What is the difference between antibiotic and antiviral

Journal Article

S Scott Sutton,

Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, College of Pharmacy

, Columbia, South Carolina,

USA

Correspondence: S. S. Sutton, Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina College of Pharmacy, 715 Sumter St 311D, Columbia, SC 29208 ().

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Joseph Magagnoli,

Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, College of Pharmacy

, Columbia, South Carolina,

USA

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Tammy Cummings,

Wm Jennings Bryan Dorn Veterans Affairs Medical Center

, Columbia, South Carolina,

USA

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James Hardin

Department of Epidemiology and Biostatistics, University of South Carolina

, Columbia, South Carolina,

USA

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Editorial decision:

23 November 2019

Accepted:

22 January 2020

Published:

24 January 2020

Corrected and typeset:

03 July 2020

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  S Scott Sutton, Joseph Magagnoli, Tammy Cummings, James Hardin, Association Between the Use of Antibiotics, Antivirals, and Hospitalizations Among Patients With Laboratory-confirmed Influenza, Clinical Infectious Diseases, Volume 72, Issue 4, 15 February 2021, Pages 566–573, //doi.org/10.1093/cid/ciaa074

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Abstract

Background

Clinicians may prescribe antibiotics to influenza patients at high risk for bacterial complications. We explored the association between antibiotics, antivirals, and hospitalization among people with influenza.

Methods

A retrospective cohort study of patients with confirmed influenza with encounters during January 2011–January 2019 was conducted using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). We compared inpatient hospitalizations (all-cause and respiratory) within 30 days of influenza diagnosis between 4 patient cohorts: (1) no treatment (n = 4228); (2) antibiotic only (n = 671); (3) antiviral only (n = 6492); and (4) antibiotic plus antiviral (n = 1415). We estimated relative risk for hospitalization using Poisson generalized linear model and robust standard errors.

Results

Among 12 806 influenza cases, most were white men (mean age, 57–60 years). Those with antivirals only, antibiotic plus antiviral, and antibiotics only all had a statistically significant lower risk of all-cause and respiratory hospitalization compared to those without treatment. Comparing the antibiotic plus antiviral cohort to those who were prescribed an antiviral alone, there was a 47% lower risk for respiratory hospitalization (relative risk, 0.53 [95% confidence interval, .31–.94]), and no other statistical differences were detected.

Conclusions

Those prescribed an antiviral, antibiotic, or both had a lower risk of hospitalization within 30 days compared to those without therapy. Furthermore, intervention with both an antibiotic and antiviral had a lower risk of respiratory hospitalization within 30 days compared to those with an antiviral alone. Importantly, the absolute magnitude of decreased risk with antibiotic plus antiviral therapy is small and must be interpreted within the context of the overall risk of antibiotic usage.

(See the Editorial Commentary by Ison and Linder on pages 574–5.)

Influenza significantly impacts school attendance, worker absenteeism, and daily productivity; fortunately, the majority of individuals recover in < 2 weeks [1, 2]. Unfortunately, influenza-related morbidity and mortality may occur 1–2 weeks after the initial infection because of bacterial infections or aggravation of an existing chronic illness [1, 3, 4]. The Centers for Disease Control and Prevention estimates that the influenza annual burden in the United States is responsible for up to 49 million flu illnesses, 959 000 hospitalizations, and 79 400 deaths [2]. Morbidity and mortality associated with influenza have increased in the last 2 decades, in part because of the aging population, underscoring the need for enhanced treatment [3, 5, 6]. Antiviral treatment with neuraminidase inhibitors may be utilized to treat influenza based upon the clinician’s discretion [7, 8]. Although the use of antivirals is associated with fewer hospitalizations and complications, clinicians may prescribe an antibiotic to patients they perceive as high risk for bacterial complications [7–13]. In the absence of an evident superinfection, antibiotics are not recommended for the management of influenza. However, a significant portion of influenza morbidity and mortality is related to bacterial coinfections [14]. The majority of studies evaluating antibiotics prescribed in influenza evaluated the rate of prescribing and not the outcome of prescribing [15–19]. Of the antibiotic outcome studies, cohorts included patients with influenza-like symptoms or evaluated a cohort at low risk of influenza complications [17–19]. In confirmed influenza cases where providers perceive a high risk for complications, the question remains whether antibacterial therapy should be prescribed [15]. For example, pulmonary pathologic findings in fatal influenza diseases demonstrate that superimposed bacterial infections are common [20]. Additionally, during influenza outbreaks bacterial coinfection was documented in 98% of deaths; lack of access to antibiotics has been reported as a factor in influenza mortality; and subsequently a systematic review states that providers should consider bacterial coinfection in hospitalized influenza patients [21–23]. The question of antibacterial treatment among influenza patients is clinically important because influenza morbidity and mortality are commonly associated with bacterial infections. However, this question has potentially serious consequences because the utilization of antibiotics comes with significant individual (eg, side effects) and public health (eg, bacterial resistance) risks. Given the increasing number of influenza hospitalizations, the risk of bacterial coinfection, and risks of antibiotic use, we sought to examine antibiotic and antiviral medication usage and hospitalization rates among patients with laboratory-confirmed influenza in a national cohort of United States Veterans.

METHODS

Data

This retrospective cohort study was conducted using data from the US Department of Veterans Affairs. The Veterans Affairs Informatics and Computing Infrastructure (VINCI) was utilized to obtain individual-level information on demographics, administrative claims, and pharmacy dispensation. The completeness, utility, accuracy, validity, and accession methods are described on the Veterans Affairs website (//www.virec.research.va.gov). The study was conducted in compliance with the Department of Veterans Affairs requirements and received institutional review board and research and development approval. The study utilized inpatient and outpatient data consisting of claims coded with the International Classification of Diseases, Ninth Revision, Clinical Modification and Tenth Revision, Clinical Modification (ICD-9/10) and Current Procedural Terminology, as well as pharmacy, laboratory, and vital sign data (pulse oximetry, heart rate, respirations, temperature) from January 2010 to February 2019.

Cohort Selection

We utilized a cohort with a laboratory-confirmed diagnosis of influenza and ICD-9/10 diagnosis codes of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. Influenza status was classified by RNA laboratory results that were extracted from the Veterans Affairs laboratory data utilizing Logical Observation Identifiers Names and Codes (LOINC). Supplementary Appendix Table 1 presents all LOINC and ICD-9/10 codes. The study index was based on the date of a positive influenza laboratory result. Index dates range from January 2011 to 31 January 2019 and patients were followed from index for 1 month. The period prior to index is designated as the baseline period and on or after index is designated the follow-up period. Patients were included in the study if they (1) had a prescription dispensed during the baseline period; (2) were diagnosed in a primary care or emergency department setting; (3) were not transferred to the emergency department; (4) had no hospitalization in the 30 days prior to influenza diagnosis; (5) were not admitted to the hospital on the same day as influenza diagnosis; and (6) had vital sign data on day of diagnosis.

Study Outcome

The study outcome is inpatient hospitalization within 30 days of influenza diagnosis. We categorized hospitalization into 2 groups: all-cause and respiratory. All-cause hospitalizations were any inpatient hospitalization within 30 days of influenza diagnosis. Respiratory hospitalizations were hospitalizations with a primary diagnosis of a respiratory condition. All respiratory codes are listed in Supplementary Appendix Table 2.

Medication Exposure

Patients were grouped into 4 mutually exclusive cohorts based on antibiotic and antiviral prescriptions dispensed on the date of influenza diagnosis. The cohorts were defined as (1) untreated (no antibiotic or antiviral); (2) antibiotic only; (3) antiviral only; or (4) antibiotic and antiviral (antibiotic + antiviral). The antibiotic classes used in this study include macrolides, quinolones, penicillins, tetracyclines, cephalosporins, lincomycins, and sulfonamides. Oseltamivir and zanamivir were included in the antiviral class.

Baseline Data

We extracted data on baseline demographics, comorbidities, and vital signs. Demographic and clinical characteristics included age, sex, race/ethnicity, body mass index, year of visit, and visit location. Comorbid conditions include all conditions included in the Charlson comorbidity index as well as drug abuse and mental health conditions. Vital sign data include heart rate, pulse oximetry, respirations, temperature, and blood pressure. All vital sign data were collected as the first set of vital results during the patient’s visit. Finally, an indicator was included if the patient received a flu shot in the previous 9 months.

Statistical Analysis

The statistical analysis occurred in several steps. First, we generated summaries of the baseline demographic and clinical characteristics for each cohort. Second, we calculate the unadjusted incidence rates for each hospitalization outcome. Third, we estimate the relative risk for each outcome using Poisson generalized linear model and robust standard errors. Last, we estimate the relative risk of hospitalization for those patients with dispensed antibiotic and/or antiviral. Models were adjusted for all baseline data. Data were analyzed using SAS version 9.1.3 (SAS Institute, Cary, North Carolina) and R (R Core Team, Vienna, Austria, 2013) software.

RESULTS

We identified a total of 12 806 influenza cases eligible for study inclusion (Figure 1). Among the influenza cases, 4228 were untreated, 6492 had only an antiviral, 1415 had an antiviral plus antibiotic, and 671 had an antibiotic only. Table 1 presents the demographic and clinical characteristics of the cohorts. Most influenza diagnoses occurred in the emergency department, with proportions ranging from approximately 75% in the antibiotic-only cohort to 85% in the antiviral-only cohort. The antibiotic plus antiviral cohort had the highest Charlson comorbidity index (1.62) while the antiviral cohort had the lowest (1.35). The antibiotic classes that were prescribed are shown in Table 2. The top classes were macrolides, penicillin, quinolones, and tetracyclines. Oseltamivir was the primary antiviral used (99.9%).

Figure 1.

Study attrition. Abbreviations: BP, blood pressure; ED, emergency department; HR, heart rate; ICD-9/10, International Classification of Diseases, Ninth/Tenth Revision; PCR, polymerase chain reaction.

Table 1.

Baseline Demographic and Clinical Characteristics

UntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic OnlyCharacteristic(n = 4228)(n = 6492)(n = 1415)(n = 671)P Value

Race					< .001
Black	1076 (25.5)	1927 (29.7)	416 (29.4)	176 (26.2)
Other/unknown	304 (7.2)	467 (7.2)	83 (5.9)	45 (6.7)
White	2848 (67.4)	4098 (63.1)	916 (64.7)	450 (67.1)
Sex					.89
Female	549 (13.0)	818 (12.6)	187 (13.2)	84 (12.5)
Male	3679 (87.0)	5674 (87.4)	1228 (86.8)	587 (87.5)
Age, y, mean (SD)	58.22 (18.7)	57.17 (16.3)	60.06 (15.4)	59.74 (16.2)	< .001
Year of visit, mean (SD)	2016.91 (1.6)	2016.9 (1.7)	2016.62 (1.8)	2016.47 (2.0)	< .001
Pulse oximetry, %					< .001
< 90	123 (2.9)	87 (1.3)	35 (2.5)	18 (2.7)
90–91	173 (4.1)	184 (2.8)	53 (3.8)	27 (4.0)
92–94	806 (19.1)	1231 (19.0)	324 (22.9)	125 (18.6)
≥ 95	3126 (74.0)	4990 (76.9)	1003 (70.9)	501 (74.7)
Respiration, breaths/min					< .001
< 16	149 (3.5)	244 (3.8)	49 (3.5)	15 (2.2)
16–20	3571 (84.5)	5736 (88.4)	1198 (84.7)	585 (87.2)
> 20	508 (12.0)	512 (7.9)	168 (11.9)	71 (10.6)
Heart rate, beats/min					< .001
< 50	6 (0.1)	21 (0.3)	5 (0.4)	1 (0.2)
50–100	2854 (67.5)	4395 (67.7)	973 (68.8)	510 (76.0)
> 100	1368 (32.4)	2076 (32.0)	437 (30.9)	160 (23.9)
Temperature, °C, mean (SD)	37.17 (0.88)	37.23 (0.89)	37.18 (0.84)	36.99 (0.8)	< .001
Systolic BP, mm Hg, mean (SD)	134.72 (20.8)	135.57 (20.1)	136.05 (20.9)	133.89 (19.1)	.021
Diastolic BP, mm Hg, mean (SD)	79.26 (12.4)	79.63 (11.9)	79.71 (12.9)	79.02 (11.6)	.267
BMI, kg/m2					.184
< 18.5	57 (1.4)	51 (0.8)	12 (0.9)	5 (0.8)
18.5–24.9	696 (16.5)	1017 (15.7)	231 (16.3)	128 (19.1)
25–29.9	1375 (32.5)	2164 (33.3)	463 (32.7)	211 (31.5)
≥ 30	2039 (48.2)	3152 (48.6)	685 (48.4)	315 (46.9)
Missing	61 (1.4)	108 (1.7)	24 (1.7)	12 (1.8)
Visit location					< .001
Emergency department	3271 (77.4)	5523 (85.1)	1194 (84.4)	503 (75.0)
Primary care	957 (22.6)	969 (14.9)	221 (15.6)	168 (25.0)
Flu shot within 9 mo	1430 (33.8)	2309 (35.6)	523 (37.0)	243 (36.2)	.106
Seasonality					.084
October–March	3934 (93.1)	6176 (95.1)	1341 (94.8)	632 (94.2)
April–September	294 (7.0)	316 (5.0)	74 (5.2)	39 (5.8)
Comorbidities
Myocardial infarction	87 (2.1)	139 (2.1)	34 (2.4)	16 (2.4)	.855
Congestive heart failure	296 (7.0)	356 (5.5)	119 (8.4)	40 (6.0)	< .001
Peripheral vascular disease	254 (6.0)	365 (5.6)	101 (7.1)	50 (7.5)	.061
Cerebrovascular disease	225 (5.3)	338 (5.2)	78 (5.5)	29 (4.3)	.7
Dementia	100 (2.4)	97 (1.5)	24 (1.7)	11 (1.6)	.011
Chronic pulmonary disease	911 (21.6)	1184 (18.2)	368 (26.0)	150 (22.4)	< .001
Connective tissue/rheumatic disease	71 (1.7)	90 (1.4)	27 (1.9)	17 (2.5)	.085
Peptic ulcer disease	28 (0.7)	37 (0.6)	10 (0.7)	2 (0.3)	.645
Mild liver disease	239 (5.7)	388 (6.0)	78 (5.5)	43 (6.4)	.763
Diabetes without complications	1144 (27.1)	1644 (25.3)	417 (29.5)	180 (26.8)	.008
Diabetes with complications	474 (11.2)	690 (10.6)	185 (13.1)	76 (11.3)	.068
Paraplegia and hemiplegia	23 (0.5)	38 (0.6)	6 (0.4)	3 (0.5)	.875
Renal disease	345 (8.2)	462 (7.1)	115 (8.1)	33 (4.9)	.01
Cancer	355 (8.4)	504 (7.8)	114 (8.1)	60 (8.9)	.548
Moderate or severe liver disease	25 (0.6)	18 (0.3)	12 (0.9)	1 (0.2)	.005
Metastatic carcinoma	33 (0.8)	42 (0.7)	10 (0.7)	3 (0.5)	.737
HIV/AIDS	50 (1.2)	77 (1.2)	16 (1.1)	11 (1.6)	.761
Drug abuse	792 (18.7)	1235 (19.0)	286 (20.2)	141 (21.0)	.38
Mental health	2370 (56.1)	3585 (55.2)	825 (58.3)	397 (59.2)	.061

UntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic OnlyCharacteristic(n = 4228)(n = 6492)(n = 1415)(n = 671)P Value

Race					< .001
Black	1076 (25.5)	1927 (29.7)	416 (29.4)	176 (26.2)
Other/unknown	304 (7.2)	467 (7.2)	83 (5.9)	45 (6.7)
White	2848 (67.4)	4098 (63.1)	916 (64.7)	450 (67.1)
Sex					.89
Female	549 (13.0)	818 (12.6)	187 (13.2)	84 (12.5)
Male	3679 (87.0)	5674 (87.4)	1228 (86.8)	587 (87.5)
Age, y, mean (SD)	58.22 (18.7)	57.17 (16.3)	60.06 (15.4)	59.74 (16.2)	< .001
Year of visit, mean (SD)	2016.91 (1.6)	2016.9 (1.7)	2016.62 (1.8)	2016.47 (2.0)	< .001
Pulse oximetry, %					< .001
< 90	123 (2.9)	87 (1.3)	35 (2.5)	18 (2.7)
90–91	173 (4.1)	184 (2.8)	53 (3.8)	27 (4.0)
92–94	806 (19.1)	1231 (19.0)	324 (22.9)	125 (18.6)
≥ 95	3126 (74.0)	4990 (76.9)	1003 (70.9)	501 (74.7)
Respiration, breaths/min					< .001
< 16	149 (3.5)	244 (3.8)	49 (3.5)	15 (2.2)
16–20	3571 (84.5)	5736 (88.4)	1198 (84.7)	585 (87.2)
> 20	508 (12.0)	512 (7.9)	168 (11.9)	71 (10.6)
Heart rate, beats/min					< .001
< 50	6 (0.1)	21 (0.3)	5 (0.4)	1 (0.2)
50–100	2854 (67.5)	4395 (67.7)	973 (68.8)	510 (76.0)
> 100	1368 (32.4)	2076 (32.0)	437 (30.9)	160 (23.9)
Temperature, °C, mean (SD)	37.17 (0.88)	37.23 (0.89)	37.18 (0.84)	36.99 (0.8)	< .001
Systolic BP, mm Hg, mean (SD)	134.72 (20.8)	135.57 (20.1)	136.05 (20.9)	133.89 (19.1)	.021
Diastolic BP, mm Hg, mean (SD)	79.26 (12.4)	79.63 (11.9)	79.71 (12.9)	79.02 (11.6)	.267
BMI, kg/m2					.184
< 18.5	57 (1.4)	51 (0.8)	12 (0.9)	5 (0.8)
18.5–24.9	696 (16.5)	1017 (15.7)	231 (16.3)	128 (19.1)
25–29.9	1375 (32.5)	2164 (33.3)	463 (32.7)	211 (31.5)
≥ 30	2039 (48.2)	3152 (48.6)	685 (48.4)	315 (46.9)
Missing	61 (1.4)	108 (1.7)	24 (1.7)	12 (1.8)
Visit location					< .001
Emergency department	3271 (77.4)	5523 (85.1)	1194 (84.4)	503 (75.0)
Primary care	957 (22.6)	969 (14.9)	221 (15.6)	168 (25.0)
Flu shot within 9 mo	1430 (33.8)	2309 (35.6)	523 (37.0)	243 (36.2)	.106
Seasonality					.084
October–March	3934 (93.1)	6176 (95.1)	1341 (94.8)	632 (94.2)
April–September	294 (7.0)	316 (5.0)	74 (5.2)	39 (5.8)
Comorbidities
Myocardial infarction	87 (2.1)	139 (2.1)	34 (2.4)	16 (2.4)	.855
Congestive heart failure	296 (7.0)	356 (5.5)	119 (8.4)	40 (6.0)	< .001
Peripheral vascular disease	254 (6.0)	365 (5.6)	101 (7.1)	50 (7.5)	.061
Cerebrovascular disease	225 (5.3)	338 (5.2)	78 (5.5)	29 (4.3)	.7
Dementia	100 (2.4)	97 (1.5)	24 (1.7)	11 (1.6)	.011
Chronic pulmonary disease	911 (21.6)	1184 (18.2)	368 (26.0)	150 (22.4)	< .001
Connective tissue/rheumatic disease	71 (1.7)	90 (1.4)	27 (1.9)	17 (2.5)	.085
Peptic ulcer disease	28 (0.7)	37 (0.6)	10 (0.7)	2 (0.3)	.645
Mild liver disease	239 (5.7)	388 (6.0)	78 (5.5)	43 (6.4)	.763
Diabetes without complications	1144 (27.1)	1644 (25.3)	417 (29.5)	180 (26.8)	.008
Diabetes with complications	474 (11.2)	690 (10.6)	185 (13.1)	76 (11.3)	.068
Paraplegia and hemiplegia	23 (0.5)	38 (0.6)	6 (0.4)	3 (0.5)	.875
Renal disease	345 (8.2)	462 (7.1)	115 (8.1)	33 (4.9)	.01
Cancer	355 (8.4)	504 (7.8)	114 (8.1)	60 (8.9)	.548
Moderate or severe liver disease	25 (0.6)	18 (0.3)	12 (0.9)	1 (0.2)	.005
Metastatic carcinoma	33 (0.8)	42 (0.7)	10 (0.7)	3 (0.5)	.737
HIV/AIDS	50 (1.2)	77 (1.2)	16 (1.1)	11 (1.6)	.761
Drug abuse	792 (18.7)	1235 (19.0)	286 (20.2)	141 (21.0)	.38
Mental health	2370 (56.1)	3585 (55.2)	825 (58.3)	397 (59.2)	.061

Data are presented as no. (%) unless otherwise indicated.

Abbreviations: BMI, body mass index; BP, blood pressure; HIV, human immunodeficiency virus; SD, standard deviation.

Table 1.

Baseline Demographic and Clinical Characteristics

UntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic OnlyCharacteristic(n = 4228)(n = 6492)(n = 1415)(n = 671)P Value

Race					< .001
Black	1076 (25.5)	1927 (29.7)	416 (29.4)	176 (26.2)
Other/unknown	304 (7.2)	467 (7.2)	83 (5.9)	45 (6.7)
White	2848 (67.4)	4098 (63.1)	916 (64.7)	450 (67.1)
Sex					.89
Female	549 (13.0)	818 (12.6)	187 (13.2)	84 (12.5)
Male	3679 (87.0)	5674 (87.4)	1228 (86.8)	587 (87.5)
Age, y, mean (SD)	58.22 (18.7)	57.17 (16.3)	60.06 (15.4)	59.74 (16.2)	< .001
Year of visit, mean (SD)	2016.91 (1.6)	2016.9 (1.7)	2016.62 (1.8)	2016.47 (2.0)	< .001
Pulse oximetry, %					< .001
< 90	123 (2.9)	87 (1.3)	35 (2.5)	18 (2.7)
90–91	173 (4.1)	184 (2.8)	53 (3.8)	27 (4.0)
92–94	806 (19.1)	1231 (19.0)	324 (22.9)	125 (18.6)
≥ 95	3126 (74.0)	4990 (76.9)	1003 (70.9)	501 (74.7)
Respiration, breaths/min					< .001
< 16	149 (3.5)	244 (3.8)	49 (3.5)	15 (2.2)
16–20	3571 (84.5)	5736 (88.4)	1198 (84.7)	585 (87.2)
> 20	508 (12.0)	512 (7.9)	168 (11.9)	71 (10.6)
Heart rate, beats/min					< .001
< 50	6 (0.1)	21 (0.3)	5 (0.4)	1 (0.2)
50–100	2854 (67.5)	4395 (67.7)	973 (68.8)	510 (76.0)
> 100	1368 (32.4)	2076 (32.0)	437 (30.9)	160 (23.9)
Temperature, °C, mean (SD)	37.17 (0.88)	37.23 (0.89)	37.18 (0.84)	36.99 (0.8)	< .001
Systolic BP, mm Hg, mean (SD)	134.72 (20.8)	135.57 (20.1)	136.05 (20.9)	133.89 (19.1)	.021
Diastolic BP, mm Hg, mean (SD)	79.26 (12.4)	79.63 (11.9)	79.71 (12.9)	79.02 (11.6)	.267
BMI, kg/m2					.184
< 18.5	57 (1.4)	51 (0.8)	12 (0.9)	5 (0.8)
18.5–24.9	696 (16.5)	1017 (15.7)	231 (16.3)	128 (19.1)
25–29.9	1375 (32.5)	2164 (33.3)	463 (32.7)	211 (31.5)
≥ 30	2039 (48.2)	3152 (48.6)	685 (48.4)	315 (46.9)
Missing	61 (1.4)	108 (1.7)	24 (1.7)	12 (1.8)
Visit location					< .001
Emergency department	3271 (77.4)	5523 (85.1)	1194 (84.4)	503 (75.0)
Primary care	957 (22.6)	969 (14.9)	221 (15.6)	168 (25.0)
Flu shot within 9 mo	1430 (33.8)	2309 (35.6)	523 (37.0)	243 (36.2)	.106
Seasonality					.084
October–March	3934 (93.1)	6176 (95.1)	1341 (94.8)	632 (94.2)
April–September	294 (7.0)	316 (5.0)	74 (5.2)	39 (5.8)
Comorbidities
Myocardial infarction	87 (2.1)	139 (2.1)	34 (2.4)	16 (2.4)	.855
Congestive heart failure	296 (7.0)	356 (5.5)	119 (8.4)	40 (6.0)	< .001
Peripheral vascular disease	254 (6.0)	365 (5.6)	101 (7.1)	50 (7.5)	.061
Cerebrovascular disease	225 (5.3)	338 (5.2)	78 (5.5)	29 (4.3)	.7
Dementia	100 (2.4)	97 (1.5)	24 (1.7)	11 (1.6)	.011
Chronic pulmonary disease	911 (21.6)	1184 (18.2)	368 (26.0)	150 (22.4)	< .001
Connective tissue/rheumatic disease	71 (1.7)	90 (1.4)	27 (1.9)	17 (2.5)	.085
Peptic ulcer disease	28 (0.7)	37 (0.6)	10 (0.7)	2 (0.3)	.645
Mild liver disease	239 (5.7)	388 (6.0)	78 (5.5)	43 (6.4)	.763
Diabetes without complications	1144 (27.1)	1644 (25.3)	417 (29.5)	180 (26.8)	.008
Diabetes with complications	474 (11.2)	690 (10.6)	185 (13.1)	76 (11.3)	.068
Paraplegia and hemiplegia	23 (0.5)	38 (0.6)	6 (0.4)	3 (0.5)	.875
Renal disease	345 (8.2)	462 (7.1)	115 (8.1)	33 (4.9)	.01
Cancer	355 (8.4)	504 (7.8)	114 (8.1)	60 (8.9)	.548
Moderate or severe liver disease	25 (0.6)	18 (0.3)	12 (0.9)	1 (0.2)	.005
Metastatic carcinoma	33 (0.8)	42 (0.7)	10 (0.7)	3 (0.5)	.737
HIV/AIDS	50 (1.2)	77 (1.2)	16 (1.1)	11 (1.6)	.761
Drug abuse	792 (18.7)	1235 (19.0)	286 (20.2)	141 (21.0)	.38
Mental health	2370 (56.1)	3585 (55.2)	825 (58.3)	397 (59.2)	.061

UntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic OnlyCharacteristic(n = 4228)(n = 6492)(n = 1415)(n = 671)P Value

Race					< .001
Black	1076 (25.5)	1927 (29.7)	416 (29.4)	176 (26.2)
Other/unknown	304 (7.2)	467 (7.2)	83 (5.9)	45 (6.7)
White	2848 (67.4)	4098 (63.1)	916 (64.7)	450 (67.1)
Sex					.89
Female	549 (13.0)	818 (12.6)	187 (13.2)	84 (12.5)
Male	3679 (87.0)	5674 (87.4)	1228 (86.8)	587 (87.5)
Age, y, mean (SD)	58.22 (18.7)	57.17 (16.3)	60.06 (15.4)	59.74 (16.2)	< .001
Year of visit, mean (SD)	2016.91 (1.6)	2016.9 (1.7)	2016.62 (1.8)	2016.47 (2.0)	< .001
Pulse oximetry, %					< .001
< 90	123 (2.9)	87 (1.3)	35 (2.5)	18 (2.7)
90–91	173 (4.1)	184 (2.8)	53 (3.8)	27 (4.0)
92–94	806 (19.1)	1231 (19.0)	324 (22.9)	125 (18.6)
≥ 95	3126 (74.0)	4990 (76.9)	1003 (70.9)	501 (74.7)
Respiration, breaths/min					< .001
< 16	149 (3.5)	244 (3.8)	49 (3.5)	15 (2.2)
16–20	3571 (84.5)	5736 (88.4)	1198 (84.7)	585 (87.2)
> 20	508 (12.0)	512 (7.9)	168 (11.9)	71 (10.6)
Heart rate, beats/min					< .001
< 50	6 (0.1)	21 (0.3)	5 (0.4)	1 (0.2)
50–100	2854 (67.5)	4395 (67.7)	973 (68.8)	510 (76.0)
> 100	1368 (32.4)	2076 (32.0)	437 (30.9)	160 (23.9)
Temperature, °C, mean (SD)	37.17 (0.88)	37.23 (0.89)	37.18 (0.84)	36.99 (0.8)	< .001
Systolic BP, mm Hg, mean (SD)	134.72 (20.8)	135.57 (20.1)	136.05 (20.9)	133.89 (19.1)	.021
Diastolic BP, mm Hg, mean (SD)	79.26 (12.4)	79.63 (11.9)	79.71 (12.9)	79.02 (11.6)	.267
BMI, kg/m2					.184
< 18.5	57 (1.4)	51 (0.8)	12 (0.9)	5 (0.8)
18.5–24.9	696 (16.5)	1017 (15.7)	231 (16.3)	128 (19.1)
25–29.9	1375 (32.5)	2164 (33.3)	463 (32.7)	211 (31.5)
≥ 30	2039 (48.2)	3152 (48.6)	685 (48.4)	315 (46.9)
Missing	61 (1.4)	108 (1.7)	24 (1.7)	12 (1.8)
Visit location					< .001
Emergency department	3271 (77.4)	5523 (85.1)	1194 (84.4)	503 (75.0)
Primary care	957 (22.6)	969 (14.9)	221 (15.6)	168 (25.0)
Flu shot within 9 mo	1430 (33.8)	2309 (35.6)	523 (37.0)	243 (36.2)	.106
Seasonality					.084
October–March	3934 (93.1)	6176 (95.1)	1341 (94.8)	632 (94.2)
April–September	294 (7.0)	316 (5.0)	74 (5.2)	39 (5.8)
Comorbidities
Myocardial infarction	87 (2.1)	139 (2.1)	34 (2.4)	16 (2.4)	.855
Congestive heart failure	296 (7.0)	356 (5.5)	119 (8.4)	40 (6.0)	< .001
Peripheral vascular disease	254 (6.0)	365 (5.6)	101 (7.1)	50 (7.5)	.061
Cerebrovascular disease	225 (5.3)	338 (5.2)	78 (5.5)	29 (4.3)	.7
Dementia	100 (2.4)	97 (1.5)	24 (1.7)	11 (1.6)	.011
Chronic pulmonary disease	911 (21.6)	1184 (18.2)	368 (26.0)	150 (22.4)	< .001
Connective tissue/rheumatic disease	71 (1.7)	90 (1.4)	27 (1.9)	17 (2.5)	.085
Peptic ulcer disease	28 (0.7)	37 (0.6)	10 (0.7)	2 (0.3)	.645
Mild liver disease	239 (5.7)	388 (6.0)	78 (5.5)	43 (6.4)	.763
Diabetes without complications	1144 (27.1)	1644 (25.3)	417 (29.5)	180 (26.8)	.008
Diabetes with complications	474 (11.2)	690 (10.6)	185 (13.1)	76 (11.3)	.068
Paraplegia and hemiplegia	23 (0.5)	38 (0.6)	6 (0.4)	3 (0.5)	.875
Renal disease	345 (8.2)	462 (7.1)	115 (8.1)	33 (4.9)	.01
Cancer	355 (8.4)	504 (7.8)	114 (8.1)	60 (8.9)	.548
Moderate or severe liver disease	25 (0.6)	18 (0.3)	12 (0.9)	1 (0.2)	.005
Metastatic carcinoma	33 (0.8)	42 (0.7)	10 (0.7)	3 (0.5)	.737
HIV/AIDS	50 (1.2)	77 (1.2)	16 (1.1)	11 (1.6)	.761
Drug abuse	792 (18.7)	1235 (19.0)	286 (20.2)	141 (21.0)	.38
Mental health	2370 (56.1)	3585 (55.2)	825 (58.3)	397 (59.2)	.061

Data are presented as no. (%) unless otherwise indicated.

Abbreviations: BMI, body mass index; BP, blood pressure; HIV, human immunodeficiency virus; SD, standard deviation.

Table 2

Antibiotic Prescribing Classes

CohortAntibiotic ClassAntibiotic + AntiviralAntibiotic Only

Macrolide	561 (39.7)	302 (45.0)
Penicillin	288 (20.4)	160 (23.9)
Quinolone	245 (17.3)	92 (13.7)
Tetracycline	237 (16.8)	100 (14.9)
Cephalosporin	91 (6.4)	25 (3.7)
Sulfonamide	26 (1.8)	9 (1.3)
Lincomycin	6 (0.4)	3 (0.5)

CohortAntibiotic ClassAntibiotic + AntiviralAntibiotic Only

Macrolide	561 (39.7)	302 (45.0)
Penicillin	288 (20.4)	160 (23.9)
Quinolone	245 (17.3)	92 (13.7)
Tetracycline	237 (16.8)	100 (14.9)
Cephalosporin	91 (6.4)	25 (3.7)
Sulfonamide	26 (1.8)	9 (1.3)
Lincomycin	6 (0.4)	3 (0.5)

Data are presented as no. (%).

Table 2

Antibiotic Prescribing Classes

CohortAntibiotic ClassAntibiotic + AntiviralAntibiotic Only

Macrolide	561 (39.7)	302 (45.0)
Penicillin	288 (20.4)	160 (23.9)
Quinolone	245 (17.3)	92 (13.7)
Tetracycline	237 (16.8)	100 (14.9)
Cephalosporin	91 (6.4)	25 (3.7)
Sulfonamide	26 (1.8)	9 (1.3)
Lincomycin	6 (0.4)	3 (0.5)

CohortAntibiotic ClassAntibiotic + AntiviralAntibiotic Only

Macrolide	561 (39.7)	302 (45.0)
Penicillin	288 (20.4)	160 (23.9)
Quinolone	245 (17.3)	92 (13.7)
Tetracycline	237 (16.8)	100 (14.9)
Cephalosporin	91 (6.4)	25 (3.7)
Sulfonamide	26 (1.8)	9 (1.3)
Lincomycin	6 (0.4)	3 (0.5)

Data are presented as no. (%).

In Table 3, we present the occurrence of hospitalization outcomes (all-cause, respiratory) for each cohort. The untreated cohort had the highest proportion of all-cause hospitalizations (10.48%) while the antibiotic plus antiviral cohort had the lowest (3.18%). Among the respiratory hospitalizations, the untreated cohort had the highest proportion (6.58%) and the antibiotic plus antiviral cohort had the lowest proportion (1.06%).

Table 3.

Hospitalization Outcomes Within 30 Days of Influenza Diagnosis

Hospitalization OutcomesUntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic Only

All-cause hospitalization	443 (10.5)	235 (3.6)	45 (3.2)	29 (4.3)
Respiratory hospitalization	278 (6.6)	100 (1.5)	15 (1.1)	14 (2.1)

Hospitalization OutcomesUntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic Only

All-cause hospitalization	443 (10.5)	235 (3.6)	45 (3.2)	29 (4.3)
Respiratory hospitalization	278 (6.6)	100 (1.5)	15 (1.1)	14 (2.1)

Data are presented as no. (%).

Table 3.

Hospitalization Outcomes Within 30 Days of Influenza Diagnosis

Hospitalization OutcomesUntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic Only

All-cause hospitalization	443 (10.5)	235 (3.6)	45 (3.2)	29 (4.3)
Respiratory hospitalization	278 (6.6)	100 (1.5)	15 (1.1)	14 (2.1)

Hospitalization OutcomesUntreatedAntiviral OnlyAntibiotic + AntiviralAntibiotic Only

All-cause hospitalization	443 (10.5)	235 (3.6)	45 (3.2)	29 (4.3)
Respiratory hospitalization	278 (6.6)	100 (1.5)	15 (1.1)	14 (2.1)

Data are presented as no. (%).

The relative risk (RR) estimates of hospitalization using the untreated cohort as the reference category are shown in Table 4. Those with antivirals only, antibiotic plus antiviral, as well as antibiotics only all have a statistically significant lower risk of all-cause hospitalization and respiratory hospitalization compared to those without an antiviral or an antibiotic. Estimates are the most protective in the first 5 days. Thus, for all-cause hospitalizations, compared to the untreated reference group, the antiviral cohort has an 80% lower risk of hospitalization (RR, 0.20 [95% confidence interval {CI}, .16–.25]); the antibiotic plus antiviral cohort has an 85% lower risk of hospitalization (RR, 0.15 [95% CI, .09–.23]); and the antibiotic-only cohort has a 65% lower risk (RR, 0.35 [95% CI, .22–.54]). Expanding the time period to 30 days, we find that for all-cause hospitalization, the antiviral-only cohort has a 63% lower risk (RR, 0.37 [95% CI, .32–.44]), the antibiotic plus antiviral cohort has a 72% lower risk (RR, 0.28 [95% CI, .21–.38]), and the antibiotic-only cohort has a 57% lower risk (RR, 0.43 [95% CI, .31–.62]). Respiratory hospitalization results are similar. In the first 5 days, the antiviral cohort has an 82% lower risk of hospitalization (RR, 0.18 [95% CI, .14–.24]); the antibiotic plus antiviral group has an 87% lower risk of hospitalization (RR, 0.13 [95% CI, .07–.23]); and the antibiotic-only cohort has a 67% lower risk (RR, 0.33 [95% CI, .19–.59]) compared to the untreated reference group. Even expanding the time period to 30 days, a decrease in risk was found in all cohorts compared to the reference group.

Table 4.

Adjusted Relative Risk of Hospitalization Outcomesa

RR (95% CI)Hospitalization OutcomesComparison (vs No Treatment)1–5 d1–10 d1–30 d

All-cause	Antiviral only	0.20 (.16–.25)	0.27 (.22–.32)	0.37 (.32–.44)
	Antibiotic + antiviral	0.15 (.09–.23)	0.19 (.13–.28)	0.28 (.21–.38)
	Antibiotic only	0.35 (.22–.54)	0.36 (.24–.55)	0.43 (.31–.62)
Respiratory	Antiviral only	0.18 (.14–.24)	0.24 (.19–.30)	0.26 (.21–.33)
	Antibiotic + antiviral	0.13 (.07–.23)	0.14 (.08–.25)	0.15 (.09–.25)
	Antibiotic only	0.33 (.19–.59)	0.36 (.21–.61)	0.34 (.20–.59)

RR (95% CI)Hospitalization OutcomesComparison (vs No Treatment)1–5 d1–10 d1–30 d

All-cause	Antiviral only	0.20 (.16–.25)	0.27 (.22–.32)	0.37 (.32–.44)
	Antibiotic + antiviral	0.15 (.09–.23)	0.19 (.13–.28)	0.28 (.21–.38)
	Antibiotic only	0.35 (.22–.54)	0.36 (.24–.55)	0.43 (.31–.62)
Respiratory	Antiviral only	0.18 (.14–.24)	0.24 (.19–.30)	0.26 (.21–.33)
	Antibiotic + antiviral	0.13 (.07–.23)	0.14 (.08–.25)	0.15 (.09–.25)
	Antibiotic only	0.33 (.19–.59)	0.36 (.21–.61)	0.34 (.20–.59)

Abbreviations: CI, confidence interval; RR, relative risk.

aRelative risks are adjusted for pulse oximetry, heart rate, respirations, temperature, flu shot, visit location, age, race, sex, body mass index, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue/rheumatic disease, peptic ulcer disease, mild liver disease, diabetes without complications, diabetes with complications, paraplegia and hemiplegia, renal disease, cancer, moderate or severe liver disease, metastatic carcinoma, human immunodeficiency virus/AIDS, drug abuse, mental health conditions.

Table 4.

Adjusted Relative Risk of Hospitalization Outcomesa

RR (95% CI)Hospitalization OutcomesComparison (vs No Treatment)1–5 d1–10 d1–30 d

All-cause	Antiviral only	0.20 (.16–.25)	0.27 (.22–.32)	0.37 (.32–.44)
	Antibiotic + antiviral	0.15 (.09–.23)	0.19 (.13–.28)	0.28 (.21–.38)
	Antibiotic only	0.35 (.22–.54)	0.36 (.24–.55)	0.43 (.31–.62)
Respiratory	Antiviral only	0.18 (.14–.24)	0.24 (.19–.30)	0.26 (.21–.33)
	Antibiotic + antiviral	0.13 (.07–.23)	0.14 (.08–.25)	0.15 (.09–.25)
	Antibiotic only	0.33 (.19–.59)	0.36 (.21–.61)	0.34 (.20–.59)

RR (95% CI)Hospitalization OutcomesComparison (vs No Treatment)1–5 d1–10 d1–30 d

All-cause	Antiviral only	0.20 (.16–.25)	0.27 (.22–.32)	0.37 (.32–.44)
	Antibiotic + antiviral	0.15 (.09–.23)	0.19 (.13–.28)	0.28 (.21–.38)
	Antibiotic only	0.35 (.22–.54)	0.36 (.24–.55)	0.43 (.31–.62)
Respiratory	Antiviral only	0.18 (.14–.24)	0.24 (.19–.30)	0.26 (.21–.33)
	Antibiotic + antiviral	0.13 (.07–.23)	0.14 (.08–.25)	0.15 (.09–.25)
	Antibiotic only	0.33 (.19–.59)	0.36 (.21–.61)	0.34 (.20–.59)

Abbreviations: CI, confidence interval; RR, relative risk.

aRelative risks are adjusted for pulse oximetry, heart rate, respirations, temperature, flu shot, visit location, age, race, sex, body mass index, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue/rheumatic disease, peptic ulcer disease, mild liver disease, diabetes without complications, diabetes with complications, paraplegia and hemiplegia, renal disease, cancer, moderate or severe liver disease, metastatic carcinoma, human immunodeficiency virus/AIDS, drug abuse, mental health conditions.

Finally, we estimate the risks between patients prescribed a pharmacologic intervention to identify which type of intervention has the best outcome related to hospitalization rates. Table 5 presents the adjusted relative risks for all-cause and respiratory hospitalizations between those with an antiviral, antibiotic, or both. Among all-cause hospitalizations, patients prescribed the combination of an antibiotic plus antiviral had a lower risk of hospitalization at all timepoints; however, the CIs crossed one for each timepoint (1–5 days: RR, 0.67 [95% CI, .41–1.11]; 1–10 days: RR, 0.67 [95% CI, .44–1.01]; 1–30 days: RR, 0.73 [95% CI, .53–1.01]). Among respiratory hospitalizations, the overall results among antibiotic plus antiviral compared to antiviral were similar, except that at the 30-day time interval, the combination intervention was statistically significant. The antibiotic plus antiviral cohort had a 47% lower risk of respiratory hospitalization at days 1–30 (RR, 0.53 [95% CI, .31–.94]). Comparing the antibiotic only and antiviral only, the antibiotic only cohort had point estimates indicating a higher risk of all-cause and respiratory hospitalizations; however, the CIs crossed 1 at all time intervals (Table 5).

Table 5.

Adjusted Relative Risk of Hospitalizations Among Those With an Antibiotic or Antivirala

RR (95% CI)Hospitalization OutcomesComparison (vs Antiviral Only)1–5 d1–10 d1–30 d

All-cause	Antibiotic + antiviral	0.67 (.41–1.11)	0.67 (.44–1.01)	0.73 (.53–1.01)
	Antibiotic only	1.47 (.90–2.41)	1.21 (.78–1.87)	1.09 (.75–1.58)
Respiratory	Antibiotic + antiviral	0.64 (.34–1.21)	0.56 (.31–1.00)	0.53 (.31–.94)
	Antibiotic only	1.59 (.83–3.03)	1.33 (.74–2.40)	1.19 (.66–2.13)

RR (95% CI)Hospitalization OutcomesComparison (vs Antiviral Only)1–5 d1–10 d1–30 d

All-cause	Antibiotic + antiviral	0.67 (.41–1.11)	0.67 (.44–1.01)	0.73 (.53–1.01)
	Antibiotic only	1.47 (.90–2.41)	1.21 (.78–1.87)	1.09 (.75–1.58)
Respiratory	Antibiotic + antiviral	0.64 (.34–1.21)	0.56 (.31–1.00)	0.53 (.31–.94)
	Antibiotic only	1.59 (.83–3.03)	1.33 (.74–2.40)	1.19 (.66–2.13)

Abbreviations: CI, confidence interval; RR, relative risk.

aRelative risks are adjusted for pulse oximetry, heart rate, respirations, temperature, flu shot, visit location, age, race, sex, body mass index, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue/rheumatic disease, peptic ulcer disease, mild liver disease, diabetes without complications, diabetes with complications, paraplegia and hemiplegia, renal disease, cancer, moderate or severe liver disease, metastatic carcinoma, human immunodeficiency virus/AIDS, drug abuse, mental health conditions.

Table 5.

Adjusted Relative Risk of Hospitalizations Among Those With an Antibiotic or Antivirala

RR (95% CI)Hospitalization OutcomesComparison (vs Antiviral Only)1–5 d1–10 d1–30 d

All-cause	Antibiotic + antiviral	0.67 (.41–1.11)	0.67 (.44–1.01)	0.73 (.53–1.01)
	Antibiotic only	1.47 (.90–2.41)	1.21 (.78–1.87)	1.09 (.75–1.58)
Respiratory	Antibiotic + antiviral	0.64 (.34–1.21)	0.56 (.31–1.00)	0.53 (.31–.94)
	Antibiotic only	1.59 (.83–3.03)	1.33 (.74–2.40)	1.19 (.66–2.13)

RR (95% CI)Hospitalization OutcomesComparison (vs Antiviral Only)1–5 d1–10 d1–30 d

All-cause	Antibiotic + antiviral	0.67 (.41–1.11)	0.67 (.44–1.01)	0.73 (.53–1.01)
	Antibiotic only	1.47 (.90–2.41)	1.21 (.78–1.87)	1.09 (.75–1.58)
Respiratory	Antibiotic + antiviral	0.64 (.34–1.21)	0.56 (.31–1.00)	0.53 (.31–.94)
	Antibiotic only	1.59 (.83–3.03)	1.33 (.74–2.40)	1.19 (.66–2.13)

Abbreviations: CI, confidence interval; RR, relative risk.

aRelative risks are adjusted for pulse oximetry, heart rate, respirations, temperature, flu shot, visit location, age, race, sex, body mass index, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue/rheumatic disease, peptic ulcer disease, mild liver disease, diabetes without complications, diabetes with complications, paraplegia and hemiplegia, renal disease, cancer, moderate or severe liver disease, metastatic carcinoma, human immunodeficiency virus/AIDS, drug abuse, mental health conditions.

DISCUSSION

Among patients with laboratory-confirmed influenza, interventions with an antiviral, antibiotic, or both had a lower risk of hospitalization compared to no treatment intervention. Furthermore, our findings are consistent with those of previous studies, which found that antiviral therapy is associated with fewer hospitalizations [7–13, 24, 25]. Therefore, the question remains whether antibiotics should be given as prophylaxis in cases at high risk for bacterial complication [26]. Our results support the use of combination antibiotic and antiviral therapy as there was a statistically significant reduction in respiratory hospitalization risk within 30 days compared to an antiviral alone. However, the absolute magnitude of decreased risk with antibiotic plus antiviral therapy is small and must be interpreted within the context of the overall risk of antibiotic usage. The utilization of antibiotics comes with significant individual (eg, side effects) and public health (eg, bacterial resistance) risks. For example, macrolide and fluoroquinolone antibiotics have been associated with QTc prolongation [27–30]. However, a study demonstrated that among patients with acute respiratory tract infections, patients treated with antibiotics were not at an increased risk of severe adverse drug events [31]. Interestingly, the patients in the study had a small decreased risk of pneumonia hospitalization. Additional risks of antibiotic therapy include the potential to develop bacterial resistance, allergic reactions, and cost [32].

Previous published studies have identified results both discordant and consistent with our findings. For example, an observational study found no clinical benefit to prescribing antibiotics in patients with influenza [18]. Additionally, a retrospective study of pediatric patients found that those treated with an antibiotic or antibiotic plus antiviral had longer hospital stays than those with an antiviral alone [19]. However, a study of influenza accounting for secondary bacterial infection showed that antibacterial interventions can lead to a significant reduction in mortality and bacterial infections [33]. Specifically, the 2009 H1N1 influenza outbreak had increased hospitalizations resulting from secondary bacterial pneumonia [20, 34, 35]. Among mortalities during the 2009 H1N1 epidemic, published findings report between 29% and 55% bacterial infection rates [20, 34–36]. The risk of bacterial superinfection, especially among elderly or risk-associated patients, resulted in researchers suggesting that prophylactic antibiotic therapy could improve and reduce influenza-related morbidity and mortality [14]. However, to date there has been no large-scale research examining the outcomes of antibiotic use with influenza. Given our sample size, we believe the data is robust in evaluating antibiotic plus antiviral usage and hospitalization among patients with laboratory-confirmed influenza. Our study is distinctive because it (1) evaluated a national cohort of patients with laboratory-confirmed influenza (we did not evaluate patients with influenza-like symptoms); (2) evaluated patients who were prescribed antivirals, antibiotics, or both; and (3) evaluated influenza-related hospitalization outcome from 2 categories (all-cause, respiratory). However, our study has limitations common to observational claims database analyses. Medication usage was measured from filled prescriptions and we cannot confirm that patients adhered to prescriptions [37]. Our study population was predominately white males with mean age between 57 and 60 years; therefore, our findings may not be generalizable to patients of different age groups or races. Specifically, the cohort of patients may have different proportions of comorbidities, and although we controlled for many comorbidities within our multivariable models, the results may subsequently not be reflective of non–Veterans Affairs populations. Furthermore, the study evaluated claims data consisting of clinical data and did not evaluate social or economic factors that could possibly impact the results of our study. Additionally, patients within the study may have had different duration of illnesses prior to diagnosis. Specifically, a provider may not have prescribed an antiviral if the influenza symptoms had been ongoing for > 48 hours. Therefore, the timing of the duration of illness could have a major impact of the results of our study [38]. The differences in outcomes could have been caused by unmeasured bias in treatment allocation and this could potentially impact our results. Prescribing practice patterns can also significantly influence the results. For example, approximately 66% of patients in our study received a pharmacotherapy intervention for influenza (50% for antiviral and 11% for combination of antiviral and antibiotic). The rates of treatment in our study are consistent with select studies [38, 39] and also discordant from select studies [40–42]. Last, and importantly, we did not evaluate the risks (side effects, resistance) of the interventions and this could significantly impact the results of utilizing antibiotics in laboratory-confirmed influenza.

Despite the limitations of this study, to our knowledge, this is one of the largest studies to evaluate the risk of all-cause and respiratory hospitalization among patients with laboratory-confirmed influenza. Although our findings for combination antibiotic plus antiviral therapy were statistically significant, the overall hospitalization numbers are low, and the findings should not drive a change in practice. Our data clearly demonstrate that for patients with confirmed influenza, a pharmacotherapeutic intervention with an antiviral is needed. Bacterial coinfection represents 0.5% of influenza cases in young healthy patients, 2.5% in elderly or risk-associated patients, between 18% and 34% in intensive care cases, and in the majority of lethal cases [14, 43]. The clinical utility and application of our findings should serve as a catalyst for investigating combination therapy for the treatment of influenza and should be tested in a randomized clinical trial(s).

Research questions that need to be further addressed include (1) the validation of our findings; (2) specific patient populations that would need an antibiotic (eg, specific comorbidities, age of the patient); (3) the specific types of combination therapy (eg, which antibiotic); and (4) the timing of starting the intervention. We completed a subanalysis of our results to identify groups that would benefit most from combination therapy as well as the specific antibiotic therapy to help guide future studies. All subgroup results appear in the Supplementary Data. Subgroup results suggests that patients aged 65 years and older with chronic pulmonary disease have a lower risk of respiratory hospitalization with combination antibiotic plus antiviral therapy compared to antiviral therapy alone. Furthermore, the antibiotic-specific subanalysis also suggests that specific antibiotics may have a role in influenza. We found that patients treated with a tetracycline and an antiviral had no subsequent respiratory hospitalization within 30 days. As with the previous subanalysis, we believe the result should be interpreted with caution because our research goal was to evaluate the utilization of antibiotics in the initial management of influenza and not specific antibiotics. However, there are mechanistic theories to support the combination therapy with a tetracycline. Specifically, doxycycline can ameliorate acute lung injury during influenza pneumonia by inhibiting myeloperoxidase and matrix metalloproteinases [44]. However, we feel that a prominent driving factor for our findings is the bacterial coinfection or superinfections associated with influenza and that administering antibiotics prophylactically to select patients with laboratory-confirmed influenza may decrease influenza morbidity. The key findings from our study show that (1) a pharmacotherapeutic intervention is needed in patients with confirmed influenza; (2) the pharmacotherapeutic intervention of combination antiviral and antibiotic may decrease overall and respiratory hospitalization rates; (3) although statistically significant, the overall results of lower hospitalization rates were small compared to antiviral vs combinations therapy; (4) patients over the age of 65 with a past medical history of respiratory disease may be a group that benefits the most from combination therapy; (5) further research is needed to further address this subject in terms of the exact patient characteristics that would benefit from combination therapy; and (6) until further research confirms the findings, this study should not drive a change in practice.

CONCLUSIONS

A nationwide cohort of United States Veterans with confirmed influenza demonstrated that patients administered an antiviral, antibiotic, or both had a lower risk of hospitalization (all-cause, respiratory) compared to those who had neither. Furthermore, the results of our primary and subanalysis demonstrate that there is a role for combination antibiotic and antiviral therapy in select patients with confirmed influenza. We are not recommending systematic use of combination treatment, and the results should not drive a change in practice for influenza at this time. However, we believe that the results demonstrate a potential role for combination therapy in select patients with documented influenza. Additionally, we hope our data can guide the needed future studies that will identify the patients who would benefit the most from this intervention.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Financial support. This paper represents original research conducted using data from the Department of Veterans Affairs. This material is the result of work supported with resources and the use of facilities at the Dorn Research Institute, WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: .

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: .

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