Vancomycin dosing in an obese patient with acute renal failure: A case report and review of literature

lNTRODUCTlON

Since 1980, the prevalence of obesity has more than doubled worldwide. It is estimated that by 2030,60% of the world's adult population will be classified as obesity[1]. In the United States from 2013 to 2014, the prevalence of obesity was 35.0% for male and 40.4% for female adults, and there was a significant linear increasing trend among women in the prevalence of obesity from 2005 through 2014[2]. Obesity has also become a major public health burden in China. Over the past 40 years, the prevalence of obesity has increased significantly. The nationally representative survey showed that more than half of the Chinese adults are obese according to the Chinese standards[3]. The increased prevalence of obesity poses a challenge for clinicians to deliver optimized doses of antimicrobial drugs in the intensive care unit. Obesity is a key risk factor for community and hospital-acquired infections[4],and increases risks of incidence and mortality compared to non-obese individuals[5]. It may affect the pharmacokinetics of antimicrobial agents, particularly in patients requiring high-dose antimicrobial therapy[6], and can also influence the immune response and increase susceptibility to infections[7],resulting in a high risk of infection in obese patients[8]. As a consequence, clinicians are increasingly facing severely obese patients requiring antibiotic treatment. However, few studies have summarised the published data and provided clinical guidance for effective dosing in these patients.

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The treatment produced significant improvement in the patient’s respiratory status and the infection.Vancomycin and CRRT treatment were subsequently discontinued on December 24. Two days later, the patient was transferred out of the ICU to continue treatment. He was well with no further complaints at the routine 1-mo follow-up.

Although the pharmacokinetics of vancomycin in the general population is well-described, to the best of our knowledge, only a few studies have investigated the effect of vancomycin dose in the obese population. This study reports the medical records of dose adjustment of vancomycin in an obese patient weighing up to 240 kg, including the dose adjustment protocol in the acute renal injury. This article also reviews the current literature on the application of vancomycin in the obese population and provides recommendations on how to make dose adjustments based on the available evidence.

今天的花卉供應市場面向大眾消費，常有新品種花卉吸引顧客，古典園林自然可以基于市場供應豐富花卉種類。當然，花卉的選擇范圍應當謹慎推敲，尤其是園林廳堂擺花的位置、品種都應與特定的園林意境要求和室內風格特點呼應，這也是蘇州古典園林造園技藝的一個部分。清代李漁在《閑情偶寄》中明確指出選擇廳堂擺設花卉的標準主要集中于芳香、姿態和花期3個方面[3]。

CASE PRESENTATlON

Chief complaints

A 40-year-old man was referred to our intensive care unit (ICU), with the complaints of chest tightness and shortness of breath with no obvious cause for 3 mo.

History of present illness

In November 2020, the patient reported chest tightness and shortness of breath with no obvious cause.Three days later, the patient’s symptoms aggravated with abdominal distension and edema of both lower limbs. He was admitted to the ICU of a local hospital for acute respiratory failure. After 2 wk of treatment, the patient still had persistent fever and was transferred to the ICU of our hospital on November 18, 2020.

History of past illness

The patient had suffered from hypertension for 3 years and erysipelas of the right lower extremity for 2 years.

Personal and family history

The patient had no specific personal or family history.

Physical examination

In summary, we report a case of adjusting the blood concentration of vancomycin with enhanced effectiveness in an obese patient. The initial TBW of the patient with normal renal function was 240 kg.Thus, the patient should receive an initial TBW-based load of 6 to 7.2 g of vancomycin every day.However, the dose of vancomycin is greater than 4 g/d, which increases the risk of nephrotoxicity[51].Following the recommended dose limit of 3 g, the patient received an initial TBW-based loading dose of 2 g and a maintenance dose of 1 g of vancomycin every 8 h. The initial serum concentration of 11.7 μg/mL was obtained, after the patient had received three doses of vancomycin. The serum concentration demonstrated that the dosing regimen is reasonable. Due to acute renal failure with reduced urine output or even anuria, intravenous injection of vancomycin at 3 g/d led to a blood concentration of vancomycin that was higher than 20 μg/mL. We immediately reduced the dose of vancomycin and monitored the blood concentration of the drug. On the 29day, the patient was treated with CRRT, the dosage regimen of vancomycin was 1 g every 12 h considering the clearance of vancomycin by CRRT,and the blood concentration was 13.3 μg/mL. The final blood concentration of vancomycin was maintained in the range of 10 to 20 mg/L.

Laboratory examinations

The culture of secretion revealedat a local hospital.

Imaging examinations

Case 2.The two sources exhibit both Gaussian distribution.

抽象執行的本質是在抽象域將程序變量的抽象表示形式作為程序變量本身帶入程序進行計算。首先要對程序的變量和程序中的函數操作進行抽象表示，然后抽象域中執行程序的運行過程。

FlNAL DlAGNOSlS

The final diagnoses were: (1) Sepsis; (2) Acute respiratory distress syndrome; (3) Pneumonia; (4) Heart failure; (5) Necrotizing fasciitis of the scrotum and left lower extremity; and (6) Severe obesity.

近年來，玉米幼苗矮小細弱，葉窄葉薄發黃，心葉扭曲不舒展，輕者生長緩慢，重者幼苗枯死。也有的玉米地塊葉片發紫逐漸枯死。因此，造成不少地塊玉米參差不齊缺苗斷條，導致部分農民對個別廠家的肥料質量產生質疑。

TREATMENT

The patient had pulmonary infection andwas detected in his secretion at the local hospital. His initial serum creatinine was 63.3 μmol/L and creatinine clearance (CrCl) was greater than 90 mL/min. Based on the patient's history and drug sensitivity testing results, intravenous levofloxacin 0.75 g/d and tigecycline 0.2 g/d were started empirically for anti-infection treatment. Then,linezolid 0.6 g intravenous injection every 12 h was prescribed to replace levofloxacin, and the patient's temperature decreased to normal after 3 d of treatment. On November 27, the patient developed a high fever (temperature up to 40.2 °C), and his high-sensitivity C-reactive protein (hs-CRP) rose to 183.51 mg/L (Table 1). Considering the infection from the lower extremity and the scrotum, the patient received enhanced drainage and dressing change. Meanwhile, the culture of sputum and scrotal revealed. The linezolid was subsequently discontinued and intravenous infusion of vancomycin was started. Because the patient was severely obese, after reviewing the literature, we determined the dosing regimen of a loading dose (vancomycin administered as continuous infusion of 2 g over 2 h) and a maintenance dose (vancomycin 1 g infused over 60 min every 8 h). The vancomycin blood trough concentration was 11.7 μg/mL after the patient had received three doses of vancomycin.The patient developed acute renal failure due to the aggravation of infection, the serum creatinine levels showed a gradual increase, and the vancomycin trough concentration was greater than 20 μg/mL (up to 34.3 μg/mL). We then adjusted the vancomycin administration dose according to the blood drug concentration monitoring. On December 16, continuous renal replacement therapy (CRRT) was used because of anuria of the patient. Given using continuous veno-venous hemodiafiltration mode, we adjusted the vancomycin administration dose to 1 g every 12 h, during which vancomycin blood drug concentration fluctuated between 10 and 20 μg/mL.

近些年來我國的公路里程不斷創下歷史新高，公路建設規模不斷擴大，這就對公路工程建設提出了新的挑戰。面對日益復雜的公路工程建設環境，只有嚴格做好公路工程質量的管理工作，才能夠確保良好的工程質量。

OUTCOME AND FOLLOW-UP

Since the early 1980s, as the number of methicillin-resistant(MRSA) infections began to increase, vancomycin has become the drug of first choice for this microbial infection[9].Vancomycin belongs to glycopeptide antibiotic which acts by inhibiting bacterial cell wall synthesis[10].It is the most widely used antibiotic worldwide for the treatment of severe Gram-positive bacterial infections[11]. The binding of vancomycin to protein is approximately 50% to 55%[10]. The volume of distribution is 0.4-1 L/kg[9]. Vancomycin is primarily clearedrenal excretion[12]. The actual body weight of obese subjects increases the chance of vancomycin exposure and the incidence of vancomycinassociated nephrotoxicity[13]. Therefore, dose adjustment is required when vancomycin is used in obese patients, because of the effect of obesity on vancomycin pharmacokinetic parameters. One study shows that therapeutic drug monitoring (TDM) significantly improves the clinical curative effect and reduces the incidence of nephrotoxicity in patients treated with vancomycin[14].

隨著我校招生門檻的降低，學生人數逐年增加，現每班均超過50人，甚至達到110人。在健康評估實訓教學中，一個班最多配備兩位教師，各負責一半學生的教學與指導，很難保證教學質量，也會導致部分監管不到的學生無事可做，出現閑聊、玩手機及其他違紀行為，課堂紀律混亂。因此，師資力量不足，教師力不從心，已經成為健康評估實訓教學急需解決的問題。

DlSCUSSlON

Vancomycin is a time-dependent antibiotic and a number of factors influence its clinical activity,including variable tissue distribution, dose size, and clearance rate[17]. One study showed that total body weight (TBW) influenced the Vand clearance (CL) of vancomycin (Table 2)[18]. As expected,obesity is a known factor affecting drug pharmacokinetics[19]. Vancomycin, as a hydrophilic drug, is able to penetrate and distribute, to a certain extent, in adipose tissues, thereby increasing the V[20]. A large retrospective study by Ducharme[21] showed that the Vwas greater in obese subjects than in normal subjects by examining pharmacokinetics of vancomycin in 704 patients. Blouin and his colleagues[22] also demonstrated statistically significant differences in weight-indexed Vbetween two groups of subjects. A recent study suggests that Vchanges in obese patients can be ascribed to the physicochemical properties of the drugs in most cases[23]. In addition, the degree of the Vdepends on the lipophilicity, hydrophilicity, protein binding, and molecular weight of the antibiotic[24]. In the obese population, higher cardiac output and blood volume may increase blood flow, and lead to larger V[25].Edema combined with fluid resuscitation can increase the Vof different antibacterial agents in obese,critically ill patients[26].

In recent years, body mass index (BMI) is a world-accepted grading method to assess the degree ofobesity. According to the criteria of the guideline, obesity is defined as a BMI of 30.0 kg/mor higher[15]. Based on the body weight and height of this patient, his BMI was calculated to be 78.4 kg/m,which met the threshold for obesity. Numerous physiopathological changes occur in obese individuals,including changes in distribution (V) and renal excretion[16].

Previous studies indicated that CL of vancomycin was much higher in the obese population,especially in young obese patients, and they required high doses to obtain adequate trough concentrations[9]. Han[27] demonstrated that obese adults exhibited higher drug clearance rates than nonobese ones. Unlike V, the physicochemical properties of drugs have little effect on CL, which is largely controlled by physiological processes[23]. The change in clearance was mainly attributed to an increase in kidney mass and renal blood flow in obese subjects[28]. Greater glomerular filtration rate and renal perfusion in obese individuals increase the CL of vancomycin[29]. At the same time, greater renal volume, hypertrophy of the renal unit, and hydrostatic pressure of the glomerulus were also associated with greater CL of vancomycin in the obese group[30]. Vancomycin is a hydrophilic drug with predominant renal excretion. Furthermore, augmented renal clearance (ARC), defined as a creatinine clearance more than or equal to 130 mL/min/1.73 m, refers to enhanced elimination of hydrophilic solutes by the kidneys[31]. The results indicate that ARC has been described in the obese, non-critically ill patient[32], and is a common finding in critically ill patients with normal plasma creatinine concentrations[33].

The option of vancomycin loading doses is dependent on the estimate of the V. Pharmacokinetic research had demonstrated that vancomycin Vincreases with increasing TBW[34]. The physicochemical properties of drugs lead us not to define a universal body-size parameter for the distribution and clearance of drugs. As a consequence, the body weight was used in dose selection for drug administration[35]. One guideline states that a reasonable approach to the initial dose of vancomycin in obese individuals is to increase the loading dose to 20 to 25 mg/kg TBW and to decrease the maintenance dose, then adjust the dose according to TDM[36]. The 2020 Infectious Diseases Society of America(IDSA) consensus recommends the use of a TBW-based loading dose of 20 to 25 mg/kg in obese adults with severe infections, and considers capping doses of 3000 mg as the most practical dosing regimen[37].

Data have shown an excellent correlation between TBW and CL[38]. Thus, the empirical maintenance dose of vancomycin is dependent on the estimated CL[39]. The initial maintenance doses of vancomycin can be calculated by vancomycin CL and target AUC for obese population[18,40]. The 2020 IDSA consensus points out that the mean vancomycin CL in obese patients is approximately 6 L/h, which corresponds to an AUC of approximately 500 mg·h/L at a daily dose of 3000 mg. The empirical vancomycin maintenance dose for obese adults should not exceed 4500 mg/d because vancomycin CL rarely goes beyond 9 L/h[37].

There were no abnormal imaging data findings.

The pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the curve (AUC) to the minimum inhibitory concentration (MIC)[9]. In adult patients with suspected or definitive serious MRSA infection, the AUC/MIC ratio (assuming a vancomycin MIC of 1 mg/L) with targets between 400 and 600 was recommended in the American Society of Health-System Pharmacists (ASHP) 2020 guideline[37]. Based on the historical difficulty of AUC estimation in clinical practice, previous expert guidelines recommended monitoring trough concentrations as a surrogate marker for the AUC/MIC ratio[41]. The 2020 Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin recommends maintaining vancomycin steady-state trough concentrations at 10-20 mg/L to achieve clinical efficacy and improve patient safety[42].

多角度寫——既從參與者（自己）的角度來寫所見、所聞、所感，也從旁觀者（他人）的角度來寫；既從面上來寫集體的表現，也從點上來寫有特點的個體表現。

The patient’s height and body weight were 175 cm and 240 kg, respectively. The patient had necrotizing fasciitis of the scrotum and left lower extremity, and large brown skin pigmentation of the left calf, and two approximately 2-cm surgical incisions with built-in gauze drainage and cloudiness drainage fluid were visible in the left thigh and the middle of the left calf (Figure 1).

CONCLUSlON

The clinical dose of drugs administered is generally determined based on the results of pharmacokinetic studies and clinical trial studies in non-obese patients, which may not be optimal in obese individuals.Hence, the difference in pharmacokinetics of different drugs between obese and non-obese patients must be considered during drug treatment. Obesity is also associated with physiological changes that can alter the pharmacokinetics of vancomycin, and the selection of the dose of vancomycin administered needs to take into account the effect of the body weight of patients. Furthermore, both the loading dose and the maintenance dose are different from non-obese patients. During treatment, we should make appropriate dose adjustments based on the patient's therapeutic drug monitoring and renal function. At the same time, altered pharmacokinetics of antibacterial drugs may require dose individualization to achieve target concentrations. Adjustment of loading dose and maintenance dose is critical for the antibiotic treatment in obese patients using vancomycin. Unfortunately, limited data are available analyzing vancomycin concentrations in obese patients.

在重組方案選擇時，應該綜合考慮重組形式、支付方式以及所得稅相關優惠條款等內容進行納稅籌劃。首先，企業應該對比分析不同形式的重組方式，結合企業戰略定位，優先選擇稅負低的方案。其次，企業可以采取現金支付、固定資產、股權支付等支付方式，其中，非股權支付方式容易產生較高的稅收成本，而股權支付可以避免一部分稅收，且能享受稅收遞延帶來的收益，因此，企業應該選擇最有利的支付方式。最后，企業在重組前應該認真研究所得稅相關優惠條款，為減少稅收做充分的準備。

ACKNOWLEDGEMENTS

We thank the intensive care unit multidisciplinary team of the Fourth Hospital of Hebei Medical University for their treatment support.

FOOTNOTES

Bai J and Du WL conceived the manuscript; Xu KY drafted the manuscript; Li D monitored blood vancomycin concentrations; Hu ZJ was involved in drug therapy; Zhao CC was responsible for the patient.

CRRT is a common treatment for critically ill patients with acute renal injury[43]. With advances in hemodialysis membrane technology, vancomycin is cleared substantially by effective and high-flux dialyzers[44]. Therefore, vancomycin dosing regimens for CRRT need to be changed, but there is no mention of CRRT dosing recommendations in the latest FDA-approved vancomycin package insert[45].Vmay be increased in CRRT patients compared to healthy individuals with normal kidney function[46]. During CRRT treatment, vancomycin CL remains a near-steady-state condition over the dosing interval, although vancomycin CL may decline over time as a result of hemodialysis filter plugging[46].Vancomycin CL is closely related to the flow rate of ultrafiltration/dialysis solution[47]. The recommended loading dose for patients receiving CRRT is based on the actual TBW, at the dose of 20 to 25 mg/kg[48]. In order to achieve the generation of steady-state concentrations between 15 and 20 mg/L, a maintenance dose of 400 to 650 mg/12 h of vancomycin at an ultrafiltration flow rate of 30-40 mg/kg/h is recommended for most critically ill patients[49]. Due to the unstable clinical situation,vancomycin concentration must be strictly monitored in critical patients[50].

the Hebei Natural Science Foundation of China, No. H2019206614.

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

The authors declare that they have no conflict of interest to disclose.

戴菲兒完全按照他的要求完成——身材，膚色，口音，性格，文化程度，童年記憶……他本想讓她完全變成妻子的模樣，可是最終，他放棄了這種打算。他認為這樣只會增加他的思念和悲傷。他認為，或許，一位看起來完全陌生的女孩更能夠讓他找到一點“從相識到相知”的感覺。后來他發現自己似乎愛上了戴菲兒，那一刻，他沒有幸福，只有恐懼。

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

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China

Kun-Yan Xu 0000-0002-5416-9288; Dan Li 0000-0002-5863-6234; Zhen-Jie Hu 0000-0002-9528-8371;Cong-Cong Zhao 0000-0002-1298-6351; Jing Bai 0000-0002-2717-6458; Wen-Li Du 0000-0002-4208-0008.

Xing YX

Wang TQ

Xing YX