Bicavitary effusion in cats: retrospective analysis of signalment, clinical investigations, diagnosis and outcome.

OBJECTIVES: The aim of this study was to describe the clinical and diagnostic findings and outcome of cats with bicavitary effusion presenting to a referral centre. METHODS: Medical records of cats presenting with bicavitary effusion were identified and their history, physical examination findings, clinicopathological data, diagnostic imaging findings, aetiology of bicavitary effusions (cardiac disease, neoplasia, infectious disease, sterile inflammatory disease, severe hypoalbuminaemia, trauma, coagulopathy or 'open' if no definitive diagnosis was reached) and outcome were recorded. Cox regression analysis was performed to identify independent predictors of death in cats with bicavitary effusion. Kaplan-Meier curves were generated for survival analysis. RESULTS: In total, 103 cats with bicavitary effusion were included. Neoplasia and cardiac disease were the most common aetiologies of bicavitary effusion, in 21 (20.4%) and 20 (19.4%) cats, respectively, followed by infectious disease (n = 11, 10.7%), trauma (n = 13, 12.6%), hypoalbuminaemia (n = 6, 5.8%), sterile inflammatory disease (n = 4, 3.9%) and coagulopathy (n = 1, 1.0%). The median survival time for all cats with bicavitary effusion was 3 days. Cats with a neoplastic aetiology had a 2.03 times greater risk of death compared with cats in which no diagnosis was achieved. Neoplasia (P = 0.030) and pedigree breed status (P = 0.016) were independent predictors of death in the multivariable Cox regression model. CONCLUSIONS AND RELEVANCE: This study highlights that bicavitary effusions in cats generally carry a guarded to poor prognosis, particularly if neoplasia is the underlying aetiology or if the cat is a pedigree breed. Cardiac disease appeared to be associated with a better prognosis, suggesting that assessment for congestive heart failure should be considered early when evaluating cats with bicavitary effusion. The prognosis for cats with feline infectious peritonitis is likely to be markedly improved by the advent of novel antiviral drugs, compared with the historical cohort of cats presented here.

The unique structural and functional characteristics of glomerular endothelial cell fenestrations and their potential as a therapeutic target in kidney disease.

Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their function in glomerular hydraulic permeability, and their aberration in disease can contribute to loss of glomerular filtration function. This review provides a comprehensive update of current understanding of the regulation and biogenesis of fenestrae. We consider diseases in which GEnC fenestration loss is recognized or may play a role and discuss methods with potential to facilitate the study of these critical structures. Literature is drawn from GEnCs as well as other fenestrated cell types such as liver sinusoidal endothelial cells that most closely parallel GEnCs.

Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

New Perspectives on Antimicrobial Agents: Molnupiravir and Nirmatrelvir/Ritonavir for Treatment of COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged to cause pandemic respiratory disease in the past 2 years, leading to significant worldwide morbidity and mortality. At the beginning of the pandemic, only nonspecific treatments were available, but recently two oral antivirals have received emergency use authorization from the U.S. Food and Drug Administration for the treatment of mild to moderate coronavirus disease (COVID-19). Molnupiravir targets the viral polymerase and causes lethal mutations within the virus during replication. Nirmatrelvir targets SARS-CoV-2's main protease, and it is combined with ritonavir to delay its metabolism and allow nirmatrelvir to inhibit proteolytic cleavage of viral polyproteins during replication, preventing efficient virus production. Both drugs inhibit in vitro viral replication of all variants tested to date. Each is taken orally twice daily for 5 days. When started in the first 5 days of illness in persons at risk for complications due to COVID-19, molnupiravir and nirmatrelvir/ritonavir significantly decreased severe outcomes (hospitalizations and death) with adjusted relative risk reductions of 30% and 88%, respectively, for the two treatments. Molnupiravir should not be used in children or pregnant persons due to concerns about potential toxicity, and reliable contraception should be used in persons of childbearing potential. Nirmatrelvir/ritonavir may cause significant drug-to-drug interactions that limit its use in persons taking certain medications metabolized by certain cytochrome P450 enzymes. Both treatment regimens are important additions to the management of early COVID-19 in at-risk patients in the outpatient setting.

The microvascular endothelial glycocalyx: An additional piece of the puzzle in veterinary medicine.

The endothelial glycocalyx (eGlx) is a critically important structure lining the luminal surface of endothelial cells. There is increasing evidence, in human patients and animal models, for its crucial role in the maintenance of health. Moreover, its damage is associated with the pathogenesis of multiple disease states. This review provides readers with an overview of the eGlx; summarising its structure, essential functions, and evidence for its role in disease. We highlight the lack of studies regarding the eGlx in cats and dogs, particularly in naturally occurring diseases. Importantly, we discuss techniques to aid its study, which can be applied to veterinary species. Finally, we present targeted therapies aimed at preserving, and in some cases, restoring damaged eGlx.

Circulating hyaluronan as a marker of endothelial glycocalyx damage in dogs with myxomatous mitral valve disease and dogs in a hypercoagulable state.

The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells, maintaining vascular health. Glycocalyx damage is pathophysiologically important in many diseases across species however few studies have investigated its breakdown in naturally occurring disease in dogs. The aims of the study were to investigate eGlx damage in dogs with myxomatous mitral valve disease (MMVD) diagnosed on echocardiography, and dogs in a hypercoagulable state diagnosed using thromboelastography (TEG), by measuring serum hyaluronan concentrations. Serum hyaluronan was quantified in dogs with MMVD (n = 27), hypercoagulability (n = 21), and in healthy controls dogs (n = 18). Serum hyaluronan concentrations were measured using a commercially-available ELISA validated for use in dogs. Hyaluronan concentrations were compared among groups using Kruskal-Wallis tests, and post-hoc with Dunn's tests. Serum hyaluronan concentrations (median [range]) were significantly increased in dogs with MMVD (62.4 [22.8-201] ng/mL; P = 0.031) and hypercoagulability (92.40 [16.9-247.6] ng/mL; P < 0.001) compared to controls (45.7 [8.7-80.2] ng/mL). Measurement of serum hyaluronan concentration offers a clinically applicable marker of eGlx health and suggests the presence of eGlx damage in dogs with MMVD and dogs in a hypercoagulable state.

Visualising the endothelial glycocalyx in dogs.

The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells. It is critical in maintaining vascular health and when damaged contributes to many diseases. Its fragility makes studying the eGlx technically challenging. The current reference standard for eGlx visualisation, by electron microscopy using glutaraldehyde/Alcian blue perfusion fixation, has not been previously reported in dogs. Established techniques were applied to achieve visualisation of the eGlx in the microvasculature of reproductive tissue in five healthy dogs undergoing elective neutering. Uterine and testicular artery samples underwent perfusion fixation, in the presence of Alcian blue, prior to transmission electron microscopy imaging. Image processing software was used to determine eGlx depth. EGlx was visualised in the arteries of two dogs, one testicular and one uterine, with median (range) eGlx depths of 68.2 nm (32.1-122.9 nm) and 47.6 nm (26.1-129.4 nm) respectively. Study of the eGlx is technically challenging, particularly its direct visualisation in clinical samples. Further research is needed to develop more clinically applicable techniques to measure eGlx health.

Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations.

BACKGROUND: Glomerular endothelial cell (GEnC) fenestrations are recognized as an essential component of the glomerular filtration barrier, yet little is known about how they are regulated and their role in disease. METHODS: We comprehensively characterized GEnC fenestral and functional renal filtration changes including measurement of glomerular Kf and GFR in diabetic mice (BTBR ob-/ob- ). We also examined and compared human samples. We evaluated Eps homology domain protein-3 (EHD3) and its association with GEnC fenestrations in diabetes in disease samples and further explored its role as a potential regulator of fenestrations in an in vitro model of fenestration formation using b.End5 cells. RESULTS: Loss of GEnC fenestration density was associated with decreased filtration function in diabetic nephropathy. We identified increased diaphragmed fenestrations in diabetes, which are posited to increase resistance to filtration and further contribute to decreased GFR. We identified decreased glomerular EHD3 expression in diabetes, which was significantly correlated with decreased fenestration density. Reduced fenestrations in EHD3 knockdown b.End5 cells in vitro further suggested a mechanistic role for EHD3 in fenestration formation. CONCLUSIONS: This study demonstrates the critical role of GEnC fenestrations in renal filtration function and suggests EHD3 may be a key regulator, loss of which may contribute to declining glomerular filtration function through aberrant GEnC fenestration regulation. This points to EHD3 as a novel therapeutic target to restore filtration function in disease.

Characteristics, safety and cost-effectiveness analysis of self-administered outpatient parenteral antibiotic therapy via a disposable elastomeric continuous infusion pump at two county hospitals in Houston, Texas, United States.

WHAT IS KNOWN AND OBJECTIVE: Outpatient parenteral antibiotic therapy (OPAT) is an attractive option for patients who require parenteral antimicrobials as outpatients. Few OPAT studies have assessed the impact of IV antibiotic therapy via elastomeric continuous pumps, with most having been conducted outside the United States and few in county hospitals. The OPAT program in Harris Health system, the county hospital system of Houston, Texas, United States, has implemented a disposable elastomeric continuous infusion pump (eCIP) for self-administered intravenous antibiotics (s-OPAT) since December 2018. Our goal was to describe the clinical characteristics of patients discharged with an eCIP, as well as the safety and cost-effectiveness of this pump. METHODS: We retrospectively analysed patients discharged from Harris Health hospitals between 12/2018 and 02/2021 with s-OPAT via eCIP at home. We extracted various patient characteristics and outcomes related to OPAT. RESULTS AND DISCUSSION: Among 481 OPAT patients during the study period, 91 patients received s-OPAT via eCIP. A total of 1925 days of s-OPAT were administered at home, with a median duration of 12 days. Eighty-three patients (93.4%) achieved a cure from infection, six patients (6.6%) had side effects, and nine patients (9.9%) experienced 30-day hospital readmission. Twenty-two patients (24.2%) presented to the ED during s-OPAT, with 13 patients (14.3%) presenting with PICC line concerns. We estimated that s-OPAT via eCIP saved $2,360,500 to $3,503,900 compared to inpatient-only therapy. WHAT IS NEW AND CONCLUSION: Our study showed that patients with s-OPAT via eCIP had a high cure rate with a relatively low incidence of side effects and 30-day hospital readmission. ED visits during therapy were relatively high, which indicates the necessity of close patient monitoring via the OPAT program. eCIP appears to be a good option to facilitate an early disposition of patients in county hospitals.

Preliminary demonstration of benchtop NMR metabolic profiling of feline urine: chronic kidney disease as a case study.

OBJECTIVE: The use of benchtop metabolic profiling technology based on nuclear magnetic resonance (NMR) was evaluated in a small cohort of cats with a view to applying this as a viable and rapid metabolic tool to support clinical decision making. RESULTS: Urinary metabolites were analysed from four subjects consisting of two healthy controls and two chronic kidney disease (CKD) IRIS stage 2 cases. The study identified 15 metabolites in cats with CKD that were different from the controls. Among them were acetate, creatinine, citrate, taurine, glycine, serine and threonine. Benchtop NMR technology is capable of distinguishing between chronic kidney disease case and control samples in a pilot feline cohort based on metabolic profile. We offer perspectives on the further development of this pilot work and the potential of the technology, when combined with sample databases and computational intelligence techniques to offer a clinical decision support tool not only for cases of renal disease but other metabolic conditions in the future.

Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease.

The endothelial glycocalyx is a key component of the glomerular filtration barrier. We have shown that matrix metalloproteinase (MMP)-mediated syndecan 4 shedding is a mechanism of glomerular endothelial glycocalyx damage in vitro, resulting in increased albumin permeability. Here we sought to determine whether this mechanism is important in early diabetic kidney disease, by studying streptozotocin-induced type 1 diabetes in DBA2/J mice. Diabetic mice were albuminuric, had increased glomerular albumin permeability and endothelial glycocalyx damage. Syndecan 4 mRNA expression was found to be upregulated in isolated glomeruli and in flow cytometry-sorted glomerular endothelial cells. In contrast, glomerular endothelial luminal surface syndecan 4 and Marasmium oreades agglutinin lectin labelling measurements were reduced in the diabetic mice. Similarly, syndecan 4 protein expression was significantly decreased in isolated glomeruli but increased in plasma and urine, suggesting syndecan 4 shedding. Mmp-2, 9 and 14 mRNA expression were upregulated in isolated glomeruli, suggesting a possible mechanism of glycocalyx damage and albuminuria. We therefore characterised in detail the activity of MMP-2 and 9 and found significant increases in kidney cortex, plasma and urine. Treatment with MMP-2/9 inhibitor I for 21 days, started six weeks after diabetes induction, restored endothelial glycocalyx depth and coverage and attenuated diabetes-induced albuminuria and reduced glomerular albumin permeability. MMP inhibitor treatment significantly attenuated glomerular endothelial and plasma syndecan 4 shedding and inhibited plasma MMP activity. Thus, our studies confirm the importance of MMPs in endothelial glycocalyx damage and albuminuria in early diabetes and demonstrate that this pathway is amenable to therapeutic intervention. Hence, treatments targeted at glycocalyx protection by MMP inhibition may be of benefit in diabetic kidney disease.

Real-World Experience with Ceftolozane-Tazobactam for Multidrug-Resistant Gram-Negative Bacterial Infections.

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

Significant Publications on Infectious Diseases Pharmacotherapy in 2018.

PURPOSE: To summarize the top 10 most influential peer-reviewed infectious diseases (ID) pharmacotherapy articles published in the year 2018. SUMMARY: Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were thought to have most notably contributed to ID pharmacotherapy in 2018, including those related to human immunodeficiency virus (HIV). A total of 26 articles were nominated: 22 articles pertaining to general ID pharmacotherapy and 4 articles involving HIV/AIDS. To select the most significant articles of 2018, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) asking members to vote on their top 10 general ID publications and 1 HIV publication. Of the 462 members surveyed, 213 (46%) and 108 (23%) voted for general ID pharmacotherapy- and HIV-related articles, respectively. The top article(s) for both categories are summarized. CONCLUSION: With the increased emphasis on antimicrobial stewardship initiatives and the growing problem of multidrug-resistant (MDR) organisms, the amount of ID literature centered on stewardship, appropriate treatment durations, and newly approved antimicrobial agents continues to expand, making it challenging for clinicians to stay informed on the most relevant publications. This review summarizes significant ID-related publications in 2018 with the goal of aiding clinicians in staying up to date on the most noteworthy publications in ID pharmacotherapy.

Development of an estimated glomerular filtration rate formula in cats.

BACKGROUND: Estimated glomerular filtration rate (eGFR) formulas are routinely used in human patients to provide a more accurate evaluation of GFR compared to serum creatinine concentration alone. Similar formulas do not exist for cats. OBJECTIVES: To validate a prediction formula for eGFR in cats based on adjusting serum creatinine concentration. ANIMALS: Client-owned cats with various levels of renal function. METHODS: The study was cross-sectional. Glomerular filtration rate was determined by iohexol clearance. Variables including signalment, biochemical markers, and noninvasive measurements considered to represent surrogate markers of muscle mass were evaluated with the reciprocal of serum creatinine concentration in a multivariable regression model. The derived eGFR formula was subsequently tested in another group of cats and agreement with GFR assessed. RESULTS: The formula was developed in 55 cats. Only a single morphometric measurement (pelvic circumference) along with the reciprocal of serum creatinine concentration (creatinine-1 ) independently predicted GFR in the final multivariate model. The derived eGFR formula was 0.408 + (243.11 × creatinine-1 [µmol/L]) - (0.014 × pelvic circumference [cm]). When the formula was tested in another 25 cats it was not found to offer any advantage over creatinine-1 alone in its relationship with GFR (eGFR, R2 = 0.44, P < .001 vs reciprocal of creatinine, R2 = 0.45, P < .001). Furthermore, agreement between eGFR and GFR was poor. CONCLUSIONS AND CLINICAL IMPORTANCE: An eGFR formula for cats that adjusted serum creatinine concentration for a marker of muscle mass was developed. The formula did not provide a reliable estimate of GFR, and therefore, its routine use cannot be recommended.

Repeated measurements of renal function in evaluating its decline in cats.

OBJECTIVES: The aim of this study was to describe the variability in renal function markers in non-azotaemic and azotaemic cats, and also the rate of change in the markers. METHODS: Plasma creatinine concentration and its reciprocal, glomerular filtration rate (GFR) and urine specific gravity (USG) were studied as markers of renal function in client-owned cats. GFR was determined using a corrected slope-intercept iohexol clearance method. Renal function testing was performed at baseline and a second time point. The within-population variability (coefficient of variation; CV%) was determined at the baseline time point. Within-individual variability (CV%) and rate of change over time were determined from the repeated measurements. RESULTS: Twenty-nine cats were included in the study, of which five had azotaemic chronic kidney disease. The within-individual variability (CV%) in creatinine concentration was lower in azotaemic cats than in non-azotaemic cats (6.81% vs 8.82%), whereas the within-individual variability in GFR was higher in azotaemic cats (28.94% vs 19.98%). The within-population variability was greatest for USG (67.86% in azotaemic cats and 38.00% in non-azotaemic cats). There was a negative rate of change in creatinine concentration in azotaemic and non-azotaemic cats (-0.0265 and -0.0344 µmol/l/day, respectively) and a positive rate of change of GFR in azotaemic and non-azotaemic cats (0.0062 and 0.0028 ml/min/day, respectively). CONCLUSIONS AND RELEVANCE: The within-individual variability data suggest creatinine concentration to be the more useful marker for serial monitoring of renal function in azotaemic cats. In contrast, in non-azotaemic cats, GFR is a more useful marker for serial monitoring of renal function. The majority of cats with azotaemic CKD did not have an appreciable decline in renal function during the study.

Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin.

Evidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximum a posteriori probability Bayesian estimation. Vancomycin AUC and minimum-concentration (Cmin) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC0-48) of ≥1,218 mg · h/liter, AUC0-24 of ≥677 mg · h/liter, AUC24-48 of ≥683 mg · h/liter, and day 1 Cmin (Cmin24) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.

Vitamin D toxicity of dietary origin in cats fed a natural complementary kitten food.

CASE SERIES SUMMARY: This case series describes two young sibling cats and an additional unrelated cat, from two separate households, that developed hypercalcaemia associated with hypervitaminosis D. Excessive vitamin D concentrations were identified in a natural complementary tinned kitten food that was fed to all three cats as part of their diet. In one of the cases, there was clinical evidence of soft tissue mineralisation. The hypercalcaemia and soft tissue mineralisation resolved following withdrawal of the affected food and medical management of the hypercalcaemia. RELEVANCE AND NOVEL INFORMATION: This case series demonstrates the importance of obtaining a thorough dietary history in patients presenting with hypercalcaemia and the measurement of vitamin D metabolites when investigating such cases. Complementary foods may have the potential to induce nutritional toxicity even when fed with complete, nutritionally balanced diets.

A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity.

Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.