Cameron J. Phillips

Experiences of using the Theoretical Domains Framework across diverse clinical environments: a qualitative study.

Background The Theoretical Domains Framework (TDF) is an integrative framework developed from a synthesis of psychological theories as a vehicle to help apply theoretical approaches to interventions aimed at behavior change. Purpose This study explores experiences of TDF use by professionals from multiple disciplines across diverse clinical settings. Methods Mixed methods were used to examine experiences, attitudes, and perspectives of health professionals in using the TDF in health care implementation projects. Individual interviews were conducted with ten health care professionals from six disciplines who used the TDF in implementation projects. Deductive content and thematic analysis were used. Results Three main themes and associated subthemes were identified including: 1) reasons for use of the TDF (increased confidence, broader perspective, and theoretical underpinnings); 2) challenges using the TDF (time and resources, operationalization of the TDF) and; 3) future use of the TDF. Conclusion The TDF provided a useful, flexible framework for a diverse group of health professionals working across different clinical settings for the assessment of barriers and targeting resources to influence behavior change for implementation projects. The development of practical tools and training or support is likely to aid the utility of TDF.

INITIAT-E.D.: Impact of timing of INITIation of Antibiotic Therapy on mortality of patients presenting to an Emergency Department with sepsis

To analyse the association between time from triage to administration of initial antibiotics and mortality in all patients presenting with sepsis to a tertiary hospital ED.

Optimizing the detection of methicillin-resistant Staphylococcus aureus with elevated vancomycin minimum inhibitory concentrations within the susceptible range

Background Determination of vancomycin minimum inhibitory concentration (MIC) can influence the agent used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. We studied diagnostic accuracy using E-test and VITEK® 2 against a gold standard broth microdilution (BMD) methodology, the correlation between methods, and associations between vancomycin MIC and MRSA phenotype from clinical isolates. Methods MRSA isolates were obtained from April 2012 to December 2013. Vancomycin MIC values were determined prospectively on all isolates by gradient diffusion E-test and automated VITEK® 2. The Clinical and Laboratory Standards Institute reference BMD method was performed retrospectively on thawed frozen isolates. Diagnostic accuracy for detecting less susceptible strains was calculated at each MIC cutoff point for E-Test and VITEK® 2 using BMD ≥1 µg/mL as a standard. The correlation between methods was assessed using Spearman’s rho (ρ). The association between MRSA phenotype and MIC for the three methods was assessed using Fisher’s exact test. Results Of 148 MRSA isolates, all except one (E-test =3 µg/mL) were susceptible to vancomycin (MIC of ≤2 µg/mL) irrespective of methodology. MICs were ≥1.0 µg/mL for 9.5% of BMD, 50.0% for VITEK® 2, and 27.7% for E-test. Spearman’s ρ showed weak correlations between methods: 0.29 E-test vs VITEK® 2 (P=0.003), 0.27 E-test vs BMD (P=0.001), and 0.31 VITEK® 2 vs BMD (P=0.002). The optimal cutoff points for detecting BMD-defined less susceptible strains were ≥1.0 µg/mL for E-test and VITEK® 2. E-test sensitivity at this cutoff point was 0.85 and specificity 0.29, while VITEK® 2 sensitivity and specificity were 0.62 and 0.51, respectively. Multiresistant MRSA strains tended to have higher MIC values compared to nonmultiresistant MRSA or epidemic MRSA 15 phenotypes by E-test (Fisher’s exact P<0.001) and VITEK® 2 (Fisher’s exact P<0.001). Conclusion Overall diagnostic accuracy and correlations between MIC methods used in routine diagnostic laboratories and the gold standard BMD showed limited overall agreement. This study helps optimize guidance on the effective use of vancomycin.

Doctors’ perspectives towards a bedside aminoglycoside therapeutic drug monitoring service: a collaboration between pharmacy and clinical pharmacology

A computerised area‐under‐the‐curve aminoglycoside therapeutic drug monitoring (A‐TDM) and dosing service was implemented at Flinders Medical Centre.

Junior doctors’ preparedness to prescribe, monitor, and treat patients with the antibiotic vancomycin in an Australian teaching hospital

Purpose We aimed to assess the preparedness of junior doctors to use vancomycin, and to determine whether attending an educational session and being provided pocket guidelines were associated with self-reported confidence and objective knowledge. Methods This was a 2-component cross-sectional study. A 60-minute educational session was implemented and pocket guidelines were provided. Preparedness was evaluated by a self-reported confidence survey in the early and late stages of each training year, and by continuing medical education (CME) knowledge scores. Results Self-confidence was higher among those later in the training year (n=75) than in those earlier (n=120) in the year for all questions. In the late group, vancomycin education was associated with higher self-confidence regarding the frequency of therapeutic drug monitoring (P=0.02) and dose amendment (P=0.05); however, the confidence for initial monitoring was lower (P<0.05). Those with pocket guidelines were more confident treating patients with vancomycin (P<0.001), choosing initial (P=0.01) and maintenance doses (P<0.001), and knowing the monitoring frequency (P=0.03). The 85 respondents who completed the knowledge assessment scored a mean±standard deviation of 8.55±1.55 on 10 questions, and the interventions had no significant effect. Conclusion Attending an educational session and possessing pocket guidelines were associated with preparedness, as measured by higher self-reported confidence using vancomycin. High knowledge scores were attained following CME; however attending an educational session or possessing pocket guidelines did not significantly increase the knowledge scores. Our findings support providing educational sessions and pocket guidelines to increase self-confidence in prescribing vancomycin, yet also highlight the importance of evaluating content, format, and delivery when seeking to improve preparedness to use vancomycin through education.

Questioning the accuracy of trough concentrations as surrogates for area under the curve in determining vancomycin safety

The glycopeptide antibiotic, vancomycin, has been in use for the treatment of serious Gram-positive infections such as methicillin-resistant Staphylococcus aureus (MRSA) infection for nearly 60 years, and therapeutic monitoring for drug safety is acknowledged as an important part of the management strategy when treating patients with this agent [Moellering, 2006; Levine, 2006]. Vancomycin is still the treatment of choice for treatment of MRSA infection, however some authors comment that its days of utility are in the twilight due to rising minimum inhibitory concentrations (MICs) of MRSA isolates, which necessitates such high dosing and drug exposure that the probability of toxicity becomes too great to use it [Van Hal et al. 2013; Patel et al. 2011]. Historically, both peak and trough concentrations have been used at times to monitor the safety of vancomycin [Rybak, 2006]. Peak concentrations, however, have been discarded as a monitoring method for vancomycin as they do not correlate with therapeutic efficacy or key safety concerns of nephrotoxicity [Saunders, 1994; Suzuki et al. 2012]. Trough concentrations have become the dominant method for monitoring vancomycin toxicity and efficacy in clinical practice today; however, the pharmacokinetic–pharmacodynamic (PKPD) index of the area under the concentration curve (AUC) to MIC ratio of the organism being treated is recommended for monitoring treatment efficacy in serious infection [Kullar et al. 2011; Li et al. 2012]. An AUC/MIC ratio of over 400 has been associated with greater clinical success and more rapid bacterial eradication compared with lower AUC/MIC ratios [Moise-Broder et al. 2004]. Trough concentrations up to 15 mg/liter have been reported to correlate with an AUC/MIC ratio of 400 or greater when the organism MIC is up to 1 mg/liter [Giuliano et al. 2010]. The US guidelines on the therapeutic monitoring of vancomycin, released some 5 years ago, were an important step forward in garnishing consensus in guiding practice for the efficacious and safe use of this antibiotic. These guidelines promote aggressive dosing of vancomycin to attain a trough target in the range of up to 15–20 mg/liter, concurring that concentrations greater than 15 mg/liter will achieve an AUC/MIC ratio greater than 400 when the organism MIC is up to 1 mg/liter [Rybak et al. 2009]. The advent of more aggressive vancomycin dosing has led to increased concerns about the safety of dosing regimens which aim to achieve trough concentrations greater than 15 mg/liter. A systematic review of higher dosing to achieve troughs of 15–20 mg/liter reported greater nephrotoxicity [odds ratio 2.67; 95% confidence interval (CI) 1.95–3.65] compared with trough concentrations less than 15 mg/liter [Van Hal et al. 2013]. Curiously, however, a systematic review and meta-analysis of vancomycin continuous infusions achieving targets of 20–30 mg/liter resulted in significantly less nephrotoxicity compared with dosing by intermittent infusion [Cataldo et al. 2012]. This anomaly poses the question as to whether trough concentrations really are a good surrogate marker for AUC and vancomycin exposure. A recently published paper by Neely and colleagues set out to determine this very question: Are trough concentrations an appropriate surrogate for AUC? Briefly, they performed PK/PD modelling on data from 47 adults with 569 vancomycin concentrations. AUCs were determined using Pmeterics (version 1.1.1, Laboratory of Applied Pharmacokinetics, University of Southern California; www.lapk.org), which employs a two-compartmental nonparametric model for vancomycin modelling and simulation. They found the AUC was underestimated by a mean of 23% (CI 11–33%, p = 0.0001), calculated from a model using trough concentration data alone compared with a full model incorporating peak and trough concentrations to determine AUC. When modelling was performed using the full model as a Bayesian prior and only incorporating trough concentrations, a 97% accuracy of AUC estimation was achieved (CI 93–102%, p = 0.23). Using Bayesian modelling they simulated over 5000 concentration–time profiles and found that in adult patients with normal renal function and an AUC of at least 400 mg⋅h/liter with an organism MIC of 1 mg/liter, some 60% are expected to have trough concentration below 15 mg/liter. Thus, dosing to achieve a trough over 15 mg/liter may lead to excessive vancomycin exposure and unnecessary risk of toxicity. Further, the authors propose that a 24 h AUC of 700 mg⋅h/liter represents a conservative upper limit of vancomycin exposure that is safe with minimal risk of nephrotoxity [Neely et al. 2014]. This assertion of a 24 h AUC 700 mg⋅h/liter as an upper limit for safe vancomycin exposure is supported by the US consensus guidelines [Rybak et al. 2009], and others [Patel et al. 2011; Avent et al. 2013], in that if the organism being treated has a higher MIC (i.e. ≥2 mg), maintaining an AUC/MIC ratio of at least 400 in patients with normal renal function will require such high drug exposure that treatment will not be viable due to the increased risk of nephrotoxicity. The study by Neely and colleagues suggests vancomycin trough concentrations alone are not a good surrogate for AUC. If computerized Bayesian modelling of vancomycin is performed to determine AUC, we may be able to achieve the desired therapeutic AUC/MIC targets with less aggressive dosing and reduced risk of toxicity. Arguments against computerized estimation of AUC are that it requires additional software, trained staff, new processes and logistics; however, these barriers have not been insurmountable as some hospitals have adopted computerized AUC monitoring of other agents such as aminoglycosides into routine clinical practice [Baysari et al. 2012]. Computerized software for AUC determination of vancomycin is freely available. A considerable amount of time and money is wasted in routine care with vancomycin treatment when inappropriately timed blood samples are collected. Morrison and colleagues analyzed nearly 2600 vancomycin serum samples over a 13-month period (Boston, MA, USA) and found that 41% of samples were drawn too early, which resulted in clinicians reducing, withholding or ceasing patients’ vancomycin doses in addition to reordering concentrations (29.2% versus 20.0%, p < 0.001) compared with concentrations taken at the appropriate time, that is, 1 h predose and at steady state [Morrison et al. 2012]. Such wasted resources could be redirected to education with regard to appropriate timing of sample collection and implementation of vancomycin monitoring using AUC computation. Monitoring of vancomycin concentrations has been demonstrated to reduce nephrotoxicity (odds ratio 0.25, 95% CI 0.13–0.48, p < 0.0001), defined as a rise in serum creatinine greater than 44 µmol/liter (5 mg/liter) or 50% increase in serum creatinine from baseline during vancomycin therapy compared with patients who do not receive vancomycin monitoring [Ye et al. 2013]. However, strategies to improve vancomycin dosing and attainment of target concentrations, such as implementation of clinical practice guidelines, are important [Phillips et al. 2013], as are electronic decision support tools [McCluggage et al. 2010]. Determining vancomycin exposure by computation of AUC may help us to truly individualize therapy and better manage toxicity risk, rather than relying on trough concentrations alone. Such a strategy may help to prolong the utility of vancomycin in the era of increasing antibiotic resistance.

Real-world incidence of patient-reported dyspnoea with ticagrelor

Dyspnoea, a common and multifactorial symptom in patients with acute coronary syndrome, has been associated with lower quality of life and hospital readmission. Prescriber preference for antiplatelet therapy, the standard of care in this patient group, is shifting to ticagrelor due to mortality benefits demonstrated in trials compared with clopidogrel. In these trials, dyspnoea was more commonly reported in patients prescribed ticagrelor but the aetiology is still debated. An observational cohort study was conducted to quantify the rates and severity of dyspnoea reported in patients with acute coronary syndrome and newly prescribed ticagrelor compared with those prescribed clopidogrel. Dyspnoea was more commonly reported in patients prescribed ticagrelor at each follow up post-discharge (p = 0.016). Rates were higher than previously reported in clinical trials. In some patients, dyspnoea necessitated drug therapy change and was associated with readmission to hospital (p = 0.046). As ticagrelor is widely prescribed as a first-line antiplatelet agent for a range of patients with acute coronary syndrome, the incidence of dyspnoea in a generalized patient cohort may result in higher rates of drug discontinuation. This in turn could lead to higher rates of rehospitalisation and potential treatment failure than that reported from the controlled setting of a clinical trial.

Real-world use of fidaxomicin in a large UK tertiary hospital: how effective is it for treating recurrent disease?

All courses of fidaxomicin use in the study hospital were reviewed. It was used for first recurrence (six times), second recurrence (eight times) and one case of third recurrence. One patients received fidaxomicin as first-line treatment. Eight patients initially responded to therapy; of these, three patients were asymptomatic at 90 days, three patients remained asymptomatic at 30 days, and two patients had recurrences five and nine days after stopping therapy. Four patients failed to respond; of these, two patients required faecal transplantation and one patient required a colectomy. Two patients deteriorated and two patients died. Fidaxomicin was well tolerated. These findings suggest that the utility of fidaxomicin at this stage of infection is unclear.

Interventions Targeting the Prescribing and Monitoring of Vancomycin for Hospitalized Patients: A Systematic Review Protocol

AbstractIntroductionVancomycin remains one of our essential antibiotics after fifty years of treating serious infections such as methicillin-resistant Staphylococcus aureus. Vancomycin, unlike many other antibiotic agents, requires individualized dosing and monitoring of serum drug levels to ensure it is efficacious, to minimize toxicity, and to limit the development of antibiotic resistance. These issues have led to numerous vancomycin clinical practice guidelines being published in recent years including several key national guidelines. Significant resources are invested during the development of such guidelines; however, there is often little or no information about how such guidelines or other vancomycin practice improvement initiatives should be implemented. The aim of this systematic review is to identify and evaluate the effect of interventions using education, guideline implementation, and dissemination of educational resources that have sought to improve therapeutic drug monitoring and dosing of vancomycin.MethodsA systematic review of the literature will be conducted for RCTs and observational studies where a vancomycin guideline or practice improvement initiative has been implemented. Electronic databases to be searched are PubMed, Medline, CINAHL, EMBASE and the Cochrane Library of Systematic Reviews. The population will be patients who have had intravenous vancomycin prescribed and monitored in hospital. The interventions will be education, implementation of guidelines or protocols, dissemination of educational materials (printed or electronic) or multifaceted interventions of the above. The comparator will be patients who have had standard-care prescribing and monitoring of vancomycin. Outcomes will be changes in prescribing and ordering of vancomycin serum tests, and serum levels attained in patients as well as reported nephrotoxicity. Two reviewers will be involved in the quality assessment and extraction of data. The Scottish Intercollegiate Guidelines Network checklist for RCTs will be used. Studies that are not randomized will be assessed for quality using the validated ROBINS-I (risk of bias in non-randomized studies of interventions) tool.DiscussionThis systematic review will identify interventions that have been used to implement guidelines and clinical practice initiatives for vancomycin. The findings of this review may be informative to those involved with the implementation of vancomycin clinical practice guidelines. Systematic review registration: PROSPERO: CRD42016049147.

Pharmacist-led implementation of a vancomycin guideline across medical and surgical units: impact on clinical behavior and therapeutic drug monitoring outcomes

Background Vancomycin is the antibiotic of choice for the treatment of serious infections such as methicillin-resistant Staphylococcus aureus (MRSA). Inappropriate prescribing of vancomycin can lead to therapeutic failure, antibiotic resistance, and drug toxicity. Objective To examine the effectiveness of pharmacist-led implementation of a clinical practice guideline for vancomycin dosing and monitoring in a teaching hospital. Methods An observational pre–post study design was undertaken to evaluate the implementation of the vancomycin guideline. The implementation strategy principally involved education, clinical vignettes, and provision of pocket guidelines to accompany release of the guideline to the hospital Intranet. The target cohort for clinical behavioral change was junior medical officers, as they perform the majority of prescribing and monitoring of vancomycin in hospitals. Assessment measures were recorded for vancomycin prescribing, therapeutic drug monitoring, and patient outcomes. Results Ninety-nine patients, 53 pre- and 46 post-implementation, were included in the study. Prescribing of a loading dose increased from 9% to 28% (P=0.02), and guideline adherence to starting maintenance dosing increased from 53% to 63% (P=0.32). Dose adjustment by doctors when blood concentrations were outside target increased from 53% to 71% (P=0.12), and correct timing of initial concentration measurement increased from 43% to 57% (P=0.23). Appropriately timed trough concentrations improved from 73% to 81% (P=0.08). Pre-dose (trough) concentrations in target range rose from 33% to 44% (P=0.10), while potentially toxic concentrations decreased from 32% to 21% (P=0.05) post-implementation. Infection cure rates for patients increased from 85% to 96% (P=0.11) after the guideline was implemented. Conclusion The implementation strategy employed in this study demonstrated potential effectiveness, and should prompt additional larger studies to optimize strategies that will translate into improved clinical practice using vancomycin.