Augmented Renal Clearance in a Case of Sepsis Leading to Vancomycin Failure Despite Increasing Dose As per the Estimated Glomerular Filtration Rate

Augmented renal clearance (ARC) is a unique clinical scenario observed in critically ill patients. We present a case of a 30-year-old male with sepsis secondary to methicillin-resistant Staphylococcus aureus (MRSA) bacteremia treated with vancomycin. ARC was observed in the patient with a maximum estimated glomerular filtration rate (eGFR) of 161.9 ml/min/1.73 m2, and therapeutic drug monitoring was used to adjust the vancomycin dosage. Despite the maximal recommended dose of vancomycin, the therapeutic vancomycin level was not achieved, leading to treatment failure and subsequent mortality. Our case report suggests the necessity of other strategies, such as early dose adjustment of vancomycin based on vancomycin clearance and continuous vancomycin infusion, not merely conventional adjustment based on eGFR and vancomycin levels.


Introduction
Dosing of drugs in intensive care has a huge impact on outcomes. Frequently, dosing is adjusted based on pharmacokinetics, which is dependent on many factors and not just limited to co-morbidities and rapidly changing hemodynamics. Active vigilance should be exercised in liaison with a dedicated pharmacist; more importantly, for those drugs with a narrow therapeutic window and those medications whose efficacy depends on the therapeutic level. In an intensive care setting, anticoagulation and antibiotics require therapeutic drug monitoring. Vancomycin-induced renal toxicity requiring hemofiltration has been reported in the intensive care setting [1][2]. Most commonly, antibiotics are adjusted based on the degree of reduction of eGFR from baseline to prevent toxicity. On the contrary, an increase in eGFR would result in therapeutic failure. Augmented renal clearance (ARC) is a unique phenomenon encountered in critically ill patients, resulting in the enhanced elimination of solutes, higher than expected for age, clinical co-morbidity, or gender. The phenomenon of ARC was documented in the 1970s in burn patients who required higher doses of aminoglycosides and was attributed to renal hyperfiltration [3]. ARC is considered when creatinine clearance exceeds 130 ml/min/1.73m 2 [4][5]. ARC has been reported among severely septic patients, traumatic brain injury, and young and healthy individuals who have undergone surgery or multiple trauma [6][7]. Many predictive scoring systems and tools are used to predict ARC. A failure to do early projection can lead to antibiotic failure resulting in mortality. We present a case of a critically ill patient with ARC secondary to methicillin-resistant Staphylococcus aureus (MRSA) sepsis, resulting in vancomycin failure and mortality.

Case Presentation
A 30-year-old male (weight 72.5 kg and height: 6 ft 3-inch, body mass index (BMI) of 20.0 kg/m 2 ) with a past medical history of intravenous drug use and schizophrenia presented to the emergency department with progressive shortness of breath, fever, and chills for three days. At presentation, his temperature was 102 °F, heart rate of ~120/min, respiratory rate ~30-35 breaths/min, and oxygen saturation of 93%-94% on room air. Physical examination revealed bilateral crepitation on the bases of the lungs. Complete blood count was significant for neutrophilia, and a preliminary diagnosis of sepsis was made. Table 1 shows the laboratory workup on admission.    In view of intravenous drug use, there was a high index of suspicion of MRSA sepsis. The patient was empirically treated with meropenem 1 gm every eight hourly and vancomycin 1 gm every 12 hourly to have synergistic action against MRSA sepsis.
Bronchoscopy was done, and bronchoalveolar lavage (BAL) revealed MRSA. Meropenem was discontinued on Day 4 when MRSA was isolated. Later on, vancomycin was continued for MRSA sepsis. The patient required endotracheal intubation owing to hypoxemic respiratory failure.
Vancomycin was started on Day 1 with 1 gram every 12 hours (27.7 mg/kg). After three initial doses, the vancomycin trough was 5.8 mg/dl. The critical care pharmacy was consulted, and vancomycin dosing was changed to 1 gm every eight hours (42.8 mg/kg). On Day 4, the vancomycin level was 9.6 mg/dl, so the dose of vancomycin was increased further to 1 gram every six hours (55.5 mg/kg). On Days 5 and 6, he received a total of 4.25 gm per day (~59mg/kg) of vancomycin. Despite these doses, the patient was not able to reach the therapeutic vancomycin levels. Consultation with the infectious disease team was done and the antibiotic was switched to ceftaroline and daptomycin. Linezolid was not considered in view of possible bone marrow suppression [8]. Table 2 shows the vancomycin dose adjustment based on eGFR while Figure 2 shows the estimated glomerular filtration rate (eGFR) trend based on the Modification of Diet in Renal Disease (MDRD) study equation.

Discussion
The incidence of ARC ranges from 4.1% to 32.8% in studies done in intensive care settings [4,9]. Neurohormonal, temperature, vascular changes like cerebral autoregulation, fluid resuscitations, alteration of the physiology of nephrons, including but not limited to higher glomerular filtration, and variable tubular secretion and reabsorption have been suggested as the underlying pathophysiology of ARC [10][11].
Vancomycin being hydrophilic and excreted by up to 90% in urine in unchanged form, it is evident that vancomycin clearance depends on renal functioning and the phenomenon of ARC has a significant impact on [12].    Many patients need dose adjustment due to the phenomenon of ARC, requiring extensive therapeutic drug monitoring (TDM) to ensure optimal therapy. In our case, vancomycin was started at 27.7 mg/kg and increased up-to ~59 mg/kg on Days 5 and 6. Despite these vancomycin doses, vancomycin levels were subtherapeutic, which led us to believe that the phenomenon of ARC is the reason for the therapeutic failure. Of note, vancomycin infusion therapy and therapeutic drug monitoring were successful strategies to achieve therapeutic vancomycin levels as observed by Udy

Conclusions
ARC is commonly associated with subtherapeutic vancomycin levels in critically ill patients. Early recognition of ARC is vital to reduce mortality. Despite the maximum recommended dose for severe infection like sepsis, ARC could lead to the therapeutic failure of vancomycin. Either measurement of vancomycin clearance or continuous infusion in liaison with the Infectious Disease or Pharmacy department could be a possible strategy for achieving the therapeutic level.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.