Access to a polymerase chain reaction assay method targeting 13 respiratory viruses can reduce antibiotics: a randomised, controlled trial

Acute respiratory tract infections (ARTIs) represent a major global health burden [1], and viruses cause a large proportion of ARTIs. Distinguishing bacterial ARTIs that require antibiotic treatment from viral ARTIs not needing an antibiotic prescription can be difficult on clinical grounds alone and causes unnecessary use of antibiotics, with the highest rates occurring in the primary care setting [2, 3]. Excess use of antibiotics has major implications for health economics and, more importantly, for the development of bacterial resistance [3, 4], as well as for the individual patient in terms of adverse events such as allergic reactions and antibiotic-associated diarrhoea [5, 6]. The predictive value of vital signs, C-reactive protein (CRP) and X-ray findings for diagnosing pneumonia requiring antibiotics is low [7, 8]. The treatment of acute bronchitis serves as an illustrative example of the unnecessary use of antibiotics, where the recommended therapy for immune competent adults does not include antibiotic treatment [9, 10], yet antibiotics were found to have been prescribed for this condition at high rates in studies conducted in the United Kingdom (64%) [11], Sweden (50% to 60%) [12, 13] and the United States (59%) [14].

The use of improved diagnostic methods such as nucleic acid amplification tests (NAATs), including multiplex real-time polymerase chain reaction (RT-PCR) assays, has increased in recent years. These methods have proven to be equivalent or superior to conventional methods [15–19] and to have a short turnaround time at the laboratory, as well as affording clinicians the ability to analyse several respiratory agents within the same patient sample.

It has been suggested that the use of NAATs, including multiplex PCR methods, for the detection of respiratory pathogens could reduce antibiotic prescription rates [14, 18]. The present study was designed to evaluate whether access to a multiplex RT-PCR method targeting thirteen viruses would have an impact on antibiotic prescription rates for ARTI in a primary care setting.

We have shown that access to a rapid result using a method for aetiologic diagnosis of ARTIs in an outpatient setting significantly reduced antibiotic prescriptions at the initial visit. However, this effect was no longer significant at the time of follow-up. In our study, we evaluated the impact of access to a rapid diagnostic tool rather than the impact of the actual test result, which implies that the mere prospect of a rapid aetiologic diagnosis can influence therapeutic decisions made for patients with an indistinct clinical presentation.

In the subgroup of patients with a CRP level ≥50 mg/L, this effect was even more pronounced. Among patients with positive PCR results for viruses, significantly fewer patients in the rapid result group received antibiotics than in the delayed result group. Our results are in line with the reduction of antibiotic prescriptions when rapid diagnostic tests for IfA virus were used systematically for hospitalised adult patients [26] and children [27], although these studies evaluated the impact of the result of the test and thus are not fully comparable.

The limitations of this study include the choice of antibiotic prescription as the primary outcome and its open-label design, which might have led to performance bias; that is, the physicians might have been influenced by the randomisation in making the decision whether to prescribe antibiotics. Also, on the basis of the study design with an optional follow-up visit, a large number of patients were lost to follow-up, and because of the relatively short follow-up period, the effect and duration of antibiotic treatment in relation to the diagnosis could not be properly evaluated. To influence antibiotic resistance and adverse events following antibiotic therapy, it is necessary to reduce the total rate of antibiotic prescriptions, which was not achieved in our study. However, at the time of planning for the study, limited prospective data were available on the performance of a multiplex PCR panel for the diagnosis of viral and bacterial ARTIs in clinical practise. It was not possible to define whether patients should be prescribed an antibiotic depending on the test result. We therefore chose antibiotic prescriptions at the initial visit as a straightforward primary outcome measure to evaluate whether access to the test would have any effect on antibiotic prescription rates, and this should be included in future studies of algorithms for the management of patients with ARTIs.

Systematic testing for bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis was not conducted in this study. These bacteria may act as potential respiratory pathogens (PRPs) harbouring in the upper respiratory tract, and an extension of the panel to include these bacterial agents might improve the clinical utility of the test. However, the interpretation of the detection of bacterial pathogens in nasopharyngeal samples in heterogeneous syndromes such as ARTIs is unclear. Cultured S. pneumoniae from the nasopharynx of adults has been shown to have high specificity but low sensitivity for the diagnosis of pneumococcal pneumonia [28]. PCR-based detection of S. pneumoniae from the oropharynx and nasopharynx without codetection of other commensal Streptococcus spp. poses technical difficulties.

Lieberman et al. [29] reported higher sensitivity in using nasopharyngeal washing compared to nasopharyngeal swabs in the detection of PRPs. To keep sampling simple, nasopharyngeal washing was not used in this study, which may constitute a study limitation. However, we used flocked nasopharyngeal swabs, which probably yield higher detection rates than previously reported in studies in which cotton-tipped nasopharyngeal swabs were used [30]. The study population consisted of patients with a broad spectrum of clinical manifestations, many of whom had mild symptoms. However, since the prescription of antibiotics for these patients is not uncommon, this was a deliberate study design.

Previously, Oosterheert et al. [18] investigated the impact of a PCR method for aetiologic diagnosis of lower RTIs in adults but failed to show any reduction in the use of antibiotics. However, their study included only hospitalised patients, and the end point was to register a change of ongoing treatment regimen rather than whether to make the initial decision to prescribe antibiotic treatment.

At follow-up, our study no longer showed any significant difference in antibiotic use between the two study groups. However, since a large number of patients were lost to follow-up, the selection of patients may have been biased. Moreover, physicians outside the study prescribed antibiotics for some patients between the initial visit and the follow-up visit. Because of the study design, the accuracy of prescriptions during follow-up could not be properly evaluated. Thus, our results must be interpreted with caution. In the absence of an algorithm to determine how to follow the patients and act upon the results of PCR testing, including a predefined antibiotic management plan, the observed reduction of antibiotic use at the initial visit may be lost by the time of follow-up. However, our study represents a proof of concept that access to a rapid etiologic diagnostic tool may affect therapeutic decision in this setting.

The antibiotic prescription rate in our study was low. A recent retrospective study of primary care patients in a comparable Swedish region recorded an antibiotic prescription rate of 45% for all patients with ARTIs, 60% for patients with acute bronchitis and 16% for patients with the 'common cold' [13]. The low prescription rate in our series could be due partly to a tendency to adhere more strictly than usual to current guidelines for the restrictive use of antibiotics.

We detected an infectious agent in 47% of patient samples taken at the initial visit, which is in line with previous studies in which detection rates between 43% and 63% in adults have been described [11, 31]. Detection of a virus does not exclude concomitant bacterial infections or other noninfectious causes. This safety issue was discussed at the beginning of our study, and physicians were encouraged to treat bacterial complications at their own discretion. No SAEs were reported, but because of the relatively large number of patients lost to follow-up and the short duration of the study, we cannot exclude the possibility that some patients experienced late SAEs. Patient-relevant outcomes, such as the severity of symptoms over time, were not recorded, which is another limitation of this study. We deliberately chose not to include such outcomes, as the primary objective of the study was to evaluate the impact on antibiotic prescription rates at the initial visit. This study design also reduced the resources needed to conduct the study.

Analysis of CRP is frequently used to discriminate viral from bacterial infections [32]. Prescription rates increase with rising CRP levels [32, 13]. In the group of patients with CRP levels > 100 mg/L, approximately one-third carried a respiratory virus, supporting the need for reliable tools for the aetiologic diagnosis of ARTIs. Distinguishing a viral from a bacterial aetiology in ARTIs is difficult on clinical grounds alone, and the predictive value of vital signs, CRP and X-ray findings is low [7, 8]. Procalcitonin (PCT) has been proven to be useful in reducing antibiotic prescriptions in hospitalised patients with lower RTIs [33, 34], whereas in primary care, the evidence of PCT for this purpose is more ambiguous. One study of adults with ARTI (one to twenty-eight days' illness duration) judged to be in need of antibiotics and treated as outpatients reported a positive effect of antibiotic use [35], but another study of children with community-acquired pneumonia, a significant proportion of whom were treated in the hospital, showed a negative effect [36].

No distinct pattern of symptoms that could guide the clinician towards a correct aetiologic diagnosis was identified in our study. Vomiting, which was the only independent variable predicting antibiotic use, may be interpreted as a sign of serious illness justifying antibiotic treatment.

Reducing the unnecessary use of antibiotics in the treatment of patients with ARTIs is of utmost importance and cannot be accomplished by using a single strategy. Patient- and physician-oriented educational programmes could play an important role as previously suggested [37]. However, these programmes do not solve the issue of the lack of an aetiologic diagnosis, which is important not only for adequate use of antibiotics but also for addressing issues such as possible complications, prognosis, antiviral treatment options, surveillance and infection control.

In conclusion, we have shown that access to a multiplex RT-PCR assay for the aetiologic diagnosis of ARTIs may reduce the prescription rate of antibiotics at the initial visit in an outpatient setting. To sustain the effect, it seems necessary to define how to follow and manage the patient according to the result of the test, which warrants further investigation. We believe that the implementation of similar methods in routine clinical care may be a useful tool to reduce the overprescription of antibiotics in patients with ARTIs.