Rune Aabenhus

Mortality in enterococcal bloodstream infections increases with inappropriate antimicrobial therapy

Enterococcus species are common in nosocomial bloodstream infections and their incidence is rising. Although well recognized in several serious bacterial infections, the influence of appropriate antimicrobial therapy in enterococcal bacteraemia has not been fully settled. The aim of the study was to determine whether administration of inappropriate antibiotics in enterococcal bacteraemia is an independent risk factor for mortality, among other known and suspected risk factors. We conducted a cohort study of E. faecalis/faecium bacteraemia during a 3-year period at a single tertiary care hospital in Denmark. Patients with growth of non-enterococcus co-pathogens apart from the enterococcal bacteraemia were also included, as were patients with repeated enterococcal bacteraemia. Time to appropriate antimicrobial therapy was counted from the first episode. Appropriate antibiotic therapy was defined as any therapy with documented clinical effect, in vitro activity and a minimum treatment length of 6 days. Multivariate regression models were built to determine the independent risk factors for mortality. We included 196 patients with enterococcal bacteraemia. Appropriate antibiotics for at least 6 days were administered in 146 of these (74%). Thirty-day mortality was 26%. Multivariate logistic regression identified independent predictors of 30-day all-cause mortality: appropriate antimicrobial therapy for ≥ 6 days (odds ratio for mortality 0.33, 0.14-0.79), ICU admission (4.2, 1.7-10), thrombocytopenia (3.9, 1.6-9.3), chronic liver failure (3.3, 1.1-10) and age ≥ 60 years (2.2, 0.99-5.0). Antibiotics not appropriately covering enterococci are frequently administered empirically in suspected bloodstream infections. Inappropriate antibiotic therapy was an independent risk factor for mortality in enterococcal bacteraemia.

Use of antibiotics in children: a Danish nationwide drug utilization study.

Background: We aimed to describe the use of systemic antibiotics among children in Denmark. Methods: National data on drug use in Denmark were extracted from the Danish National Prescription Database. We used prescription data for all children in Denmark aged 0 to 11 years from January 1, 2000 to December 31, 2012. Results: We obtained data on 5,884,301 prescriptions for systemic antibiotics issued to 1,206,107 children. The most used single substances were phenoxymethylpenicillin (45%), amoxicillin (34%) and erythromycin (6%). The highest incidence rate of antibiotic treatment episodes was observed among children younger than 2 at 827 per 1000 children in 2012. Incidence rates were relatively stable throughout the study period. One-year prevalences in 2012 were 485, 363 and 190 per 1000 children among children aged 0–1, 2–4 and 5–11, respectively. A gradual shift from narrow-spectrum penicillin V to the broader-spectrum amoxicillin was found among children younger than 5. The use of macrolides decreased slightly, especially among those aged 0–1. Minor regional differences were noted, with somewhat higher use in the Capital Region. Skewness in use was most notable among those aged 0–1. There was little evidence of heavy users. Conclusion: Prescribing rate of antibiotics to children in Denmark remained stable at a high level from 2000 to 2012. An increase in the use of broad-spectrum beta-lactam penicillin was noted, but otherwise the prescribing pattern adhered well to National guidelines with respect to choice of antibiotics.

Childhood asthma in low income countries: an invisible killer?

Bacterial pneumonia has hitherto been considered the key cause of the high respiratory morbidity and mortality in children under five years of age (under-5s) in low-income countries, while asthma has not been stated as a significant reason. This paper explores the definitions and concepts of pneumonia and asthma/wheezing/bronchiolitis and examines whether asthma in under-5s may be confused with pneumonia. Over-diagnosing of bacterial pneumonia can be suspected from the limited association between clinical pneumonia and confirmatory test results such as chest x-ray and microbiological findings and poor treatment results using antibiotics. Moreover, children diagnosed with recurrent pneumonia in infancy were often later diagnosed with asthma. Recent studies showed a 10-15% prevalence of preschool asthma in low-income countries, although under-5s with long-term cough and difficulty breathing remain undiagnosed. New studies demonstrate that approximately 50% of acutely admitted under-5s diagnosed with pneumonia according to Integrated Management of Childhood Illnesses could be re-diagnosed with asthma or wheezing when using re-defined diagnostic criteria and treatment. It is hypothesised that untreated asthma may contribute to respiratory mortality since respiratory syncytial virus (RSV) is an important cause of respiratory death in childhood, and asthma in under-5s is often exacerbated by viral infections, including RSV. Furthermore, acute respiratory treatment failures were predominantly seen in under-5s without fever, which suggests the diagnosis of asthma/wheezing rather than bacterial pneumonia. Ultimately, underlying asthma may have contributed to malnutrition and fatal bacterial pneumonia. In conclusion, preschool asthma in low-income countries may be significantly under-diagnosed and misdiagnosed as pneumonia, and may be the cause of much morbidity and mortality.

Prescribing style and variation in antibiotic prescriptions for sore throat: cross-sectional study across six countries

BackgroundVariation in prescription of antibiotics in primary care can indicate poor clinical practice that contributes to the increase of resistant strains. General Practitioners (GPs), as a professional group, are expected to have a fairly homogeneous prescribing style. In this paper, we describe variation in prescribing style within and across groups of GPs from six countries.MethodsCross-sectional study with the inclusion of 457 GPs and 6394 sore throat patients. We describe variation in prescribing antibiotics for sore throat patients across six countries and assess whether variation in “prescribing style” – understood as a subjective tendency to prescribe – has an important effect on variation in prescription of antibiotics by using the concept of prescribing style as a latent variable in a multivariable model. We report variation as a Median Odds Ratio (MOR) which is the transformation of the random effect variance onto an odds ratio; Thus, MOR = 1 means similar odds or strict homogeneity between GPs’ prescribing style, while a MOR higher than 1 denotes heterogeneity in prescribing style.ResultsIn all countries some GPs always prescribed antibiotics to all their patients, while other GPs never did. After adjusting for patient and GP characteristics, prescribing style in the group of GPs from Russia was about three times more heterogeneous than the prescribing style in the group of GPs from Denmark – Median Odds Ratio (6.8, 95% CI 3.1;8.8) and (2.6, 95% CI 2.2;4.4) respectively.ConclusionPrescribing style is an important source of variation in prescription of antibiotics within and across countries, even after adjusting for patient and GP characteristics. Interventions aimed at influencing the prescribing style of GPs must encompass context-specific actions at the policy-making level alongside GP-targeted interventions to enable GPs to react more objectively to the external demands that are in place when making the decision of prescribing antibiotics or not.

Procalcitonin-guided antibiotic treatment of respiratory tract infections in a primary care setting: are we there yet?

Clinical signs of infection do not allow for correct identification of bacterial and viral aetiology in acute respiratory infections. A valid tool to assist the clinician in identifying patients who will benefit from antibiotic therapy, as well as patients with a potentially serious infection, could greatly improve patient care and limit excessive antibiotic prescriptions. Procalcitonin is a new marker of suspected bacterial infection that has shown promise in guiding antibiotic therapy in acute respiratory tract infections in hospitals without compromising patient safety. Procalcitonin concentrations in primary care are low and can be used primarily to rule out serious infection. However, procalcitonin measurement should not be used as the sole basis for clinical decisions; clinical skills are prerequisites for the correct use of this new tool in practice. At present there is no point-of-care test for procalcitonin with acceptable precision, severely hampering its application in primary care. This article reviews the physiology of procalcitonin, describes the assays available for its measurement, evaluates the present evidence from primary care on its use to identify correctly patients who are likely to benefit from antibiotic treatment and to rule out serious infections, and comments on further research to determine a future role for procalcitonin in primary care.

Urine sampling techniques in symptomatic primary-care patients: a diagnostic accuracy review

BackgroundChoice of urine sampling technique in urinary tract infection may impact diagnostic accuracy and thus lead to possible over- or undertreatment. Currently no evidencebased consensus exists regarding correct sampling technique of urine from women with symptoms of urinary tract infection in primary care. The aim of this study was to determine the accuracy of urine culture from different sampling-techniques in symptomatic non-pregnant women in primary care.MethodsA systematic review was conducted by searching Medline and Embase for clinical studies conducted in primary care using a randomized or paired design to compare the result of urine culture obtained with two or more collection techniques in adult, female, non-pregnant patients with symptoms of urinary tract infection. We evaluated quality of the studies and compared accuracy based on dichotomized outcomes.ResultsWe included seven studies investigating urine sampling technique in 1062 symptomatic patients in primary care. Mid-stream-clean-catch had a positive predictive value of 0.79 to 0.95 and a negative predictive value close to 1 compared to sterile techniques. Two randomized controlled trials found no difference in infection rate between mid-stream-clean-catch, mid-stream-urine and random samples.ConclusionsAt present, no evidence suggests that sampling technique affects the accuracy of the microbiological diagnosis in non-pregnant women with symptoms of urinary tract infection in primary care. However, the evidence presented is in-direct and the difference between mid-stream-clean-catch, mid-stream-urine and random samples remains to be investigated in a paired design to verify the present findings.

Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish general practice: a retrospective registry based cohort study

Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed. We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice. Acute respiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 and June 2013. Pneumonia was the most common indication with 178,354 prescriptions (39%), followed by acute tonsillitis (21%) and acute otitis media (19%). In total, penicillin V accounted for 58% of all prescriptions, followed by macrolides (18%) and amoxicillin (15%). The use of second-line agents increased with age for all indications, and comprised more than 40% of the prescriptions in patients aged >75 years. Women were more often prescribed antibiotics regardless of clinical indication. This is the first Danish study to characterise antibiotic prescription patterns for acute respiratory tract infections by data linkage of clinical indications. The findings confirm that penicillin V is the most commonly prescribed antibiotic agent for treatment of patients with an acute respiratory tract infection in Danish general practice. However, second-line agents like macrolides and amoxicillin with or without clavulanic acid are overused. Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitis media and acute rhinosinusitis are warranted.Respiratory tract infections: Tracking the overuse of antibioticsBetter adherence to guidelines for prescribing antibiotics for different respiratory tract infections are warranted in Danish general practice. The over-use of antibiotics, particularly so-called ‘second-line’ agents such as amoxicillin, increases resistance and may lead to a potentially catastrophic scenario where antibiotics are no longer effective. Exactly how widespread the over-use of antibiotics is for different infections, however, is not clear. Rune Aabenhus at the University of Copenhagen and co-workers analyzed primary care data regarding antibiotic prescriptions for acute respiratory tract infections including pneumonia and ear infections in Denmark. They found that penicillin V—the current recommended first-line drug in Scandinavian countries—accounted for 58 per cent of prescriptions, a figure which should be improved. Amoxicillin and macrolides were over-prescribed, particularly in elderly patients. The team also call for further analysis of prescriptions given by out-of-hours clinics.

Biomarker-guided antibiotic use in primary care in resource-constrained environments

Because of antimicrobial resistance, the global overuse of antibiotics is now a threat to one of the most eff ective and mortality-lowering interventions in modern medicine. One of the most important challenges is to substantially lower the use of antibiotics when these drugs are not needed. The fear of missing a severe case of pneumonia can incit e health-care providers to ignore the fact that, in many non-severe cases of respiratory tract infections, antibiotic treatment will probably not markedly alter the outcome for the individual patient. Reduction of antibiotic use will require reliable and broadly applicable segregation of non-bacterial infection and trivial bacterial infections from serious bacterial infections. In The Lancet Global Health, Nga Do and colleagues report the results of a large (more than 2000 participants) randomised controlled trial of a point-of-care antibiotic strategy guided by C-reactive protein concentrations compared with usual best practice in primary care patients with non-severe acute respiratory tract infection in Vietnam. The results demonstrate that a point-of-care C-reactive protein intervention can reduce antibiotic prescribing in this setting, albeit with only a moderate reduction in absolute risk (adjusted 12·5%; intervention 64·4% vs control 77·9%). Importantly, there were no apparent diff erences in serious adverse eff ects or delayed patient recovery. Do and colleagues should be congratulated on completing this ambitious, large-scale trial to assess a point-of-care biomarker-guided antibiotic strategy in a resource-constrained environment. The results expand the current evidence base by showing that such a stewardship approach is applicable in lowincome and middle-income countries. Furthermore, Do and colleagues performed a very sensitive sample size calculation to prove the trial robust for subgroup analysis in children. The eff ect size was similar to adults. The results support the fi ndings from randomised trials in Europe, summarised in a 2014 Cochrane review, which found C-reactive protein eff ective in reducing antibiotic use with no apparent risk to patient safety. So, why was the eff ect of the current approach only moderate? Some limitations to the study should be mentioned. First, the cut-off applied in the current study (10 mg/L in children younger than 6 years, 20 mg/L in all other patients) is low, allowing for antibiotic use in many low-risk patients and patients without bacterial infection. Second, overruling of the algorithm was very common; in fact, 88% of all C-reactive protein measurements were below 20 mg/L and thus the potential to reduce antibiotic use seems much higher than the actual numbers in the current study. In order to improve the eff ect size we should start looking at ways to optimise use of this tool. Undoubtedly, part of this optimisation comes down to issues of public health and cultural habits among both patients and physicians. Physicians should be trained to adhere to the algorithm to a much larger extent. Improved education and associated increased adherence to the algorithm could lead to further reductions in antibiotic use, as can be read from the large degree of heterogeneity detected (I2=84%) corresponding to diff erences in eff ect size among sites, which is a specifi c concern and limitation of the current study. Previous studies have shown that education in communicative skills works well together with point-of-care C-reactive protein testing. It has also been shown that doctors that do not understand a specifi c strategy well use it poorly. Arguably, many of these patients should not have a C-reactive protein test done in the fi rst place. Only nonsevere infections were included, thus increasing the risk of spectrum bias. Biomarker tests should ideally be used to rule out a high risk of severe infection when the provider is uncertain if antibiotic prescribing is likely to be benefi cial, and to negotiate a perceived strong patient demand for an antibiotic prescription. Future trials in settings like the current should consider increasing the cutoff for no antibiotic therapy. If the patient is in no acute distress, with a C-reactive protein level below 50 mg/L, a serious bacterial infection is rarely present. Alternatively, all cases of acute respiratory tract infections that do not need urgent admission to hospital could be included. However, reduction of antimicrobial resistance cannot be achieved merely by the introduction of a Published Online August 2, 2016 http://dx.doi.org/10.1016/ S2214-109X(16)30170-X

Clinical indications for antibiotic use in Danish general practice: results from a nationwide electronic prescription database

Abstract Objective: To assess the availability and applicability of clinical indications from electronic prescriptions on antibiotic use in Danish general practice. Design: Retrospective cohort register-based study including the Danish National Prescription Register. Setting: Population-based study of routine electronic antibiotic prescriptions from Danish general practice. Subjects: All 975,626 patients who redeemed an antibiotic prescription at outpatient pharmacies during the 1-year study period (July 2012 to June 2013). Main outcome measures: Number of prescriptions per clinical indication. Number of antibiotic prescriptions per 1000 inhabitants by age and gender. Logistic regression analysis estimated the association between patient and provider factors and missing clinical indications on antibiotic prescriptions. Results: A total of 2.381.083 systemic antibiotic prescriptions were issued by Danish general practitioners in the study period. We identified three main clinical entities: urinary tract infections (n = 506.634), respiratory tract infections (n = 456.354) and unspecified infections (n = 416.354). Women were more exposed to antibiotics than men. Antibiotic use was high in children under 5 years and even higher in elderly people. In 32% of the issued prescriptions, the clinical indication was missing. This was mainly associated with antibiotic types. We found that a prescription for a urinary tract agent without a specific clinical indication was uncommon. Conclusion: Clinical indications from electronic prescriptions are accessible and available to provide an overview of drug use, in casu antibiotic prescriptions, in Danish general practice. These clinical indications may be further explored in detail to assess rational drug use and congruence with guidelines, but validation and optimisation of the system is preferable.

Identifying practice-related factors for high-volume prescribers of antibiotics in Danish general practice

Objectives In Denmark, general practice is responsible for 75% of antibiotic prescribing in the primary care sector. We aimed to identify practice-related factors associated with high prescribers, including prescribers of critically important antibiotics as defined by WHO, after accounting for case mix by practice. Methods We performed a nationwide register-based survey of antibiotic prescribing in Danish general practice from 2012 to 2013. The unit of analysis was the individual practice. We used multivariable regression analyses and an assessment of relative importance to identify practice-related factors driving high antibiotic prescribing rates. Results We included 98% of general practices in Denmark ( n  =   1962) and identified a 10% group of high prescribers who accounted for 15% of total antibiotic prescriptions and 18% of critically important antibiotic prescriptions. Once case mix had been accounted for, the following practice-related factors were associated with being a high prescriber: lack of access to diagnostic tests in practice (C-reactive protein and urine culture); high use of diagnostic tests (urine culture and strep A throat test); a low percentage of antibiotic prescriptions issued over the phone compared with all antibiotic prescriptions; and a high number of consultations per 1000 patients. We also found that a low number of consultations per 1000 patients was associated with a reduced likelihood of being a high prescriber of antibiotics. Conclusions An apparent underuse or overuse of diagnostic tests in general practice as well as organizational factors were associated with high-prescribing practices. Furthermore, the choice of antibiotic type seemed less rational among high prescribers.