Impact of appropriate empirical antibiotic treatment on recurrence and mortality in patients with bacteraemia: a population-based cohort study

The mortality from bacteraemia remains high and bacteraemia is associated with serious patient morbidity [1‐4]. Antibiotic therapy is imperative in the treatment of bacteraemia and treatment cannot await isolation and identification of the microorganisms involved and their antibiogram. Antibiotics are therefore given on an empirical basis and early initiation of appropriate empirical antibiotic treatment (EAT) has been associated with markedly improved survival in patients with septic shock [5]. Nevertheless, existing studies have provided conflicting evidence of the association between appropriate EAT and short-term mortality for bacteraemic patients [6‐20]. It is likely that much of the controversy stems from heterogeneity and inadequacy in study designs, which make the comparisons of EAT and bacteraemia outcomes difficult [21, 22]. Moreover, there are little data on the association between EAT and long-term mortality following bacteraemia [23‐25].

Another important adverse outcome of bacteraemia is a recurrent bacteraemic episode. Few studies have investigated recurrence of bacteraemia and even more seldom with the inclusion of all aetiologic agents [26‐29]. Recent population-based studies have demonstrated that roughly one tenth of patients who survive their first bacteraemic episode experience a recurrent episode within the following year. This subsequent episode has been identified as an important predictor of mortality [26, 28, 30]. Only one prior study has investigated the association between EAT and recurrence, finding that inappropriate EAT was a predictor of recurrence [26].

The present population-based cohort study of patients with a first episode of bacteraemia aimed to examine (i) the incidence of recurrence by EAT status, and (ii) the 2–30-day and 31–365-day mortality by EAT status.

This population-based study demonstrates that inappropriate EAT is associated with an increased risk of bacteraemia recurrence and of long-term mortality. We found that 11% of the bacteraemic patients experienced a recurrent episode and the 1-year recurrence incidence proportion was 1.4-fold higher for patients receiving inappropriate EAT than for patients receiving appropriate EAT.

Our findings are consistent with prior studies that have found recurrence rates around 10% in both non-selected and selected populations [26‐30, 47, 48]. Our finding of inappropriate EAT as an independent predictor of recurrent bacteraemia is in accordance with another Danish bacteraemia cohort for which we found an adjusted OR of 1.29 (95% CI = 1.10–1.52) [26].

Inappropriate EAT was not associated with short-term (2–30 days) mortality, an outcome measure that has been studied intensively. Similar to our findings, several studies have reported that inappropriate EAT was not associated with short-term mortality with the cautions that most of these studies included relatively few patients and investigated either individual microorganisms or groups of microorganisms or only reported in-hospital mortality [6, 11, 12, 20, 49‐52]. Nonetheless, the majority of studies focusing on short-term mortality have shown that inappropriate EAT is associated with all-cause mortality as summarised by two major reviews [21, 22]. Both reviews pointed out that heterogeneity in study design, study populations, time to outcome measures and methodological pitfalls (e.g. the definition of inappropriate EAT and the distinction between empirical and definitive treatment) contributes to the conflicting results.

In contrast, inappropriate EAT was a prognostic factor for long-term mortality (31–365 days).

Our study’s 1-year mortality of 39.7% (including the 347 dying on day 0 or 1, cf. Fig. 1) is in accordance with the few other population-based bacteremia studies that have assessed this [25, 53]. Long-term mortality of bacteraemia is related to age and underlying disorders while infection presumably plays a less direct role, although the nature and severity of the initial infection as well as direct and indirect complications arising from the acute disease (e.g. organ dysfunction) may lead to considerable mortality months or years later [25, 54]. Appropriate EAT may reduce the harmful inflammatory response leading to organ dysfunction by clearing the pathogen and thereby influencing long-term mortality. The positive association between inappropriate EAT and long-term mortality has previously been demonstrated for Staphylocuccus aureus bacteraemia in a hospital-based study [23, 24], but to the best of our knowledge only in one study with a non-selected patient population comprising all common bacteraemia microorganisms [25].

The strengths of our study include the population-based design, a large cohort, the recording of the patients’ clinical data by physicians during the course of disease, and virtually complete follow-up. Still, there are limitations that require consideration. Firstly, our retrospective study data were obtained through existing databases in which the clinical data were inadequate. In particular, 22% of the patients lacked information on EAT. We categorized these patients separately which may have introduced bias. Due to limited clinical data, we were not able to control for baseline severity of illness, which is one important recommendation in designing outcome studies of bacteraemia according to EAT [21, 22]. However, we adjusted for speciality as a surrogate marker for the acute disease. Secondly, selected data from the DACOBAN research database were from 2007 to 2008 though newer data exist. This was due to physicians’ meticulous and prospective registration of clinical information related to the focus of infection and antibiotic treatment during these two years. This partly compensated for the inadequacy of clinical data. We do not believe that data of newer antibiotic treatment regimes in recent years would materially alter the results, which conform to studies from other settings [12, 50]. Thirdly, the patient populations from the three DCMs were heterogeneous in several respects. Fourthly, the clinical data were recorded by many different registrars and consultants leaving room for both missing data and variations reflecting individual judgement which may lead to information bias. Also, ampicillin MIC break-points were defined differently at DCM Hvidovre, which may have introduced misclassification bias. However, this error potentially affected less than 10 patients as ampicillin was rarely given as monotherapy. Fifthly, we cannot rule out confounding by indication as the efficacy of the different empirical antibiotic regimens may not have been homogeneous. Confounding by indication is an inevitable problem in observational studies that involve drugs and the severity of illness can lead to a broader coverage of EAT, especially in acute infectious disorders. We distinguished between appropriate and inappropriate EAT, but did not stratify for which of the antibiotic(s) that provided the appropriate EAT, e.g. a betalactam or an aminoglucoside, nor dosage regimes and the actual timing of EAT, which is important as shown previously [5, 7].

This study showed that inappropriate EAT was a predictor of recurrent bacteraemia and increased the long-term mortality following bacteraemia, whereas it had no impact on the short-term mortality. These findings have clinical importance and highlight the importance of vigilance in the identification and antibiotic treatment of bacteraemia. Identification of patients and characteristics associated with inappropriate EAT may contribute to empirical prescribing guidelines and thereby improve EAT.