Developing a Tool for Prospective Assessment of Treatment Appropriateness in Urinary Tract Infections.

Background: Antimicrobial resistance is an increasingly serious threat to global public health. Antimicrobial stewardship programs need to identify inappropriate antibiotic use patterns and offer practical recommendations to prescribers and institutions. Urinary tract infection (UTI) is a common syndrome for which a standardized tool would be useful when treatment appropriateness is assessed. To date, few UTI treatment assessment tools have been published, and the available tools do not support appropriateness assessment against published guidelines, or consistent adjudication from one auditor to another. Objective: To develop a tool for auditing UTI antibiotic therapy that assesses treatment appropriateness based on guideline concordance, and with high inter-rater reliability. Methods: An audit tool was developed iteratively by the local antimicrobial stewardship team. Two auditors used the tool to adjudicate treatment appropriateness in a sample of UTI cases against local treatment guidelines. Inter-rater agreement was estimated with Cohen's kappa statistic. Results: The final design of the tool had individual sections for evaluating five aspects of treatment appropriateness, depending on the stage at which a patient was in his or her course of antibiotic therapy: diagnosis, empiric therapy, culture-directed therapy, route of antimicrobial administration, and duration of therapy. A total of 50 cases were assessed; among these, the two auditors agreed on 45 cases (90% agreement). The estimated kappa was 0.8. Conclusion: A unique tool with substantial inter-rater agreement was developed for assessing appropriateness of antimicrobial therapy in UTI. The process and design features that were outlined can be adapted by other antimicrobial stewardship programs to monitor antimicrobial use and improve quality of care.

Systematic Review of Efficacy, Pharmacokinetics, and Administration of Intraventricular Aminoglycosides in Adults.

Due to increasing prevalence of intracranial device use and multidrug-resistant and nosocomial organisms, central nervous system (CNS) infections requiring treatment with intraventricular (IVT) aminoglycosides are becoming increasingly common. This article systematically reviews IVT aminoglycoside literature in adults and integrates available evidence to serve as a practical reference for clinicians. Medline (1946 to December 2015), Embase (1974 to December 2015), PubMed (1966 to December 2015), Google, and Google Scholar were searched using the term aminoglycoside combined individually with the terms IVT, meningitis, shunt infection, ventriculitis, and cerebral spinal fluid. Eighteen articles were included. IVT aminoglycosides were assessed in meningitis, ventriculitis, intracranial device infections and neurosurgery prophylaxis. No serious adverse effects following IVT aminoglycoside were reported. Dosages ranged from IVT gentamicin 4-10 mg daily, IVT tobramycin 5-10 mg daily, and IVT amikacin 5-50 mg daily. Duration of therapy should be individualized; however, continuing IVT antibiotics for 3 days and up to 21 days after cerebrospinal fluid (CSF) sterilization has been reported in literature. Most studies included concomitant intravenous antibiotic use. Therapeutic drug monitoring (TDM) was reported in five studies, with varying timing of CSF concentrations obtained. No clear relationship between CSF levels and efficacy or toxicity was evident. Based on current literature, IVT aminoglycosides for the treatment of sensitive gram-negative meningitis, ventriculitis, and CNS device-associated infections appear safe and effective. Optimal dosing regimens are unclear. It is reasonable to initiate IVT aminoglycoside at lowest dose in combination with IV therapy and continuing post CSF sterilization. Preservative-free formulations should be utilized to minimize adverse drug reactions. TDM should not be routinely utilized but reserved for more complicated patients. Further pharmacokinetic and clinical trials of IVT aminoglycosides are necessary to fill current therapeutic gaps. Due to the relatively limited cases of IVT aminoglycoside utilization, prospective, randomized, controlled trials are likely not feasible, and clinicians will have to rely on data from non-randomized and/or retrospective studies.

Evaluating outcomes of alternative dosing strategies for cefepime: a qualitative systematic review.

OBJECTIVE: To perform a qualitative systematic review of the evidence comparing traditional with prolonged intermittent or continuous infusions of cefepime based on clinical and pharmacodynamic outcomes. DATA SOURCES: PubMed (1946 to October 2014), EMBASE (1980 to October 2014), CENTRAL, Cochrane Database of Systematic Reviews, Web of Science, and International Pharmaceutical Abstracts (1970 to October 2014) were searched using the terms cefepime, pharmacokinetics, pharmacodynamics, drug administration, intravenous infusions, intravenous drug administration, continuous infusion, extended infusion, and intermittent therapy. Reference lists from relevant materials were reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating administration regimens of cefepime, one of which included the traditional, manufacturer-recommended 0.5-hour infusion and the other a prolonged or continuous infusion were included. Prespecified clinical outcomes of interest included all-cause mortality, length of hospital stay, clinical cure, and adverse events. The primary pharmacodynamic outcome was percentage time of unbound drug concentration remaining above the minimum inhibitory concentration. DATA SYNTHESIS: In all, 18 studies were included; 6 studies assessed clinical outcomes, and 12 assessed pharmacodynamic outcomes. Prolonged or continuous infusions of cefepime achieved the pharmacodynamic targets more often than traditional infusions. The association of improved clinical outcomes with prolonged or continuous infusions is unclear. All-cause mortality was significantly decreased with the use of a prolonged cefepime infusion in a retrospective study. Two prospective, randomized studies demonstrated no statistically significant difference in mortality between prolonged and intermittent infusions. CONCLUSIONS: The available literature on prolonged and continuous infusions of cefepime demonstrated an improved achievement of pharmacodynamic targets; however, the effect on clinical outcomes is inconclusive. Well-designed prospective studies are required to determine optimal dosing and administration strategies.

Systematic review of efficacy, pharmacokinetics, and administration of intraventricular vancomycin in adults.

Central nervous system infections requiring treatment with intraventricular (IVT) vancomycin are becoming increasingly common with advent of intracranial devices and increasing prevalence of multi-drug resistant and nosocomial organisms. Administering vancomycin via IVT route bypasses the blood-brain barrier to allow localized and controlled delivery directly to the desired site of action, achieving high concentrations for more reliable bactericidal action. This article systematically reviews current literature on IVT vancomycin in adults, compiles current knowledge, and integrates available evidence to serve as a practical reference.Medline (1946-July 2012), Embase (1974-July 2012), and International Pharmaceutical Abstracts (1970-July 2012) were searched using terms vancomycin, intraventricular, shunt infection, cerebrospinal fluid, and intraventriculitis. Seventeen articles were included in this review. Indications for IVT vancomycin included meningitis unresponsive to intravenous antibiotics, ventriculitis, and intracranial device infections. No serious adverse effects following IVT vancomycin have been reported. Dosages reported in literature ranged from 0.075-50 mg/day, with the most evidence for dosages of 5 to 20 mg/day. Duration of therapy most commonly ranged from 7 to 21 days. Therapeutic drug monitoring was reported in 11 studies, with CSF vancomycin levels varying widely from 1.1 to 812.6 mg/L, without clear relationships between CSF levels and efficacy or toxicity. Using IVT vancomycin to treat meningitis, ventriculitis, and CNS device-associated infections appears safe and effective based on current evidence. Optimal regimens are still unclear, and dosing of IVT vancomycin requires intricate consideration of patient specific factors and their impact on CNS pathophysiology. Higher-quality clinical trials are necessary to characterize the disposition of vancomycin within CNS, and to determine models for various pathophysiological conditions to facilitate better understanding of effects on pharmacokinetic and pharmacodynamic parameters.

Evaluating outcomes associated with alternative dosing strategies for piperacillin/tazobactam: a qualitative systematic review.

OBJECTIVE: To perform a qualitative systematic review of the evidence comparing traditional strategies against prolonged intermittent or continuous infusion strategies for piperacillin/tazobactam, based on clinical and pharmacodynamic outcomes. DATA SOURCES: MEDLINE (1950-September 2011), EMBASE (1980-September 2011), and International Pharmaceutical Abstracts (1970-September 2011) were searched, using the terms piperacillin, tazobactam, pharmacokinetics, pharmacodynamics, dosing, and infusion. Reference lists from relevant publications were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating the administration of piperacillin/tazobactam to adults and comparing at least 2 dosing regimens (1 of which included the traditional, manufacturer-recommended 30-minute infusion; the other, a prolonged or continuous infusion strategy) were included. Prespecified clinical outcomes of interest included mortality, clinical cures, and adverse events. The pharmacodynamic endpoint of interest was percent time of unbound drug concentration remaining above the minimum inhibitory concentration. DATA SYNTHESIS: Twelve studies were included in this review, 7 of which assessed clinical outcomes and 5 that assessed pharmacodynamic endpoints using Monte Carlo simulations. Prolonged or continuous infusions of piperacillin/tazobactam consistently achieved higher pharmacodynamic endpoints than did traditional infusions. The association of prolonged or continuous infusions with improved clinical outcomes, however, is unclear. Two retrospective studies found improved mortality rates with prolonged infusions (1 in a subgroup of patients with higher APACHE II [Acute Physiology and Chronic Health Evaluation II] scores), while another retrospective study found improved clinical cure rates with continuous infusions in patients with ventilator-associated pneumonia. These clinical benefits have not been substantiated in prospective randomized trials. No study has provided evidence of reduced adverse effects with prolonged or continuous infusions. CONCLUSIONS: The limited evidence available does not firmly support widespread adoption of administering piperacillin/tazobactam as prolonged intermittent or continuous infusions to improve clinical outcomes despite the achievement of higher pharmacodynamic targets in simulated studies. Retrospective studies indicate that critical care patients are the subgroup most likely to benefit from these dosing strategies. Well-designed prospective clinical trials are required to confirm potential benefits observed in retrospective studies.

Antibiotics Utilization for Community Acquired Pneumonia in a Community Hospital Emergency Department.

BACKGROUND: A local health authority in Canada implemented its own Antimicrobial Stewardship Program (ASP) which provide guidelines to clinicians to utilize when treating infectious diseases such as community-acquired pneumonia (CAP). Objectives: The primary objective is to describe antibiotic usage patterns at the community hospital's emergency department (ED) and to analyze the patterns in relation to ASP goals of reducing risk of infections, adverse drug events and antibiotic resistance, and to identify potential areas of improvement. METHODS: This retrospective chart review included 156 adult patients with a diagnosis of CAP admitted to a community hospital ED from December 1, 2015 to November 30, 2016. RESULTS: 50.6% patients were prescribed moxifloxacin across all severity of CAP patients. Low and moderate severity CAP patients were most often prescribed antibiotic duration > 7 days. In low, moderate and high severity CAP patients who were treated using ceftriaxone, 100%, 88.9% and 66.6% patients were treated with ceftriaxone 2000 mg daily respectively. CONCLUSIONS: Antibiotic prescribing patterns suggest fluoroquinolones were frequently being over-prescribed, ceftriaxone dosages were often too high, and duration of antibiotics for low and moderate severity CAP were too long. More efforts are needed to promote appropriate antibiotic usage and optimize patient care.

Management and prevention of diabetic foot ulcers and infections: a health economic review.

Diabetic foot ulcers and infections are common and incur substantial economic burden for society, patients and families. We performed a comprehensive review, on a number of databases, of health economic evaluations of a variety of different prevention, diagnostic and treatment strategies in the area of diabetic foot ulcers and infections. We included English-language, peer-reviewed, cost-effectiveness, cost-minimization, cost-utility and cost-benefit studies that evaluated a treatment modality against placebo or comparator (i.e. drug, standard of care), regardless of year. Differences were settled through consensus. The search resulted in 1885 potential citations, of which 20 studies were retained for analysis (3 cost minimization, 13 cost effectiveness and 4 cost utility). Quality scores of studies ranged from 70.8% (fair) to 87.5% (good); mean = 78.4% +/- 5.33%.In diagnosing osteomyelitis in patients with diabetic foot infection, magnetic resonance imaging (MRI) showed 82% sensitivity and 80% specificity. MRI cost less than 3-phase bone scanning + Indium (In)-111/Gallium (Ga)-67; however, when compared with prolonged antibacterials, MRI cost $US120 (year 1993 value) more without additional quality-adjusted life-expectancy. Prevention strategies improved life expectancy and QALYs and reduced foot ulcer rates and amputations.Ampicillin/sulbactam and imipenem/cilastatin were both 80% successful in treating diabetic foot infections but the latter cost $US2924 more (year 1994 value). Linezolid cure rates were higher (97.7%) than vancomycin (86.0%) and cost $US873 less (year 2004 value). Ertapenem costs were significantly lower than piperacillin/tazobactam ($US356 vs $US503, respectively; year 2005 values). Becaplermin plus good wound care may be cost effective in specific populations. Bioengineered living-skin equivalents increased ulcer-free months and ulcers healed, but costs varied between countries. Promogran produced more ulcer-free months than wound care alone (3.75 vs 3.41 months, respectively). Treatment with cadexomer iodine resulted in higher rates of healed ulcer (29% vs 11%) and lower weekly treatment costs (Swedish krona [SEK]903 vs SEK1421; year 1993 values) than standard care. Filgrastim decreased hospital stays, time to resolution and costs (36% lower) compared with usual care. Adjunctive hyperbaric oxygen produced an incremental cost per QALY at year 1 of $US27 310 and $US2255 at year 12 (year 2001 values).Overall, preventive strategies were shown to be cost effective and potentially cost saving. Various antibacterial regimens are cost effective but empiric choices should be based on local resistance patterns. MRI was cost effective compared with three-phase bone scanning + In-111/Ga-67 but not against prolonged antibacterial therapy. Other innovations (becaplermin, bioengineered living-skin equivalents, filgrastim, cadexomer iodine ointment, hyperbaric oxygen, Promogran may be cost effective in this population but more studies are needed to confirm these findings.

Meropenem Assessment before and after Implementation of a Small-Dose, Short-Interval Standard Dosing Regimen.

BACKGROUND: Small-dose, short-interval dosing for meropenem has been shown to yield pharmacokinetic and pharmacodynamic properties similar to those associated with traditional dosing of this drug. However, few studies have examined clinical outcomes in the general population. OBJECTIVES: To characterize differences in effects between a small-dose, short-interval dosing regimen for meropenem (500 mg every 6 h) and the traditional regimen (1000 mg every 8 h) on clinical outcomes and costs to the health care system. METHODS: This retrospective cohort study included 194 patients who received the traditional meropenem dosage (July 2006 to August 2008) and 188 patients who received the small-dose, short-interval regimen (December 2008 and October 2009) at a large tertiary care hospital and a community hospital. The primary outcome (clinical success), the secondary outcomes (30-day in-hospital mortality, time to defervescence, duration of therapy, and length of stay), and drug costs were compared between cohorts. RESULTS: The 2 cohorts did not differ significantly in terms of baseline characteristics. There was no statistically significant difference between the small-dose, short-interval regimen and the traditional dosing regimen in terms of the primary outcome: clinical success was achieved in 83.5% (162/194) and 80.8% (152/188) of the patients, respectively. Likewise, there was no statistically significant difference in any of the secondary outcomes. The average drug cost per patient per visit was $222.23 with small-dose, short-interval dosing and $355.90 with traditional dosing, a significant difference of more than $130 per patient per visit. CONCLUSION: The small-dose, short-interval meropenem dosing regimen resulted in clinical outcomes similar to those achieved with the traditional dosing regimen at significantly lower cost.

CONTEXTE: Selon des études, un schéma posologique de méropénème avec administration d'une faible dose à intervalle réduit produit des résultats pharmacocinétiques et pharmacodynamiques semblables à ceux obtenus avec une posologie traditionnelle. Mais peu d'études ont examiné les résultats cliniques dans la population générale. OBJECTIF: Offrir un portrait des différences entre les effets d'un schéma posologique de méropénème avec administration d'une faible dose à intervalle réduit (500 mg toutes les 6 heures) et d'une posologie traditionnelle (1000 mg toutes les 8 heures) pour ce qui est des résultats cliniques et des coûts pour le système de santé. MÉTHODES: La présente étude de cohorte rétrospective incluait 194 patients ayant reçu le méropénème selon le schéma posologique traditionnel (entre juillet 2006 et août 2008) et 188 patients l'ayant reçu avec administration d'une faible dose à intervalle réduit (entre décembre 2008 et octobre 2009) dans un grand hôpital de soins tertiaires et un hôpital communautaire. Le principal paramètre d'évaluation (succès clinique), les paramètres d'évaluation secondaires (taux de mortalité à l'hôpital dans les 30 jours, période de défervescence, durée du traitement et durée du séjour) et les coûts des médicaments ont été comparés entre les cohortes. RÉSULTATS: Les deux cohortes n'étaient pas significativement différentes en ce qui touche aux caractéristiques de base. Il n'y avait aucune différence statistiquement significative entre le schéma posologique avec administration d'une faible dose à intervalle réduit et la posologie traditionnelle en ce qui concerne le principal paramètre d'évaluation : le succès clinique a été obtenu respectivement chez 83,5 % (162/194) et chez 80,8 % (152/188) des patients. De même, aucune différence statistiquement significative n'a été relevée pour les paramètres d'évaluation secondaires. Par contre, le coût moyen des médicaments par patient par visite était de 222,23 $ pour le schéma posologique avec administration d'une faible dose à intervalle réduit et de 355,90 $ pour la posologie traditionnelle, une différence significative de plus de 130 $ par patient par visite (p < 0,001). CONCLUSION: Le schéma posologique de méropénème avec administration d'une faible dose à intervalle réduit produisait des résultats cliniques semblables à ceux de le posologie traditionnelle, et ce, pour un prix significativement plus faible.

Evaluation of an alcohol withdrawal protocol and a preprinted order set at a tertiary care hospital.

BACKGROUND: Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear. OBJECTIVE: To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital. METHODS: A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications. RESULTS: A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups. CONCLUSIONS: Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration of benzodiazepine use and a lower incidence of severe complications of alcohol withdrawal.