PK/PD study of ceftazidime/avibactam in patients with severe intra-abdominal infections treated by continuous veno–venous hemofiltration

PK/PD study of ceftazidime/avibactam in patients with severe intra-abdominal infections treated by continuous veno–venous hemofiltration | 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 PK/PD study of ceftazidime/avibactam in patients with severe intra-abdominal infections treated by continuous veno–venous hemofiltration Sai Tian, Yong Chen, Mingjie Qiu, Wenqi Wu, Liuqing Dou, Jiajie Wang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7319086/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Nov, 2025 Read the published version in European Journal of Clinical Microbiology & Infectious Diseases → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose: To investigate the pharmacokinetics (PK) of ceftazidime/avibactam and optimize dosing regimens in patients with severe intra-abdominal infection (sIAI) receiving continuous veno–venous hemofiltration (CVVH). Methods: Seven patients with sIAI treated with ceftazidime/avibactam and CVVH were enrolled. Blood samples were collected at pre-dose and post-dose (2, 3, 4, 6, and 8 h) during hemodynamic stability. Plasma concentrations were measured, and PK parameters were calculated. Monte Carlo simulations (MCSs) were used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different dosing regimens. Results: CVVH increased the clearance (CL) significantly (ceftazidime: 2.46 ± 0.29 vs . 0.9 ± 0.11 L/h; avibactam: 2.89 ± 0.41 vs . 1.09 ± 0.08 L/h, p 90% at MIC ≤ 8 mg/L. Outside CVVH, PTA > 90% at MIC ≤ 16 mg/L, and only 3000 mg + 750 mg q8h achieved PTA > 90% at MIC = 64 mg/L. For the target of 100%fT ≥ 4× MIC (ceftazidime) + 100%fT ≥ C T = 4.0 mg/L (avibactam), during CVVH, PTA > 90% at MIC ≤ 2 mg/L. Outside CVVH, PTA > 90% at MIC ≤ 4 mg/L, and only 3000 mg + 750 mg q8h achieved PTA > 90% at MIC = 16 mg/L. No regimen met the optimal dosing criteria for this target. Conclusion: CVVH enhanced the CL significantly. Dosing should be “individualized” based on the MIC and patient-specific factors. ceftazidime/avibactam severe intra-abdominal infection continuous veno–venous hemofiltration pharmacokinetic/pharmacodynamic Monte Carlo simulation Figures Figure 1 Figure 2 Figure 3 Introduction Intra-abdominal infections (IAIs) represent a prevalent clinical challenge in abdominal surgery, ranking as the second most common infection type necessitating hospitalization [ 1 , 2 ]. Often, patients with severe intra-abdominal infections (sIAIs) are complicated with acute kidney injury or multiple-organ failure [ 3 , 4 ], which can require continuous renal replacement therapy (CRRT). As the predominant modality of CRRT, continuous veno–venous hemofiltration (CVVH) provides sustained solute clearance through convective transport mechanisms [ 5 ], thereby augmenting the elimination of antimicrobial agents with low molecular weight. A combination of a β-lactam/β-lactamase-inhibitor, ceftazidime/avibactam, received approval from the US Food and Drug Administration in 2015 for the treatment of complicated IAIs and infections caused by multidrug-resistant Gram-negative pathogens (including Pseudomonas aeruginosa ) in adults [ 6 , 7 ]. This antimicrobial combination demonstrates favorable therapeutic potential due to the complementary pharmacokinetic (PK) profiles of its components, which permit fixed-ratio dosing [ 8 ]. As a renally eliminated antimicrobial combination, ceftazidime/avibactam demonstrates renal function-dependent PK, with the added complexity of extracorporeal clearance during CVVH in critically ill patients [ 9 , 10 ]. Subtherapeutic levels risk treatment failure, whereas excessive dosing increases toxicity [ 11 ]. Mortality due to multidrug-resistant Gram-negative infections remains high [ 12 , 13 ], making achievement of PK/pharmacodynamic (PD) targets critical for therapeutic success [ 14 ]. For carbapenem-resistant infections, in order to maximize clinical efficacy and microbial clearance as well as to reduce the risk of drug resistance, higher PK/PD targets (ceftazidime: 100%fT > 4 × minimum inhibitory concentration [MIC]; avibactam: 100%fT > 4 mg/L) are typically required [ 15 , 16 ]. During CVVH, the efficacy and safety of the drug must be balanced. Clinical challenges include: (1) limited PK/PD data for ceftazidime/avibactam in patients [ 17 , 18 ]; (2) lack of CVVH-specific dosing recommendations in prescribing information; (3) inconsistent dose-adjustment criteria [ 19 ]. We investigated the PK characteristics of ceftazidime/avibactam during and outside periods of CVVH treatment. We aimed to provide “individualized” dosing regimens using Monte Carlo simulation (MCS) based on PK/PD theory. Materials and Methods Inclusion and exclusion criteria This prospective study was conducted at Jinling Hospital between October and December 2024. The inclusion criteria were as follows: (1) age ≥ 18 years; (2) IAI diagnosis; (3) Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 10 or sepsis (defined as Sequential Organ Failure Assessment (SOFA) score ≥ 2); and (4) treatment with ceftazidime/avibactam and CVVH. The exclusion criteria were as follows: (1) incomplete clinical data; (2) pregnant or lactating women; (3) unavailability of blood samples; (4) receiving ceftazidime/avibactam for < 48 h; (5) receiving CVVH for < 24 h; or (6) expected survival < 72 h. Data collection Demographic and clinical data were collected from electronic medical records. The clinical data of patients were as follows: (1) general demographic information (sex, age, height, weight, APACHE II score, SOFA score [ 20 ], and hospitalization duration); (2) clinical information (diagnosis upon admission, underlying disease, culture results of pathogenic microorganisms, creatinine clearance (CrCL), estimated glomerular filtration rate (eGFR), as well as levels of serum creatinine (Scr), blood urea nitrogen, albumin, total bilirubin, procalcitonin, alanine aminotransferase, and aspartate aminotransferase); (3) ceftazidime/avibactam dose administered, dosing interval, duration of infusion, and number of days of treatment; (4) comorbidities; (5) duration of stay in the intensive care unit (ICU); and (6) CVVH information (flow rate of blood and effluent). CrCL was calculated using the Cockcroft–Gault equation [ 21 ]. The eGFR was estimated from Scr using the Chronic Kidney Disease Epidemiology Collaboration formula [ 22 ]. Collection of blood samples and analyses of drug concentration Ceftazidime/avibactam was administered as instructed by the physician. At a steady state, blood samples (2 mL) were collected from CVVH filters at 0 (pre-dose), 2, 3, 4, 6, and 8 h post-infusion using heparinized tubes. The samples were centrifuged immediately (3,900 × g , 10 min, 4°C). Post-CVVH samples were collected similarly from the arterial blood ≥ 24 h after discontinuation. Plasma concentrations of ceftazidime/avibactam were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK model and statistical methods The PK parameters we measured were peak concentration in serum (C max ), trough concentration in serum (C min ), terminal elimination half-life (t 1/2 ), area under the concentration–time curve from 0 h to 8 h (AUC 0–8 ), plasma clearance (CL), and steady-state volume of distribution (V ss ). These parameters were calculated from plasma concentrations using Phoenix WinNonlin (a non-compartmental model) and expressed as the mean ± standard deviation (SD). Continuous demographic variables were analyzed using SPSS 25.0 (IBM, Armonk, NY, USA), and they are presented as the mean ± SD or median (interquartile range, IQR). Categorical variables are presented as percentages. MCS MCS analyses utilized published European Committee for Antimicrobial Susceptibility Testing (EUCAST) data for MIC distribution (accessed 7 March 2025) for Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa to evaluate four intravenous dosing regimens for ceftazidime/avibactam [ 23 ]. These four intravenous dosing regimens were simulated based on the following: (1) the PK/PD characteristics of ceftazidime/avibactam; (2) the prescribing information; (3) clinical guidelines; and (4) real-world dosing experience to evaluate efficacy differences between regimens. The dosing regimens (all at q8h) were 750 mg + 187.5 mg; 1000 mg + 250 mg; 2000 mg + 500 mg; and 3000 mg + 750 mg. Using Crystal Ball 11.1.3.0 (Oracle Corporation, Austin, TX, USA), we undertook 10,000 simulations with PK parameters following a lognormal distribution and PD parameters following a customized distribution (95% confidence intervals). The analysis assessed two PK/PD targets: the standard target of 100%fT ≥ MIC for ceftazidime combined with 100%fT ≥ C T = 1.0 mg/L for avibactam and the intensive target of 100%fT ≥ 4× MIC for ceftazidime with 100%fT ≥ C T = 4.0 mg/L for avibactam. The probability of target attainment (PTA) and cumulative fraction of response (CFR) were calculated using established PK formulae, with regimens achieving PTA or CFR ≥ 90% considered “optimal” and those with 80% ≤ CFR < 90% classified as “suboptimal” dosing regimens. The target calculation method for β-lactam and β-lactamase inhibitors is as follows, Results Patients The flowchart of patient screening is shown in Fig. 1 . Twenty-nine patients were assessed for eligibility. Seven patients (five men, two women) were enrolled and assessed in this study, and all of them completed the study. The cohort had a mean age of 56.4 ± 15.5 years, a body mass index of 24.4 ± 2.8 kg/m 2 , a median CrCl of 24.34 mL/min, and a median eGFR of 28.81 mL/min/1.73 m 2 . The average duration of CVVH was 21.4 days. The average duration of ICU stay was 64.9 days. Microbiological analyses identified E. coli (n = 5), K. pneumoniae (n = 2), and P. aeruginosa (n = 5), with four patients having polymicrobial infections. The demographics of patients are shown in Table 1 . Table 1 Demographic characteristics of patients (n = 7) Characteristics Total (n = 7) Sex; n (%) Male 5 (71.4) Female 2 (28.6) Age (years) 56.4 ± 15.5 BMI (kg/m 2 ) 24.4 ± 2.8 Comorbid conditions (%) Hypertensive 2 (28.6) Diabetes 1 (14.3) History of cerebral infarction 1 (14.3) Scr (µmol/L) 275.9 ± 106.2 CrCL (mL/min) 24.34 (18.43–29.84) eGFR (mL/min/1.73 m²) 28.81 (18.76–30.37) BUN (mmol/L) 25.1 ± 8.8 ALB (g/L) 32.2 ± 4.5 TB (µmol/L) 128.2 (67.9-160.6) PCT (ng/mL) 9.44 (2.2-21.25) ALT (U/L) 45 (23–63) AST (U/L) 93.4 (41–141) Isolated microorganisms; n (%) P. aeruginosa 5 (71.4) E. coli 5 (71.4) K. pneumoniae 2 (28.6) Treatment duration of CVVH (days) 21.4 ± 15.5 APACHE II score 20.7 ± 4.5 SOFA score 17.7 ± 6.3 Mechanical ventilation (%) 7 (100) Vasoactive Agents 6 (85.7) Treatment duration of Ceftazidime/avibactam (days) 36.9 ± 20.8 Concomitant drugs (%) Teicoplanin 5 (71.4) Polymyxin E 5 (71.4) Meropenem 4 (57.1) Imipenem/cilastatin 3 (42.9) Voriconazole 3 (42.9) Tigecycline 2 (28.6) Aztreonam 2 (28.6) ICU length of stay (days) 64.9 ± 36.3 CVVH parameters Blood flow (mL/min) 150 (150,160) Effluent flow rate (mL/kg/h) 29.48 ± 4.18 BMI, body mass index; Scr, serum creatinine; CrCL, creatinine clearance; eGFR, estimate glomerular filtration rate; BUN, blood urea nitrogen; ALB, albumin; TB, total bilirubin; PCT, procalcitonin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment; CVVH, continuous veno-venous hemofiltration; P. aeruginosa , Pseudomonas aeruginosa ; E. coli , Escherichia coli ; K. pneumoniae , Klebsiella pneumoniae ; ICU, intensive care unit. PK parameters Eighty-four blood samples were collected from seven patients. The blood concentrations of ceftazidime/avibactam were measured by LC-MS/MS. The PK parameters of ceftazidime/avibactam were calculated using a non-compartmental model based on the plasma concentrations of ceftazidime/avibactam (Table 2 ). Comparative analyses of the PK parameters of ceftazidime/avibactam during versus outside periods of CVVH are presented in Fig. 2 . Table 2 Pharmacokinetic parameters of ceftazidime/avibactam Parameters Ceftazidime Avibactam During CVVH Outside CVVH During CVVH Outside CVVH C max (mg/L) 145.7 ± 22.25 324 ± 38.33 29.14 ± 5.56 65.17 ± 5.53 C min (mg/L) 66.03 ± 5.62 237.14 ± 25.14 14.29 ± 1.99 47.49 ± 4.07 t 1/2 (h) 6.44 ± 1.03 19.91 ± 1.33 7.55 ± 2.2 33.08 ± 7.8 AUC 0 − 8 (mg·h/L) 823.41 ± 100.2 2249.93 ± 259.22 176.21 ± 28.34 459.81 ± 30.88 CL (L/h) 2.46 ± 0.29 0.9 ± 0.11 2.89 ± 0.41 1.09 ± 0.08 V ss (L) 22.49 ± 3.84 25.64 ± 2.58 31.85 ± 12.14 52.2 ± 13.6 CVVH, continuous veno-venous hemofiltration; C max , peak concentration; C min , trough concentration; t 1/2 , half-life; AUC 0 − 8 , area under the plasma concentration-time curve at 0–8 h; CL, clearance; V ss , steady-state volume of distribution. CVVH increased the CL of both drugs significantly (ceftazidime: 2.46 ± 0.29 vs . 0.9 ± 0.11 L/h; avibactam: 2.89 ± 0.41 vs . 1.09 ± 0.08 L/h; both p < 0.001). C min during CVVH was markedly lower for ceftazidime (66.03 ± 5.62 vs . 237.14 ± 25.14 mg/L) and avibactam (14.29 ± 1.99 vs . 47.49 ± 4.07 mg/L; both p < 0.0001). Similarly, the AUC 0–8 was reduced significantly during CVVH for ceftazidime (823.41 ± 100.2 vs . 2,249.93 ± 259.22 mg·h/L) and avibactam (176.21 ± 28.34 vs . 459.81 ± 30.88 mg·h/L; both p 90% at MIC ≤ 8 mg/L. All dosing regimens, except the dosing regimen of 750 mg + 187.5 mg q8h, had a PTA > 90% at MIC = 16 mg/L. Only 2000 + 500 mg q8h maintained a PTA > 90% at MIC = 32 mg/L. All dosing regimens had a PTA 90% at MIC ≤ 16 mg/L. The conventional dosing regimen of 2000 mg + 500 mg q8h had a PTA > 90% for MIC = 32 mg/L. When the MIC rose to 64 mg/L, only 3000 + 750 mg q8h was effective at MIC = 64 mg/L. All dosing regimens had a PTA 90% at MIC ≤ 2 mg/L. All regimens except 750 mg + 187.5 mg q8h achieved a PTA > 90% at MIC = 4 mg/L. Only 2000 + 500 mg q8h was effective at MIC = 8 mg/L. All dosing regimens had a PTA 90% at MIC ≤ 4 mg/L. The conventional dosing regimen of 2000 mg + 500 mg q8h had PTA > 90% at MIC = 8 mg/L. Only 3000 + 750 mg q8h was effective at MIC = 16 mg/L. All dosing regimens had PTA < 90% at MIC ≥ 32 mg/L. CFR for patients For the target of 100%fT ≥ MIC + 100%fT ≥ C T = 1.0 mg/L , during and outside periods of CVVH treatment, for P. aeruginosa , the administration regimens of 2000 mg + 500 mg q8h and 3000 mg + 750 mg q8h had a CFR > 90%, both of which were optimal, whereas the regimens of 750 mg + 187.5 mg q8h and 1000 mg + 250 mg q8h had a CFR between 80% and 90%, both of which were suboptimal regimens (Table 3 ). For E. coli and K. pneumoniae , all four dosing regimens were suboptimal. For the intensive target (100%fT ≥ 4× MIC + 100%fT ≥ C T = 4.0 mg/L ), 750 mg + 187.5 mg q8h and 1000 mg + 250 mg q8h were not considered to be optimal or suboptimal regimens for all three types of bacteria. We found 2000 mg + 500 mg q8h and 3000 mg + 750 mg q8h to be suboptimal regimens for all three types of bacteria outside periods of CVVH and for E. coli and K. pneumoniae during CVVH. Table 3 CFR of the different ceftazidime/avibactam dosing regimens Target value Regimens During CVVH Outside CVVH P. aeruginosa E. coli K. pneumoniae P. aeruginosa E. coli K. pneumoniae 100%fT ≥ MIC 100%fT ≥ C T = 1.0 mg/L 750 mg + 187.5 mg q8h 87.86% 82.85% 82.17% 89.10% 83.28% 82.31% 1000 mg + 250 mg q8h 88.86% 83.20% 82.28% 89.24% 83.33% 82.32% 2000 mg + 500 mg q8h 93.44% 83.84% 82.32% 93.67% 83.87% 82.32% 3000 mg + 750 mg q8h 96.80% 84.72% 82.32% 97.58% 84.93% 82.32% 100%fT ≥ 4× MIC 100%fT ≥ C T = 4.0 mg/L 750 mg + 187.5 mg q8h 45.03% 75.23% 75.00% 76.34% 77.42% 77.03% 1000 mg + 250 mg q8h 48.93% 77.72% 77.58% 78.38% 78.61% 78.47% 2000 mg + 500 mg q8h 54.43% 80.94% 81.47% 82.91% 81.18% 81.77% 3000 mg + 750 mg q8h 59.84% 82.86% 82.17% 89.10% 83.28% 82.31% CVVH, continuous veno-venous hemofiltration; fT ≥ MIC, time fraction of free drug above the minimum inhibitory concentration; fT ≥ C T , time fraction of free drug above a threshold concentration; P. aeruginosa , Pseudomonas aeruginosa ; E. coli , Escherichia coli ; K. pneumoniae , Klebsiella pneumoniae . Discussion As the first systematic PK evaluation of ceftazidime/avibactam in patients suffering from sIAI receiving CVVH, we revealed significant CVVH-mediated alterations in drug CL. Our comparative PK analysis demonstrated substantial differences during and outside CVVH periods. Based on PK/PD theory, different dosing regimens of ceftazidime/avibactam were evaluated using MCS. The calculation of PTA and CFR provided a scientific basis for individualized dosing in patients with sIAI treated with combined CVVH. Pathophysiologic changes and CRRT use in patients with sIAI can affect the PK/PD properties of ceftazidime/avibactam significantly [ 24 ]. In the present study, the median eGFR of patients was 28.81 mL/min/1.73 m 2 . According to the staging criteria of chronic kidney disease (CKD) (GFR of 15–29 mL/min is CKD stage 4) [ 25 ], some patients in our study population had severe renal insufficiency. The efficiency of solute removal by CVVH based on the principle of convection is not limited by molecular weight until the membrane sieving cutoff is reached. The molecular weights of ceftazidime and avibactam are well below the membrane sieving cutoff, so both can be removed efficiently by CVVH. The Vd of a drug is another key factor influencing the CL efficiency of CRRT. Lower Vd values (usually < 0.3 L/kg) suggest that the drug is distributed mainly in the intravascular space [ 9 , 26 ], and such drugs are more likely to be cleared significantly by CRRT. Ceftazidime/avibactam, as a highly hydrophilic antimicrobial drug, has a low Vd (~ 0.3 L/kg), which determines its relatively high efficiency of CL by convection through CVVH. Ceftazidime/avibactam is cleared substantially by CRRT, particularly at high intensities or with residual renal function [ 27 ]. Wenzler et al. [ 28 ] administered ceftazidime/avibactam at 1.25 g q8h for the treatment of a critically ill patient with multidrug-resistant P. aeruginosa bacteremia undergoing CVVH. The mean CL of CVVH to ceftazidime and avibactam was 1.64 L/h and 1.59 L/h, respectively, accounting for 57.1% and 57.3% of total CL of ceftazidime and avibactam, respectively. Our findings demonstrated higher CL (ceftazidime: 2.46 L/h; avibactam: 2.89 L/h) during CVVH than outside periods of CVVH conditions (0.9 and 1.09 L/h, respectively), which was consistent with exposure levels. However, the CL remained markedly lower than that in healthy individuals (ceftazidime: 10.07 L/h; avibactam: 13.36 L/h) [ 29 ], likely due to the severe renal impairment in our cohort. This impaired CL may prolong t 1/2 , potentially leading to drug accumulation and increased toxicity. Studies have shown that the use of high-dose regimens in patients outside CVVH treatment periods may increase the risk of developing drug-related renal injury significantly. Therefore, treatment planning for these patients requires particular attention to dose adjustment and therapeutic drug monitoring to balance efficacy and safety. Optimizing population-based and individualized dosing strategies for ceftazidime/avibactam during CRRT is a clinical challenge [ 30 ]. Often, dosing strategies rely on empirical approaches, lacking systematic evidence for rational individualization. Conventional PK/PD simulations typically employ average PK parameters and single MIC values, failing to account for interpatient variability and differences in pathogen susceptibility. In contrast, MCS integrates population PK variability with MIC distributions to predict PTA, enabling more accurate, individualized regimen optimization [ 31 ]. We targeted ceftazidime 100%fT ≥ MIC combined with avibactam 100%fT ≥ C T = 1.0 mg/L . During CVVH, all four regimens achieved PTA > 90% for strains with MIC ≤ 8 mg/L, indicating that dose adjustment was not required for common susceptible bacteria. At MIC = 64 mg/L, all regimens showed PTA 90% at MIC = 64 mg/L. This finding suggests that CVVH increased drug CL significantly, thereby hampering maintenance of therapeutic blood concentrations of ceftazidime/avibactam at high MIC values. For such high-MIC-resistant strains, alternative treatment regimens may need to be considered. For P. aeruginosa , CFR > 90% was achieved with dosing regimens of 2000 mg + 500 mg q8h and 3000 mg + 750 mg q8h, both of which were preferred regimens, significantly better than the regimens of 750 mg + 187.5 mg q8h and 1000 mg + 250 mg q8h. During CVVH, CFR was, in general, lower compared with that outside CVVH treatment periods. For the target of ceftazidime 100%fT ≥ 4× MIC + avibactam 100%fT ≥ C T = 4.0 mg/L , the high-dose regimen of 3000 mg + 750 mg benefited only a subset of patients with an MIC ≤ 16 mg/L during CVVH. Consistent with data from other studies, the targets of 100%fT ≥ 4× MIC and 100%fT ≥ C T = 4.0 mg/L could be achieved only by continuous infusion of higher doses [ 32 ]. During CVVH, 2000 mg + 500 mg q8h and 3000 mg + 750 mg q8h were suboptimal regimens for E. coli and K. pneumoniae , respectively. However, even with high doses, achievement of intensification targets for P. aeruginosa remained challenging. In addition, no dosing regimen could be considered as a preferred regimen, and high doses were less important for CFR increase than conventional doses. Moreover, high concentrations of ceftazidime/avibactam may trigger neurotoxicity, including seizures and encephalopathy [ 33 , 34 ]. Kang et al. demonstrated superior bactericidal activity against P. aeruginosa (MIC > 16 mg/L) with a two-step infusion regimen (1.25 g over 0.5 h, followed by 1.25 g over 2 h) compared with conventional dosing (2.5 g q8h) while mitigating toxicity risks [ 35 ]. Optimizing the antimicrobial drug regimen for patients on CRRT requires comprehensive consideration of multiple factors. In addition to the physicochemical properties of the drug, it should also include the specific parameter settings of CRRT, residual renal function, the infection site, and the MIC of the pathogen to achieve the optimal balance between efficacy and safety [ 36 ]. Our study has four main limitations. First, the study cohort comprised only seven patients. This limitation would have affected the reliability of our findings. Also, the limited number of measurements of the blood concentration at six time points may have introduced a bias in CL calculations. Second, due to most patients being oliguric or anuric, the drug concentration in urine was not monitored, thereby impairing assessment of the role of residual renal function upon drug CL. Third, only CVVH mode was examined, leaving the impact of other CRRT modalities unexplored. Fourth, the safety of high-dose regimens was not evaluated. Future research should improve assessment of residual renal function, incorporate multiple CRRT modes, and better evaluate the efficacy–safety balance of high-dose treatments. In conclusion, CVVH enhanced the CL of ceftazidime/avibactam significantly. Plasma concentrations in patients with severe renal impairment remained high compared with those of healthy individuals, thereby necessitating monitoring for potential accumulation. MCS revealed distinct dosing requirements during CVVH as well as outside CVVH periods. Conventional dosing sufficed for low-MIC pathogens, whereas infections with high MICs required intensified regimens. For MICs exceeding critical thresholds, no existing regimen achieved targets. Therefore, individualized dosing incorporating renal function, CRRT modality, and the MIC of the pathogen is critical for optimizing efficacy while minimizing toxicity and drug resistance. Declarations Acknowledgments The authors declare that this study is exclusively based on pharmacokinetic and pharmacodynamic analyses, and they are thankful to all staff in the Department of Critical Care Medicine and Clinical Pharmacy at Jinling Hospital for their support in patient management and sample collection. Author contributions Jianan Ren, Xiuwen Wu and Jiayang Li conceived of the presented idea. Sai Tian and Yong Chen wrote the main manuscript text and prepared figures/tables. Mingjie Qiu and Wenqi Wu carried out the experiment. Liuqing Dou, Jiajie Wang, Li Xu, Zhitao Zhou and Meilin Wu authors contributed to the final version of the manuscript. All authors reviewed the manuscript. Funding The study was supported by the Key Research and Development Program of Jiangsu Province (BE2022823) and the Navigation Project of Clinical Research (22LCYY-LH4). Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was approved (2024DZKY-067-02) by the Clinical Research and Ethics Committee of Jinling Hospital. Competing Interests The authors declare no competing interests. References De Corte W, Dhondt A, Vanholder R, De Waele J, Decruyenaere J, Sergoyne V, Vanhalst J, Claus S, Hoste EAJ (2016) Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study. 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Critical Care Medicine 36 (8):2433-2440. http://doi.org/10.1097/CCM.0b013e318180fe62 Li J, Ren J, Wang W, Wang G, Gu G, Wu X, Wang Y, Huang M, Li J (2017) Risk factors and clinical outcomes of hypervirulent Klebsiella pneumoniae induced bloodstream infections. European Journal of Clinical Microbiology & Infectious Diseases 37 (4):679-689. http://doi.org/10.1007/s10096-017-3160-z Li J, Wu W, Wu M, Zhou Z, Wang J, Qiu M, Xu L, Ren J, Wu X (2024) Clinical and Molecular Characteristics of Patients with Bloodstream Infections Caused by KPC and NDM Co-Producing Carbapenem-Resistant Klebsiella pneumoniae. Infection and Drug Resistance Volume 17:1685-1697. http://doi.org/10.2147/idr.S455146 Bidell MR, Lodise TP (2018) Suboptimal Clinical Response Rates with Newer Antibiotics Among Patients with Moderate Renal Impairment: Review of the Literature and Potential Pharmacokinetic and Pharmacodynamic Considerations for Observed Findings. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 38 (12):1205-1215. http://doi.org/10.1002/phar.2184 Guilhaumou R, Benaboud S, Bennis Y, Dahyot-Fizelier C, Dailly E, Gandia P, Goutelle S, Lefeuvre S, Mongardon N, Roger C, Scala-Bertola J, Lemaitre F, Garnier M (2019) Optimization of the treatment with beta-lactam antibiotics in critically ill patients—guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique—SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d’Anesthésie et Réanimation—SFAR). Critical Care 23 (1):104. http://doi.org/10.1186/s13054-019-2378-9 Bakdach D, Elajez R, Bakdach AR, Awaisu A, De Pascale G, Ait Hssain A (2022) Pharmacokinetics, Pharmacodynamics, and Dosing Considerations of Novel β-Lactams and β-Lactam/β-Lactamase Inhibitors in Critically Ill Adult Patients: Focus on Obesity, Augmented Renal Clearance, Renal Replacement Therapies, and Extracorporeal Membrane Oxygenation. Journal of Clinical Medicine 11 (23):6898. http://doi.org/10.3390/jcm11236898 Zhang X-S, Wang Y-Z, Shi D-W, Xu F-M, Yu J-H, Chen J, Lin G-Y, Zhang C-H, Yu X-B, Tang C-R (2022) Efficacy and Pharmacodynamic Target Attainment for Ceftazidime–Avibactam Off-Label Dose Regimens in Patients with Continuous or Intermittent Venovenous Hemodialysis: Two Case Reports. Infectious Diseases and Therapy 11 (6):2311-2319. http://doi.org/10.1007/s40121-022-00621-z Soukup P, Faust AC, Edpuganti V, Putnam WC, McKinnell JA (2019) Steady‐State Ceftazidime‐Avibactam Serum Concentrations and Dosing Recommendations in a Critically Ill Patient Being Treated for Pseudomonas aeruginosa Pneumonia and Undergoing Continuous Venovenous Hemodiafiltration. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 39 (12):1216-1222. http://doi.org/10.1002/phar.2338 Gatti M, Fornaro G, Viale P, Pea F, Giannella M (2022) Clinical efficacy of renal dosing adjustments of ceftazidime–avibactam in patients affected by carbapenem‐resistant Gram‐negative infections: A systematic review and meta‐analysis of observational studies. British Journal of Clinical Pharmacology 89 (2):617-629. http://doi.org/10.1111/bcp.15586 Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med 26 (11):1793-1800. http://doi.org/10.1097/00003246-199811000-00016 Cockcroft DW, Gault H (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16 (1):31-41. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, Kusek JW, Eggers P, Lente FV, Greene T (2009) A new equation to estimate glomerular filtration rate. Annals of internal medicine 150 (9):604-612. EUCAST (2025) Antimicrobial wild type distributions of microorganisms, https://mic.eucast.org/. Cited 2025-3-7 Yan YY, Jin Y, Ni X-yC-yC-hL-RS-sQ-mS (2023) A therapeutic regimen of ceftazidime-avibactam for a critical patient receiving prolonged intermittent renal replacement therapy. Journal of infection and chemotherapy : 29 (6):620-623. Group KDIGOKAKIW (2012) KDIGO clinical practice guidelines for acute kidney injury. Kidney International Supplements 2 (1):1-138. Agency EM (2018) Zavicefta: summary of product characteristics, http://www.ema.europa.eu. Cited 16 March 2018 Gatti M, Pea F (2021) Antimicrobial Dose Reduction in Continuous Renal Replacement Therapy: Myth or Real Need? A Practical Approach for Guiding Dose Optimization of Novel Antibiotics. Clinical Pharmacokinetics 60 (10):1271-1289. http://doi.org/10.1007/s40262-021-01040-y Wenzler E, Bunnell KL, Bleasdale SC, Benken S, Danziger LH, Rodvold KA (2017) Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration. Antimicrobial Agents and Chemotherapy 61 (7):e00464-00417. http://doi.org/10.1128/aac.00464-17 Merdjan H, Rangaraju M, Tarral A (2015) Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies. Clinical Drug Investigation 35 (5):307-317. http://doi.org/10.1007/s40261-015-0283-9 DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clinical Infectious Diseases 58 (8):1072-1083. Ambrose PG (2006) Monte Carlo Simulation in the Evaluation of Susceptibility Breakpoints: Predicting the Future: Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 26 (1):129-134. Han Y, Zhu J, Liu J, Zheng Y, Liang G, Yang Y, Yu L, Yu Z, Han G (2024) Adequacy of the Dosing and Infusion Time of Ceftazidime/Avibactam for the Treatment of Gram-Negative Bacterial Infections: A PK/PD Simulation Study. Infection and Drug Resistance Volume 17:2823-2832. http://doi.org/10.2147/idr.S469313 Yu J, Zuo W, Fan H, Wu J, Qiao L, Yang B, Li W, Yang Y, Zhang B (2023) Ceftazidime-Avibactam for Carbapenem-Resistant Gram-Negative Bacteria Infections: A Real-World Experience in the ICU. Infection and Drug Resistance Volume 16:6209-6216. http://doi.org/10.2147/idr.S422545 Guo X, Guo M, Li J, Cui X (2022) Central nervous system adverse events of ceftazidime/avibactam: A retrospective study using Food and Drug Administration Adverse Event Reporting System. Journal of Clinical Pharmacy and Therapeutics 47 (12):2369-2372. http://doi.org/10.1111/jcpt.13796 Kang Y, Cui J (2023) Evaluation of the Efficacy of Optimized Two-Step-Administration Therapy with Ceftazidime/Avibactam for Treating Extensively Drug-Resistant Pseudomonas aeruginosa Pulmonary Infections: a Pharmacokinetic/Pharmacodynamic Analysis. Japanese Journal of Infectious Diseases 76 (1):1-6. http://doi.org/10.7883/yoken.JJID.2022.289 Gatti M, Pascale R, Cojutti PG, Rinaldi M, Ambretti S, Conti M, Tedeschi S, Giannella M, Viale P, Pea F (2023) A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia. International Journal of Antimicrobial Agents 61 (1):106699. http://doi.org/10.1016/j.ijantimicag.2022.106699 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Nov, 2025 Read the published version in European Journal of Clinical Microbiology & Infectious Diseases → Version 1 posted Editorial decision: Revision requested 28 Aug, 2025 Reviews received at journal 26 Aug, 2025 Reviews received at journal 25 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers invited by journal 11 Aug, 2025 Editor assigned by journal 07 Aug, 2025 Submission checks completed at journal 07 Aug, 2025 First submitted to journal 07 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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School, Nanjing University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Chen","suffix":""},{"id":501305433,"identity":"8c455b3b-cfff-44e6-b98f-4ec14756309f","order_by":2,"name":"Mingjie Qiu","email":"","orcid":"","institution":"Jinling Clinical Medical College, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mingjie","middleName":"","lastName":"Qiu","suffix":""},{"id":501305434,"identity":"6fd5ce85-6da6-41ff-bf0b-f96c11ee7efe","order_by":3,"name":"Wenqi Wu","email":"","orcid":"","institution":"Jinling Hospital, the Affiliated Hospital of Medical School, Nanjing University","correspondingAuthor":false,"prefix":"","firstName":"Wenqi","middleName":"","lastName":"Wu","suffix":""},{"id":501305435,"identity":"7ff51379-5aa3-4828-b543-2a6b7b54e90a","order_by":4,"name":"Liuqing Dou","email":"","orcid":"","institution":"Jinling Clinical Medical College, Nanjing University of Chinese 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University","correspondingAuthor":false,"prefix":"","firstName":"Zhitao","middleName":"","lastName":"Zhou","suffix":""},{"id":501305439,"identity":"dd60af9e-e4ec-4c1f-8cfc-0f728755a017","order_by":8,"name":"Meilin Wu","email":"","orcid":"","institution":"Jinling Clinical Medical College, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Meilin","middleName":"","lastName":"Wu","suffix":""},{"id":501305440,"identity":"c0f4ada3-3ec0-4877-af44-16f4c1dff22d","order_by":9,"name":"Jiayang Li","email":"","orcid":"","institution":"Jinling Hospital, the Affiliated Hospital of Medical School, Nanjing University","correspondingAuthor":false,"prefix":"","firstName":"Jiayang","middleName":"","lastName":"Li","suffix":""},{"id":501305442,"identity":"2235eb89-6ee3-4d32-8f4c-b37e51117f88","order_by":10,"name":"Xiuwen Wu","email":"","orcid":"","institution":"Jinling Clinical Medical College, Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiuwen","middleName":"","lastName":"Wu","suffix":""},{"id":501305446,"identity":"2b33ce5b-b5f9-4de8-88ee-a109d2bdceec","order_by":11,"name":"Jianan Ren","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBACxmYILcfAcABIsZGgxZh4LTCQ2ACmiNHC3M787MHPHffStzOeMWD4UHaYgX92AyGHsZkb9p4pzt3ZcMaAcca5wwwSdw4Q0sJgJsHblpC74cAZA2betsMMBhIJhLSwf5P825aQbgDS8pc4LTxm0kBbEsBaGInUUiYt25ZguOHAsYKDPefSeSRuENBi2H98m+TbtgR5gxuHNz74UWYtxz+DkJYGGEviADgyefCrBwJ5OIu/AbeqUTAKRsEoGNkAAPwRQx5Ep49+AAAAAElFTkSuQmCC","orcid":"","institution":"Jinling Clinical Medical College, Nanjing University of Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jianan","middleName":"","lastName":"Ren","suffix":""}],"badges":[],"createdAt":"2025-08-07 13:08:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7319086/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7319086/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10096-025-05343-x","type":"published","date":"2025-11-14T15:56:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89396091,"identity":"ddc1eecc-a9f3-4112-b1ed-f736f74319e0","added_by":"auto","created_at":"2025-08-19 13:39:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32941,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient screening.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7319086/v1/55c6d51e76009c084d20f05d.jpg"},{"id":89397434,"identity":"4c34c48e-605d-442c-afec-540a12299fe7","added_by":"auto","created_at":"2025-08-19 13:47:28","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57778,"visible":true,"origin":"","legend":"\u003cp\u003ePharmacokinetic parameters of ceftazidime/avibactam. \u003cstrong\u003e(A)\u003c/strong\u003e CL of ceftazidime. \u003cstrong\u003e(B)\u003c/strong\u003e CL of avibactam. \u003cstrong\u003e(C)\u003c/strong\u003e C\u003csub\u003emin \u003c/sub\u003eof ceftazidime. \u003cstrong\u003e(D)\u003c/strong\u003e C\u003csub\u003emin \u003c/sub\u003eof avibactam. \u003cstrong\u003e(E)\u003c/strong\u003e AUC\u003csub\u003e0–8\u003c/sub\u003e of ceftazidime. \u003cstrong\u003e(F)\u003c/strong\u003e AUC\u003csub\u003e0–8\u003c/sub\u003e of avibactam. Abbreviations: CAZ = ceftazidime; AVI = avibactam; CVVH = continuous veno–venous hemofiltration; CL = clearance; C\u003csub\u003emin\u003c/sub\u003e = trough concentration in serum; AUC\u003csub\u003e0–8\u003c/sub\u003e = area under the plasma concentration–time curve at 0–8 h. ***\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7319086/v1/c4d7c3c6626de3bba0eaea77.jpg"},{"id":89396094,"identity":"6f0ecfcb-cf25-4b89-ba81-9b7b269043b1","added_by":"auto","created_at":"2025-08-19 13:39:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56536,"visible":true,"origin":"","legend":"\u003cp\u003ePTA in patients with different dosing regimens during or outside CVVH sessions. \u003cstrong\u003e(A-1)\u003c/strong\u003e PTA for patients during CVVH for achieving 100%fT ≥ MIC for ceftazidime with 100%fT ≥ C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e for avibactam. \u003cstrong\u003e(A-2)\u003c/strong\u003e PTA for patients outisde CVVH treatment for achieving 100%fT ≥ MIC for ceftazidime with 100%fT ≥ C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e for avibactam. \u003cstrong\u003e(B-1)\u003c/strong\u003e PTA for patients during CVVH for achieving 100%fT ≥ 4× MIC for ceftazidime with 100%fT ≥ C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e for avibactam. \u003cstrong\u003e(B-2)\u003c/strong\u003e PTA for patients outside CVVH treatment for achieving 100%fT ≥ 4× MIC for ceftazidime with 100%fT ≥ C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e for avibactam. Abbreviations: PTA = probability of target attainment; MIC = minimum inhibitory concentration; CVVH = continuous veno–venous hemofiltration.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7319086/v1/02ad1d289fb096172e49aa93.jpg"},{"id":96104958,"identity":"9343dfc4-ce1b-4660-b129-585452e8b0b6","added_by":"auto","created_at":"2025-11-17 16:04:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":927699,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7319086/v1/6c909e33-84a0-4a0a-aa5c-2f34206f50a9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"PK/PD study of ceftazidime/avibactam in patients with severe intra-abdominal infections treated by continuous veno–venous hemofiltration","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntra-abdominal infections (IAIs) represent a prevalent clinical challenge in abdominal surgery, ranking as the second most common infection type necessitating hospitalization [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Often, patients with severe intra-abdominal infections (sIAIs) are complicated with acute kidney injury or multiple-organ failure [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], which can require continuous renal replacement therapy (CRRT). As the predominant modality of CRRT, continuous veno\u0026ndash;venous hemofiltration (CVVH) provides sustained solute clearance through convective transport mechanisms [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], thereby augmenting the elimination of antimicrobial agents with low molecular weight.\u003c/p\u003e\u003cp\u003eA combination of a β-lactam/β-lactamase-inhibitor, ceftazidime/avibactam, received approval from the US Food and Drug Administration in 2015 for the treatment of complicated IAIs and infections caused by multidrug-resistant Gram-negative pathogens (including \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e) in adults [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This antimicrobial combination demonstrates favorable therapeutic potential due to the complementary pharmacokinetic (PK) profiles of its components, which permit fixed-ratio dosing [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. As a renally eliminated antimicrobial combination, ceftazidime/avibactam demonstrates renal function-dependent PK, with the added complexity of extracorporeal clearance during CVVH in critically ill patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Subtherapeutic levels risk treatment failure, whereas excessive dosing increases toxicity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Mortality due to multidrug-resistant Gram-negative infections remains high [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], making achievement of PK/pharmacodynamic (PD) targets critical for therapeutic success [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. For carbapenem-resistant infections, in order to maximize clinical efficacy and microbial clearance as well as to reduce the risk of drug resistance, higher PK/PD targets (ceftazidime: 100%fT\u0026thinsp;\u0026gt;\u0026thinsp;4 \u0026times; minimum inhibitory concentration [MIC]; avibactam: 100%fT\u0026thinsp;\u0026gt;\u0026thinsp;4 mg/L) are typically required [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. During CVVH, the efficacy and safety of the drug must be balanced. Clinical challenges include: (1) limited PK/PD data for ceftazidime/avibactam in patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; (2) lack of CVVH-specific dosing recommendations in prescribing information; (3) inconsistent dose-adjustment criteria [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe investigated the PK characteristics of ceftazidime/avibactam during and outside periods of CVVH treatment. We aimed to provide \u0026ldquo;individualized\u0026rdquo; dosing regimens using Monte Carlo simulation (MCS) based on PK/PD theory.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e\n \u003cp\u003eThis prospective study was conducted at Jinling Hospital between October and December 2024. The inclusion criteria were as follows: (1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (2) IAI diagnosis; (3) Acute Physiology and Chronic Health Evaluation II (APACHE II) score\u0026thinsp;\u0026ge;\u0026thinsp;10 or sepsis (defined as Sequential Organ Failure Assessment (SOFA) score\u0026thinsp;\u0026ge;\u0026thinsp;2); and (4) treatment with ceftazidime/avibactam and CVVH. The exclusion criteria were as follows: (1) incomplete clinical data; (2) pregnant or lactating women; (3) unavailability of blood samples; (4) receiving ceftazidime/avibactam for \u0026lt;\u0026thinsp;48 h; (5) receiving CVVH for \u0026lt;\u0026thinsp;24 h; or (6) expected survival\u0026thinsp;\u0026lt;\u0026thinsp;72 h.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eDemographic and clinical data were collected from electronic medical records. The clinical data of patients were as follows: (1) general demographic information (sex, age, height, weight, APACHE II score, SOFA score [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e], and hospitalization duration); (2) clinical information (diagnosis upon admission, underlying disease, culture results of pathogenic microorganisms, creatinine clearance (CrCL), estimated glomerular filtration rate (eGFR), as well as levels of serum creatinine (Scr), blood urea nitrogen, albumin, total bilirubin, procalcitonin, alanine aminotransferase, and aspartate aminotransferase); (3) ceftazidime/avibactam dose administered, dosing interval, duration of infusion, and number of days of treatment; (4) comorbidities; (5) duration of stay in the intensive care unit (ICU); and (6) CVVH information (flow rate of blood and effluent).\u003c/p\u003e\n\u003cp\u003eCrCL was calculated using the Cockcroft\u0026ndash;Gault equation [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. The eGFR was estimated from Scr using the Chronic Kidney Disease Epidemiology Collaboration formula [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eCollection of blood samples and analyses of drug concentration\u003c/h3\u003e\n\u003cp\u003eCeftazidime/avibactam was administered as instructed by the physician. At a steady state, blood samples (2 mL) were collected from CVVH filters at 0 (pre-dose), 2, 3, 4, 6, and 8 h post-infusion using heparinized tubes. The samples were centrifuged immediately (3,900 \u0026times; \u003cem\u003eg\u003c/em\u003e, 10 min, 4\u0026deg;C). Post-CVVH samples were collected similarly from the arterial blood\u0026thinsp;\u0026ge;\u0026thinsp;24 h after discontinuation. Plasma concentrations of ceftazidime/avibactam were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).\u003c/p\u003e\n\u003ch3\u003ePK model and statistical methods\u003c/h3\u003e\n\u003cp\u003eThe PK parameters we measured were peak concentration in serum (C\u003csub\u003emax\u003c/sub\u003e), trough concentration in serum (C\u003csub\u003emin\u003c/sub\u003e), terminal elimination half-life (t\u003csub\u003e1/2\u003c/sub\u003e), area under the concentration\u0026ndash;time curve from 0 h to 8 h (AUC\u003csub\u003e0\u0026ndash;8\u003c/sub\u003e), plasma clearance (CL), and steady-state volume of distribution (V\u003csub\u003ess\u003c/sub\u003e). These parameters were calculated from plasma concentrations using Phoenix WinNonlin (a non-compartmental model) and expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Continuous demographic variables were analyzed using SPSS 25.0 (IBM, Armonk, NY, USA), and they are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (interquartile range, IQR). Categorical variables are presented as percentages.\u003c/p\u003e\n\u003ch3\u003eMCS\u003c/h3\u003e\n\u003cp\u003eMCS analyses utilized published European Committee for Antimicrobial Susceptibility Testing (EUCAST) data for MIC distribution (accessed 7 March 2025) for \u003cem\u003eEscherichia coli\u003c/em\u003e, \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e, and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e to evaluate four intravenous dosing regimens for ceftazidime/avibactam [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. These four intravenous dosing regimens were simulated based on the following: (1) the PK/PD characteristics of ceftazidime/avibactam; (2) the prescribing information; (3) clinical guidelines; and (4) real-world dosing experience to evaluate efficacy differences between regimens. The dosing regimens (all at q8h) were 750 mg\u0026thinsp;+\u0026thinsp;187.5 mg; 1000 mg\u0026thinsp;+\u0026thinsp;250 mg; 2000 mg\u0026thinsp;+\u0026thinsp;500 mg; and 3000 mg\u0026thinsp;+\u0026thinsp;750 mg.\u003c/p\u003e\n\u003cp\u003eUsing Crystal Ball 11.1.3.0 (Oracle Corporation, Austin, TX, USA), we undertook 10,000 simulations with PK parameters following a lognormal distribution and PD parameters following a customized distribution (95% confidence intervals). The analysis assessed two PK/PD targets: the standard target of 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;MIC for ceftazidime combined with 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e for avibactam and the intensive target of 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;4\u0026times; MIC for ceftazidime with 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e for avibactam. The probability of target attainment (PTA) and cumulative fraction of response (CFR) were calculated using established PK formulae, with regimens achieving PTA or CFR\u0026thinsp;\u0026ge;\u0026thinsp;90% considered \u0026ldquo;optimal\u0026rdquo; and those with 80% \u0026le; CFR\u0026thinsp;\u0026lt;\u0026thinsp;90% classified as \u0026ldquo;suboptimal\u0026rdquo; dosing regimens.\u003c/p\u003e\n\u003cp\u003eThe target calculation method for \u0026beta;-lactam and \u0026beta;-lactamase inhibitors is as follows,\u003c/p\u003e\n\u003cdiv id=\"Equ1\" class=\"Equation\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e\u003cimg 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\"\u003e\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eThe flowchart of patient screening is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Twenty-nine patients were assessed for eligibility. Seven patients (five men, two women) were enrolled and assessed in this study, and all of them completed the study. The cohort had a mean age of 56.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5 years, a body mass index of 24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8 kg/m\u003csup\u003e2\u003c/sup\u003e, a median CrCl of 24.34 mL/min, and a median eGFR of 28.81 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e. The average duration of CVVH was 21.4 days. The average duration of ICU stay was 64.9 days. Microbiological analyses identified \u003cem\u003eE. coli\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;5), \u003cem\u003eK. pneumoniae\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;2), and \u003cem\u003eP. aeruginosa\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;5), with four patients having polymicrobial infections. The demographics of patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic characteristics of patients (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSex; n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e5 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e2 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e56.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eComorbid conditions (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertensive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e2 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\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\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e1 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of cerebral infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e1 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eScr (\u0026micro;mol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e275.9\u0026thinsp;\u0026plusmn;\u0026thinsp;106.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCrCL (mL/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e24.34 (18.43\u0026ndash;29.84)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eeGFR (mL/min/1.73 m\u0026sup2;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e28.81 (18.76\u0026ndash;30.37)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eBUN (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eALB (g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e32.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTB (\u0026micro;mol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e128.2 (67.9-160.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ePCT (ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e9.44 (2.2-21.25)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eALT (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e45 (23\u0026ndash;63)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAST (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e93.4 (41\u0026ndash;141)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eIsolated microorganisms; n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eP. aeruginosa\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e5 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e5 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eK. pneumoniae\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e2 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTreatment\u0026nbsp;duration\u0026nbsp;of\u0026nbsp;CVVH (days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e21.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAPACHE II score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e20.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSOFA score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e17.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMechanical ventilation (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e7 (100)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eVasoactive Agents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e6 (85.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTreatment\u0026nbsp;duration\u0026nbsp;of Ceftazidime/avibactam (days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e36.9\u0026thinsp;\u0026plusmn;\u0026thinsp;20.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eConcomitant drugs (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTeicoplanin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolymyxin E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (57.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImipenem/cilastatin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVoriconazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\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\u003e2 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAztreonam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eICU length of stay (days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e64.9\u0026thinsp;\u0026plusmn;\u0026thinsp;36.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCVVH parameters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood flow (mL/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e150 (150,160)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEffluent flow rate (mL/kg/h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e29.48\u0026thinsp;\u0026plusmn;\u0026thinsp;4.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eBMI, body mass index; Scr, serum creatinine; CrCL, creatinine clearance; eGFR, estimate glomerular filtration rate; BUN, blood urea nitrogen; ALB, albumin; TB, total bilirubin; PCT, procalcitonin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment; CVVH, continuous veno-venous hemofiltration; \u003cem\u003eP. aeruginosa\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e; \u003cem\u003eE. coli\u003c/em\u003e, \u003cem\u003eEscherichia coli\u003c/em\u003e; \u003cem\u003eK. pneumoniae\u003c/em\u003e, \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e; ICU, intensive care unit.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePK parameters\u003c/h3\u003e\n\u003cp\u003eEighty-four blood samples were collected from seven patients. The blood concentrations of ceftazidime/avibactam were measured by LC-MS/MS. The PK parameters of ceftazidime/avibactam were calculated using a non-compartmental model based on the plasma concentrations of ceftazidime/avibactam (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Comparative analyses of the PK parameters of ceftazidime/avibactam during \u003cem\u003eversus\u003c/em\u003e outside periods of CVVH are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" 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\u003ePharmacokinetic parameters of ceftazidime/avibactam\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\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCeftazidime\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eAvibactam\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDuring CVVH\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOutside CVVH\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDuring CVVH\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOutside CVVH\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e (mg/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e145.7\u0026thinsp;\u0026plusmn;\u0026thinsp;22.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e324\u0026thinsp;\u0026plusmn;\u0026thinsp;38.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29.14\u0026thinsp;\u0026plusmn;\u0026thinsp;5.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e65.17\u0026thinsp;\u0026plusmn;\u0026thinsp;5.53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e (mg/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.03\u0026thinsp;\u0026plusmn;\u0026thinsp;5.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e237.14\u0026thinsp;\u0026plusmn;\u0026thinsp;25.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e47.49\u0026thinsp;\u0026plusmn;\u0026thinsp;4.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003et\u003csub\u003e1/2\u003c/sub\u003e (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.44\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19.91\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.55\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33.08\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;8\u003c/sub\u003e (mg\u0026middot;h/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e823.41\u0026thinsp;\u0026plusmn;\u0026thinsp;100.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2249.93\u0026thinsp;\u0026plusmn;\u0026thinsp;259.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e176.21\u0026thinsp;\u0026plusmn;\u0026thinsp;28.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e459.81\u0026thinsp;\u0026plusmn;\u0026thinsp;30.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCL (L/h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eV\u003csub\u003ess\u003c/sub\u003e (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.49\u0026thinsp;\u0026plusmn;\u0026thinsp;3.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31.85\u0026thinsp;\u0026plusmn;\u0026thinsp;12.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e52.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eCVVH, continuous veno-venous hemofiltration; C\u003csub\u003emax\u003c/sub\u003e, peak concentration; C\u003csub\u003emin\u003c/sub\u003e, trough concentration; t\u003csub\u003e1/2\u003c/sub\u003e, half-life; AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;8\u003c/sub\u003e, area under the plasma concentration-time curve at 0\u0026ndash;8 h; CL, clearance; V\u003csub\u003ess\u003c/sub\u003e, steady-state volume of distribution.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCVVH increased the CL of both drugs significantly (ceftazidime: 2.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29 \u003cem\u003evs\u003c/em\u003e. 0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 L/h; avibactam: 2.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41 \u003cem\u003evs\u003c/em\u003e. 1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08 L/h; both \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). C\u003csub\u003emin\u003c/sub\u003e during CVVH was markedly lower for ceftazidime (66.03\u0026thinsp;\u0026plusmn;\u0026thinsp;5.62 \u003cem\u003evs\u003c/em\u003e. 237.14\u0026thinsp;\u0026plusmn;\u0026thinsp;25.14 mg/L) and avibactam (14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.99 \u003cem\u003evs\u003c/em\u003e. 47.49\u0026thinsp;\u0026plusmn;\u0026thinsp;4.07 mg/L; both \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Similarly, the AUC\u003csub\u003e0\u0026ndash;8\u003c/sub\u003e was reduced significantly during CVVH for ceftazidime (823.41\u0026thinsp;\u0026plusmn;\u0026thinsp;100.2 \u003cem\u003evs\u003c/em\u003e. 2,249.93\u0026thinsp;\u0026plusmn;\u0026thinsp;259.22 mg\u0026middot;h/L) and avibactam (176.21\u0026thinsp;\u0026plusmn;\u0026thinsp;28.34 \u003cem\u003evs\u003c/em\u003e. 459.81\u0026thinsp;\u0026plusmn;\u0026thinsp;30.88 mg\u0026middot;h/L; both \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePTA for patients\u003c/h2\u003e\u003cp\u003eFor the target of 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;MIC (ceftazidime)\u0026thinsp;+\u0026thinsp;100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e (avibactam), during CVVH, all regimens achieved a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026le;\u0026thinsp;8 mg/L. All dosing regimens, except the dosing regimen of 750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h, had a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;=\u0026thinsp;16 mg/L. Only 2000\u0026thinsp;+\u0026thinsp;500 mg q8h maintained a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;=\u0026thinsp;32 mg/L. All dosing regimens had a PTA\u0026thinsp;\u0026lt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026ge;\u0026thinsp;64 mg/L (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Outside periods of CVVH, all regimens achieved a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026le;\u0026thinsp;16 mg/L. The conventional dosing regimen of 2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h had a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% for MIC\u0026thinsp;=\u0026thinsp;32 mg/L. When the MIC rose to 64 mg/L, only 3000\u0026thinsp;+\u0026thinsp;750 mg q8h was effective at MIC\u0026thinsp;=\u0026thinsp;64 mg/L. All dosing regimens had a PTA\u0026thinsp;\u0026lt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026ge;\u0026thinsp;128 mg/L.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFor the intensive target (100%fT\u0026thinsp;\u0026ge;\u0026thinsp;4\u0026times; MIC\u0026thinsp;+\u0026thinsp;100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e), during CVVH, all regimens achieved a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026le;\u0026thinsp;2 mg/L. All regimens except 750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h achieved a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;=\u0026thinsp;4 mg/L. Only 2000\u0026thinsp;+\u0026thinsp;500 mg q8h was effective at MIC\u0026thinsp;=\u0026thinsp;8 mg/L. All dosing regimens had a PTA\u0026thinsp;\u0026lt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026ge;\u0026thinsp;16 mg/L. Outside periods of CVVH, all regimens achieved a PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026le;\u0026thinsp;4 mg/L. The conventional dosing regimen of 2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h had PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;=\u0026thinsp;8 mg/L. Only 3000\u0026thinsp;+\u0026thinsp;750 mg q8h was effective at MIC\u0026thinsp;=\u0026thinsp;16 mg/L. All dosing regimens had PTA\u0026thinsp;\u0026lt;\u0026thinsp;90% at MIC\u0026thinsp;\u0026ge;\u0026thinsp;32 mg/L.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eCFR for patients\u003c/h2\u003e\u003cp\u003eFor the target of 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;MIC\u0026thinsp;+\u0026thinsp;100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e, during and outside periods of CVVH treatment, for \u003cem\u003eP. aeruginosa\u003c/em\u003e, the administration regimens of 2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h and 3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h had a CFR\u0026thinsp;\u0026gt;\u0026thinsp;90%, both of which were optimal, whereas the regimens of 750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h and 1000 mg\u0026thinsp;+\u0026thinsp;250 mg q8h had a CFR between 80% and 90%, both of which were suboptimal regimens (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For \u003cem\u003eE. coli\u003c/em\u003e and \u003cem\u003eK. pneumoniae\u003c/em\u003e, all four dosing regimens were suboptimal. For the intensive target (100%fT\u0026thinsp;\u0026ge;\u0026thinsp;4\u0026times; MIC\u0026thinsp;+\u0026thinsp;100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e), 750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h and 1000 mg\u0026thinsp;+\u0026thinsp;250 mg q8h were not considered to be optimal or suboptimal regimens for all three types of bacteria. We found 2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h and 3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h to be suboptimal regimens for all three types of bacteria outside periods of CVVH and for \u003cem\u003eE. coli\u003c/em\u003e and \u003cem\u003eK. pneumoniae\u003c/em\u003e during CVVH.\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\u003eCFR of the different ceftazidime/avibactam dosing regimens\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\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eTarget value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRegimens\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eDuring CVVH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u003cp\u003eOutside CVVH\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eP. aeruginosa\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eK. pneumoniae\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eP. aeruginosa\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eK. pneumoniae\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e100%fT\u0026thinsp;\u0026ge;\u0026thinsp;MIC\u003c/p\u003e\u003cp\u003e100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e87.86%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.85%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e82.17%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e89.10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e83.28%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.31%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1000 mg\u0026thinsp;+\u0026thinsp;250 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.86%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83.20%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e82.28%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e89.24%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e83.33%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.32%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e93.44%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83.84%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e82.32%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e93.67%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e83.87%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.32%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e84.72%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e82.32%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e97.58%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e84.93%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.32%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e100%fT\u0026thinsp;\u0026ge;\u0026thinsp;4\u0026times; MIC\u003c/p\u003e\u003cp\u003e100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.03%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e75.23%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e75.00%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e76.34%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e77.42%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e77.03%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1000 mg\u0026thinsp;+\u0026thinsp;250 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48.93%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77.72%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e77.58%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e78.38%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e78.61%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e78.47%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54.43%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e80.94%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e81.47%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e82.91%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e81.18%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e81.77%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59.84%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.86%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e82.17%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e89.10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e83.28%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.31%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eCVVH, continuous veno-venous hemofiltration; fT\u0026thinsp;\u0026ge;\u0026thinsp;MIC, time fraction of free drug above the minimum inhibitory concentration; fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT\u003c/sub\u003e, time fraction of free drug above a threshold concentration; \u003cem\u003eP. aeruginosa\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e; \u003cem\u003eE. coli\u003c/em\u003e, \u003cem\u003eEscherichia coli\u003c/em\u003e; \u003cem\u003eK. pneumoniae\u003c/em\u003e, \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs the first systematic PK evaluation of ceftazidime/avibactam in patients suffering from sIAI receiving CVVH, we revealed significant CVVH-mediated alterations in drug CL. Our comparative PK analysis demonstrated substantial differences during and outside CVVH periods. Based on PK/PD theory, different dosing regimens of ceftazidime/avibactam were evaluated using MCS. The calculation of PTA and CFR provided a scientific basis for individualized dosing in patients with sIAI treated with combined CVVH.\u003c/p\u003e\u003cp\u003ePathophysiologic changes and CRRT use in patients with sIAI can affect the PK/PD properties of ceftazidime/avibactam significantly [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In the present study, the median eGFR of patients was 28.81 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e. According to the staging criteria of chronic kidney disease (CKD) (GFR of 15\u0026ndash;29 mL/min is CKD stage 4) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], some patients in our study population had severe renal insufficiency. The efficiency of solute removal by CVVH based on the principle of convection is not limited by molecular weight until the membrane sieving cutoff is reached. The molecular weights of ceftazidime and avibactam are well below the membrane sieving cutoff, so both can be removed efficiently by CVVH. The Vd of a drug is another key factor influencing the CL efficiency of CRRT. Lower Vd values (usually\u0026thinsp;\u0026lt;\u0026thinsp;0.3 L/kg) suggest that the drug is distributed mainly in the intravascular space [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], and such drugs are more likely to be cleared significantly by CRRT. Ceftazidime/avibactam, as a highly hydrophilic antimicrobial drug, has a low Vd (~\u0026thinsp;0.3 L/kg), which determines its relatively high efficiency of CL by convection through CVVH.\u003c/p\u003e\u003cp\u003eCeftazidime/avibactam is cleared substantially by CRRT, particularly at high intensities or with residual renal function [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Wenzler et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] administered ceftazidime/avibactam at 1.25 g q8h for the treatment of a critically ill patient with multidrug-resistant \u003cem\u003eP. aeruginosa\u003c/em\u003e bacteremia undergoing CVVH. The mean CL of CVVH to ceftazidime and avibactam was 1.64 L/h and 1.59 L/h, respectively, accounting for 57.1% and 57.3% of total CL of ceftazidime and avibactam, respectively. Our findings demonstrated higher CL (ceftazidime: 2.46 L/h; avibactam: 2.89 L/h) during CVVH than outside periods of CVVH conditions (0.9 and 1.09 L/h, respectively), which was consistent with exposure levels. However, the CL remained markedly lower than that in healthy individuals (ceftazidime: 10.07 L/h; avibactam: 13.36 L/h) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], likely due to the severe renal impairment in our cohort. This impaired CL may prolong t\u003csub\u003e1/2\u003c/sub\u003e, potentially leading to drug accumulation and increased toxicity. Studies have shown that the use of high-dose regimens in patients outside CVVH treatment periods may increase the risk of developing drug-related renal injury significantly. Therefore, treatment planning for these patients requires particular attention to dose adjustment and therapeutic drug monitoring to balance efficacy and safety.\u003c/p\u003e\u003cp\u003eOptimizing population-based and individualized dosing strategies for ceftazidime/avibactam during CRRT is a clinical challenge [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Often, dosing strategies rely on empirical approaches, lacking systematic evidence for rational individualization. Conventional PK/PD simulations typically employ average PK parameters and single MIC values, failing to account for interpatient variability and differences in pathogen susceptibility. In contrast, MCS integrates population PK variability with MIC distributions to predict PTA, enabling more accurate, individualized regimen optimization [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe targeted ceftazidime 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;MIC combined with avibactam 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e. During CVVH, all four regimens achieved PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% for strains with MIC\u0026thinsp;\u0026le;\u0026thinsp;8 mg/L, indicating that dose adjustment was not required for common susceptible bacteria. At MIC\u0026thinsp;=\u0026thinsp;64 mg/L, all regimens showed PTA\u0026thinsp;\u0026lt;\u0026thinsp;90%. In contrast, outside CVVH periods, the regimen of 3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h achieved PTA\u0026thinsp;\u0026gt;\u0026thinsp;90% at MIC\u0026thinsp;=\u0026thinsp;64 mg/L. This finding suggests that CVVH increased drug CL significantly, thereby hampering maintenance of therapeutic blood concentrations of ceftazidime/avibactam at high MIC values. For such high-MIC-resistant strains, alternative treatment regimens may need to be considered.\u003c/p\u003e\u003cp\u003eFor \u003cem\u003eP. aeruginosa\u003c/em\u003e, CFR\u0026thinsp;\u0026gt;\u0026thinsp;90% was achieved with dosing regimens of 2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h and 3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h, both of which were preferred regimens, significantly better than the regimens of 750 mg\u0026thinsp;+\u0026thinsp;187.5 mg q8h and 1000 mg\u0026thinsp;+\u0026thinsp;250 mg q8h. During CVVH, CFR was, in general, lower compared with that outside CVVH treatment periods. For the target of ceftazidime 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;4\u0026times; MIC\u0026thinsp;+\u0026thinsp;avibactam 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e, the high-dose regimen of 3000 mg\u0026thinsp;+\u0026thinsp;750 mg benefited only a subset of patients with an MIC\u0026thinsp;\u0026le;\u0026thinsp;16 mg/L during CVVH. Consistent with data from other studies, the targets of 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;4\u0026times; MIC and 100%fT\u0026thinsp;\u0026ge;\u0026thinsp;C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e could be achieved only by continuous infusion of higher doses [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. During CVVH, 2000 mg\u0026thinsp;+\u0026thinsp;500 mg q8h and 3000 mg\u0026thinsp;+\u0026thinsp;750 mg q8h were suboptimal regimens for \u003cem\u003eE. coli\u003c/em\u003e and \u003cem\u003eK. pneumoniae\u003c/em\u003e, respectively. However, even with high doses, achievement of intensification targets for \u003cem\u003eP. aeruginosa\u003c/em\u003e remained challenging. In addition, no dosing regimen could be considered as a preferred regimen, and high doses were less important for CFR increase than conventional doses. Moreover, high concentrations of ceftazidime/avibactam may trigger neurotoxicity, including seizures and encephalopathy [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Kang et al. demonstrated superior bactericidal activity against \u003cem\u003eP. aeruginosa\u003c/em\u003e (MIC\u0026thinsp;\u0026gt;\u0026thinsp;16 mg/L) with a two-step infusion regimen (1.25 g over 0.5 h, followed by 1.25 g over 2 h) compared with conventional dosing (2.5 g q8h) while mitigating toxicity risks [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Optimizing the antimicrobial drug regimen for patients on CRRT requires comprehensive consideration of multiple factors. In addition to the physicochemical properties of the drug, it should also include the specific parameter settings of CRRT, residual renal function, the infection site, and the MIC of the pathogen to achieve the optimal balance between efficacy and safety [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study has four main limitations. First, the study cohort comprised only seven patients. This limitation would have affected the reliability of our findings. Also, the limited number of measurements of the blood concentration at six time points may have introduced a bias in CL calculations. Second, due to most patients being oliguric or anuric, the drug concentration in urine was not monitored, thereby impairing assessment of the role of residual renal function upon drug CL. Third, only CVVH mode was examined, leaving the impact of other CRRT modalities unexplored. Fourth, the safety of high-dose regimens was not evaluated. Future research should improve assessment of residual renal function, incorporate multiple CRRT modes, and better evaluate the efficacy\u0026ndash;safety balance of high-dose treatments.\u003c/p\u003e\u003cp\u003eIn conclusion, CVVH enhanced the CL of ceftazidime/avibactam significantly. Plasma concentrations in patients with severe renal impairment remained high compared with those of healthy individuals, thereby necessitating monitoring for potential accumulation. MCS revealed distinct dosing requirements during CVVH as well as outside CVVH periods. Conventional dosing sufficed for low-MIC pathogens, whereas infections with high MICs required intensified regimens. For MICs exceeding critical thresholds, no existing regimen achieved targets. Therefore, individualized dosing incorporating renal function, CRRT modality, and the MIC of the pathogen is critical for optimizing efficacy while minimizing toxicity and drug resistance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that this study is exclusively based on pharmacokinetic and pharmacodynamic analyses, and they are thankful to all staff in the Department of Critical Care Medicine and Clinical Pharmacy at Jinling Hospital for their support in patient management and sample collection. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJianan Ren, Xiuwen Wu and Jiayang Li conceived of the presented idea. Sai Tian and Yong Chen wrote the main manuscript text and prepared figures/tables. Mingjie Qiu and Wenqi Wu carried out the experiment. Liuqing Dou, Jiajie Wang, Li Xu, Zhitao Zhou and Meilin Wu authors contributed to the final version of the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the Key Research and Development Program of Jiangsu Province (BE2022823) and the Navigation Project of Clinical Research (22LCYY-LH4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was approved (2024DZKY-067-02) by the Clinical Research and Ethics Committee of Jinling Hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eDe Corte W, Dhondt A, Vanholder R, De Waele J, Decruyenaere J, Sergoyne V, Vanhalst J, Claus S, Hoste EAJ (2016) Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study. 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Japanese Journal of Infectious Diseases 76 (1):1-6. http://doi.org/10.7883/yoken.JJID.2022.289\u003c/li\u003e\n \u003cli\u003eGatti M, Pascale R, Cojutti PG, Rinaldi M, Ambretti S, Conti M, Tedeschi S, Giannella M, Viale P, Pea F (2023) A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia. 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Blood samples were collected at pre-dose and post-dose (2, 3, 4, 6, and 8 h) during hemodynamic stability. Plasma concentrations were measured, and PK parameters were calculated. Monte Carlo simulations (MCSs) were used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different dosing regimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e CVVH increased the clearance (CL) significantly (ceftazidime: 2.46 ± 0.29 \u003cem\u003evs\u003c/em\u003e. 0.9 ± 0.11 L/h; avibactam: 2.89 ± 0.41 \u003cem\u003evs\u003c/em\u003e. 1.09 ± 0.08 L/h, \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.001). For the target of 100%fT ≥ MIC + 100%fT ≥ C\u003csub\u003eT = 1.0 mg/L\u003c/sub\u003e, during CVVH, PTA \u0026gt; 90% at MIC ≤ 8 mg/L. Outside CVVH, PTA \u0026gt; 90% at MIC ≤ 16 mg/L, and only 3000 mg + 750 mg q8h achieved PTA \u0026gt; 90% at MIC = 64 mg/L. For the target of 100%fT ≥ 4× MIC (ceftazidime) + 100%fT ≥ C\u003csub\u003eT = 4.0 mg/L\u003c/sub\u003e (avibactam), during CVVH, PTA \u0026gt; 90% at MIC ≤ 2 mg/L. Outside CVVH, PTA \u0026gt; 90% at MIC ≤ 4 mg/L, and only 3000 mg + 750 mg q8h achieved PTA \u0026gt; 90% at MIC = 16 mg/L. No regimen met the optimal dosing criteria for this target.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e CVVH enhanced the CL significantly. Dosing should be “individualized” based on the MIC and patient-specific factors.\u003c/p\u003e","manuscriptTitle":"PK/PD study of ceftazidime/avibactam in patients with severe intra-abdominal infections treated by continuous veno–venous hemofiltration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-19 13:39:23","doi":"10.21203/rs.3.rs-7319086/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-28T13:33:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-26T11:00:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T10:43:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"287864200616789768029530448286652737065","date":"2025-08-12T16:20:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42045773430488015932366994814069879569","date":"2025-08-12T09:26:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-11T14:07:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-08T01:12:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-08T01:11:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","date":"2025-08-07T13:00:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcm","sideBox":"Learn more about [European Journal of Clinical Microbiology \u0026 Infectious Diseases](https://www.springer.com/journal/10096)","snPcode":"10096","submissionUrl":"https://submission.nature.com/new-submission/10096/3","title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a42afdaa-96f4-477c-be42-e6a550720c99","owner":[],"postedDate":"August 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T15:59:37+00:00","versionOfRecord":{"articleIdentity":"rs-7319086","link":"https://doi.org/10.1007/s10096-025-05343-x","journal":{"identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isVorOnly":false,"title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases"},"publishedOn":"2025-11-14 15:56:58","publishedOnDateReadable":"November 14th, 2025"},"versionCreatedAt":"2025-08-19 13:39:23","video":"","vorDoi":"10.1007/s10096-025-05343-x","vorDoiUrl":"https://doi.org/10.1007/s10096-025-05343-x","workflowStages":[]},"version":"v1","identity":"rs-7319086","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7319086","identity":"rs-7319086","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}