Calvin J. Meaney

Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors.

The prevalence of vancomycin‐associated nephrotoxicity (VAN) is reported to vary from 1.0–42.6%, with most data from critically ill patients. Evaluation of VAN among internal medicine patients is lacking. Our objectives were to determine the incidence, time‐course, outcomes, and risk factors of VAN in adult internal medicine patients.

Review of Tolvaptan for Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts, kidney pain, hypertension, and progressive loss of renal function. It is a leading cause of end‐stage renal disease and the most common inherited kidney disease in the United States. Despite its prevalence, disease‐modifying treatment options do not currently exist. Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist already in use for hyponatremia. Tolvaptan exhibits dose‐proportional pharmacokinetics with a half‐life of ~12 hours. Metabolism occurs through the cytochrome P450 3A4 isoenzyme, and tolvaptan is a substrate for P‐glycoprotein, resulting in numerous drug interactions. Recent research has highlighted the beneficial effect of tolvaptan on delaying the progression of ADPKD, which is the focus of this review. Pharmacologic, preclinical, and phase II and III clinical trial studies have demonstrated that tolvaptan is an effective treatment option that targets underlying pathogenic mechanisms of ADPKD. Tolvaptan delays the increase in total kidney volume (surrogate marker for disease progression), slows the decline in renal function, and reduces kidney pain. However, tolvaptan has significant adverse effects including aquaretic effects (polyuria, nocturia, polydipsia) and elevation of aminotransferase enzyme concentrations with the potential for acute liver failure. Appropriate patient selection is critical to optimize long‐term benefits while minimizing adverse effects and hepatotoxic risk factors. Overall, tolvaptan is the first pharmacotherapeutic intervention to demonstrate significant benefit in the treatment of ADPKD, but practitioners and regulatory agencies must carefully weigh the risks versus benefits. Additional research should focus on incidence and risk factors of liver injury, cost‐effectiveness, clinical management of drug–drug interactions, and long‐term disease outcomes.

Intravenous lipid emulsion in the management of amlodipine overdose.

Objective To report a case of amlodipine overdose successfully treated with intravenous lipid emulsion (ILE). Case Summary A 47-year-old, 110 kg female ingested at least 350 mg of amlodipine with an unknown amount of ethanol. Initial blood pressure was 103/57 mm Hg, mean arterial pressure (MAP) 72 mm Hg, and heart rate 113 beats per minute. In the early clinical course, activated charcoal, intravenous fluid, and calcium boluses were administered. Worsening hypotension prompted a 100 mL bolus of 20% ILE. Stable hemodynamics were maintained for 2 hours. Subsequently, profound hypotension and shock developed (MAP 38 mm Hg), which failed to fully respond to 3 vasopressor agents, calcium, and glucagon. With continuing shock despite optimized vasopressors, an infusion of 2,300 mL 20% ILE was administered over 4.5 hours (20.9 mL/kg infusion total). By completion of the infusion, 2 vasopressors were tapered off and MAP remained above 70 mm Hg; within 12 hours, no further interventions were required. Possible adverse events of ILE, lipemia and hypoxia, were experienced but quickly resolved. The patient survived to hospital discharge within 8 days. Discussion Toxicity of amlodipine presents similar to distributive shock as both are due to marked peripheral vasodilation. There are numerous interventions in the management of amlodipine overdose, despite which many patients continue to suffer life-threatening shock as observed with this patient. ILE has been used with promising preliminary results as salvage therapy in case reports of other lipophilic molecules. This is the first report of lone amlodipine overdose treated with ILE. Conclusion ILE is a novel antidote for overdoses of lipophilic substances and demonstrated efficacy in this case of amlodipine overdose without the use of hyperinsulinemic euglycemia.

Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia

To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS‐9) in the treatment of hyperkalemia.

Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure

ABSTRACT Staphylococcus aureus possesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined the in vitro evolution of S. aureus in response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (108 CFU/ml) of methicillin-resistant S. aureus (MRSA) USA300 and USA400. Host-pathogen interactions using Galleria mellonella and accessory gene regulator (agr) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereas fAUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease in G. mellonella mortality (P = 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases in agr expression and virulence during therapy may be an adaptive mechanism of S. aureus persistence.

Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients

BackgroundAfter renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy.MethodsThe scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation.ResultsA total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse effects (p = 0.008) in renal transplant recipients receiving tacrolimus and mycophenolic acid compared to the cyclosporine regimen. This finding demonstrated construct validity. Intra-class correlation was 0.81 (95% confidence interval: 0.65-0.90) and Kappa statistic of 0.68 ± 0.25 for all 18 adverse effects and verified substantial inter-rater reliability.ConclusionsThis immunosuppressive adverse effects scoring system in stable renal transplant recipients was evaluated and substantiated face, content and construct validity with inter-rater reliability. The scoring system may facilitate prospective, standardized clinical monitoring of immunosuppressive adverse drug effects in stable renal transplant recipients and improve medication adherence.

Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review

Introduction Hyperkalemia is a serious medical condition that often manifests in patients with chronic kidney disease and heart failure. Renin–angiotensin–aldosterone system inhibitors are known to improve outcomes in these disease states but can also cause drug-induced hyperkalemia. New therapeutic options exist for managing hyperkalemia in these patients which warrant evidence-based evaluation. Aim The objective of this article was to review the efficacy and safety evidence for patiromer, sodium zirconium cyclosilicate (ZS9), and sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia. Evidence review Current treatment options to enhance potassium excretion are SPS and loop diuretics, which are complicated by ambiguous efficacy and known toxicities. Patiromer and ZS9 are new agents designed to address this treatment gap. Both unabsorbable compounds bind potassium in the gastrointestinal (GI) tract to facilitate fecal excretion. The capacity to bind other medications in the GI tract infers high drug–drug interaction potential, which has been demonstrated with patiromer but not yet investigated with ZS9 or SPS. Phase II and III clinical trials of patiromer and ZS9 demonstrated clear evidence of a dose-dependent potassium-lowering effect and the ability to initiate, maintain, or titrate renin–angiotensin–aldosterone system inhibitors. There is limited evidence base for SPS: two small clinical trials indicated potassium reduction in chronic hyperkalemia. All agents may cause adverse GI effects, although they are less frequent with ZS9. Concerns remain for SPS to cause rare GI damage. Electrolyte abnormalities occurred with patiromer and SPS, whereas urinary tract infections, edema, and corrected QT-interval prolongations were reported with ZS9. Conclusion Patiromer and ZS9 have improved upon the age-old standard SPS for the treatment of hyperkalemia. Additional research should focus on drug–drug interactions in patients on multiple medications, incidence of rare adverse events, and use in high-risk populations.

Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes.

Abstract Extrarenal adverse effects (AEs) associated with calcineurin inhibitor (CNI) and mycophenolic acid (MPA) occur frequently but are unpredictable posttransplant complications. AEs may result from intracellular CNI accumulation and low activity of P-glycoprotein, encoded by the ABCB1 gene. Since ABCB1 single nucleotide polymorphisms (SNPs) and sex influence P-glycoprotein, we investigated haplotypes and extrarenal AEs. A prospective, cross-sectional study evaluated 149 patients receiving tacrolimus and enteric coated mycophenolate sodium or cyclosporine and mycophenolate mofetil. Immunosuppressive AE assessment determined individual and composite gastrointestinal, neurologic, aesthetic, and cumulative AEs. Lipids were quantitated after 12-hour fast. ABCB1 SNPs: c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) were determined with haplotype associations computed using the THESIAS program, and evaluated by immunosuppression, sex and race using multivariate general linear models. Tacrolimus patients exhibited more frequent and higher gastrointestinal AE scores compared with cyclosporine with association to CTT (P = 0.018) and sex (P = 0.01). Aesthetic AE score was 3 times greater for cyclosporine with TTC haplotype (P = 0.005). Females had higher gastrointestinal (P = 0.022), aesthetic (P < 0.001), neurologic (P = 0.022), and cumulative AE ratios (P < 0.001). Total cholesterol (TCHOL), low-density lipoproteins (LDL), and triglycerides were higher with cyclosporine. The TTC haplotype had higher TCHOL (P < 0.001) and LDL (P = 0.005). Higher triglyceride (P = 0.034) and lower high-density lipoproteins (P = 0.057) were associated with TTT with sex-adjusted analysis. ABCB1 haplotypes and sex were associated with extrarenal AEs. Using haplotypes, certain female patients manifested more AEs regardless of CNI. Haplotype testing may identify patients with greater susceptibility to AEs and facilitate CNI individualization.

Association of Vancomycin Trough Concentration With Response to Treatment for Acute Pulmonary Exacerbation of Cystic Fibrosis

Background Our goal was to determine the relationship between serum vancomycin trough concentrations (VTCs) and changes in pulmonary function among individuals with an acute pulmonary exacerbation (APE) of cystic fibrosis (CF). Methods We included subjects who were ≥6 years of age, were hospitalized for an APE of CF between May 1, 2012, and April 30, 2014, were administered vancomycin for ≥48 hours, and had a history of airway infection with methicillin-resistant Staphylococcus aureus. Pearson correlations were performed to characterize the relationship between VTC and pulmonary function. Results The mean final VTC (± standard deviation) was 12.6 ± 3.3 µg/mL; 40 (81.6%) of 49 final VTCs were in the range of 10 to <15 µg/mL. The mean change in forced expiratory volume in 1 second (FEV1) between admission and discharge was 24.5% ± 24.4% (P < .001) of predicted values. Forty-two (85.7%) patients returned to their baseline FEV1. No correlation between the change in FEV1 and VTC (Pearson r = -0.10; P = .49) was identified. Similarly, VTC, daily weight-adjusted vancomycin dose, and vancomycin area under the concentration-time curve normalized to the minimum inhibitory concentration (AUC/MIC) were not significant predictors of change in FEV1 or return to baseline FEV1 on multivariate analysis. One (2%) subject experienced acute kidney injury. Conclusions The majority of patients experienced improvement in pulmonary function and a return to their baseline FEV1 while achieving a VTC in the range of 10 to <15 µg/mL. We were unable to identify a correlation between markers of vancomycin exposure and change in pulmonary function test results. Additional studies are needed to reinforce the efficacy of VTCs of 10 to 15 µg/mL for treating APEs of CF.

Vancomycin Versus Vancomycin Plus Rifampin for the Treatment of Acute Pulmonary Exacerbations of Cystic Fibrosis.

OBJECTIVES This study aimed to compare the change in pulmonary function in children and adolescents with cystic fibrosis (CF) who were infected with methicillin-resistant Staphylococcus aureus (MRSA) treated with either vancomycin (VAN) alone or vancomycin plus rifampin (VAN-RIF). METHODS Included patients were ages 6 to 20 years; hospitalized for an acute pulmonary exacerbation (APE) of CF from May 1, 2012, to April 30, 2014; had a respiratory tract culture positive for MRSA within 1 month of index hospital admission; received at least 48 consecutive hours of VAN or VAN-RIF; and had admission and discharge pulmonary function tests. The primary end point was change in percent predicted forced expiratory volume in 1 second (FEV1). RESULTS A total of 39 encounters met inclusion criteria: 24 in the VAN group (mean age 15.1 years) and 15 in the VAN-RIF group (mean age 13.7 years). There were no between-group differences in mean percent change in FEV1 (32.6% ± 28.8% vs. 21.1% ± 12.1%; p = 0.091), mean percent change in forced vital capacity (22.6% ± 25.8% vs. 14% ± 9.4%; p = 0.127), or return to baseline FEV1 (20 [83.3%] vs. 14 [93.3%] patients; p = 0.631). Median (IQR) length of stay (13 days [11-14 days] vs. 13 days [9-14 days]; p = 0.6) and median (IQR) time to readmission (82 days [43-129 days] vs. 147 days [78-219 days]; p = 0.2) were similar between the VAN and VAN-RIF groups, respectively. CONCLUSIONS Vancomycin monotherapy appears to be adequate when treating APEs of CF in children and adolescents with moderate lung disease and high MRSA VAN minimum inhibitory concentrations. Therefore, the addition of RIF may be unnecessary; however, larger studies are needed to confirm these findings.