Improving appropriateness of antibiotic therapy: randomized trial of an intervention to foster reassessment of prescription after 3 days

Laurence Senn1,*, Bernard Burnand2, Patrick Francioli1,3 and Giorgio Zanetti1,3

1 Division of Hospital Hygiene, University Hospital, Lausanne; 2 Clinical Epidemiology Center, Institute of Social and Preventive Medicine, University Hospital, Lausanne; 3 Service of Infectious Diseases, Department of Medicine, University Hospital, Lausanne, Switzerland

Received 6 November 2003; returned 8 January 2004; revised 19 February 2004; accepted 15 March 2004


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives: Reassessment of ongoing antibiotic therapy is an important step towards appropriate use of antibiotics. This study was conducted to evaluate the impact of a short questionnaire designed to encourage reassessment of intravenous antibiotic therapy after 3 days.

Patients and methods: Patients hospitalized on the surgical and medical wards of a university hospital and treated with an intravenous antibiotic for 3–4 days were randomly allocated to either an intervention or control group. The intervention consisted of mailing to the physician in charge of the patient a three-item questionnaire referring to possible adaptation of the antibiotic therapy. The primary outcome was the time elapsed from randomization until a first modification of the initial intravenous antibiotic therapy. It was compared within both groups using Cox proportional-hazard modelling.

Results: One hundred and twenty-six eligible patients were randomized in the intervention group and 125 in the control group. Time to modification of intravenous antibiotic therapy was 14% shorter in the intervention group (adjusted hazard ratio for modification 1.28, 95% CI 0.99–1.67, P = 0.06). It was significantly shorter in the intervention group compared with a similar group of 151 patients observed during a 2 month period preceding the study (adjusted hazard ratio 1.17, 95% CI 1.03–1.32, P = 0.02).

Conclusion: The results suggest that a short questionnaire, easily adaptable to automatization, has the potential to foster reassessment of antibiotic therapy.

Keywords: anti-infective agents, decision support systems, quality of healthcare, comparative study


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The implementation of programmes aiming at improving the appropriate use of antibiotics in hospitals is strongly recommended.17 The rationale for this recommendation is the recognized frequent misuse and overuse of antibiotics in hospitals,811 and their impact on therapeutic efficacy, bacterial resistance1220 and costs.3,11,21,22

Commonly, the decision to start antibiotic therapy and the choice of an antibiotic is empirical, because clinical signs and symptoms are often not specific for an infection, and the organism causing the presumed infection has usually not yet been identified. Empirical antibiotic therapy, added to a wide therapeutic margin, may encourage caution in therapeutic strategies, such as a low threshold for prescription and the choice of broad-spectrum antibiotics.

A possible pathway towards increasing the appropriateness of use of antibiotics could, therefore, be a formal reassessment of therapy after 2–4 days. At this time, culture results and the clinical evolution will allow for re-evaluation of a case.3,11,2325 Physicians often neglect this reassessment. This could be due to time constraints, change of physician in charge during the first days of hospital stay, unwillingness to modify empirical therapy in case of satisfactory evolution, or insufficient training.7

The aim of the study was to improve the appropriateness of antibiotic therapy through reassessment after 3 days. For this purpose, we designed a short questionnaire to be sent to the physician in charge of the patient 3–4 days after initiation of intravenous antibiotic therapy in order to encourage reassessment of ongoing therapy and to provide key points for this reassessment. We undertook the present randomized trial to evaluate the impact of this questionnaire.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This was a randomized, controlled, open trial conducted over 5 months in an 800-bed general university hospital. The study was approved by the hospital quality improvement committee.

Inclusion and exclusion criteria

All patients hospitalized on the surgical (77 beds) and the medical (101 beds) wards were screened daily for possible inclusion in the study by review of their charts. To be eligible, patients had to be treated with an intravenous antibiotic for 3–4 days. Exclusion criteria were a modification of the antibiotic therapy within the first 3–4 days from intravenous antibiotic initiation, and the discontinuation of any previous antibiotic therapy <48 h before the study therapy. Patients who met eligibility criteria on a weekend were not included (see below).

Intervention

Eligible patients were allocated to either the intervention or control group by using a computer-generated randomization list, which was sequentially and strictly followed by one of us (L.S.). Concealment of allocation was achieved, as the physician in charge of the patient was involved after randomization. The intervention consisted of mailing a printed questionnaire to the resident in charge of the patient. This questionnaire asked three questions regarding possible adaptation of antibiotic therapy on day 3 or 4 (Figure 1). It was collected 24 h later. If the resident had not yet completed it at that time, he/she was reminded once to do so. No intervention was made in the control group.



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Figure 1. Questionnaire.

 
Data collection

The following characteristics of patients were collected from the patients’ charts: age, sex, date of hospitalization, date of discharge from hospital (or from ward if different) or date of death while hospitalized, resident and chief resident in charge, Karnofsky functional score (A: able to carry on normal activity and to work, no special care is needed; B: unable to work, able to live at home, care for most personal needs, a varying degree of assistance is needed; C: unable to care for self, requires equivalent of institutional care), serum level of C-reactive protein, white blood cell count, results of microbiological investigations, immune suppression (immunosuppressive treatment or neutropenia) and antibiotic treatment prior to the course implemented at the time of this study.

For each antibiotic treatment, we collected the name of the antibiotic, the date of prescription (with a half-day precision), the ward where prescription was initiated (study ward, emergency room or intensive care unit), presumed indication for antibiotic therapy, consultation by a specialist in infectious diseases, spectrum of antibacterial activity (usually including activity against Pseudomonas aeruginosa or not), the date of the first modification of the initial prescription after randomization (with a half-day precision) and the nature of this modification.

The same data had also been prospectively collected for a group of patients during a 2 month period preceding the study to estimate the magnitude of a possible observation bias (i.e. a change in the practice of antibiotic therapy due to awareness of the ongoing study).

Outcomes

The primary outcome of the study consisted of the time elapsed from randomization until a first modification of the initial intravenous antibiotic therapy, or until discharge or death, in all patients who fulfilled the inclusion criteria. A modification was prospectively defined as one of the following events: discontinuation of antibiotic, switch to oral therapy, or streamlining of therapy by targeting documented pathogens.

A secondary outcome was the appropriateness of the decisions regarding continuation and modification of antibiotic therapy within 2 days after inclusion. The decisions evaluated were those addressed by the questionnaire (Figure 1). Appropriateness was evaluated in a random sample of 20% of the study population. It was based on an independent chart review by two investigators. Investigators’ opinions were only taken into account when they were in agreement.

Statistical analysis

The sample size was estimated according to the Freedman26 method of sample size estimation under the proportional-hazards model, on the basis of pre-study observation. One hundred and thirty-five patients were required in each group to reach 80% power of demonstrating a 40% increase in the hazard ratio (a difference that would approximately correspond to a 25% reduction in the expected number of antibiotic-days until modification). For practical reasons, study duration was determined before the beginning of prospective data collection: we chose a 5 month period, which was the estimated time necessary to achieve the calculated sample size.

The significance level was set at 0.05 in all tests. The null hypothesis was a similar hazard of treatment modification in both study groups.

To compare both groups, we used the two-sided Wilcoxon rank sum test for continuous variables and the {chi}2 test, or the Fisher’s exact test when appropriate, for proportions. All tests were two-sided.

Time to modification of antibiotic therapy was represented with the Kaplan–Meier method. It was compared within both groups using Cox proportional-hazard modelling, with censoring when one of the following events occurred before primary outcome: discharge from ward or from hospital, or death. All covariates were candidates to enter the model through a stepwise process. The model was then tested for possible confounding by the excluded covariates. The same strategy was used to compare the intervention group and the patients in the pre-study period. Treatment modifications were also compared across the pre-study period, the control group and the intervention group, with the likelihood ratio test used to assess deviance from linearity.

Statistical analyses were performed with STATA 6.0 statistical software (Stata Corporation, College Station, TX, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 260 patients were randomly assigned to either the intervention or control group. The analysis was restricted to 251 patients (after exclusion of nine patients for violation of the inclusion criteria): 126 in the intervention group and 125 in the control group. Patients’ characteristics were similar in both groups (Table 1). Among 126 questionnaires sent to the residents in charge of the patients in the intervention group, 88 (70%) were returned (66 spontaneously and 22 on recall). The most frequently prescribed antibiotics were co-amoxiclav (42%), ceftriaxone (29%), cefepime (10%), imipenem-cilastin (5%) and ciprofloxacin (4%). The length of hospital stay in days (S.D.) was 19.30 (16.22) in the control group versus 19.40 (24.51) in the intervention group (P = 0.30). Hospital mortality was 5/125 (4%) in the control group versus 8/126 (6%) in the intervention group (P = 0.57).


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Table 1. Characteristics of patientsa
 
The distribution of the first modification of intravenous antibiotic therapy is shown in Table 2. Figure 2 represents the time elapsed from the inclusion until this first modification.


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Table 2. Characteristics of antibiotic therapies
 


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Figure 2. Time elapsed (in days) from inclusion until first modification of the intravenous antibiotic therapy: comparison between the intervention group (thick line), the control group (narrow line) and the pre-study group (broken line).

 
The adjusted hazard ratio for modification of intravenous antibiotic therapy with intervention versus without intervention was 1.28 (95% CI 0.99–1.67, P = 0.06) (Table 3). This corresponded to a 14% shortening of the total days of initial antibiotic therapy until a modification occurred.


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Table 3. Impact of the questionnaire on the course of intravenous antibiotic therapy (Cox modelling of hazard ratio for treatment modification)
 
Time to treatment modification was significantly shorter in the intervention group compared with the 2 month period preceding the study (151 patients). Similarly, there was a significant linear trend towards more rapid modification of treatment when comparing groups rank-ordered as pre-study, control and intervention.

For exploratory purposes, we restricted the analysis of the intervention group to those patients for whom the questionnaire was returned, and compared them to controls. The adjusted hazard ratio of treatment modification was 1.36 (95% CI 1.02–1.80, P = 0.04).

The decision to continue antibiotic therapy or not within 2 days after inclusion was assessed in a random sample of 50 patients through detailed review of full-text medical records. The two investigators disagreed on one case, leaving 49 available for analysis. None of the three decisions to discontinue antibiotic therapy was disapproved. Seven of 46 (15%) continuations of antibiotics were considered inappropriate. There were 5/25 (20%) disapprovals in the control group, compared with 2/24 (8%) in the intervention group.

The decisions regarding adjustment of the initial therapy at day 3 or 4 (i.e. streamlining and/or switch to oral therapy) was then evaluated in the 39 cases for which continuation was approved. There was again discordance among evaluators in one case, leaving 38 for analysis. Decisions were disapproved in 15/38 (39%) cases (10 failures to adapt the antibacterial coverage to a documented pathogen, five missed opportunities to switch to oral therapy), 7/18 (39%) in the control group, and 8/20 (40%) in the intervention group.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study evaluated a questionnaire that had been developed to foster reassessment of intravenous antibiotic therapies after 3–4 days. The impact of the questionnaire, i.e. a 14% reduction in time elapsed until discontinuation or adjustment of the antibiotic therapy, was close to statistical significance. This difference was quantitatively lower than expected. Therefore, the study only had a power of 0.41 to demonstrate such an impact. However, this result may reflect a real effect of the questionnaire. Indeed, this effect was significant when the intervention group was compared with the situation observed in the pre-study period, suggesting that the intervention also had some effect on the control group due to the awareness of the ongoing study. This would result in a reduction in the power of the study.

In this study, the benefit observed from using a questionnaire to remind physicians to reassess antibiotic therapy, if it does exist, may seem modest. However, this must be balanced against the very simple implementation and possible further improvements of such intervention. Moreover, it is likely to depend on the persistent use of the intervention. Administration of the questionnaire could indeed easily be implemented permanently through automatization in hospitals where computerized prescription is available.11,2729 Although its acceptability by physicians was not formally evaluated in the study, we do not anticipate significant inconvenience from asking three short questions. An intervention embedded in a computerized order renewal process has the advantage of appearing to physicians at a time when they are already thinking about medication orders, as mentioned by Fischer et al.29 in their study of a computer-generated reminder to prompt conversion from intravenous to oral routes.

Patients’ outcome was similar in both groups. In addition, the questionnaire did not lead to hazardous decisions regarding discontinuation or modification of therapy, according to a detailed evaluation of 20% of the study population. Of note, detailed evaluation showed that 39% of the decisions regarding antibiotic therapy were disapproved by investigators. This clearly illustrates that there is room for innovative improvement strategies.

The benefit of the questionnaire could possibly be enhanced, depending on the context of its implementation. First, one limitation of the intervention was the 70% response rate to the questionnaire. Computerized prescription may enable the questionnaire to be a mandatory step in dispensing an antibiotic beyond 3 days, which could presumably increase the impact of the intervention. Indeed, the time to treatment modification in patients for whom the questionnaire was returned was significantly higher than in control patients. Second, eliciting reassessment of antibiotics after 3–4 days should be placed in the perspective of an institutional antibiotic management intervention. A programme that aims at improving antibiotic use should include multiple approaches,30,31 similar to any intervention targeting prescription behaviour in healthcare. This characteristic partly results from the fact that antibiotic policies have to deal with very heterogeneous clinical situations. In the literature, questionnaires used as reminders to physicians have been particularly effective in improving antibiotic use in standardized settings, such as intraoperative antibiotic prophylaxis32 or indications to use vancomycin.33

In our study, in contrast, a comparable strategy was evaluated in non-selected inpatient infections. In this context, each component of an antibiotic management programme will only have a limited contribution, which should not preclude its implementation.

In conclusion, the present study suggests that a short questionnaire, addressed to the physician in charge of an inpatient treated with intravenous antibiotics for 3–4 days, has the potential to foster reassessment of this therapy and speed up its adjustment. This intervention could be one helpful, automatic component of a multi-approach programme to improve the appropriateness of antibiotic use.


    Acknowledgements
 
L. Senn is supported by a grant from the Quality Improvement Committee of the Lausanne University Hospital. G. Zanetti is supported by grant 32–63128.00 of the Swiss National Science Foundation.


    Footnotes
 
* Correspondence address. Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. Fax: +41-21-314-02-62; E-mail: Laurence.Senn{at}chuv.hospvd.ch Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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