Prevalence of Clinical Signs Within Reference Ranges Among Hospitalized Patients Prescribed Antibiotics for Pneumonia

Key Points Question What is the prevalence of antibiotic therapy for possible pneumonia in hospitalized patients despite clinical signs within the reference range? Findings In this cohort study of 12 273 patients treated for possible pneumonia in 4 hospitals, all cardinal signs for pneumonia were within reference ranges in 18.6% of patients with possible community-acquired pneumonia and 13.5% of patients with possible hospital-acquired pneumonia. Antibiotics were continued for 3 days or longer after all clinical signs were normal in 34.8% of patients treated for community-acquired pneumonia and 38.4% treated for hospital-acquired pneumonia. Meaning Findings of this study suggest that antibiotics are prescribed frequently for suspected pneumonia in patients with clinical signs within reference ranges and continued for 3 days or longer after clinical signs normalize; these findings suggest potential targets to improve prescribing.


Introduction
The most common indication for antibiotics in hospitalized patients is suspected respiratory tract infection. 1,2 Diagnosing pneumonia, however, is difficult. The cardinal signs of pneumonia (fever, impaired oxygenation, tachypnea, productive cough, leukocytosis, and radiographic infiltrates) are not specific for pneumonia, individually or collectively. [3][4][5][6] Many acute and chronic conditions mimic the clinical presentation of pneumonia, including congestive heart failure, exacerbations of obstructive lung disease, atelectasis, mucus plugging, pulmonary embolism, hypersensitivity reactions, and others. Radiographic infiltrates are frequent in hospitalized patients and difficult to interpret: interobserver variability is high and specificity for pneumonia is low. [7][8][9][10] Notwithstanding the difficulty of accurately diagnosing pneumonia, it is a common diagnosis and therefore frequently invoked by clinicians to explain patients' signs and symptoms. The net result of these many potential sources of error is that overdiagnosis of pneumonia is common and may account for a substantial fraction of unnecessary antibiotic use in hospitalized patients. [11][12][13][14] The problem is often compounded by continuing antibiotic treatment for longer than needed. 15 Guidelines recommend treating community-acquired pneumonia (CAP) for 5 days and hospitalacquired pneumonia (HAP) for 7 days, but adherence to these guidelines is poor. [16][17][18][19][20] Moreover, at least 3 randomized clinical trials suggest that it is safe to stop antibiotic treatment once clinical signs are normalizing, even after as few as 3 days. [21][22][23] We sought to quantify the frequency of potentially unnecessary prescribing for pneumonia by identifying the percentage of hospitalized patients started on antibiotic therapy for possible CAP and HAP with clinical signs within reference ranges on the first day of antibiotic administration, the number of days until clinical signs normalized among patients with at least 1 abnormal clinical sign on the first day of antibiotic treatment, and the duration of therapy beyond when clinical signs normalized.

Methods
We conducted an observational cohort study of all patients aged 18 years or older admitted to 4 hospitals in the greater Boston, Massachusetts, area between May 1, 2017, and July 1, 2018. Within this cohort, we retrospectively identified nonventilated patients started on antibiotic therapy for possible pneumonia according to the indications provided by clinicians at the time antibiotic regimens were ordered. Study hospitals included 2 academic medical centers (Brigham and Women's Hospital and Massachusetts General Hospital) and 2 community hospitals (Newton Wellesley Hospital and Faulkner Hospital). We included both CAP (defined as antibiotic treatment started for pneumonia on hospital day 1 or 2) and HAP (antibiotic treatment started on hospital day 3 or thereafter) but analyzed the 2 groups separately. Antibiotic indications were determined from the indications specified by clinicians using a required field within the medication-ordering interface in the hospitals' electronic health record systems. We included the indication pneumonia selected from the structured set of options offered by the electronic health record, free-text indications added by clinicians that were concordant with pneumonia, and antibiotic courses initially prescribed for a stated indication of sepsis but modified at a later date to explicitly state pneumonia. We excluded patients with cystic fibrosis, empyema, abscess, or other pyogenic complications per discharge International Statistical Classification of Diseases, 10th Revision (ICD-10) codes E84, J86, and J85. We assessed the validity of our inclusion criteria by randomly selecting 60 eligible patients and reviewing their medical records to determine clinicians' intentions on the day antibiotic treatment was started (as opposed to their discharge diagnoses) per the diagnostic impression, differential diagnosis, or plan recorded in the free-text clinical notes.
All study hospitals used the Epic Care electronic health record system (Epic Systems). All study hospitals have longstanding antibiotic stewardship programs that include guidance on typical treatment durations for both CAP and HAP but do not provide explicit guidance on how to diagnose pneumonia. The study was approved by the Partners Healthcare Institutional Review Board with a waiver of informed consent because findings are only presented in aggregate. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
Patients' comorbidities were derived from their discharge ICD-10 codes using the Charlson 24 and Elixhauser 25 scales. We determined the percentages of patients with clinical signs within the reference ranges on the first calendar day of antibiotic therapy both per sign and collectively across all signs. We defined temperature as normal if the daily maximum temperature was greater than 36°C and less than 38°C, respiratory rate as normal if the median daily respiratory rate was less than 22 breaths/min, white blood cell count as normal if greater than 4000/μL and less than 12 000/μL (to convert to ×10 9 /L, multiply by 0.001), and oxygenation as normal if the median daily oxygen saturation was 95% or greater without supplementary oxygen. We used median values for respiratory rates and oxygen saturations to minimize the impact of outlier values due to data entry errors, machine misreadings, or transient fluctuations in clinical status. We then determined mean and median calendar days until normalization for each clinical sign and for all clinical signs. We did not evaluate chest radiographic imaging findings due to their subjectivity, lack of specificity, the lag between acute disease and radiographic resolution, the difficulty reliably parsing free-text narratives electronically, and low likelihood that a patient has pneumonia if their sole abnormality is a radiographic opacity and all other clinical signs are within reference ranges. 7-10, 26 We excluded patients missing any reports of temperature, respiratory rate, white blood cell count, or oxygen saturation on the first day of antibiotic administration.

Statistical Analysis
We assessed mean (SD) and median (interquartile range [IQR]) durations of antibiotic treatment among all patients, those with at least 1 abnormal clinical sign on the first day of treatment, and those with all clinical signs within reference ranges on the first day of antibiotic administration. We calculated the duration of antibiotic treatment beyond the first day of clinical signs within reference ranges in each of these 3 groups (starting from the first calendar day of antibiotic administration for patients in whom all signs were within reference ranges and from the first calendar day that all signs normalized for patients with initially abnormal clinical signs). We further assessed the count and percentage of patients who were given 3 or more and 5 or more days of antibiotic therapy beyond when all clinical signs normalized. Discharge antibiotic courses were included in all calculations.
We conducted multiple sensitivity analyses. The first analysis was restricted to patients with discharge ICD-10 diagnosis codes for pneumonia (J13-J18) in order to focus on a subset of patients in whom clinicians' had a sustained impression of pneumonia (thus excluding patients whose diagnosis might have evolved from pneumonia to some other infection that merited a longer course of antibiotic treatment). The second sensitivity analysis was restricted to patients with negative results of blood and sputum cultures to exclude antibiotic administration being continued to treat bacteremia or in case clinicians believed that sputum culture-positive disease required longer treatment courses. The third sensitivity analysis excluded immunocompromised patients, defined as all patients admitted to an oncology service, transplant service, or with discharge diagnosis codes Characteristics of patients who received antibiotics for possible CAP and HAP are summarized in Table 1. Clinicians' specified indications for antibiotic treatment were consistent with the clinical impressions documented in clinical notes: suspicion for pneumonia on the day antibiotic administration was started was confirmed in 56 of 60 medical records randomly selected for review (positive predictive value, 93%; 95% CI, 85%-98%). The 4 false-positive findings included 2 patients prescribed antibiotic therapy for chronic obstructive lung disease exacerbations, 1 patient with acute   Duration of antibiotic therapy is reported in Table 3. Antibiotics were prescribed for a median of 5 days (IQR, 2-7) for CAP but for 7 days or longer in 2951 of 9540 patients with CAP (30.9%).
Antibiotics were also prescribed for a median of 5 days for HAP (IQR, [3][4][5][6][7][8]  Frequencies of clinical signs within reference ranges, overall treatment durations, and duration of treatment beyond the time that clinical signs normalized were generally similar in all sensitivity analyses, albeit slightly longer among patients with discharge diagnosis codes for pneumonia

Discussion
Using detailed electronic health record data from 4 hospitals, we found that all the cardinal clinical signs typically associated with pneumonia were within reference ranges among 18. Our finding that antibiotics are frequently prescribed for patients with clinical signs within reference ranges is consistent with other studies. Braykov and colleagues, 27 for example, reviewed the medical records of 1200 patients treated with antibiotics in 6 US hospitals. The investigators reported that 30% of patients were afebrile and had white blood cell counts within the reference range on the first day of antibiotic treatment. Russell and colleagues 28 reported that 35% of inpatients prescribed antibiotic treatment for HAP did not have new or progressive infiltrates on chest imaging. Burton and colleagues 29 reported that 48% of patients treated for nonventilator HAP did not have compatible radiographic infiltrates, inflammatory signs, and/or respiratory signs.
Our observation that up to a third of antibiotics prescribed for possible pneumonia may be unnecessary suggests 2 potential antibiotic stewardship strategies: decrease initiation of antibiotic therapy for patients with clinical signs within reference ranges and tailor antibiotic courses to patients' clinical trajectories. To decrease unnecessary antibiotic therapy, stewardship programs could encourage clinicians to weigh patients' objective clinical data more heavily before prescribing antibiotics for possible pneumonia. Patients with clinical signs within reference ranges typically do not need immediate antibiotic treatment, regardless of their subjective symptoms. This concept is supported by a growing body of observational and interventional data that affirm the safety and possible benefit of awaiting confirmation of diagnosis before prescribing antibiotic treatment for clinically stable patients with possible but uncertain infections. 30,31 Analyses of associations between time to antibiotic initiation and mortality in patients with sepsis suggest that delays in antibiotic therapy are associated with higher mortality in patients with septic shock but not those without shock. [32][33][34] Quality improvement initiatives in which clinicians empirically prescribed antibiotic therapy only for patients with signs of possible sepsis but waited for confirmatory data before prescribing for those without sepsis suggest that this strategy is not only safe but may even confer a mortality benefit. [35][36][37][38] Similarly, clinicians are advised to follow patients' physiologic trajectories after starting ranges. [21][22][23] Integrating serial procalcitonin monitoring may further facilitate this strategy. 39 Our estimate of potential excess antibiotic days is likely conservative because we only counted excess antibiotic days starting 3 days after all clinical signs had returned to the reference ranges, whereas clinical trials evaluating the safety of shorter treatment courses have permitted stopping antibiotic therapy so long as patients were improving even if some of their signs were still abnormal.
Clinical sign monitoring could potentially be the basis for a new antibiotic stewardship measurement. Rather than comparing hospitals on the average duration of antibiotic treatment prescribed for fixed diagnoses (eg, pneumonia), it might make more sense to compare average duration of antibiotic treatment beyond when clinical signs have normalized. The advantage of this approach is that it accounts for differences in clinical trajectories between patients who differ in comorbidities, infecting pathogens, and extent of infection. A measure of this nature would allow for longer courses for patients who are slow to improve and shorter courses for patients who rapidly improve. The key parameter is simply whether antibiotic therapy was continued for more than 2 days beyond when clinical signs normalized.

Strengths and Limitations
Strengths of our study include the large sample size, the use of detailed electronic health record data to determine vital signs, inclusion of both tertiary and community hospitals, consistency of findings among hospitals, and inclusion of discharge prescriptions when calculating antibiotic durations. A further strength is our use of the indications specified by clinicians at the time of prescribing to determine why antibiotics were ordered. Using the indications specified by clinicians at the time of prescribing helps to overcome a major limitation of studies restricted to patients with either confirmed infections or discharge diagnosis codes for infections: these restrictions render these studies blind to empirical antibiotics prescribed for suspected respiratory tract infections but subsequently diagnosed with other conditions and patients with confirmed pneumonias but incomplete coding. We found that only 30% of patients who received antibiotics for pneumonia were assigned discharge diagnosis codes for pneumonia, suggesting a sustained clinical impression of pneumonia-this result is consistent with other investigations. 40 Conversely, it is possible that clinicians may misspecify their reasons for prescribing. Our audit, however, suggested that the indications provided by clinicians largely reflected the working diagnoses recorded in their clinical notes.
Limitations of our study include the possibility that clinicians' impressions and working diagnoses may evolve as they observe patients' clinical courses and obtain test results. Some presentations that initially appear to be pneumonia may be due to other conditions that perhaps require longer courses of antibiotics even in the absence of ongoing symptoms (eg, endocarditis, empyema). We tried to account for this possibility by excluding patients with diagnosis codes for pyogenic complications and by conducting sensitivity analyses restricted to patients with discharge diagnosis codes for pneumonia and those with negative blood and sputum culture results. We likely underestimated the frequency of stable oxygenation on the first day of antibiotic therapy because findings of patients receiving oxygen at home or with baseline oxygen saturations below 95% were all counted as abnormal. Another limitation is the omission of radiographic imaging interpretations from our analysis. Radiographic imaging interpretations, however, are subjective, nonspecific, and correspond variably with histologic findings, and it is unlikely that a patient has pneumonia if their sole clinical sign is a radiographic opacity. [7][8][9][10] Similarly, some patients may have had other signs or symptoms that we did not include in our analysis, such as dyspnea, cough, or chest pain. Some of these patients may have had bona fide pneumonias despite normal temperatures, respiratory rates, white blood cell counts, and oxygenation levels. In addition, our findings may not be generalizable to other hospitals and regions.

Conclusions
In this study, we noted possible widespread overuse of antibiotics for suspected respiratory tract infections. Almost a fifth of patients started on antibiotics for possible respiratory infections had clinical signs within reference ranges and antibiotics were continued for 3 days or more beyond when clinical signs normalized in more than a third of patients. Our analysis suggests 2 potential strategies to decrease inappropriate antibiotic use for suspected respiratory infections: do not prescribe antibiotics for possible pneumonia in patients with clinical signs within reference ranges and customize treatment durations to patients' clinical trajectories rather than prospectively specifying fixed courses for all patients. The safety and effectiveness of these strategies merit formal evaluation in future trials.