The association between adherence to national antibiotic guidelines and mortality, readmission and length of stay in hospital inpatients: results from a Norwegian multicentre, observational cohort study

Antibiotics constitute an important class of medicines, where the use of a substance has implications beyond the patient being treated. Antimicrobial stewardship is a systematic way to improve antibiotic use in hospitals and has most recently been defined as “a coherent set of actions which promote using antimicrobials responsibly” [1]. Clinical guidelines for antibiotic use are essential in defining responsible use in the local context and are one of the core elements of stewardship programmes [2]. Studying the association between antibiotic use and patient outcomes is of great importance and can imply whether guideline-adherent prescribing practice is safe and secures equal – or better patient outcome. Most studies in this field are performed within lower respiratory tract infections and many are prone to confounding by indication, because patients with less severe illness are more likely to have received the more narrow-spectrum, guideline adherent therapy [3].

Norway has low, but steadily increasing antibiotic resistance rates [4]. Seven months prior to this study, new national guidelines for antibiotic use in hospitals were published [5]. We aimed to investigate if appropriate prescribing practices for hospitalised patients with a broad spectrum of infectious diseases were associated with patient outcomes when adjusted for major confounding factors.

During the study period, 1783 patients were eligible for inclusion. We were not able to retrieve comorbidity data for 22 patients. For 5 patients who were tourists, outcome data was unavailable. In final analyses, 1756 patients were therefore included.

The main findings of this study are that adherence to antibiotic guidelines at initiation of antibiotic therapy is associated with lower in-hospital- and 30-day mortality and shorter LOS. Adherence to guidelines was not significantly associated with 30-day readmission.

Structure and process indicators can help us evaluate whether our antibiotic stewardship efforts are moving us in the right direction [13–16]. A frequently asked question is whether behavioural change interventions lead to more appropriate antibiotic use, often measured as adherence to guidelines or profile of antibiotic consumption [3, 6, 17]. An equally important question is whether appropriate antibiotic use leads to the desired outcomes, like reduction in bacterial resistance rates, adverse events and mortality [3, 18]. Overprescribing outside guidelines often result from fear for the patients’ wellbeing, and are linked to patients who are severely ill or have an unclear diagnosis [19]. The expectation of clinicians’ to change their antibiotic prescribing behaviours needs to be supported by evidence-based guidelines and expert advice to reassure clinicians that guideline adherent antibiotic prescribing is safe and effective.

Readmission as an outcome measure in relation to antibiotic prescribing is not frequently reported [18]. Three studies within community acquired pneumonia show no association between guideline adherence and 30-day readmission, which is in agreement with the findings in this present study [20–22].

Evidence on the association between guideline adherence and mortality is diverse. Arnold et al. found that in-hospital mortality in patients receiving guideline-adherent treatment for community acquired pneumonia was 8% (95% CI, 7–10%), compared to 17% (95% CI, 14–20%) in the group of nonadherence [23]. Asadi et al. did not find any effect on mortality alone when looking at this variable in hospitalised patients with community acquired pneumonia, although the composite endpoint of death or ICU-admissions favoured guideline adherence [24]. In a Danish study of CAP, with similar resistance rates and treatment guidelines as Norway, Egelund et al. found that patients treated with guideline adherent penicillin monotherapy had lower CURB-65 score, less comorbidity and less in-hospital mortality in unadjusted analysis, while no association between mortality and guideline adherence was found in adjusted analysis [25]. However, a systematic review by Schuts et al., including 37 studies, showed that when empirical therapy was prescribed according to guidelines, the relative risk reduction of mortality was 35% [18]. The majority of patients included in these studies had pulmonary infections. These patients constituted almost half of our patient material. Our findings are coherent with this recent review, as we found that the odds ratio of in-hospital and 30-day mortality for the entire patient material was 0.46 and 0.48, respectively when guidelines were followed.

LOS was also favourably associated with adherent treatment in this study. The SHR was 1.17 for patients with guideline-adherent treatment, meaning that the rate of discharge was 17% higher for this group compared to the rate for the non-adherent group. Although not significant, there was a trend towards shorter LOS when analysed with linear regression analysis. 0.47 days constitutes 6.8% of the mean LOS for the study population (6.9 days) and 10.9% of a mean hospital stay in Norway, which is currently 4.3 days for patients outside the psychiatric wards [26]. The finding is in line with Schuts et al. which found that LOS was lower in 17 of the 24 included studies assessing association between adherence to guideline and LOS, favouring adherence [18]. The studies included in this review did however mainly include patients with lower respiratory tract infections, while our cohort had a large diversity of infectious diseases, and a maximum LOS of 21 days.

In observational cohort studies, the major limitation will be the potential for selection bias, in this case meaning that the patients with less severe illness may be more likely to receive guideline-adherent treatment [3]. By adjusting for indication for treatment, comorbidity, age, sex and seasonality, we have aimed to reduce the chance of confounding, but there could be differences in severity within each of the groups of indications, which could explain some of the difference seen in mortality between the adherent and non-adherent group. We did not have data on severity score, which could have helped us limit this factor. The grouping of indications is both a strength and a limitation. Looking at patient outcome and adherence across some of the most common infections seen in hospitals, makes the results more generalizable, but may also be more difficult to interpret. When working diagnosis on initiation of treatment was uncertain (eg “suspected UTI”) or there were more than one working diagnoses, we assessed adherence based on the most likely indication for treatment. Using working diagnoses for this purpose is limiting the generalizability of the results to individual groups of patients with more strict definitions of diagnoses. It does however reflect the daily challenge in the clinical setting where decisions about treatment have to be made before all diagnostic tools have been applied and results received and indicates that adhering to the most relevant guideline is a strength in this situation.

There were more patients admitted from an institution in the non-adherent group. This may be because patients admitted from institutions have more co-morbid disease and therefore present with more challenging diagnoses. Physicians may also consider the risk of resistant pathogens as higher and therefore prescribe more broad-spectrum agents. Furthermore, patients admitted from other institutions may already have received first line agents. Patient characteristics such as age, sex and comorbidity were very similar between the groups of patients receiving adherent or non-adherent treatment according to guidelines. The groups of UTI’s, “other” infections and GI-infections were however larger in the non-adherent group and LRTIs were larger in the adherent group. Prescribing for pneumonia and COPD exacerbations was the focus of the audit with feedback performed in the study wards in the underlying intervention study [6]. The mix of patients within the groups of indications varied to some extent, such as a higher number of pyelonephritis in the non-adherent group (38.8%) compared to the adherent group (23.2%) and higher number of sepsis with abdominal focus in non-adherent group (4.5%) compared to adherent group (0.6%). In a sensitivity analysis for 30-day mortality, the grouped indications were substituted with the individual indications. This only changed the estimated OR slightly, to 0.53. The difference seen between the groups can therefore not be explained by these factors alone. Another mechanism is of course that treatment recommended in guidelines is best practice - securing evidence based effective treatment of the infection, while minimizing ecologic effects, side effects and impact on the microbiotia and therefore is associated with better patient outcomes than non-adherent treatment.

We analysed according to the first indication for treatment, which was usually a working diagnosis on admission to the hospital. The diagnosis may have changed during the hospital stay. We therefore did a sensitivity analysis for 30-day mortality, where indication for treatment was substituted with discharge diagnosis. The OR for the association between adherent treatment and mortality only changed slightly, from 0.48 to 0.51.

Thirty-day readmission was defined as readmissions to the same hospital that the patient was discharged from. This could have caused an underestimation of readmissions if the patients were readmitted to other hospitals. As inclusion of patients were limited to a LOS of a maximum of 21 days, the mean LOS may be underestimated. Adherence to guideline within the group of excluded patients was not collected and is therefore unknown.

This was a multicentre study with patients included from three hospitals and three specialties, which increases generalizability. The number of included patients is also substantial and we adjusted for known risk factors for morbidity and mortality, such as age, comorbidity and admittance from an institution. Given that patients with a LOS longer than 21 days were excluded, this limits generalizability of the estimate for this outcome.

Norwegian guidelines were developed with broad involvement of more than 80 clinicians from all over the country [5, 27]. They are prudent, with mainly narrow-spectrum antibiotics as first-line empirical treatment [5]. It is of great importance that guidelines constitute best practice, to provide security for both the patient and the treating clinician, and secures standardized, safe and effective antibiotic treatment, also in the absence of an infectious diseases specialist.

This study builds on findings in previous studies, indicating that up-to-date, hospital antibiotic guidelines are safe and are associated with favourable clinical outcomes for inpatients. Antibiotic guidelines should be developed and regularly updated to ensure that they always promote best practice in the treatment of infectious diseases in the local context. Accurate, structured and easy-to-access documentation on severity of infections should be included in the electronic medical record to secure availability of this data in quality improvement processes, evaluation of treatment and research.

To be able to control for more factors in analyses, future studies should aim to collect information about severity of infections and whether empirical treatment provided adequate coverage for the individual patients.

Empirical treatment according to guidelines on initiation of antibiotic therapy is associated with favourable clinical outcomes, such as in-hospital and 30-day mortality in our population of hospital inpatients.