Evaluation of Standard Dosing for Selected Broad Spectrum Hydrophilic Antibiotics in Critically Ill Patients with Augmented Renal Clearance: An Observational Study


 Background: Inappropriate antibiotics dosing in critically ill patients with augmented renal clearance (ARC) may be associated with pathogens resistance and worse outcomes. Unfortunately, studies regarding the relationship between ARC and clinical outcomes in patients treated with antibiotics medication are rare. The study aims to evaluate the efficacy and clinical outcomes of selected broad spectrum hydrophilic antibiotics (Meropenem, Imipinem, Piperacillin/Tazobactam) in augmented renal function critically ill patients with confirmed infections.Methods: A retrospective cohort study in critically ill patients who were admitted to intensive care units (ICUs) at King Abdulaziz Medical City (KAMC)-Riyadh and received broad-spectrum Hydrophilic antibiotics (Meropenem, Imipenem, or Piperacillin/Tazobactam) with confirmed infection. All the patients who met our inclusion criteria during the study period (01/01/2018 – 31/12/2019) were included. Eligible patients have been divided into two groups (augmented renal clearance (ARC) Vs. Non-ARC) according to the estimated creatinine clearance (CrCl) to assess pathogen eradication at 10-14 days. Results: A total of 2682 patients were screened; 133 patients were included in the study. The eradication of pathogen at 10-14 days in ARC group was non-inferior to non-ARC group (OR 1.08; 95% CI, 0.41–2.78 p = 0.88). The Resistance (OR 0.78; 95% CI, 0.25–2.40 p = 0.66), and Persistence after 3 days (OR 0.88; 95% CI, 0.35–2.18 p = 0.78) were not significantly different between the groups. In other words, patients with ARC have the same rate of resistance and persistence of pathogen after three days. There was no difference in the 30-day mortality between the two groups (OR 0.22; 95% CI, 0.04–1.40 p = 0.11). Also, there was no difference in the ICU length of stay (LOS) nor in hospital LOS between the two groups (22.0 days vs. 17.5 days, p = 0.37), and (51.0 days vs. 30.0 days, p = 0.07) respectively. Conclusion: Using standard dosing of hydrophilic broad-spectrum antibiotics in ARC patients was not inferior to non-ARC patients in terms of the pathogen eradication, resistance, and persistence. Further randomized clinical and interventional studies are required to confirm our findings.

Many of the studies published about ARC were focused on the antimicrobial therapy because it might lead to the emergence of drug resistance (6). Beta-lactams antibiotics are a time-dependent antibacterial activity that will be highly eliminated by the kidney and decrease the exposure time of the drug. Several studies in this eld have reported beta-lactam treatment failures based on sub-therapeutic serum level attainment when using standard dosing regimens in patients with ARC (6, 10). A Retrospective observational study conducted by Drust et al. 2011 in ICU patients with CrCl greater than 120mL/min by measuring meropenem plasma concentrations found that 67% of patients required higher doses of meropenem than standard doses to achieve therapeutic plasma concentration (11). Moreover, Carlier et al. 2013, conducted a prospective observational study in the ICU population, found that high creatinine clearance is an independent predictor for not achieving target concentrations levels of meropenem and piperacillin/tazobactam (12). Another prospective observational study conducted by Huttner et al. 2015 in ICU patients with ARC found a correlation with ARC and undetectable antimicrobials concentrations without signi cant clinical failure (13).
Inappropriate antibiotics dosing in critically ill patients with ARC may be associated with pathogens resistance as well as worse outcomes. Unfortunately, studies regard the relationship between ARC and clinical outcomes in patients treated with antibiotics medication are scarce. Our study will evaluate the e cacy as well the clinical outcomes of selected broad spectrum hydrophilic antibiotics (Meropenem, Imipinem, Piperacillin/Tazobactam) in augmented renal function critically ill patients with con rmed infections.

Study design
A retrospective cohort study in critically ill patients who received standard dosing of selected broadspectrum Hydrophilic antibiotics (Meropenem, Imipenem, or Piperacillin/Tazobactam) for con rmed infection (Bacteremia, pneumonia, and Urinary Tract Infection (UTI)). The diagnosis of infection was con rmed by lab culture depend on the site of infection. All the patients who met our inclusion criteria during the study period (01/01/2018 -31/12/2019) were included. Eligible patients have been divided into two groups (augmented renal clearance (ARC) Vs. Non-ARC) according to the estimated creatinine clearance (CrCl) (By Cockroft equation). Patients were followed during their ICU Length of stay (LOS) until ICU discharge after improving or in-hospital death, whichever occurred rst.

Participants
Patients were enrolled in the study if they were critically ill admitted to ICU, aged 18-65 years, had a con rmed infection (Bacteremia, pneumonia, and Urinary Tract Infection (UTI)) and received standard dosing of broad-spectrum Hydrophilic antibiotics (Meropenem, Imipenem or Piperacillin/Tazobactam) for these infections. Patients were excluded if the Weight < 40 kg or BMI <16 Kg/m2, on any dialysis, no-code status, previous multi-drug resistance within three months of admission, if the patient received any antibiotics during 90 days before admission or previous admission within 90 days if the rst culture for the de ned infection resistance to selected antibiotics, an inappropriate dose of antibiotics for selected indication, early dose adjustment (less than three days), duration of antibiotics less than three days, uncontrolled source of infection.

Setting
This study was conducted in the adult medical, surgical, trauma, and burn ICUs at KAMC, a tertiary-care academic referral hospital in Riyadh, Saudi Arabia. The ICU admits medical, surgical, trauma, burn patients and operates as closed units with 71 ICU beds capacity with 24/7 onsite coverage by critical care board-certi ed intensivists (14).

Ethics approval and consent to participate
The study was approved by the Ministry of National Guard Health Affairs Institutional Review Board, Riyadh, Saudi Arabia (Study Number: RC20/012/R). Participants' con dentiality was strictly observed throughout the study using the anonymous unique serial number for each subject and restricting data only to the investigators. Informed consent was not required due to the research's method as per the governmental and local research center's policy.

Data collection
We collected the following information, demographic data (Table 1, Supplemental), Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, comorbidities, vital signs, laboratory tests within 24 hours of ICU admission, and CrCl (By Cockroft equation) at day #1 AND #3, Antibiotics, baseline cultures, follow-up cultures, evaluation of pathogen resistance, persistence after three days and eradication at 10-14 days. Additionally, ICU LOS, hospital LOS, and ICU mortality were collected and followed. Patients were followed during ICU LOS until ICU discharge after improving, or in-hospital death, whichever occurred rst.

Outcomes
The aim of this study is to evaluate the e cacy and clinical outcomes of using standard dosing of selected broad spectrum antibiotics. The primary endpoint was to assess the eradication of pathogen at 10-14 days. The secondary endpoints include the development of resistance and persistence pathogen growth after three days, ICU mortality within 30-day, ICU LOS, and hospital LOS.
De nition (s) The ARC de ned as an estimated CrCl ≥130 ml/min and Non-ARC as an estimated CrCl 50-129 ml/min. b. The average of estimated CrCl depend on day 0 and day 3 from admission. If Body Mass Index (BMI)> 30 will use Adjusted Body weight (adjBW) and Adjusted Creatinine Clearance (AdjCrCl), BMI<30 will use Actual Body weight (ActBW) and actual CrCl.
c. Infection was identi ed through the blood, urine, and/or respiratory cultures. The bacterial growth considered signi cant if the growth is ≥ of 100,000 CFU/ml in sputum or endotracheal aspiration shows; bronchoalveolar lavage (BAL) shows growth ≥of 10,000 CFU of single organism/ml for protected specimen brushes (PSBs), and ≥100,000 CFU of single organism/ml for BAL uid. Additionally, urinary cultures were considered signi cant if showing a growth of ≥100,000 CFU/ml of no more than two species of microorganisms. Cultures were excluded if the laboratory reported them as a "contaminant sample" (15 Table 2).

Discussion
Our study is a single-center retrospective cohort of critically ill patients admitted to different ICUs with con rmed infections. It aims to evaluate the e cacy and the association between augmented renal function (ARC) and various clinical outcomes of selected broad spectrum hydrophilic antibiotics (Meropenem, Imipenem, Piperacillin/Tazobactam). Patients with ARC were younger and mainly admitted with a traumatic injury which is a common risk factor for ARC (4,5). In our cohort, there was no signi cant difference in terms of infection distribution and the types of pathogens. However, there was a signi cant difference in terms of the prescribed beta-lactam antibiotics between both groups; Piperacillin/Tazobactam was the most administered antibiotics (ARC vs. non-ARC, 36 (54.5%) vs. 32 (47.8%)) (13).
The main nding of eradicating pathogen at 10-14 days by utilizing standard dosing of broad-spectrum hydrophilic antibiotics in the ARC group was non-inferior to the non-ARC group with a p-value of (p=0.88) after adjusting for possible confounders. Several studies have addressed the link between ARC treatment failure based on antibiotics serum level measurements without assessing pathogen eradication (6, 7,8,9,10). In contrast, in our cohort we identi ed the treatment failure based on various clinical factors such as the eradication and the persistence of the pathogen. Our nding agrees with the results of one retrospective cohort study, where patients with ARC have a subthreshold beta-lactam antibiotics concentration that was not associated with clinical failure. However, this study was limited by MIC testing, patient heterogeneity, and an estimated Crcl calculation instead of measurement (13).
Additionally, we assessed the resistance after three days of using standard antibiotics dosing and found no signi cant difference among the groups with a p-value of (p = 0.66). Clinical failure could be identi ed by the persistence and resistance of the pathogen after three days, which all were not statistically different in our cohort. In contrary, a prospective observational study found that 27% of patients with ARC (CrCl > 130 mL/min/1.73 m2) had a therapeutic failure more often than non-ARC patients (13%) (p = 0.04) (18). However, the external validity of our outcome could be limited due to the small sample size in our study.
ARC group was similar in infection persistence rate after three days compared to non-ARC (p = 0.78). The association between ARC and infection persistence rate was not clearly assessed in previous studies. A single-center prospective study was conducted in the Surgical and Trauma ICU to assess the rate of therapeutic failure by evaluating the impaired clinical response, which is de ned as persistent or recurrent clinical and biological symptoms of the initial infection. This study showed that within the rst three days of antibiotics therapy, a mean CrCl value ≥of 170 mL/min was not associated with low antibiotic exposure and did not lead to therapeutic failure (19). Similarly, we de ned treatment failure by infection persistence after three days and found no signi cant difference between the two groups. The negative impact of ARC related to decreasing the antibiotic concentration and its correlation with infection persistence needs to be further investigated in critically ill patients.
There is an increasing concern about the therapeutic failure due to ARC and its association with prolonged ICU length of stay and mortality. We have investigated the effect of ARC on ICU-related outcomes and found no signi cant differences in the ICU mortality rate as well as ICU length of stay. Our nding agrees with the results of a sub-study driven from a large clinical trial that assessed ARC's in uence determined by creatinine clearance measurement on the ICU-related clinical outcomes. Similarly, this study has found no signi cant difference in ICU-free days and 90-day mortality with p values of 0.89 and 0.33, respectively (20)(21). The presumed ARC negative impact on clinical outcomes due to lower antibiotic exposure was not evident in our study and other studies (120). This point could be justi ed that in ARC patients, the low antibiotics exposure is not only the main driving factor for negative outcomes but also other factors such as the severity of illness and organ dysfunction.
Our study might have strength points to address, such as the clear de nition of ARC and the speci c inclusion criteria and our adjustment for possible confounders and including several types of ICU patients. However, our conclusion might have several limitations. First, the study's retrospective nature, data extracted from a single-center, and the small sample size could limit the study's external validity. Second, the exact MIC value was not reported, and the unavailability of antibiotics serum concentration measurements. Lastly, we utilized an estimated CrCl by Cockcroft-Gault method due to the lack of 24hrs CrCl measurements, to overcome the estimated CrCl shortcomings, we calculated the average of estimated CrCl depend on day zero and three from admission taking into consideration the BMI.

Conclusion
Using standard dosing of hydrophilic broad-spectrum antibiotics in ARC patients was not inferior to non-ARC patients in terms of pathogen eradication, resistance, and persistence. Further randomized clinical and interventional studies are required to con rm our ndings.