Antimicrobial stewardship in the primary care setting: from dream to reality?

BACKGROUND: Clinicians who work in primary care are potentially the most influential healthcare professionals to address the problem of antibiotic resistance because this is where most antibiotics are prescribed. Despite a number of evidence based interventions targeting the management of community infections, the inappropriate antibiotic prescribing rates remain high. DISCUSSION: The question is how can appropriate prescribing of antibiotics through the use of Antimicrobial Stewardship (AMS) programs be successfully implemented in primary care. We discuss that a top-down approach utilising a combination of strategies to ensure the sustainable implementation and uptake of AMS interventions in the community is necessary to support clinicians and ensure a robust implementation of AMS in primary care. Specifically, we recommend a national accreditation standard linked to the framework of Core Elements of Outpatient Antibiotic Stewardship, supported by resources to fund the implementation of AMS interventions that are connected to quality improvement initiatives. This article debates how this can be achieved. The paper highlights that in order to support the sustainable uptake of AMS programs in primary care, an approach similar to the hospital and post-acute care settings needs to be adopted, utilising a combination of behavioural and regulatory processes supported by sustainable funding. Without these strategies the problem of inappropriate antibiotic prescribing will not be adequately addressed in the community and the successful implementation and uptake of AMS programs will remain a dream.

McArdle disease causing rhabdomyolysis following vaginal delivery.

McArdle disease (glycogen storage disease type V) is a rare, autosomal recessive disorder with an incidence of roughly 1:100,000. Despite concern that labour could predispose these patients to muscle damage, there are no evidence-based guidelines for the management of labour and delivery in this population. We describe the case of a nulliparous parturient with both McArdle disease and adenosine monophosphate deaminase 1 deficiency who developed rhabdomyolysis after vaginal delivery. In the absence of common triggers, we believe that prolonged pushing efforts contributed to the increase in postpartum creatinine kinase. There are no previous cases of postpartum rhabdomyolysis after caesarean or assisted vaginal delivery within 45 min. We recommend that practitioners be alert to the possibility of rhabdomyolysis occurring with greater than 2 h of pushing efforts in parturients with McArdle disease.

A comparison of drug substance predicted chemical stability with ICH compliant stability studies.

OBJECTIVE: The aim of this study is to demonstrate the applicability of predictive stability studies to the degradation of drug substances. SIGNIFICANCE: The use of predicted stability studies during pharmaceutical development and in regulatory submissions is increasing, particularly in early phase to support an initial retest period/shelf life claim in the absence of standard stability data. These studies offer an alternative to standard stability testing and can facilitate clinical trials to be started earlier and medicines to reach patients faster. They involve a short-term stressed stability study, typically designed to degrade a drug substance or product to the specification level of the shelf life limiting attribute. The results are used to predict degradation under long-term storage conditions and enable stability understanding to be gained over a short time frame, using limited amounts of material. METHODS: In this work, Accelerated Stability Assessment Program (ASAP) studies were performed for 10 different drug substances and the predictions obtained for chemical degradation were compared to ICH compliant stability data. RESULTS: Across the studies good agreement was achieved, with the initial retest period predictions from the ASAP studies being conservative by design. When minimal degradation was observed during an ASAP study, it was demonstrated that at least a 12-month initial retest period could be supported. CONCLUSION: This comparison of ASAP predictions and ICH compliant stability data has demonstrated the ability of well-designed ASAP studies to predict the long-term chemical stability of drug substances.

Antibiotic use and childhood body mass index trajectory.

BACKGROUND/OBJECTIVES: Antibiotics are commonly prescribed for children. Use of antibiotics early in life has been linked to weight gain but there are no large-scale, population-based, longitudinal studies of the full age range among mainly healthy children. SUBJECTS/METHODS: We used electronic health record data on 163 820 children aged 3-18 years and mixed effects linear regression to model associations of antibiotic orders with growth curve trajectories of annual body mass index (BMI) controlling for confounders. Models evaluated three kinds of antibiotic associations-reversible (time-varying indicator for an order in year before each BMI), persistent (time-varying cumulative orders up to BMIj) and progressive (cumulative orders up to prior BMI (BMIj-1))-and whether these varied by age. RESULTS: Among 142 824 children under care in the prior year, a reversible association was observed and this short-term BMI gain was modified by age (P<0.001); effect size peaked in mid-teen years. A persistent association was observed and this association was stronger with increasing age (P<0.001). The addition of the progressive association among children with at least three BMIs (n=79 752) revealed that higher cumulative orders were associated with progressive weight gain; this did not vary by age. Among children with an antibiotic order in the prior year and at least seven lifetime orders, antibiotics (all classes combined) were associated with an average weight gain of approximately 1.4 kg at age 15 years. When antibiotic classes were evaluated separately, the largest weight gain at 15 years was associated with macrolide use. CONCLUSIONS: We found evidence of reversible, persistent and progressive effects of antibiotic use on BMI trajectories, with different effects by age, among mainly healthy children. The results suggest that antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies.

A population-based study of the epidemiology and clinical features of methicillin-resistant Staphylococcus aureus infection in Pennsylvania, 2001-2010.

No U.S. general population-based study has characterized the epidemiology and risk factors, including skin and soft tissue infection (SSTI), for healthcare-associated (HA) and community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA). We estimated the incidence of HA- and CA-MRSA and SSTI over a 9-year period using electronic health record data from the Geisinger Clinic in Pennsylvania. MRSA cases were frequency-matched to SSTI cases and controls in a nested case-control analysis. Logistic regression was used to assess risk factors, while accounting for antibiotic administration. We identified 1713 incident CA- and 1506 HA-MRSA cases and 78 216 SSTI cases. On average, from 2005 to 2009, the annual incidence of CA-MRSA increased by 34%, HA-MRSA by 7%, and SSTI by 4%. Age, season, community socioeconomic deprivation, obesity, smoking, previous SSTI, and antibiotic administration were identified as independent risk factors for CA-MRSA.

Multistate outbreak of Escherichia coli O157:H7 infections associated with in-store sampling of an aged raw-milk Gouda cheese, 2010.

In 2010, 41 patients ill with Escherichia coli O157:H7 isolates determined to be indistinguishable by pulsed-field gel electrophoresis were identified among residents of five Southwestern U.S. states. A majority of patients reported consuming complimentary samples of aged raw-milk Gouda cheese at national warehouse chain store locations; sampling Gouda cheese was significantly associated with illness (odds ratio, 9.0; 95 % confidence interval, 1.7 to 47). Several Gouda samples yielded the O157:H7 outbreak strain, confirming the food vehicle and source of infections. Implicated retail food-sampling operations were inconsistently regulated among affected states, and sanitation deficiencies were common among sampling venues. Inspection of the cheese manufacturer indicated deficient sanitation practices and insufficient cheese curing times. Policymakers should continue to reexamine the adequacy and enforcement of existing rules intended to ensure the safety of raw-milk cheeses and retail food sampling. Additional research is necessary to clarify the food safety hazards posed to patrons who consume free food samples while shopping.

Early prediction of cardiac allograft vasculopathy and heart transplant failure.

Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.

Multiple risk factors associated with a large statewide increase in cryptosporidiosis.

Cryptosporidium species have emerged as a major cause of outbreaks of diarrhoea and have been associated with consumption of contaminated recreational and drinking water and food as well as contact with infected attendees of child-care programmes. In August 2007, the Colorado Department of Public Health and Environment detected an increase in cryptosporidiosis cases over baseline values. We conducted a case-control study to assess risk factors for infection and collected stool specimens from ill persons for microscopy and molecular analysis. Laboratory-confirmed cases (n=47) were more likely to have swallowed untreated water from a lake, river, or stream [adjusted matched odds ratio (aOR) 8.0, 95% confidence interval (CI) 1.3-48.1], have had exposure to recreational water (aOR 4.6, 95% CI 1.4-14.6), or have had contact with a child in a child-care programme or in diapers (aOR 3.8, 95% CI 1.5-9.6). Although exposure to recreational water is commonly implicated in summertime cryptosporidiosis outbreaks, this study demonstrates that investigations of increased incidence of cases in summer should also examine other potential risk factors. This study emphasizes the need for public health education efforts that address the multiple transmission routes for Cryptosporidium and appropriate prevention measures to avoid future transmission.

Contribution of calcium-containing crystals to cartilage degradation and synovial inflammation in osteoarthritis.

OBJECTIVES: The role of calcium phosphate and pyrophosphate crystals in osteoarthritis (OA) is unclear: are they a symptom of the damage that occurs to the joint or a key intermediate in the progression of inflammation and joint damage that occurs in OA? The proinflammatory and catabolic response of synthetic calcium phosphate and pyrophosphate crystals and crystals extracted from human osteoarthritic knee cartilage has been investigated. The crystal forms eliciting a response have been characterised allowing a comparison of the biological effects of synthetic and native calcium crystals on human osteoarthritic chondrocytes and synoviocytes to be carried out. METHODS: Calcium phosphate and pyrophosphate crystals were synthesised in vitro and their crystal forms characterised by X-ray powder diffraction (XRPD). The inorganic crystalline material present in human osteoarthritic cartilage was extracted and its structural composition elucidated by XRPD. These crystals were applied to human primary osteoarthritic chondrocytes and synoviocytes and the production of proinflammatory and catabolic mediators measured. RESULTS: The crystals extracted from human osteoarthritic knee cartilage were identified as consisting of a mixture of monoclinic and triclinic calcium pyrophosphate dihydrate (m-CPPD and t-CPPD). These crystals elicited an inflammatory and catabolic response in human primary osteoarthritic chondrocytes and synoviocytes as measured by an increase in nitric oxide (NO), matrix metalloproteinase 13 (MMP-13) and prostaglandin E2 (PGE(2)) production. NO, MMP-13 and PGE(2) production was also increased when the synthetic calcium hydrogen phosphate dihydrate (DCPD) and calcium pyrophosphate hydrates were applied to the cells. CONCLUSIONS: Crystals extracted from human osteoarthritic knee cartilage induce the production of proinflammatory and catabolic mediators (NO, MMP-13 and PGE(2)) in human primary chondrocytes and synoviocytes. Synthetic calcium phosphate and pyrophosphate crystals elicit a similar response in those cells. Our findings suggest that these crystals could contribute to cartilage degradation and synovitis in OA.

Outcomes with daptomycin versus standard therapy for osteoarticular infections associated with Staphylococcus aureus bacteraemia.

OBJECTIVES: To evaluate the clinical characteristics, treatment and outcomes of patients with osteoarticular infections (OAIs) associated with Staphylococcus aureus bacteraemia (SAB). METHODS: The clinical characteristics and outcomes for patients with OAI were described using a post hoc analysis of an open label, randomized trial comparing daptomycin with standard therapy (vancomycin or anti-staphylococcal penicillin with initial gentamicin) for the treatment of SAB. RESULTS: OAI occurred in 32 of 121 patients (21 daptomycin and 11 standard therapy) with complicated SAB (18 septic arthritis, 9 vertebral osteomyelitis and 7 others). Two patients had osteomyelitis in more than one site. Success rates seen in two groups were as follows: vertebral osteomyelitis [3/5 (60%) daptomycin versus 0/2 (0%) comparator], septic arthritis [7/11 (64%) versus 3/5 (60%)], sternal osteomyelitis [3/3 (100%) versus 1/2 (50%)] and long bone osteomyelitis [0/1 (0%) versus 1/1 (100%)]. Success rates in both treatment groups improved with surgical therapy. Creatine phosphokinase elevations to >500 IU/L occurred in one patient on daptomycin who discontinued therapy, whereas renal impairment developed in three patients on standard therapy, two of whom discontinued therapy. Two patients treated with daptomycin and one patient on vancomycin had increases in S. aureus MICs to daptomycin and vancomycin, respectively. Three patients treated with daptomycin died following completion of therapy, with mortality attributed to multiple co-morbid conditions and inadequate debridement of OAIs in these patients. No deaths were reported in the standard therapy group. CONCLUSIONS: Daptomycin may be considered an alternative to standard therapy in the treatment of patients with complicated SAB and OAI.

Poverty, health and participation.

Poverty is an important influence on health and despite continuing economic growth, poverty and health inequalities persist. Current public policy aims to reduce the inequalities in the health, by focussing on the social factors influencing health, improving access to health and personal social services for those who are poor or socially excluded and by improving the information and research base in respect of the health status and service access for the poor and socially excluded groups. It is important that processes for target setting and evaluation involve people experiencing poverty, at all levels through consultative and participative structures and processes and in the roll-out of primary care teams. A number of projects throughout the country aim to address health inequalities using community development. These are essentially about widening participation in the development, planning and delivery of health services and ensuring that the community is actively involved in the decision making process about health services in their area.

Understanding the polymorphic behavior of sibenadet hydrochloride through detailed studies integrating structural and dynamical assessment.

Three polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan) have been shown to exist at ambient temperature and have been characterized. Each undergoes a solid-state transition to a common high temperature form, which melts at approximately 220 degrees C. X-ray powder diffraction (XRPD) indicates that Polymorphs I and II share a similar layered structure not exhibited by Polymorph III. All three ambient temperature polymorphs show evidence of varying degrees of dynamic disorder of the terminal phenyl group as shown by solid-state NMR spectroscopy. Furthermore, the carbons alpha to the ether link also undergo different rates of mobility in Polymorphs I and II. This variation in the extent of dynamic disorder results in an alteration in the short-range structure resulting in distinct polymorphs. Polymorph I is the thermodynamically stable form at room temperature as indicated by solution calorimetry and assessment by thermodynamically driven solution mediated phase transition studies. The present study aims to address the types of discriminatory data required to make a clear distinction between physical forms and define, unequivocally, the presence of polymorphism.

Staphylococcus aureus with reduced susceptibility to vancomycin.

Infections with Staphylococcus aureus with reduced susceptibility to vancomycin continue to be reported, including 2 cases caused by S. aureus isolates with full resistance to vancomycin. This review first outlines the definitions of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) and risk factors for infection. Next, we describe the mechanisms of resistance and methods of laboratory detection of the organisms. Finally, we address infection control and management issues associated with isolation of VISA and VRSA.

Risk factors for emergence of resistance to broad-spectrum cephalosporins among Enterobacter spp.

Among 477 patients with susceptible Enterobacter spp., 49 subsequently harbored third-generation cephalosporin-resistant Enterobacter spp. Broad-spectrum cephalosporins were independent risk factors for resistance (relative risk [OR] = 2.3, P = 0.01); quinolone therapy was protective (OR = 0.4, P = 0.03). There were trends toward decreased risk for resistance among patients receiving broad-spectrum cephalosporins and either aminoglycosides or imipenem. Of the patients receiving broad-spectrum cephalosporins, 19% developed resistance.

Complications of treatment with local field external beam radiotherapy for localized prostate cancer.

We performed this analysis to document the rate and severity of complications both during and after local field irradiation for localized prostate cancer and to assess the influence of three-dimensional conformal radiation therapy (3DCRT) on these complications. Bowel, urinary and cutaneous toxicities were noted in all patients treated with primary radiotherapy (RT) for prostate cancer using Radiation Therapy Oncology Group/European Organization for Research on Treatment of Cancer scores. Evaluations were performed weekly during RT, 6 weeks after RT and 3 monthly thereafter. Data on 111 were analysed. We also compared the complications of conventional and 3DCRT. The serious complication rates identified in this study compare favourably with those reported in the literature. Only 3.6%, 0.8% and 0% had acute grade 3 or 4 urinary, bowel or skin reactions respectively. Only two patients had chronic grade 3 or 4 urinary complications. Thus far no patients have developed chronic bowel or skin complications greater than grade 2. Despite dose escalation from 66 Gy to 70 Gy (with 3DCRT), there was a trend towards reduced toxicity when 3DCRT was compared with conventional radiation. RT is a well-tolerated treatment for early stage carcinoma of the prostate and our complication rates are compatible with international experiences. Further follow-up is required to determine the efficacy of treatment, the incidence of impotence and the final number of late complications.

Efficacy of florfenicol for treatment of naturally occurring infectious bovine keratoconjunctivitis.

OBJECTIVE: To determine the efficacy of florfenicol for treatment of calves with naturally occurring infectious bovine keratoconjunctivitis (IBK). DESIGN: Randomized controlled field trial. ANIMALS: 63 beef calves and 80 dairy calves between 4 and 12 months of age. PROCEDURE: Calves were randomly assigned to 1 of 3 treatment groups. Calves in the SC treatment group received a single dose of florfenicol (40 mg/kg [18.2 mg/lb of body weight), SC, on day 0. Calves in the IM treatment group received florfenicol (20 mg/kg [9.1 mg/lb]), IM, on days 0 and 2. Calves in the control group received injections of saline solution (0.9% NaCl), IM, on days 0 and 2. Calves were reevaluated every other day for 20 days after treatment. RESULTS: Corneal ulcers healed by day 20 in 48 of 49 (98%) calves treated with florfenicol IM, 39 of 42 (93%) calves treated with florfenicol SC, and 33 of 52 (63%) control calves. CONCLUSIONS AND CLINICAL RELEVANCE: Florfenicol administered SC (1 dose) or IM (2 doses 48 hours apart) was effective for treatment of calves with naturally occurring IBK.

Efficacy of florfenicol in the treatment of experimentally induced infectious bovine keratoconjunctivitis.

OBJECTIVE: To evaluate efficacy of florfenicol in an induced model of infectious bovine keratoconjunctivitis, using a blinded randomized, controlled trial. ANIMALS: 48 male Holstein calves, 2 to 4 months old. PROCEDURE: Moraxella bovis infection was induced in all calves. When corneal ulcers developed, each calf was assigned randomly to 1 of 3 treatment groups, using a block design determined by corneal ulcer size (day 0). Calves were treated with florfenicol (20 mg/kg of body weight, IM) on days 0 and 2 (IM group; n = 16). Calves of a second group received a single dose of florfenicol (40 mg/kg, SC) on day 0 (SC group; n = 16). The third group of calves was not treated (control group; n = 16). Corneal ulcers were photographed, and each calf was assessed for 30 days after treatment for 10 clinical signs of infection. Corneal ulcer surface areas were measured, and clinical scores were calculated. Ocular secretions for microbiologic culture were obtained weekly from each eye. RESULTS: A Cox regression model indicated that, after adjustment for initial ulcer size, healing rates were 6.2 and 4.8 times greater in calves of the IM and SC groups, respectively, compared with the control group. Clinical scores and surface area measurements for treatment groups were significantly smaller than those for controls during posttreatment weeks 1 through 4. From day 8 through day 29, M bovis was isolated from ocular secretions of 14 of 16 control calves and 1 of 32 treated calves. CONCLUSIONS AND CLINICAL RELEVANCE: Parenterally administered florfenicol reduces corneal ulcer healing time, lessens clinical severity, and reduces the amount of bacterial shedding from calves infected with M bovis.

[Reasons for anxiety in primary care professionals. A resident-tutor comparison]. / Motivos de ansiedad en los profesionales de atención primaria. Comparación residentes-tutores.

OBJECTIVES: 1) To find the reasons for PC professionals' anxiety when going about their normal work. 2) To check whether training and experience affect the assessment of the reasons of Family Doctors for anxiety. DESIGN: A descriptive study using a questionnaire. SETTING: PC health centres with second-year family and community medicine (FCM) residents from the Murcia Teaching Unit. PARTICIPANTS: All second-year FCM residents from the Teaching Unit (28) in December 1995 and their tutors. MEASUREMENTS: Open questionnaire based on three points: Causes of anxiety in on-demand consultations; causes of anxiety in scheduled consultations; other reasons for anxiety connected with the Health Centre. RESULTS: The three most anxiety-producing causes in relation to each question were: a) on-demand consultation: residents (R)--unfinishable consultations, lack of time, clinical problems; tutors (T)--unfinishable consultations, a lot of patients waiting outside, manipulative patients. b) Scheduled consultation: R--clinical problems, consultation too long, difficulties in reaching a solution; T--consultation too long, patients without an appointment and interruptions in the middle of the consultation. c) Other reasons for anxiety: R--not being off the day after being on call, having to do research work, and emergency calls; T--emergency calls, research work and temperature problems. CONCLUSIONS: Clinical problems are the causes of anxiety with the greatest difference between tutors and residents. Regulated training in the health centre and professional experience seem to act positively on some of the causes of anxiety.