Introduction

Augmented renal Clearance (ARC) refers to the increase in renal elimination of circulating solutes and medicines compared to the normal range and is typically defined as creatinine clearance CrCl of more than 130 ml/min [1]. However, In respective literature, there is no agreed-upon cutoff for CrCl levels over which a patient is precisely diagnosed with ARC, nor is there a staging system for individuals with CrCl levels greater than 150 ml/min/1.73 m² or even 200 ml/min/1.73 m², if compared to renal impairment stages [2].

While not fully understood, this phenomenon could account for a variety of therapeutic failures for renally cleared medicines, primarily because ARC often goes unnoticed until practitioners actively monitor for its occurrence [3], adding the shortage of reliable information and guidelines regarding the dosage regimen adjustments in patients with augmented renal function, which mainly causes expedited elimination, wind-up in subtherapeutic levels and suboptimal outcomes and even treatment failure in some cases [4–7]_.

Furthermore, reports of ARC in children have been made; it is not limited to adulthood [8, 9]. Conferring to recent publications, ARC is a significant phenomenon with explicit criteria for ICU patients in adults and children [10].

The ARC state influences the bioavailability and clearance of anticoagulants, antiepileptics, β-lactams, and vancomycin [5, 11–13]. For instance, the consequence of ARC on pharmacokinetic and pharmacodynamic exposure is particularly pertinent for β-lactams antibiotics owing to their time-dependent PK/PD property and short half-life [5]. Principally, standard dosage regimens are doubtful and incompetent in keeping free antibiotic blood concentrations above the minimum inhibitory concentration in the presence of ARC, as they are time-dependent antibiotics, and the minimum required MIC differs by class. Moreover, other antibiotics, such as vancomycin, necessitate therapeutic drug monitoring to maximize clinical effectiveness and lower the risk of nephrotoxicity [14]. Vancomycin trough concentrations of 15 to 20 mg/L were traditionally thought to be an ideal surrogate for the therapeutic AUC/MIC of 400 against Methicillin-Resistant Staphylococcus Aureus (MRSA) infections with a maximum MIC of 1 mg/L and were acceptable for customizing dosing regimens [15]. The effects of ARC on vancomycin have been well documented over the past ten years because of its kidney elimination and required monitoring. Data reinforces that ARC increases vancomycin clearance and decreases the likelihood of reaching a therapeutic trough, potentially jeopardizing infected patients’ lives [12]. Hence, Ignorance of healthcare providers about ARC and its related risk factors can seriously impact the patients’ outcomes. Afterwards, this study aims to evaluate clinical pharmacists and physicians’ knowledge about risk factors associated with ARC and antibiotic regimen modification required in ARC patients, as well as their attitudes toward ARC workshops and guidelines applications in Al-Ain in UAE.

Methods

Results

Demographic characteristics of the study population

The total number of participants involved in the study was 92, including physicians under different professional titles and clinical pharmacists. About 55% were under 35 years old. More than half of the participants, 67.4%, are female Table 1. Fig 1 illustrates the sources of information about Augmented Renal Clearance (ARC). Evidence-based clinical resources accounted for 41.3% of the sources, while hospital guidelines accounted for 29.3%.

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Fig 1. Participants’ source of information about ARC.

ARC; augmented renal clearance, CME; continuing medical education.

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Table 1. Demographic data of the participants.

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Physicians and clinical pharmacists’ knowledge about ARC

Approximately more than half, 57(62.0%) of the participants affirmed that they are aware of ARC, while 35(38.0%) stated that they are unaware of this condition. A scale of nine questions was used to assess the participant’s knowledge. Table 2 shows the items used to measure the knowledge score of the participants about ARC. β-lactams was the most identified antibiotic for the medications which could be affected by the ARC by 51.1%. Almost 12 participants did not recognize any risk factors, while only two could recognize all of them Table 2.

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Table 2. Pharmacists and physicians knowledge regarding ARC.

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Regarding the risk factors associated with Augmented Renal Clearance (ARC), sepsis was the most recognized risk factor, with 67.4% of participants correctly identifying it, while major surgeries were the least known risk factor, recognized by only 16.3% of participants. Only 27 participants (29%) were able to identify four or more risk factors, whereas 65 participants (70.6%) did not (Fig 2). Participants were categorized into three groups based on their knowledge level, with the majority demonstrating poor knowledge. Specifically, 72 participants (78%) were categorized as having poor knowledge (Fig 3).

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Fig 2. Risk factors knowledge score.

ARC, augmented renal clearance.

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Fig 3. Pharmacists and physicians’ knowledge categories.

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Physicians and clinical pharmacists’ attitudes about ARC

Four questions were used to assess the healthcare provider’s attitude. The analysis showed that 83.7% would seek more information about antibiotic adjustment in the case of ARC. The majority, 87.0%, are interested in attending workshops about ARC. Moreover, the participants showed 96.7% willingness to apply antibiotic adjustment guidelines once established in case of ARC occurrence. The participants were categorized into two groups according to their attitudes. Most participants were positive at 85 (92%) as shown in (Fig 4). About 79 (85.9%) of respondents perceived that ARC status could affect the treatment outcomes of antibiotic therapy. Moreover, only 28 (30.4%) participants have managed patients with ARC.

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Fig 4. Pharmacists and physicians’ attitude categories.

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Association between participants’ demographic, knowledge, and attitude

The association between demographic factors and participants’ knowledge and attitude towards ARC have has been assessed using Chi-square analysis. Significant associations were found among two participant groups, clinical pharmacists and physicians, regarding their knowledge of ARC, with p-values of ≤0.05, suggesting a notably low level of knowledge among these medical professionals. A similar trend was observed for speciality. Additionally, significant associations were found between positive attitude and speciality, as well as particular sources of information such as research literature, hospital guidelines, and evidence-based resources, as illustrated in Table 3. Further nonparametric analysis revealed that clinical pharmacists had a significantly higher mean rank of 59.13 compared to physicians, whose mean rank was 39.77, with a significance value of less than 0.001.

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Table 3. Association between participants’ demographic, attitude, and their knowledge.

https://doi.org/10.1371/journal.pone.0310081.t003

Discussion

This study assessed physicians’ and clinical pharmacists’ knowledge and attitudes towards ARC. Findings indicate generally inadequate knowledge, consistent with a study from Saudi Arabia [18] but on a lower scale than in China [19]. Unfortunately, only a minor percentage of participants could define the ARC threshold of 130 ml/min, which is less than the Zhou et al. study with the difference that the e threshold in paediatrics is 160 ml/min [6].

Concerning the source of information, a good portion of our participants relied on evidence-based clinical resources, which contradicts the Zhou et al., 2021 study, which stated that paediatric practitioners are using social networking to gain information about ARC. However, noticeably, participants under 35 depended on the social networking platform to get information. The same result was shown in a similar study by [19].

Moreover, As defined in the literature, those risk factors can increase the probability of being vulnerable to ARC: burns, young age <55, male gender, febrile neutropenia, haematological disorder, malignancies, trauma, and sepsis [5, 20–24]. Only 2.2% could define all risk factors aligned, while only 0.7% of the Almulhim Batool et al. study participants achieved it [18]. Comparative analysis indicates that participants in this study had lower awareness of risk factors for ARC than the 70% observed by Zhou et al. [19]. While the study identified all significant risk factors, the only one widely recognized among participants was being under 55 years of age. Although severe trauma is a well-established risk factor for ARC, it was acknowledged by only a minority of participants [25].

A remarkable finding is that the clinical pharmacist achieved a higher knowledge score than physicians with a significant value, which is the opposite of the findings of the Almulhim et al. 2020 study [8]. Their study was among inpatient pharmacists (with clinical experience) and concluded that pharmacists had limited knowledge about ARC.

Furthermore, around 38% of participants chose the accurate method to evaluate ARC, which is urine collection, and it is the only precise method to measure CRCL in ARC patients [26].

The previous research revealed that β-lactams, aminoglycosides, glycopeptides, anticoagulants, and antiepileptics are among the medications that are impacted by the ARC [7, 8, 11, 19, 27–29]. This effect can cause subtherapeutic levels, which could lead to treatment failure [30]. Half the participants agreed that ARC affects β-lactams antibiotics glycopeptides, but less than a quarter identified anticoagulant and antiepileptic.

Aminoglycosides are an additional medication to be mentioned because of their reputation for renal clearance [7]. Nevertheless, the literature found that ARC incidence does not affect the pharmacokinetics-dynamics of aminoglycoside, although 36 participants chose it as an affected antibiotic [7].

It is imperative to optimize the dosing regimen for patients who require antibiotics and are susceptible to ARC. Two primary approaches exist for managing such patients since enhanced clearance results in subtherapeutic concentrations, which can endanger the patient’s life. The first is to increase the dosing regimen to the upper known limit as much as possible. The other approach is to change the administration time into extended or continuous infusions to benefit from time-dependent antibiotics [20]. Less than half of the participants could recognize the proper methods of dealing with ARC patients when it comes to managing antibiotic dosing; these numbers oppose Almulhim et al., 2020 study as they showed the appropriate dose and frequency of administration of piperacillin-tazobactam in ARC patients were chosen by the majority of respondents (60.4%) [18].

More profound questions were used to clarify the knowledge concerning β-lactams and vancomycin for their high prescription rate, and they were considered among the most prescribed antibiotics in the ICU units [31]. As approved in the literature, the proper action is to extend the infusion. Only 6% recognize it, but increasing the dose is another successful approach to dealing with ARC patients [32].

Surprisingly, about 27% choose to decrease the dose in the case of ARC, which is the opposite and wrong practice [25]. Only three respondents chose the appropriate modification for Linezolid to extend the infusion time; as Barrasa et al. study stated, "augmented renal clearance (ARC) increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA (PK/PD target attainment) [33].

As well known, vancomycin is a game changer in critically ill patients as a final resort to treat resistant bacteria, and practitioners must be aware of its loading dose, maintenance dosing, and monitoring [34–36]. Unfortunately, only a quarter of the participant practitioners knew the proper management of vancomycin in ARC patients, which complies with the Zhou et al., 2021 study [19]. These results showed that current practitioners do not recognize the new guideline to monitor vancomycin levels by AUC/MIC [14]. Our study had some limitations. Due to geographical limitations, we could only involve one city in the UAE; this resulted in a small sample size, making it difficult to generalize our findings to the GCC region. The study was conducted over a relatively short period (three months), which may not capture potential variations in knowledge and practices over more extended periods.

Conclusion and recommendation

We concluded that physicians and clinical pharmacists know little about ARC. Half of the participants could not answer the knowledge-related questions correctly. The difference in knowledge score between clinical pharmacists and physicians is significant, indicating that the clinical pharmacy is more knowledgeable. We recommend that policymakers give special attention to educational programs to fill the knowledge gap in ARC management among medical professionals. Conducting more webinars and continuing medical education (CME) programs could effectively educate healthcare providers about ARC, especially since they are willing to apply established guidelines and are open to attending related conferences. These initiatives should include comprehensive training programs and guidelines covering ARC recognition, risk factors, and optimal antibiotic dosing strategies to prevent treatment failure in this vulnerable population.

Supporting information