A multicentre cluster-randomized clinical trial to improve antibiotic use and reduce length of stay in hospitals: comparison of three measurement and feedback methods.

BACKGROUND: Various metrics of hospital antibiotic use might assist in guiding antimicrobial stewardship (AMS). OBJECTIVES: To compare patient outcomes in association with three methods to measure and feedback information on hospital antibiotic use when used in developing an AMS intervention. METHODS: Three methods were randomly allocated to 42 clusters from 21 Dutch hospitals: (1) feedback on quantity of antibiotic use [DDD, days-of-therapy (DOT) from hospital pharmacy data], versus feedback on (2) validated, or (3) non-validated quality indicators from point prevalence studies. Using this feedback together with an implementation tool, stewardship teams systematically developed and performed improvement strategies. The hospital length of stay (LOS) was the primary outcome and secondary outcomes included DOT, ICU stay and hospital mortality. Data were collected before (February-May 2015) and after (February-May 2017) the intervention period. RESULTS: The geometric mean hospital LOS decreased from 9.5 days (95% CI 8.9-10.1, 4245 patients) at baseline to 9.0 days (95% CI 8.5-9.6, 4195 patients) after intervention (P < 0.001). No differences in effect on LOS or secondary outcomes were found between methods. Feedback on quality of antibiotic use was used more often to identify improvement targets and was preferred over feedback on quantity of use. Consistent use of the implementation tool seemed to increase effectiveness of the AMS intervention. CONCLUSIONS: The decrease in LOS versus baseline likely reflects improvement in the quality of antibiotic use with the stewardship intervention. While the outcomes with the three methods were otherwise similar, stewardship teams preferred data on the quality over the quantity of antibiotic use.

How to measure quantitative antibiotic use in order to support antimicrobial stewardship in acute care hospitals: a retrospective observational study.

A cornerstone of antimicrobial stewardship programs (ASPs) is monitoring quantitative antibiotic use. Frequently used metrics are defined daily dose (DDD) and days of therapy (DOT). The purpose of this study was (1) to explore for the hospital setting the possibilities of quantitative data retrieval on the level of medical specialty and (2) to describe factors affecting the usability and interpretation of these quantitative metrics. We performed a retrospective observational study, measuring overall systemic antibiotic use at specialty level over a 1-year period, from December 1st 2014 to December 1st 2015, in one university and 13 non-university hospitals in the Netherlands. We distinguished surgical and non-surgical adult specialties. The association between DDDs, calculated from aggregated dispensing data, and DOTs, calculated from patient-level prescription data, was explored descriptively and related to organizational factors, data sources (prescription versus dispensing data), data registration, and data extraction. Twelve hospitals were able to extract dispensing data (DDD), three of which on the level of medical specialty; 13 hospitals were able to extract prescription data (DOT), 11 of which by medical specialty. A large variation in quantitative antibiotic use was found between hospitals and the correlation between DDDs and DOTs at specialty level was low. Differences between hospitals related to organizational factors, data sources, data registration, and data extraction procedures likely contributed to the variation in quantitative use and the low correlation between DDDs and DOTs. The differences in healthcare organization, data sources, data registration, and data extraction procedures contributed to the variation in reported quantitative use between hospitals. Uniform registration and extraction procedures are necessary for appropriate measurement and interpretation and benchmarking of quantitative antibiotic use.

Applicability of generic quality indicators for appropriate antibiotic use in daily hospital practice: a cross-sectional point-prevalence multicenter study.

The ability to monitor the appropriateness of hospital antibiotic use is a key element of an effective antibiotic stewardship program. A set of 11 generic quality indicators (QIs) was previously developed to assess the quality of antibiotic use in hospitalized adults treated for a bacterial infection. The primary aim of the current study was to assess the clinimetric properties of these QIs (nine process and two structure indicators) in daily clinical practice. In a cross-sectional point-prevalence survey, performed in 2011 and 2012, 1890 inpatients from 22 hospitals in the Netherlands treated with antibiotics for a suspected bacterial infection were included, and data were extracted from medical records. In this cohort we tested the measurability, applicability, reliability, room for improvement and case mix stability of the previously developed QIs. Low applicability (≤10% of reviewed patients) was found for the QIs 'therapeutic drug monitoring', 'adapting antibiotics to renal function' and 'discontinue empirical therapy in case of lack of clinical and/or microbiological evidence of infection'. For the latter, we also found a low inter-observer agreement (kappa <0.4). One QI showed low improvement potential. The remaining seven QIs had sound clinimetric properties. Case-mix correction was necessary for most process QIs. For all QIs, we found ample room for improvement and large variation between hospitals. Establishing the clinimetric properties was essential, as four of the 11 previously selected QIs showed unsatisfactory properties in this practice test. Since the quality of antibiotic use and the process of documenting data is changing over time and may vary per country, QIs should always be tested in practice first.

Identifying targets for quality improvement in hospital antibiotic prescribing.

OBJECTIVES: To audit antibiotic use in a university hospital and to identify targets for quality improvement in a setting with low antibiotic use and resistance rates. METHODOLOGY: A point-prevalence survey (PPS), using a patient-based audit tool for antibiotic use, was executed in the Radboud University Medical Centre in May 2013. On one index day, all patients on systemic antibiotics hospitalised > 24 hours were included. Data regarding antibiotic prescriptions were extracted from the medical records. Multiple logistic regression analysis was performed in order to predict whether a variable was associated with low guideline compliance or a low rate of consulting an infectious disease specialist. RESULTS: 428 hospitalised patients were included, of whom 40.9% received antibiotics. Overall, 75.7% of all prescriptions were compliant with the guidelines in place and for 87.8% the reason for prescription was documented. Amoxicillin/clavulanic acid (OR = 4.08, 95% CI 1.57-10.56), and respiratory tract infections (RTI) (OR = 6.17, 95% CI 2.55-14.94) were associated with low compliance with guidelines. An infectious disease physician or medical microbiologist was less often consulted for empirical therapy (OR 23.21, 95% CI 6.37-84.51) or empirical therapy continued > 72 hours (OR 14.69, 95% CI 3.56-60.56) compared with prescriptions that were based on culture results. In addition, fewer consultations were requested for RTI (OR 4.47, 95% CI 1.39-14.35). CONCLUSION: A PPS is a good tool to identify targets for antibiotic stewardship in routine clinical practice. Several areas for improvement, such as a low compliance with guidelines for amoxicillin/clavulanic acid and RTI, and a low rate of consulting an infectious disease physician or medical microbiologist concerning antibiotic therapy in case of RTI and empirical therapy continued > 72 hours were identified.

Intensification of antibiotic use within acute care hospitals in the Netherlands.

OBJECTIVES: To report and analyse trends in antibiotic use in Dutch university hospitals, large teaching hospitals and general hospitals over the period 2003 to 2009. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDDs) per 100 patient-days, per 100 admissions and per 1000 inhabitants per day. The latter was achieved by extrapolating sample data by means of imputation and up-scaling. RESULTS: From 2003 to 2009, the mean length of hospital stay decreased from 6.27 to 4.50 days (-28%). Total systemic antibiotic use significantly increased from 52.3 to 69.8 DDDs per 100 patient-days (P < 0.001). Despite the overall constant use when expressed in DDDs per 100 admissions, we found a significant increase in the total use of piperacillin/tazobactam, cefazolin, ceftriaxone, meropenem, azithromycin, gentamicin, ciprofloxacin and vancomycin. Mean total systemic use expressed in DDDs per 1000 inhabitants per day gradually increased by 38% from 0.73 in 2003 to 1.01 in 2009. CONCLUSIONS: Total hospital antibiotic consumption is still low in the Netherlands compared with other European countries. Also, between 2003 and 2009 the use of antibiotics in individual hospitalized patients remained stable. However, since they remained in the hospital for a shorter period of time, the number of DDDs per 100 patient-days increased. This results in an intensification of antibiotic treatment per hospital bed, leading to a possible increase in selection pressure towards resistance. This may create a problem for future patients. To limit the emergence and transmission of antimicrobial-resistant bacteria, effective antibiotic stewardship is essential.

[Optimalisation of the antibiotic policy in The Netherlands. XI. The national electronic antibiotic guide'SWAB-ID' for use in hospitals]. / Optimaliseren van het antibioticabeleid in Nederland. XI. Het nationale elektronische antibioticaboekje SWAB-ID voor ziekenhuizen.

The 'Stichting Werkgroep Antibioticabeleid' (Dutch Working Party on Antibiotic Policy) has developed an electronic national antibiotic guide for the antibiotic treatment and prophylaxis of common infectious diseases in hospitals. This guide also contains information on the most important characteristics of antimicrobial drugs. Advice on antibiotic treatment is based on existing national evidence-based guidelines, where available. Where no guideline is available, the advice is based on an inventory of the antibiotic policies of the 12 Dutch centres with an infectious disease or medical microbiology training programme. The national antibiotic guide can be accessed through the SWAB website (www.swab.nl) and can also be downloaded on PDA/PocketPC, free of charge. Every hospital antibiotic formulary committee in the Netherlands will be offered the opportunity to edit The national version for local use.

Changes in antibiotic use in Dutch hospitals over a six-year period: 1997 to 2002.

OBJECTIVE: To analyse trends in antibiotic use in Dutch hospitals over the period 1997 to 2002. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDD) per 100 patient-days and as DDD per 100 admissions. RESULTS: Between 1997 and 2002, the mean length of stay decreased by 18%. The mean number of admissions remained almost constant. Total antibiotic use significantly increased by 24%, from 47.2 in 1997 to 58.5 DDD per 100 patient-days in 2002 (p<0.01), whereas expressed as DDD per admissions it remained constant. Antibiotic use varied greatly between the hospitals. Moreover, the mean number of DDD per hospital of amoxicillin with clavulanic acid, clarithromycin, cefazolin, clindamycin and ciprofloxacin increased by 16, 38, 39, 50 and 52%, respectively. Total antibiotic use was higher in university hospitals than in general hospitals. CONCLUSIONS: Between 1997 and 2002, patients hospitalised in the Netherlands did not receive more antibiotics but, since they remained in the hospital for fewer days, the number of DDD per 100 patient-days increased. For macrolides, lincosamides and fluoroquinolones increases in both DDD per 100 patient-days and in DDD per 100 admissions were observed. It is arguable whether these trends result in an increase in selection pressure towards resistance in the hospitals. Continuous surveillance of antibiotic use and resistance is warranted to maintain efficacy and safety of antibiotic treatment.

An additional measure for quantifying antibiotic use in hospitals.

OBJECTIVES: The number of defined daily doses (DDD) per 100 patient days is often used as an indicator for the selection pressure exerted by antibiotics in the hospital setting. However, this unit of measurement does not fully describe the selection pressure and is sensitive to changes in hospital resource indicators. Additional information is required to facilitate interpretation of this indicator. The number of DDD per 100 admissions could be a valuable additional tool. The aim of this study is to investigate the importance of units of measurement in quantifying antibiotic use data with regards to antibiotic resistance risks. PATIENTS AND METHODS: Trends in antibiotic use in acute care Dutch hospitals between 1997-2001 were studied. Antibiotic use was expressed in DDD per 100 patient days and in DDD per 100 admissions. RESULTS: From 1997 to 2001, total systemic antibiotic use significantly increased from 47.2 to 54.7 DDD per 100 patient days, whereas expressed in DDD per 100 admissions it remained constant. Some individual antibiotics increases in DDD per 100 patient days were not accompanied by increases in DDD per 100 admissions and vice versa. The mean number of total DDD per hospital decreased (not significantly) between 1997 and 2001. The mean number of patient days, admissions and length of stay decreased significantly. CONCLUSIONS: Knowledge of variation in resource indicators and additional expression of the data in DDD per 100 admissions is imperative for a meaningful understanding of observed trends in antibiotic use expressed in DDD per 100 patient days. Further research is needed to determine the correlation between different measures of antibiotic use and the level of antibiotic resistance.

Antibiotic control measures in Dutch secondary care hospitals.

Control measures for the use of antibiotics are essential because of the potential harmful consequences of side effects. Various methods have been developed to help curb undesirable antibiotic prescription. We performed a survey in Dutch secondary care hospitals (response rate 73%) to make an inventory of these measures and elucidate possible shortcomings. Almost every hospital was using an antibiotic formulary (97%), sometimes supported by extra restrictions in antibiotic choice (55%). Local practice guidelines (95%) were commonly present, but effective implementation, for example using intranet applications, could be improved (21%). National guidelines had received little attention in the composition process of local guidelines (19%). Other measures such as educational programmes for specialists (11%) and feedback on antibiotic prescription (52%) remained largely underused, although their effective implementation may optimise antibiotic prescription in hospitals.

[Completing a course of drug therapy is necessary to combat the infection, not to discourage emergence of resistance]. / 'Kuur afmaken': om infectie te bestrijden, niet om resistentie te voorkomen.

For the treatment of infections, it is usually recommended to 'complete the course' so as to avoid the development of resistance. There is little evidence, however, for the exact duration of treatment. Only a few pathogenic microorganisms are able to develop resistance during exposure to effective antibiotic concentrations. Commensal flora are often destroyed during treatment, which can lead to colonisation with resistant mutants. Excretion of antibiotics in the urine will expose microorganisms in the environment, leading to resistance. Longer exposure will lead to more resistance. Only the time needed to clear up the infection should determine the duration of treatment and not the arbitrary length of an antibiotic dosage schedule.

Selecting outcome parameters in studies aimed at improving rational use of antibiotics - practical considerations.

When designing studies of the optimal use of antimicrobial drugs, it is important to define at an early stage, which outcome parameters to use. It must be clear to which category a parameter to be measured belongs: the structure, the process or a clinical outcome. Attention must be paid to the measurement scales as well as the statistical tests to be used. The outcome measure must be sensitive, specific and reliable. Furthermore, the timeframe chosen for the performance of a study should be validated. Whether process parameters or clinical outcomes are to be preferred depends on the settings and the intended purpose. The essential point is the appropriate choice of outcome measure for the study. Examples drawn from the field of quality of use of antimicrobial drugs are discussed.

The role of clinical guidelines, policies and stewardship.

The purpose of guidelines is to improve the quality of care for patients and improve clinical effectiveness by implementation of evidence-based care in daily practice. However, the potential of guidelines for resolving clinical questions should not be overstated. Ideally, policy makers use input from research data, as well as current prescribing habits, when developing guidelines. Care has to be given to the quality of guidelines, as well as their effect on outcome. Prospective validation of the content and use of guidelines must be set up. Beside the quality of guidelines, efforts are necessary for an effective implementation into daily practice. Many studies have shown that a combination of different interventions is needed. Thereby, an investigation of possible barriers should be an essential part of any strategy.

Use of fluconazole in daily practice: still room for improvement.

One hundred courses of fluconazole treatment in a university hospital and 81 courses in a non-university teaching hospital have been analysed in a prospective audit to evaluate prescribing practices. The quality of treatments was assessed by an infectious disease specialist and a pharmacist according to standard guidelines. In the non-university hospital, prescribed dosages were lower than in the university hospital, and often below the recommended dose. Mean duration of treatment for oesophageal candidosis and disseminated infections was considerably shorter in the non-university hospital compared with the university hospital, and often judged too short. Microbiological samples were examined in 75% of the cases in both hospitals. The expert reviewers agreed with the indication to use fluconazole in 58-100% of cases in the university hospital and 42-80% in the non-university hospital, depending on the type of infection. There did not appear to be a major problem with inappropriate use of fluconazole. However, important issues for improvement could be identified, such as increasing the dosage and duration of treatment in cases of serious infections, and withholding treatment from patients with colonization rather than infection.

[Choice of ear drops in chronic otorrhea]. / De keuze van oordruppels voor chronische otorroe.

In chronic otitis, the use of ear drops has certain advantages over the use of systemic antibiotics. The choice of ear drop depends on the condition of the eardrum, microbial pathogens present and the efficacy of the components of the ear drop. Ototoxicity, contact allergy and the development of bacterial resistance have to be taken into account. Ototoxicity is a rare complication of the application of ear drops, most often described when aminoglycosides were applied. Contact allergy is also most often seen in aminoglycoside-containing eardrops. Evaluation of ear swabs demonstrated a 5% resistance of Pseudomonas aeruginosa to ciprofloxacin. The appearance of resistant strains may impede systemic use of fluoroquinolones. Therefore, this class of antibiotics should be considered as reserve medication only. The first choice in local application of antiseptics in case of an open eardrum is aluminium acetotartrate 1.2% and, of a combination preparation, bacitracin-colistin-hydrocortisone. In case of a closed eardrum (external otitis) aluminium acetotartrate 12%--combination preparations with corticosteroids are advised against in these cases.

Earlier initiation of antibiotic treatment for severe infections after interventions to improve the organization and specific guidelines in the emergency department.

OBJECTIVE: To examine whether combined interventions improve the timely administration of antibiotic therapy and acquisition of material for culture from patients admitted to the emergency department with a serious infectious disease. METHODS: Guidelines and educational programs were developed to facilitate timely antibiotic administration: guidelines on handling patients with serious infections and on ordering immediate treatment, guidelines on obtaining culture samples, lectures to medical and nursing staff, improvement of availability of antibiotics in the emergency department, and removal of financial restraints on stocking and ordering of antibiotics. Fifty consecutive patients were evaluated after this series of interventions and compared with the results in 50 patients evaluated before the interventions. The interval from presentation to the emergency department until the administration of antibiotics, number of samples taken for microbiological investigations, and number of patients receiving a first dose of antibiotic at routinely scheduled drug distribution rounds were evaluated. RESULTS: The median time to the initial dose of antibiotics administered decreased from 5.0 hours to 3.2 hours (P = .04). The number of blood cultures obtained did not change. The percentage of sputum cultures obtained increased from 28% to 50%, and the percentage of urine cultures obtained increased from 50% to 100%. The percentage of patients whose first dose of antibiotic was delayed until a routinely scheduled drug distribution round decreased from 54% to 32% (P = .03). CONCLUSIONS: Combined interventions to expedite diagnostic and therapeutic actions through directed clinical practice guidelines and organizational measures are successful. This may lead to a substantial quality improvement in the process of care.

Anaphylactic reactions to proton-pump inhibitors.

OBJECTIVE: To report two cases of anaphylactic reactions to proton-pump inhibitors (PPIs). CASE SUMMARIES: A 54-year-old woman who had taken omeprazole in the past was treated with omeprazole 40 mg and developed periorbital edema, edema of the skin, pruritus, nausea, and vomiting about 45 minutes after taking one capsule. Five months later, she was treated with lansoprazole 30-mg capsules. Again, within 45 minutes she developed an even more serious reaction, with pruritus and urticaria on her whole body, increased sweating, facial edema, and loss of consciousness. A 61 -year-old man took one tablet of pantoprazole 40 mg one year after first being treated with the drug. Within hours after ingestion, he developed malaise, generalized pruritus and urticaria, a swollen tongue and eyes, and diffuse sweating; his blood pressure decreased to 75/50 mm Hg. DISCUSSION: Because of the acute onset of symptoms and close temporal association with exposure to the drug, as well as previous exposure to it, the reactions can be classified as anaphylactic shock to PPIs. These benzimidazole derivatives are chemically related; observations in a few patients, such as the first case above, suggest that cross-sensitivity may occur. The Uppsala Monitoring Centre (UMC) has received a total of 42 reports of anaphylactic reactions or anaphylactic shock in association with PPIs. These reports account for 0.2% of the total of reported suspected adverse drug reactions to PPIs, compared with 0.8% anaphylactic reactions in the UMC database as a whole. CONCLUSIONS: These findings suggest that the chemically related PPIs can, as a group, cause anaphylactic reactions; however, the rate is comparatively low. Since anaphylaxis is a potentially serious reaction, more precise information is needed regarding its frequency, and healthcare professionals need to be aware of this possibility when prescribing these agents.

The use of eardrops in an ENT department.

A survey of the pattern of usage of ototopical preparations in out-patients of the ENT department of a Dutch University Hospital has been performed. Data on clinical presentation and previous treatment of the patient, otoscopic results, prescribed current treatment and, if available, results of microbiological examination were collected. One-hundred and twenty-one evaluable patients were prospectively included. For 20% of the patients it concerned a first manifestation of the symptoms, 35% had a recurrence after a period free of symptoms and in 37% it concerned patients with persisting symptoms despite treatment. Forty-five percent of the patients' ears concerned had an intact tympanic membrane, in 25% a perforation was present and in 12% middle ear ventilation tubes were in situ. Thirty-five percent had already received previous treatment with ear drops. The species most often isolated was Staphylococcus aureus, followed by Pseudomonas aeruginosa. A wide range of products were prescribed. While previous treatment occurred with combination preparations, for current prescriptions, ofloxacin was most often used. Most patients received 2 to 3 drops 3 times a day for 7 to 10 days, which is in accordance with recommendations in the literature. Potentially ototoxic substances are regularly used in daily practice. Ofloxacin is widely used even thought it is not registered for this indication in the Netherlands and the development of resistance has to be taken into account. A new policy based on this survey is proposed, which will reduce the number of different preparations used and will eliminate ofloxacin from first the treatment.