Creatine Phosphokinase Monitoring Research Articles

Utility Assessment of a Pharmacy to Dose Daptomycin Protocol: A Retrospective Cohort Study.

Pharmacy-to-dose (PTD) services describe an established practice where providers consult pharmacists for various medication dosing. In 2019, several institutions approved a daptomycin protocol, which allowed pharmacists to select doses based on provider-selected indications, renal function, and body mass index (BMI). This study aims to determine the utility of a daptomycin PTD consult service. A retrospective analysis was conducted using data from 4 community hospitals between July 19, 2019 and October 31, 2021. The 2 comparative cohorts included patients who started on daptomycin with and without PTD services. The primary endpoint was the proportion of patients receiving appropriate initial dosing of daptomycin. A total of 297 patients met the inclusion criteria, with 128 (43.1%) in the PTD group and 169 (56.9%) in the non-PTD group. The primary endpoint of appropriate initial dosing occurred significantly more in the PTD group (92.2% vs 82.8%, P = 0.02). Baseline creatine phosphokinase (CPK) was ordered significantly more in the PTD group (88.3% vs 77.5%, P = 0.02). A nonsignificant trend was seen in favor of the PTD arm (80% vs 58.3%, P = 0.22) for dose adjustments required within the first 24 hours. The use of a PTD daptomycin protocol was associated with a significant increase in appropriate initial dosing and baseline CPK monitoring compared with traditional provider order entry.

Factors affecting creatine phosphokinase elevation during daptomycin therapy using a combination of machine learning and conventional methods

Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and >200 IU/L, and (2) >1000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. Of the 2970 patients who received DAP, 706 were included. Elevation of CPK values >200 IU/L and >1000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In decision tree analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

Absence of significant clinical benefit for a systematic routine creatine phosphokinase measurement in asymptomatic patients treated with anti-programmed death protein (ligand) 1 immune checkpoint inhibitor to screen cardiac or neuromuscular immune-related toxicities

AimDespite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown. MethodsIn this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD–(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic. ResultsOverall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention. ConclusionMost patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.

Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4–6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 μg/mL. For an MIC of 1 μg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable.

A Retrospective Multisite Case-Control Series of Concomitant Use of Daptomycin and Statins and the Effect on Creatine Phosphokinase.

ObjectiveDaptomycin has been associated with increased creatine phosphokinase (CPK) due to muscle injury leading to myalgias and muscle weakness. Statins have been proven to cause the same effects and it is recommended to discontinue the use of statins while on daptomycin. Evidence regarding this drug interaction is mixed. This study evaluated the risk of CPK elevation in concomitant use of daptomycin and statins compared to daptomycin alone.MethodThis is a multisite retrospective case-control study of patients who received daptomycin therapy with monitoring of CPK. Rates of CPK elevations were compared in patients receiving daptomycin with a statin versus daptomycin alone. To estimate the association between CPK elevation and daptomycin therapy controlling for other risk factors, logistic regression was used to analyze data. Statistical significance was determined at ɑ of 0.05.ResultsA total of 3658 patients were included in the study, with 2787 on daptomycin therapy alone and 871 with concurrent statin use. The incidence of CPK elevation was 90 events (3.2%) in the daptomycin group and 26 events (3.0%) in the concurrent statin group. Patients who received daptomycin therapy in addition to statins had no statistically significant difference from patients on daptomycin alone (hazard ratio, 1.05; P = .85; 95% confidence interval, 0.61–1.84). After adjusting for potential risk factors, the hazards ratio remained almost the same.ConclusionsConcomitant use of daptomycin and statin did not show an increase risk of CPK elevation. Clinicians may consider concomitant use of daptomycin and statin therapy with weekly CPK monitoring.

Effect of Statin Coadministration on the Risk of Daptomycin-Associated Myopathy.

Daptomycin-associated myopathy has been identified in 2%-14% of patients, and rhabdomyolysis is a known adverse effect. Although risk factors for daptomycin-associated myopathy are poorly defined, creatine phosphokinase (CPK) monitoring and temporary discontinuation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," has been recommended. We conducted a single-center, retrospective, matched case-control risk factor analysis in adult and pediatric patients from 2004 to 2015. Patients in whom myopathy (defined as CPK values above the upper limit of normal) developed during daptomycin treatment were matched 1:1 to no-myopathy controls with at least the same duration of therapy. Risk factors independently associated with myopathy were determined using multivariable conditional logistic regression. Secondary analysis was performed in patients with rhabdomyolysis, defined as CPK values ≥10 times the upper limit of normal. Of 3042 patients reviewed, 128 (4.2%) were identified as having daptomycin-associated myopathy, 25 (0.8%) of whom had rhabdomyolysis; 121 (95%) of the 128 were adults, and the mean duration of therapy before CPK elevation was 16.7 days (range, 1-58 days). In multivariate analysis, deep abscess treatment (odds ratio, 2.80; P = .03), antihistamine coadministration (3.50; P = .03), and statin coadministration (2.60; P = .03) were independent risk factors for myopathy. Obesity (odds ratio, 3.28; P = .03) and statin coadministration (4.67; P = .03) were found to be independent risk factors for rhabdomyolysis, and older age was associated with reduced risk (0.97; P = .05). Statin coadministration with daptomycin was independently associated with myopathy and rhabdomyolysis. This is the first study to provide strong evidence supporting this association. During coadministration, we recommend twice-weekly CPK monitoring and consideration of withholding statins.

Efficacy and Safety of Daptomycin in Patients with Renal Impairment: A Multicenter Retrospective Analysis

Daptomycin is a therapeutic option for patients with underlying renal insufficiency who are vulnerable to nephrotoxicity from vancomycin. We evaluated the efficacy and safety of daptomycin in patients with renal impairment. Multicenter, retrospective, observational, case series analysis. Two academic medical centers. One hundred and sixty adults with creatinine clearance (Clcr ) of 50 ml/minute or less who received daptomycin for at least 72 hours for complicated Gram-positive infections from 2008-2011. Clinical and microbiologic outcomes were assessed at the end of daptomycin therapy. Safety evaluations were documented for all patients, and when available, creatine phosphokinase (CPK) levels were recorded. Thirty-eight (23.8%) patients were on hemodialysis, and 122 (76.3%) had a decreased baseline renal clearance not requiring hemodialysis with a median interquartile range (IQR) Clcr of 32.4 ml/minute (24.2-40.4 ml/min). The median (IQR) daptomycin dose was 6.0 mg/kg (5.8-7.8 mg/kg) administered every 24 hours in 68 patients (42.5%) and every 48 hours in 92 patients (57.5%). Daptomycin success, including cure or improvement, (Cure: signs and symptoms resolved and no additional antibiotic therapy required, or infection cleared with negative cultures reported at the end of daptomycin therapy; Improvement: partial resolution of signs and symptoms and additional antibiotic therapy necessary at the end of daptomycin therapy) was achieved in 128 of 160 (80.0%) patients at the end of therapy. Methicillin-resistant Staphylococcus aureus (MRSA) was the most common pathogen (45%) isolated. The most frequent reason for using daptomycin was due to vancomycin-associated nephrotoxicity (20%). Daptomycin therapy was discontinued in six patients (3.8%) because of elevated CPK (median time to onset, 11.5 days). Loss of daptomycin susceptibility occurred in two patients with complex endovascular infections who were on hemodialysis. Daptomycin demonstrated clinical and microbiologic success rates comparable with prior studies. Discontinuation of therapy because of elevated CPK levels may have been avoided in some patients with adjustment to every 48-hour dosing for Clcr less than 30 ml/minute. The relatively early time to onset suggests the need for CPK monitoring more frequently than once/week in renally impaired patients receiving daptomycin. The treatment of bacteremia in patients with renal insufficiency warrants further study.

Evaluation of Impact of Statin Use on Development of CPK Elevation During Daptomycin Therapy

Because both daptomycin and statins may increase creatine phosphokinase (CPK) levels, the manufacturer of daptomycin suggests considering holding statins during daptomycin therapy. Published evidence suggests potential detrimental effects of withdrawing statin therapy. The objectives of this study were to determine the impact of concurrent statin therapy on peak CPK values, incidence of CPK elevation in patients receiving daptomycin therapy, and clinical factors associated with increased risk of developing CPK elevation. This was a single-center, retrospective cohort study of patients ≥18 years of age who received daptomycin for ≥72 hours and had ≥1 follow-up CPK during a 5-year period. A Kaplan-Meier curve was used to evaluate time to CPK elevation. Cox regression analyses were used to compare the risk of developing elevated CPK between 3 study groups: those receiving daptomycin alone, daptomycin with concurrent statin therapy, and statin therapy held while on daptomycin. 498 patients were included in the study-384 received daptomycin alone, 63 received daptomycin concurrent with statin, and 51 with statin held during daptomycin therapy. Cumulative incidence of CPK elevation was 5.1% and 12% at 7 and 14 days. Those on daptomycin and statin concurrent therapy demonstrated an approximately 2-fold risk of CPK elevation compared with those having their statin therapy held, but the overall group effect was not statistically significant (P = .17). Our findings suggest that holding statin during daptomycin therapy may not be necessary, but may indicate need for increased frequency of CPK monitoring when these medications are used concurrently.

Serum creatine phosphokinase monitoring in patients infected with HIV

Creatine phosphokinase (CPK) estimations are done routinely in some HIV clinics, irrespective of patient symptoms. We studied patients attending the Worcestershire HIV clinic between 1987 and 2001 to identify whether routine elevations in serum levels of CPK in patients with HIV were associated with clinical features of muscle disease (CFMD), and whether such elevations influenced patient management. There was no association between CFMD and a rise in CPK. Major rises of CPK >400 IU/L were significantly associated with CFMD. No individual had a persistent CPK rise >200 IU/L without CFMD. In the great majority of cases, there was no change in management consequent to enzyme rises. In patients with HIV infection and no CFMD, the chance of finding a major and persistent CPK rise is low. This study does not support the practice of routine monitoring of CPK in asymptomatic patients attending HIV clinics.

Is there value in liver function test and creatine phosphokinase monitoring with statin use?

Statins have transformed the care of patients with vascular disease. Patients in almost every category that has been studied have benefited substantially. On the other hand, although the incidence of side effects is remarkably low, statins, like any other therapy, are not entirely free of serious risks. From the outset, based on the mechanism of action of statins, hepatotoxicity has been a concern. Moreover, although the mechanisms remain obscure, significant skeletal muscle injury, which can lead to renal failure and death, unquestionably does occur. To mitigate these risks, screening and monitoring programs for hepatic and skeletal muscle injury were put in place when statins were introduced into clinical practice. This article reviews the benefits and the costs of these efforts. Although the benefits have not been shown, the costs are real and substantial. These include the harm caused by inappropriate withdrawal of therapy, which has been shown to be life-saving, as well as the considerable financial expenditure. The conclusion that follows, based on the evidence in hand, is that although these programs were appropriate at the time statins were introduced, they are not appropriate now.

High rates of adverse effects and patient unawareness of withdrawn lipid-lowering drug combination in a public hospital clinic.

Examine use, patient awareness and outcomes of concurrent cerivastatin and gemfibrozil in a public hospital clinic system 2 weeks following cerivastatin withdrawal. Electronic pharmacy records for cerivastatin prescriptions for 1 year preceding withdrawal were downloaded and linked to gemfibrozil prescriptions. Patients with concurrent prescriptions were surveyed for current use, awareness of withdrawal/warnings, adverse effects and creatine phosphokinase (CK) results. From August 2000 to August 2001, 29,377 prescriptions for cerivastatin were dispensed for 10,780 unique patients; 211 (2%) also received gemfibrozil. Prescription time frames for the two drugs overlapped for 67 patients. Interview of 47 patients revealed 35 actually taking both. 18/35 (51.4%) were still taking both drugs 2 weeks after market-withdrawal of cerivastatin. Only 7/46 (21.2%) had 'heard the news' about withdrawal. 19/46 (41.3%) described muscle-related symptoms; nine reported severe symptoms. Only 13 (28.3%) had CK monitoring. 5/8 symptomatic patients monitored had CK values > 200 U/L. (> 1000 U/L in two cases.) Despite escalating labeled warnings, nearly 2% of patients prescribed cerivastatin received gemfibrozil prescriptions, 1/3 concurrently. Most were still taking this combination 2 weeks after cerivastatin withdrawal and unaware of publicized warnings. Nearly half experienced muscle-related symptoms. More reliable methods for preventing prescription/dispensing of interacting medications and alerting patients about drug recalls are warranted.