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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 2  |  Page : 43-49

Evaluation of standard dosing for selected broad-spectrum Hydrophilic antibiotics in critically ill patients with Augmented renal clearance: An Observational Study


1 Department of Pharmaceutical Care, King Abdulaziz Medical City, Riyadh, Saudi Arabia
2 Department of Pharmaceutical Care, King Abdulaziz Medical City; Department of Pharmaceutical Care, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center; Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
3 Department of Pharmaceutical Care, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
4 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
5 Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

Date of Submission15-Oct-2021
Date of Decision22-Nov-2021
Date of Acceptance19-Dec-2021
Date of Web Publication30-Sep-2022

Correspondence Address:
Khalid Al Sulaiman
Abdulaziz Medical City (KAMC) - Ministry of National Guard Health Affairs (MNGHA), King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, 11426 Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sccj.sccj_26_21

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  Abstract 


Background: Inappropriate antibiotic 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 are scarce. This study aims to evaluate selected broad-spectrum hydrophilic antibiotics' effectiveness and clinical outcomes in ARC critically ill patients with confirmed infections. Methods: A retrospective a retrospective cohort study in adult critically ill patients who were admitted to intensive care units at King Abdulaziz Medical City, Riyadh, and received standard dosing of selected broad-spectrum hydrophilic antibiotics (meropenem, imipenem, or piperacillin/tazobactam) with confirmed infection. All the patients who met our eligibility criteria during the study period (January 1, 2018, to December 31, 2019) were included. According to the calculated creatinine clearance using the Cockcroft-Gault equation, eligible patients had been classified into two groups: ARC versus non-ARC. The primary outcome was to assess pathogen eradication at 10–14 days; other outcomes were considered secondary. Multivariate logistic and generalized linear regression analyses were used. We considered P < 0.05 statistically significant. Results: A total of 133 patients were included in the study; 66 patients had ARC. The distribution of infections and types of pathogens between the groups were similar. The pathogen eradication at 10–14 days was similar between the two groups (odds ratio [OR] 1.08; 95% confidence interval [CI], 0.41–2.78; P = 0.88). Moreover, the odds of resistance development and persistence after three days were not significantly different between the two groups ([OR 0.78; 95% CI, 0.25–2.40; P = 0.66] and [OR 0.88; 95% CI, 0.35–2.18; P = 0.78], respectively). Conclusion: In terms of pathogen eradication, resistance, and persistence, ARC patients and non-ARC patients responded similarly to conventional doses of hydrophilic broad-spectrum antibiotics. To confirm our findings, further randomized controlled clinical trials are needed.

Keywords: Augmented renal clearance, confirmed infections, critically ill, eradication, hydrophilic antibiotics, imipenem, meropenem, persistence, piperacillin/tazobactam, resistance


How to cite this article:
Almutairi M, Sulaiman KA, Enazi SA, Vishwakarma R, Aljuhani O. Evaluation of standard dosing for selected broad-spectrum Hydrophilic antibiotics in critically ill patients with Augmented renal clearance: An Observational Study. Saudi Crit Care J 2022;6:43-9

How to cite this URL:
Almutairi M, Sulaiman KA, Enazi SA, Vishwakarma R, Aljuhani O. Evaluation of standard dosing for selected broad-spectrum Hydrophilic antibiotics in critically ill patients with Augmented renal clearance: An Observational Study. Saudi Crit Care J [serial online] 2022 [cited 2022 Dec 6];6:43-9. Available from: https://www.sccj-sa.org/text.asp?2022/6/2/43/357645




  Introduction Top


Augmented renal clearance (ARC) is defined by creatinine clearance (CrCl) value ranging from more than 120 ml/min to more than 150 ml/min using the Cockcroft-Gault (CG) formula.[1] Patients younger than 50 years, male gender, and who had a recent history of trauma, subarachnoid hemorrhage, burns, or lower critical illness severity scores (e.g., sequential organ failure assessment score [SOFA], Acute Physiology and Chronic Health Evaluation [APACHE II]) were all found to have a higher risk of developing ARC, i.e., 20%–65%.[2],[3] ARC might lead to an increase in the rate of renally eliminated medications.[1] Therefore, standard doses of some antimicrobials may not be sufficient, and a higher dose is needed in selected patients with ARC.[4],[5],[6],[7]

Several studies on ARC that was published focused on antimicrobial therapy because it could lead to drug resistance. Beta-lactam antibiotics have a time-dependent antibacterial effect and are significantly removed by the kidney, reducing the drug's exposure duration. Numerous studies in this field have reported beta-lactam treatment failures based on subtherapeutic serum level attainment when using standard dosing regimens in patients with ARC.[7],[8] Tröger et al., 2012 observed that 67% of intensive care unit (ICU) patients with CrCl >120 ml/min required higher meropenem doses than normal doses to achieve therapeutic plasma concentration.[9] Furthermore, in a prospective observational study in the ICU population, Carlier et al. found that high CrCl is an independent predictor of not achieving therapeutic concentrations of meropenem and piperacillin/tazobactam.[10] Huttner et al. published a prospective observational study in 2015 on ICU patients with ARC that demonstrated a correlation between ARC and undetectable antimicrobials concentrations without significant clinical failure.[11]

Inappropriate antibiotic dosing in critically ill patients with ARC has been linked with pathogens' resistance and poor outcomes. Few studies address the relationship between ARC and clinical outcomes in antibiotic-treated patients. Our study will evaluate the effectiveness as well the clinical outcomes of standard dosing for selected broad-spectrum hydrophilic antibiotics (meropenem, imipenem, piperacillin/tazobactam) in ARC critically ill patients with confirmed infections.


  Methods Top


Study design

A retrospective cohort study in critically ill patients who received standard dosing of selected broad-spectrum hydrophilic antibiotics (Meropenem, Imipenem, or Piperacillin/Tazobactam) for confirmed infection (Bacteremia, pneumonia, and Urinary Tract Infection (UTI)). The diagnosis of infection was confirmed by laboratory culture depending on the site of infection. All the patients who met our inclusion criteria during the study period (January 1, 2018, to December 31, 2019) were included. Eligible patients have been classified into two groups (ARC vs. non-ARC) according to the calculated CrCl using CG formula. All patients were observed until they were discharged from the hospital or died during their stay, whichever occurred first.

Participants

Patients aged 18–65 years were enrolled in the study if they admitted to the ICUs with confirmed infection (bacteremia, pneumonia, and UTI) and received standard dosing of selected broad-spectrum hydrophilic antibiotics (meropenem, imipenem, or piperacillin/tazobactam) according to the type of infection. Patients were excluded if they had uncontrolled source of infection, history of (multi-drug resistance or antibiotics use within three months before admission). Patients who were underweight (weight<40 kg or body mass index [BMI] <16 kg/m2), patient with CrCl <50 ml/min or on dialysis, or designated a “Do-Not-Resuscitate” status were excluded. Moreover, patients with an initial culture resistant to selected antibiotics, using an inappropriate dose of antibiotics for selected indication, early dose adjustment (<3 days), or using antibiotics for less than three days were excluded [Figure 1].
Figure 1: Eligibility criteria flowchart

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Setting

This study was conducted in the adult medical, surgical, trauma, and burn ICUs at King Abdulaziz Medical City, a tertiary care academic referral hospital in Riyadh, Saudi Arabia. The ICUs operate as closed units with 24/7 onsite coverage by critical care board-certified intensivists and clinical pharmacists.[12]

Ethics approval and consent to participate

The study was approved by King Abdullah International Medical Research Center Institutional Review Board, Riyadh, Saudi Arabia (study number: RC20/012/R). Participants' confidentiality 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, comorbidities, vital signs, laboratory tests, and severity scores (i.e., APACHE II and SOFA) within 24 h of ICU admission. In addition, CrCl using the Cockcroft equation on day 0 and 3 was calculated and recorded. Moreover, antibiotics, baseline cultures, follow-up cultures, evaluation of pathogen resistance, persistence after three days, and eradication at 10–14 days were evaluated and documented.

Outcomes

This study evaluates the effectiveness and clinical outcomes of standard dosing of selected broad-spectrum antibiotics in critically ill patients with ARC. The primary end point was to assess the eradication of pathogens at 10–14 days. At the same time, secondary end points include persistence of pathogen growth after three days of antibiotic initiation, development of resistant pathogens, 30-day mortality, ICU length of stay (LOS), and hospital LOS.

Definition(s)

  1. ARC is defined as an estimated CrCl ≥130 ml/min, while non-ARC has an estimated CrCl of 50–129 ml/min using the CG equation


  2. Estimated CrCl by CG method:


    1. CrCl (male) = ([140 − age (years)] × weight [in kg])/(serum creatinine (SrCr) [mg/dL] × 72)
    2. CrCl (female) = CrCl (male) × 0.85


  3. The average of estimated CrCl is determined by the days 0 and 3 following admission. If BMI >30, adjusted body weight and CrCl are utilized; if BMI <30, actual body weight and CrCl are used
  4. Infection was identified through the blood, urine, and/or respiratory cultures. The bacterial growth in respiratory cultures was considered significant if the growth is ≥100,000 CFU/ml in the sputum or endotracheal aspiration shows; bronchoalveolar lavage (BAL) shows growth of ≥10,000 CFU of single organism/ml for protected specimen brushes and ≥100,000 CFU of single organism/ml for BAL fluid. In addition, urinary cultures were considered significant if they showed 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”[13]
  5. Resistant organisms were defined as the nonsusceptibility to at least three or more antimicrobial agents. Susceptibility of microorganisms created using documents and breakpoints based on Clinical Laboratory Standards Institute[14]
  6. Persistence organisms were defined as the presence of the same pathogen in the repeated culture after 3 days[15]
  7. Standard dosing of antibiotics in Lexicomp® depends on microorganism and type of infection:


  1. Meropenem

    Pneumonia, bacteremia, and UTI: 1 g every 8 h.
  2. Imipenem

    Pneumonia, bacteremia, and UTI: 500 mg every 6 h
  3. Piperacillin/tazobactam


  1. Pneumonia infection: 4.5 g every 6 h
  2. Bacteremia infection: 4.5 g every 6 h
  3. UTI: 3.375 g every 6 h if Pseudomonas 4.5 g every 6 h.


Data management and statistical analysis

We summarized categorical variables as numbers (percentage) and continuous variables as mean with standard deviation. The normality assumptions were assessed for all numerical variables using statistical tests (i.e., Shapiro–Wilk test) and graphical representation (i.e., histograms and Q–Q plots). We compared categorical variables using the Chi-square or Fisher's exact test, normally distributed numerical variables with the t-test, and other non-normally distributed variables with the Mann–Whitney U-test. Baseline characteristics, baseline severity, and outcome variables were compared between the two groups. No imputation was made for missing data as the cohort of patients in our study was not derived from random selection.

Multivariate logistic and generalized linear regression analyses were used based on the patient's gender and mean body weight based on the BMI to determine the relationship between the two groups and the different outcomes considered in this study. We considered a P < 0.05 statistically significant and used SAS version 9.4 (SAS Institute Inc. 2013. SAS® 9.4 Statements: Reference. Cary, NC: SAS Institute Inc.) for all statistical analyses.


  Results Top


Demographic and clinical characteristics

Among 2682 critically ill patients screened, 133 were included in the study. Among them, 66 patients have ARC [Figure 1]. Patient characteristics and demographic data are described in [Table 1]. Most patients were men (83.5%), and the mean age was 42.2 ± 14.7 years in the whole cohort. The mean CrCl based on BMI (day 0 and 3) is 161.7 (±27.22) and 97.1 (±19.44) for the ARC and non-ARC groups, respectively. The most common comorbidities were diabetes mellitus (17.3%) and hypertension (23.3%); they were significantly different between the two groups [Table 1].
Table 1: Baseline characteristics

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Patients with ARC group were more traumatic, neuro, and burn patients (34 [51.5%], 11 [16.7%] and 9 [13.6%], respectively, P = 0.0003). The baseline severity scores (i.e., APACHE II and SOFA), Glasgow coma score, lactic acid, platelet count, and PaO2/FiO2 ratio within 24 h of ICU admission were not significantly different between the two groups. The median APACHE II score was 15, while the median SOFA score was 7 in both groups. About 87.2% of patients needed mechanical ventilation within 24 h of ICU admission [Table 1].

The most common antibiotic administered was piperacillin/tazobactam (51.1%), followed by meropenem (39.1%) and imipenem (9.8%). The distribution of infections and pathogens between the groups was similar, and there were no differences [Table 2].
Table 2: Infections and antibiotics distribution

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Primary endpoint

In crude analysis, the pathogen eradication at 10–14 days was similar between the two groups (72.7% vs. 71.6%, P = 0.89). The differences between the two groups were not statistically significant using multivariate logistic regression analyses (odds ratio [OR] 1.08; 95% confidence interval [CI], 0.41–2.78, P = 0.88) [Table 3]a.
Table 3

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Secondary end-points

The odds of development resistance after three days of antibiotic initiation and persistence of pathogen were similar between the two groups (OR 0.78; 95% CI, 0.25–2.40, P = 0.66 and OR 0.88; 95% CI, 0.35–2.18, P = 0.78, respectively) [Table 3]a.

The 30-day mortality was 4.5% (n = 3) and 13.4% (n = 9), P = 0.07 in ARC and non-ARC groups, respectively. Moreover, it was not significantly different between the groups after adjusting for the patient's gender and mean weight (OR 0.22; 95% CI, 0.04–1.40, P = 0.11) [Table 3a]. In addition, there were no differences in the ICU LOS (22.0 vs. 17.5 days, P = 0.37) and hospital LOS (51.0 vs. 30.0 days, P = 0.07) [Table 3]b.


  Discussion Top


Our study is a single-center retrospective cohort of critically ill patients admitted to different ICUs with confirmed infections. It aims to evaluate the effectiveness and the association between ARC and various clinical outcomes of selected broad-spectrum hydrophilic antibiotics (meropenem, imipenem, and piperacillin/tazobactam). In our cohort, patients with ARC were younger and had a traumatic injury, a common risk factor for the ARC.[4],[5] Regarding infection distribution and pathogen types, there were no significant differences in our cohort. However, there was a significant difference in the frequency of beta-lactam antibiotics prescribed between the two groups; piperacillin/tazobactam was the most commonly prescribed antibiotic (ARC vs. non-ARC, 36 [54.5%] vs. 32 [47.8%]).[11]

After adjusting for possible confounding, the main finding of eradicating pathogen in the ARC group after 10–14 days using standard dosing of broad-spectrum hydrophilic antibiotics was noninferior to the non-ARC group, with a P = 0.88. Several studies have examined the relationship between ARC treatment failure and antibiotic serum levels without considering pathogen eradication.[4],[5],[6],[7],[8] In contrast, we identified treatment failure in our cohort based on various clinical factors such as pathogen eradication and persistence. Our findings are consistent with one retrospective cohort study, which found that patients with ARC have a subthreshold beta-lactam antibiotic concentration that was not associated with clinical failure. Their investigation, like ours, was limited by Minimum Inhibitory concentration (MIC) testing, patient heterogeneity, and an estimated CrCl calculation instead of actual measurement.[11]

In addition, we assessed the resistance after three days of using standard antibiotics dosing and found no significant difference among the groups with a P = 0.66. Clinical failure could be identified by the persistence and resistance of the pathogen after three days, which all were not statistically different in our cohort. On the 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).[16] 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). Previous studies did not assess the association between ARC and infection persistence rate. 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 defined as persistent or recurrent clinical and biological symptoms of the initial infection. This study showed that within the first three days of antibiotic therapy, a mean CrCl value ≥170 mL/min was associated with low antibiotic exposure and did not lead to therapeutic failure.[17] Similarly, we defined treatment failure by infection persistence after three days and found no significant difference between the two groups. The negative impact of ARC on decreasing 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 significant differences in the 30-day mortality rate as well as ICU length of stay. Our findings are consistent with those of a sub-study derived from a larger clinical trial that evaluated the impact of ARC as measured by CrCl on ICU-related clinical outcomes. Similarly, this study has found no significant difference in ICU-free days and 90-day mortality, with P values of 0.89 and 0.33, respectively.[18],[19] The presumed ARC negative impact on clinical outcomes due to lower antibiotic exposure was not evident in our study and other previous reports. This finding could be supported by the fact that in ARC patients, insufficient antibiotic exposure is not the only contributing factor to poor outcomes but also other determinants such as illness severity and organ failure.

Some strength in our study needs to be highlighted, such as the explicit definition of ARC and the specific inclusion criteria, as well as our adjustment for possible confounders and the inclusion of a diversity of ICU patients. However, our conclusion might have several limitations. First, the study's retrospective nature, data extracted from a single center, patient heterogeneity, and the small sample size could limit the study's external validity. Second, the unavailability of the exact measurements for Minimal Inhibitory Concentration (MIC) values and antibiotics serum concentration monitoring might limit the applicability of our findings. Finally, we utilized an estimated CrCl by CG method due to the lack of 24 hours CrCl measurements. Therefore, this study's findings should be interpreted cautiously. Further well-designed studies with a larger sample size are required to confirm our findings.


  Conclusion Top


In terms of pathogen eradication, resistance, and persistence, ARC patients and non-ARC patients responded similarly to conventional doses of hydrophilic broad-spectrum antibiotics. To confirm our findings, further randomized controlled clinical trials are needed.

Authors' contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Consent for publication

Not applicable.

Acknowledgments

We would like to acknowledge the investigators in the Saudi Critical Care Pharmacy Research (SCAPE) platform who participated in this project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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