculated standardized mean differences (SMDs), which confirmed large differences between carbapenem- and cephalosporin-treated patients, particularly for age, shock, and Foley catheter use (Supplementary Table X). In contrast, cephalosporin and piperacillin\u0026ndash;tazobactam groups were more balanced, though some moderate differences remained.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Conclusion\u003c/h2\u003e\u003cp\u003eIn conclusion, while there is a debate and conflicting results regarding resistance emergence with 3GCs and piperacillin-tazobactam, this study observed lower mortality and clinical failure with these agents compared to carbapenems. These findings are consistent with several other reports suggesting that non-carbapenem regimens may have comparable outcomes in selected patients.However, patients receiving carbapenems had greater baseline illness severity, and the possibility of residual confounding cannot be excluded. Given the single-centre design and limited sample size, these results should be interpreted as associations rather than causal effects. Based on these limitations, the results should be interpreted as exploratory associations rather than evidence of causal effects. Larger, prospective, multicenter studies are needed to validate these findings and to define the optimal role of carbapenem-sparing strategies in AmpC-producing Enterobacterales infections..\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAcute kidney injury (AKI)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Acute Physiology and Chronic Health Evaluation (APACHE)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AmpC \u0026beta;-lactamase (AmpC)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AmpC-associated Enterobacterales (AmpC-E)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Body mass index (BMI)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Bloodstream infection (BSI)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Carbapenem-resistant Enterobacterales (CRE)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Confidence interval (CI)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;C-reactive protein (CRP)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Endotracheal tube (ETT)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Intensive care unit (ICU)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Infectious Diseases Society of America (IDSA)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Institutional Review Board (IRB)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Mechanical ventilation (MV)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Multidrug-resistant (MDR)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Odds ratio (OR)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Propensity score (PS)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Sequential Organ Failure Assessment (SOFA)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Standard deviation (SD)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Standardized mean difference (SMD)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Third-generation cephalosporins (3GCs)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Ventilator-associated pneumonia (VAP)\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e5.1 Ethics approval\u0026nbsp;\u003cbr\u003e\u003c/strong\u003eThis study was approved by the Institutional Review Board (IRB) of An-Najah National University.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.2 Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e5.3 Availability of data and materials\u003cbr\u003e\u003c/strong\u003eThe datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.4 Competing interests\u003cbr\u003e\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.5Funding\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;No external funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.6 Declaration of AI Use\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eThe authors declare that generative artificial intelligence (AI) and AI-assisted technologies were used solely to improve the readability and language of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.7 Declaration of Helsinki for human-subject research\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in compliance with the World Medical Association Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6. Acknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the microbiology departments at An-Najah National University Hospital for their support in data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. Author Contributions:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;MG and AAB contributed to supervision and conceptualization of the study. RR contributed to conceptualization, data collection, data analysis, and writing the original draft. MWS, GO, and JA were involved in data collection, manuscript revision, and provided final approval. AS contributed to conceptualization and critically revised the manuscript for final approval. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTheuretzbacher U. Resistance drives antibacterial drug development. Current Opinion in Pharmacology. 2011;11:433\u0026ndash;8. https://doi.org/10.1016/j.coph.2011.07.008.\u003c/li\u003e\n\u003cli\u003eMizrahi A, Delerue T, Morel H, Le Monnier A, Carbonnelle E, Pilmis B, et al. Infections caused by naturally AmpC-producing Enterobacteriaceae: Can we use third-generation cephalosporins? A narrative review. Int J Antimicrob Agents. 2020;55:105834. https://doi.org/10.1016/j.ijantimicag.2019.10.015.\u003c/li\u003e\n\u003cli\u003eJacoby GA. AmpC \u0026beta;-Lactamases. Clinical Microbiology Reviews. 2009;22:161\u0026ndash;82. https://doi.org/10.1128/cmr.00036-08.\u003c/li\u003e\n\u003cli\u003ePeters DM, Winter JB, Droege CA, Ernst NE, Liao S. Comparison of Ceftriaxone and Antipseudomonal \u0026beta;-Lactam Antibiotics Utilized for Potential AmpC \u0026beta;-Lactamase-Producing Organisms. Hosp Pharm. 2021;56:560\u0026ndash;8. https://doi.org/10.1177/0018578720931463.\u003c/li\u003e\n\u003cli\u003eKohlmann R, B\u0026auml;hr T, Gatermann SG. Species-specific mutation rates for ampC derepression in Enterobacterales with chromosomally encoded inducible AmpC \u0026beta;-lactamase. Journal of Antimicrobial Chemotherapy. 2018;73:1530\u0026ndash;6. https://doi.org/10.1093/jac/dky084.\u003c/li\u003e\n\u003cli\u003eStewart AG, Paterson DL, Young B, Lye DC, Davis JS, Schneider K, et al. Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC \u0026beta;-Lactamase\u0026ndash;Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2). Open Forum Infectious Diseases. 2021;8:ofab387. https://doi.org/10.1093/ofid/ofab387.\u003c/li\u003e\n\u003cli\u003eMaillard A, Delory T, Bernier J, Villa A, Chaibi K, Escaut L, et al. Effectiveness of third-generation cephalosporins or piperacillin compared with cefepime or carbapenems for severe infections caused by wild-type AmpC \u0026beta;-lactamase-producing Enterobacterales: A multi-centre retrospective propensity-weighted study. Int J Antimicrob Agents. 2023;62:106809. https://doi.org/10.1016/j.ijantimicag.2023.106809.\u003c/li\u003e\n\u003cli\u003eDerrick C, Bookstaver PB, Lu ZK, Bland CM, King ST, Stover KR, et al. Multicenter, Observational Cohort Study Evaluating Third-Generation Cephalosporin Therapy for Bloodstream Infections Secondary to Enterobacter, Serratia, and Citrobacter Species. Antibiotics (Basel). 2020;9:254. https://doi.org/10.3390/antibiotics9050254.\u003c/li\u003e\n\u003cli\u003eTan SH, Ng TM, Chew KL, Yong J, Wu JE, Yap MY, et al. Outcomes of treating AmpC-producing Enterobacterales bacteraemia with carbapenems vs. non-carbapenems. Int J Antimicrob Agents. 2020;55:105860. https://doi.org/10.1016/j.ijantimicag.2019.105860.\u003c/li\u003e\n\u003cli\u003eMounier R, Le Guen R, Woerther P-L, Nacher M, Bonnefon C, Mongardon N, et al. Clinical outcome of wild-type AmpC-producing Enterobacterales infection in critically ill patients treated with \u0026beta;-lactams: a prospective multicenter study. Ann Intensive Care. 2022;12:107. https://doi.org/10.1186/s13613-022-01079-5.\u003c/li\u003e\n\u003cli\u003eCarri\u0026eacute; C, Bardonneau G, Petit L, Ouattara A, Gruson D, Pereira B, et al. Piperacillin-tazobactam should be preferred to third-generation cephalosporins to treat wild-type inducible AmpC-producing Enterobacterales in critically ill patients with hospital or ventilator-acquired pneumonia. J Crit Care. 2020;56:6\u0026ndash;11. https://doi.org/10.1016/j.jcrc.2019.11.005.\u003c/li\u003e\n\u003cli\u003eHerrmann L, Kimmig A, R\u0026ouml;del J, Hagel S, Rose N, Pletz MW, et al. Early Treatment Outcomes for Bloodstream Infections Caused by Potential AmpC Beta-Lactamase-Producing Enterobacterales with Focus on Piperacillin/Tazobactam: A Retrospective Cohort Study. Antibiotics (Basel). 2021;10:665. https://doi.org/10.3390/antibiotics10060665.\u003c/li\u003e\n\u003cli\u003eMcKamey L, Venugopalan V, Cherabuddi K, Borgert S, Voils S, Shah K, et al. Assessing antimicrobial stewardship initiatives: Clinical evaluation of cefepime or piperacillin/tazobactam in patients with bloodstream infections secondary to AmpC-producing organisms. Int J Antimicrob Agents. 2018;52:719\u0026ndash;23. https://doi.org/10.1016/j.ijantimicag.2018.08.007.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"AmpC β-lactamase, Enterobacterales, third-generation cephalosporins, piperacillin-tazobactam, carbapenems","lastPublishedDoi":"10.21203/rs.3.rs-7651779/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7651779/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAmpC-producing Enterobacterales are associated with resistance to many β-lactam antibiotics, and the optimal treatment approach remains challenging. The primary aim is to describe real-world outcomes of hospitalised patients with AmpC-associated Enterobacterales infections treated with different antibiotics.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis was a retrospective cohort study, including hospitalised patients with confirmed infections based on clinical evaluation and laboratory confirmation caused by AmpC-producing Enterobacterales. Patients received definitive therapy using 3GCss, piperacillin-tazobactam, or carbapenems, based on final culture results showing full susceptibility to the administered antibiotics.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003ePatients were categorised into 3GCs, piperacillin-tazobactam, and carbapenem treatment groups. Significant baseline differences were observed; the carbapenem group included patients with higher rates of shock (32.4%) and mechanical ventilation (26.5%), compared to lower rates in the 3GCs group (shock 7%, mechanical ventilation 17%). After adjustment for potential confounders, Clinical failure rates were 17% for the 3GCs group, 32% for the piperacillin-tazobactam group, and 41% for the carbapenem group. The 28-day mortality (7%) and overall mortality (12%) were lowest in the 3GC group, followed by the piperacillin-tazobactam group (14.7% 28-day mortality).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIn this real-world cohort, mortality and clinical failure appeared lower among patients with AmpC-associated Enterobacterales infections who received third-generation cephalosporins or piperacillin-tazobactam compared with carbapenems. These findings suggest that third-generation cephalosporins and piperacillin-tazobactam might be reasonable options in selected, less critically ill patients, but larger prospective studies are needed to better define their role, as these results are exploratory.\u003c/p\u003e","manuscriptTitle":"Clinical Outcomes of Third-Generation Cephalosporins, Carbapenems, and Piperacillin-Tazobactam in the Treatment of AmpC- Associated Enterobacterales Species Sepsis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-01 11:53:09","doi":"10.21203/rs.3.rs-7651779/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8d54c448-cca7-4a0c-a0dc-cabf23c283d0","owner":[],"postedDate":"November 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-21T08:24:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-01 11:53:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7651779","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7651779","identity":"rs-7651779","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}