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Journal of General Internal Medicine

, Volume 33, Issue 7, pp 1060–1068 | Cite as

National Estimates of Emergency Department Visits for Antibiotic Adverse Events Among Adults—United States, 2011–2015

  • Andrew I. GellerEmail author
  • Maribeth C. Lovegrove
  • Nadine Shehab
  • Lauri A. Hicks
  • Mathew R. P. Sapiano
  • Daniel S. Budnitz
Original Research

Abstract

Background

Detailed, nationally representative data describing high-risk populations and circumstances involved in antibiotic adverse events (AEs) can inform approaches to prevention.

Objective

Describe US burden, rates, and characteristics of emergency department (ED) visits by adults for antibiotic AEs.

Design

Nationally representative, public health surveillance of adverse drug events (National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance [NEISS-CADES]) and a nationally projected database of dispensed prescriptions (QuintilesIMS), 2011–2015.

Patients

Antibiotic-treated adults (≥ 20 years) seeking ED care.

Main Measures

Estimated annual numbers and rates of ED visits for antibiotic AEs among outpatients treated with systemically administered antibiotics.

Key Results

Based on 10,225 cases, US adults aged ≥ 20 years made an estimated 145,490 (95% confidence interval, 115,279–175,701) ED visits for antibiotic AEs each year in 2011–2015. Antibiotics were implicated in 13.7% (12.3–15.2%) of all estimated adult ED visits for adverse drug events. Most (56.6%; 54.8–58.4%) antibiotic AE visits involved adults aged < 50 years, and 71.8% (70.4–73.1%) involved females. Accounting for prescriptions dispensed from retail and long-term care pharmacies, adults aged 20–34 years had twice the estimated rate of ED visits for oral antibiotic AEs compared with those aged ≥ 65 years (9.7 [7.6–11.8] versus 4.6 [3.6–5.7] visits per 10,000 dispensed prescriptions, respectively). Allergic reactions accounted for three quarters (74.3%; 70.0–78.6%) of estimated ED visits for antibiotic AEs. The three most frequently implicated antibiotic classes in ED visits for antibiotic AEs were oral sulfonamides (23.2%; 20.6–25.8%), penicillins (20.8%; 19.3–22.4%), and quinolones (15.7%; 14.2–17.1%). Per-prescription rates declined with increasing age group.

Conclusions

Antibiotics are a common cause of ED visits by adults for adverse drug events and represent an important safety issue. Quantifying risks of AEs from specific antibiotics for specific patient populations, such as younger adults, provides additional information to help clinicians assess risks versus benefits when making the decision to prescribe or not prescribe an antibiotic. AE rates may also facilitate communication with patients about antibiotic risks.

KEY WORDS

pharmaceutical care patient safety community health primary care evidence-based medicine 

BACKGROUND

Antibiotics are one of the most commonly prescribed medications in the USA.1 In 2014, almost 200 million antibiotic prescriptions were written for adult outpatients aged ≥ 20 years, approximately five prescriptions for every six Americans.2,3 Increased use of antibiotics is correlated with development of antibiotic resistance,4,5 and the outpatient setting, which accounts for the majority of antibiotic expenditures,6 has been identified as a target for interventions to improve quality of care.7 Approximately one in ten adult outpatient visits results in an antibiotic prescription,8 of which an estimated one third are unnecessary,9 and even more may be inappropriate in antibiotic selection, dosing or duration.812 Unnecessary prescribing of antibiotics has been attributed to both demand-side factors (e.g., patient expectations) and supply-side factors (e.g., clinician concerns about patient satisfaction and/or time constraints).1220

In addition to long-term antibiotic resistance, the use of antibiotics causes acute adverse drug events.21 Systemically administered antibiotics are the second most common cause of estimated emergency department (ED) visits for adverse drug events, accounting for one sixth of all estimated adverse drug event ED visits in the USA.22,23 We assessed the frequency, rates, and clinical characteristics of adult ED visits for adverse events (AEs) from antibiotics in the USA to help inform efforts to encourage appropriate prescribing. Pediatric antibiotic AEs were assessed in a separate analysis.

METHODS

Data Source and Collection Methods

National estimates of ED visits for antibiotic AEs by adults (aged ≥ 20 years) were obtained using 5 years of data (January 1, 2011 through December 31, 2015) from hospitals participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance (NEISS-CADES) project. NEISS-CADES is a nationally representative, size-stratified probability sample of hospitals with at least six beds and 24-h EDs (excluding psychiatric and penal institutions) in the USA and its territories. From 2011 through 2015, 55 to 62 hospitals participated in NEISS-CADES each year. As described previously,24 trained abstractors at each participating hospital review clinical records of ED visits to identify clinician-diagnosed adverse drug events, reporting up to two implicated drugs and ten concomitant drugs. Abstractors also record narrative descriptions of the event, including preceding circumstances, clinician diagnoses, testing, treatments administered in the ED or by emergency medical services, and disposition. Narrative data are coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 9.1. Data collection is considered a public health surveillance activity and does not require human subjects review or institutional review board approval.25

To contextualize ED visit numbers relative to antibiotic exposure, national estimates of antibiotic prescriptions dispensed at outpatient retail and long-term care pharmacies were obtained from the 2011–2015 QuintilesIMS National Prescription Audit (NPA). NPA tracks national prescription trends and activity for pharmaceutical products; NPA aggregates prescription data from participating US pharmacies and uses a proprietary algorithm to project national-level estimates of dispensed outpatient prescriptions.1 NPA data have previously been used to provide outpatient dispensed prescription estimates on a national level.26 The NPA sample included pharmacy records from nearly 48,000 retail pharmacies across the USA, representing approximately 80% of all retail prescription activity from independent and chain pharmacies and pharmacies in food and mass merchandise stores, and an additional 1800 pharmacies serving long-term care facilities.1

Definitions

Antibiotic AE cases were defined as visits for problems the treating ED clinician explicitly attributed to the use of systemically administered antibiotics (excluding antitubercular agents). ED visits for AEs involving all other systemically administered medications (prescription and over-the-counter medications, dietary supplements, homeopathic products, and vaccines) were used as a comparison group. Systemically administered antibiotics and other medications were defined as medications administered by oral, injectable, rectal, sublingual, or transdermal routes.

For the purposes of this analysis, AEs were categorized as allergic reactions (immunologically mediated effects, including severe hypersensitivity reactions such as Stevens-Johnson syndrome), non-allergic adverse effects (undesirable pharmacologic or idiosyncratic effects at recommended doses), supratherapeutic effects of dose or intake of excess dose, or other effects (including those secondary to drug administration [e.g., choking on pill] or vaccination reactions). The MedDRA-coded narrative terms for each case were used to assign a single AE manifestation in a mutually exclusive and hierarchical manner based on severity; for example, a case involving anaphylactic respiratory distress and dyspepsia would be classified as a moderate-to-severe allergic reaction based on the anaphylaxis. Cases involving death in or prior to arrival in the ED and visits involving intentional self-harm, drug abuse, therapeutic failure, non-adherence, medication withdrawal, occupational exposure, and AEs from treatments received in the ED were not included. Cases usually diagnosed as antibiotic AEs only after the patient departs the ED (e.g., most Clostridium difficile infections) were not included.

Statistical Analysis

Cases were weighted based on inverse probability of selection, adjusted for non-response and hospital non-participation, and post-stratified to account for changes in the number of US ED visits each year.27 Nationally estimated (projected) numbers and proportions, with corresponding 95% confidence intervals (CIs), were calculated using the SURVEYMEANS procedure in SAS 9.4 (SAS Institute, Cary, NC). Cumulative 5-year (2011–2015) estimates and corresponding CIs were divided by 5 to calculate average annual estimates and CIs, accounting for weighting and complex sample design. Cumulative estimates less than 1200, based on fewer than 20 cases, or with coefficients of variation greater than 30% were considered statistically unreliable and are noted.

Population rates of ED visits for antibiotic AEs were calculated by dividing the ED visit estimate (from NEISS-CADES) in each age group by the corresponding US Census Bureau bridged-race population estimates from the National Center for Health Statistics, Centers for Disease Control and Prevention.28 Prescription-based rates of ED visits for antibiotic AEs were calculated by dividing the ED visit estimate (from NEISS-CADES) by the corresponding dispensed prescription estimate for retail and long-term care pharmacies (from NPA). Prescription-based rates were also calculated for specific drug products and patient demographics (age group, sex) for oral antibiotic classes with statistically reliable estimates. Accompanying 95% CIs for rate estimates were calculated incorporating the variance of the numerator (NEISS-CADES) estimates of ED visits for antibiotic AEs. Because of the large sample size (approximately 3.8 billion dispensed prescriptions annually), the variance of NPA estimates was considered negligible.

RESULTS

Based on 10,225 NEISS-CADES cases, US adults aged ≥ 20 years made an estimated 145,490 (95% CI, 115,279–175,701) ED visits for AEs from antibiotics each year in 2011–2015, causing 13.7% (95% CI, 12.3–15.2%) of estimated adult ED visits for AEs from all systemically administered medications (Table 1). One third (33.0%) of estimated ED visits for antibiotic AEs involved adults 20 to 34 years of age, representing 27.1% (95% CI, 25.1–29.1%) of estimated ED visits for AEs from all systemically administered medications in young adults. Adults younger than 50 years of age were involved in over one half (56.6%) of estimated ED visits for AEs from antibiotics (95% CI, 54.8–58.4%), but less than a third (31.0%) of estimated ED visits for AEs from all other systemically administered medications (95% CI, 27.7–34.3%).
Table 1

US Emergency Department (ED) Visits Among Adults for Adverse Events (AEs) from Systemically Administered Medications, by Case Characteristics, 2011–2015

Case characteristic

Antibiotics

All other medications

Cases, no.

Annualized national estimate

Cases, no.

Annualized national estimate

No.

% (95% CI)

No.

% (95% CI)

Patient age (years)

 20–34

3500

48,073

33.0 (31.5–34.6)

10,270

129,493

14.2 (12.4–16.0)

 35–49

2509

34,265

23.6 (22.3–24.8)

12,151

153,667

16.8 (15.2–18.4)

 50–64

2288

33,223

22.8 (21.6–24.0)

18,318

228,645

25.0 (23.5–26.5)

  ≥ 65

1928

29,929

20.6 (18.8–22.3)

30,224

401,841

44.0 (39.5–48.4)

Patient sex*

 Female

7275

104,440

71.8 (70.4–73.1)

39,912

514,201

56.3 (54.4–58.2)

Number of implicated medications

 One

8707

125,756

86.4 (84.4–88.5)

60,133

781,097

85.5 (83.6–87.4)

 Two or more

1518

19,734

13.6 (11.5–15.6)

10,830

132,549

14.5 (12.6–16.4)

AE type

 Allergic reaction

7643

108,125

74.3 (70.0–78.6)

11,071

145,688

15.9 (14.0–17.9)

 Adverse effect (non-allergic)

2365

34,687

23.8 (19.6–28.1)

23,139

296,290

32.4 (29.4–35.4)

 Supratherapeutic effect or intake of excess dose

124

1524

1.0 (0.8–1.3)

34,588

442,483

48.4 (45.8–51.1)

 Other

93

1154

0.8 (0.6–1.0)

2165

29,185

3.2 (2.8–3.6)

Documented medication error

 Yes

273

3466

2.4 (1.8–2.9)

9339

114,429

12.5 (10.4–14.7)

Disposition§

 Hospitalized

961

13,444

9.2 (7.1–11.4)

24,380

296,217

32.4 (26.8–38.0)

 Treated/released or left against medical advice

9264

132,046

90.8 (88.6–92.9)

46,574

617,338

67.6 (62.0–73.1)

Total

10,225

145,490

N/A

70,963

913,646

N/A

Case counts and estimates are from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, CDC. “Systemically Administered Medications” refers to medications administered by oral, injectable, rectal, sublingual, or transdermal routes

CI confidence interval, N/A not applicable

*Sex not reported for one case of ED visits for AEs from antibiotics

“Allergic reaction” refers to immunologically mediated effects; “adverse effect” refers to undesirable pharmacologic or idiosyncratic effects at recommended doses; “other” refers to other adverse effects secondary to drug administration (such as choking on tablet or pill) or vaccination reactions

Refers to drug prescribing, dispensing, or administration errors (e.g., wrong drug, wrong dose, wrong duration, wrong route, expired drug, or old prescription), administration of another individual’s medication, or accidental needle stick

§Disposition not reported for nine cases of ED visits for AEs from all other systemically administered medications

The population rate of estimated ED visits for AEs from antibiotics was similar for younger and older age groups (7.3 per 10,000 individuals aged 20–34 years [95% CI, 5.8–8.9] versus 6.7 per 10,000 individuals aged ≥ 65 years [95% CI, 5.1–8.3]). In contrast, the population rate of estimated ED visits for AEs from non-antibiotic, systemically administered medications increased significantly with age, from 19.7 per 10,000 individuals aged 20–34 years (95% CI, 16.0–23.4) to 90.0 per 10,000 individuals aged ≥ 65 years (95% CI, 61.2–118.9).

Accounting for prescribing frequency of oral antibiotics, young adults aged 20–34 years had twice the estimated rate of ED visits for AEs from oral antibiotics compared with those aged ≥ 65 years (9.7 visits per 10,000 dispensed prescriptions versus 4.6 visits per 10,000 dispensed prescriptions; 95% CI, 7.6–11.8 versus 3.6–5.7). The estimated rate of ED visits for AEs from oral antibiotics among females was 7.2 per 10,000 dispensed prescriptions (95% CI, 5.8–8.7), compared with 5.0 per 10,000 dispensed prescriptions among males (95% CI, 3.9–6.0) (Online Supplementary Table).

Females accounted for 71.8% of estimated ED visits for AEs from antibiotics, compared with 56.3% of visits due to AEs from non-antibiotics (Table 1). A single medication was almost always implicated in ED visits for antibiotic AEs (86.4%), and nearly all estimated ED visits for antibiotic AEs were attributed to oral preparations (96.9%; 95% CI, 96.2–97.6%). Allergic reactions were more common among ED visits for antibiotic AEs, compared with AEs from non-antibiotics (74.3 versus 15.9%), and ED visits for antibiotic AEs less commonly had documented medication errors (2.4 versus 12.5%) or required hospitalization (9.2 versus 32.4%).

Antibiotic Classes Implicated in Adverse Events

The three most frequently implicated antibiotic classes in ED visits by adults for AEs were oral sulfonamides (23.2%), penicillins (20.8%), and quinolones (15.7%) (Table 2). Oral oxazolidinones (linezolid) accounted for just 0.2% of ED visits for antibiotic AEs but, accounting for dispensed prescriptions from retail and long-term care pharmacies, had the highest estimated rate of ED visits for AEs (19.9 ED visits per 10,000 dispensed prescriptions), followed by oral sulfonamides (19.4 ED visits per 10,000 dispensed prescriptions) and lincomycins (clindamycin) (13.2 ED visits per 10,000 dispensed prescriptions).
Table 2

US Emergency Department (ED) Visits Among Adults for Adverse Events (AEs) from Antibiotics, by Drug Class, 2011–2015

Drug class*

Annualized national estimate

ED visits for AEs

Rate per 10,000 dispensed prescriptions

No.

% (95% CI)

Rate (95% CI)

Oral antibiotics

 Sulfonamides

33,725

23.2 (20.6–25.8)

19.4 (14.9–23.8)

 Penicillins

30,298

20.8 (19.3–22.4)

5.9 (4.6–7.1)

 Quinolones

22,770

15.7 (14.2–17.1)

6.7 (5.1–8.2)

 Cephalosporins

15,616

10.7 (9.7–11.8)

6.6 (5.1–8.2)

 Lincomycins (clindamycin)

10,685

7.3 (6.5–8.2)

13.2 (10.4–16.0)

 Macrolides

10,279

7.1 (6.3–7.8)

2.6 (1.9–3.3)

 Tetracyclines

7391

5.1 (4.3–5.8)

4.3 (3.1–5.5)

 Nitroimidazoles (metronidazole)

6159

4.2 (3.4–5.1)

7.4 (5.6–9.1)

 Nitrofurans (nitrofurantoin)

3961

2.7 (2.3–3.1)

4.7 (3.6–5.7)

 Oxazolidinones (linezolid)

336

0.2 (0.1–0.4)

19.9 (8.2–31.5)

 Other or unspecified oral antibiotics

7023

4.8 (4.0–5.7)

N/A

Injectable antibiotics

 Cephalosporins

1598

1.1 (0.8–1.4)

N/A§

 Glycopeptides (vancomycin)

756

0.5 (0.3–0.7)

 Penicillins

1355

0.9 (0.6–1.3)

 Other injectable antibiotics

1133

0.8 (0.5–1.1)

Estimates of ED visits for antibiotic AEs are from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, CDC. Estimates of dispensed prescriptions (from retail and long-term care pharmacies) are from QuintilesIMS National Prescription Audit (2011–2015)

CI confidence interval, N/A not applicable

*ED visits that involve antibiotics from two different drug classes are included in estimates for each class

“Other or unspecified oral antibiotics” includes unspecified antibiotics, vancomycin, dapsone, rifaximin, trimethoprim, neomycin, rifabutin, and chloramphenicol

“Other injectable antibiotics” includes carbapenems, quinolones, lipopeptides (daptomycin), aminoglycosides, lincomycins (clindamycin), tetracyclines, sulfonamides, macrolides, monobactams (aztreonam), lipoglycopeptides (dalbavancin), oxazolidinones (linezolid), and pentamidine isethionate

§Rate estimates not calculated because outpatient dispensing of injectable antibiotics is less reliably measured from the denominator data source (prescriptions dispensed from retail and long-term care pharmacies)

Antibiotic Drug Products Implicated in Adverse Events

Sulfamethoxazole/trimethoprim was the most commonly implicated oral antibiotic product across all age groups, accounting for between one fifth (19.7%) and one quarter (25.8%) of estimated ED visits for oral antibiotic AEs (Table 3). Amoxicillin was the second most commonly implicated oral antibiotic product among adults aged 20–34, 35–49, and 50–64 years, accounting for an estimated 14.6, 10.8, and 11.0% of visits, respectively, while among older adults aged ≥ 65 years, ciprofloxacin was the second most commonly implicated oral antibiotic product (12.2%).
Table 3

US Emergency Department (ED) Visits Among Adults for Adverse Events (AEs) from Oral Antibiotics, by Patient Age and Drug Product, 2011–2015

Oral antibiotic product*

Annualized national estimate

ED visits for AEs

Rate per 10,000 dispensed prescriptions

No.

% (95% CI)

Rate (95% CI)

NNH

Age 20–34

 Sulfamethoxazole/trimethoprim

11,811

25.1 (21.2–28.9)

29.7 (21.9–37.5)

337

 Amoxicillin

6876

14.6 (12.5–16.7)

9.3 (6.7–11.8)

1079

 Cephalexin

4672

9.9 (7.7–12.1)

12.6 (8.6–16.7)

792

 Azithromycin

3363

7.1 (6.1–8.1)

3.9 (2.9–5.0)

2541

 Clindamycin

3219

6.8 (5.7–8.0)

17.6 (12.7–22.5)

568

 Ciprofloxacin

2926

6.2 (4.9–7.5)

8.8 (6.1–11.6)

1131

 Metronidazole

2716

5.8 (4.4–7.2)

8.9 (6.4–11.4)

1126

 Doxycycline

2613

5.5 (4.2–6.9)

7.9 (5.1–10.7)

1265

 Amoxicillin/clavulanate

2539

5.4 (4.3–6.5)

7.1 (4.8–9.4)

1415

 Penicillin

2211

4.7 (3.8–5.6)

12.5 (9.4–15.5)

802

 Levofloxacin

1025

2.2 (1.5–2.9)

10.0 (6.6–13.4)

1001

 Nitrofurantoin

941

2.0 (1.4–2.6)

4.5 (2.7–6.2)

2243

 Moxifloxacin

520

1.1 (0.7–1.5)

50.0 (30.2–69.8)

200

 Clarithromycin

503

1.1 (0.6–1.6)

11.2 (5.1–17.3)

895

 Other or unspecified oral antibiotics

2989

6.3 (5.2–7.5)

N/A

 Total for age group

47,120

N/A

N/A

Age 35–49

 Sulfamethoxazole/trimethoprim

8617

25.8 (22.4–29.3)

21.6 (17.0–26.2)

464

 Amoxicillin

3604

10.8 (9.4–12.2)

5.1 (4.1–6.2)

1948

 Clindamycin

2929

8.8 (7.4–10.1)

15.2 (11.9–18.5)

658

 Ciprofloxacin

2512

7.5 (5.1–10.0)

6.0 (3.9–8.1)

1667

 Cephalexin

2411

7.2 (5.7–8.8)

6.7 (5.0–8.5)

1486

 Amoxicillin/clavulanate

2302

6.9 (5.4–8.4)

5.2 (3.7–6.6)

1930

 Azithromycin

1586

4.8 (3.8–5.7)

1.7 (1.1–2.2)

6057

 Doxycycline

1453

4.4 (3.4–5.3)

4.4 (3.1–5.7)

2276

 Levofloxacin

1405

4.2 (3.1–5.3)

6.7 (4.5–8.8)

1501

 Metronidazole

1349

4.0 (2.9–5.2)

6.4 (4.2–8.5)

1570

 Penicillin

1296

3.9 (3.0–4.8)

9.3 (6.5–12.1)

1079

 Moxifloxacin

1043

3.1 (2.2–4.1)

42.5 (26.2–58.8)

236

 Nitrofurantoin

803

2.4 (1.8–3.0)

5.3 (3.4–7.3)

1871

 Cefuroxime

463

1.4 (0.7–2.1)

7.3 (3.2–11.4)

1372

 Clarithromycin

434

1.3 (0.6–2.0)

6.0 (2.5–9.5)

1658

 Other or unspecified oral antibiotics

2359

7.1 (5.2–9.0)

N/A

 Total for age group

33,340

N/A

N/A

Age 50–64

 Sulfamethoxazole/trimethoprim

7232

22.7 (20.0–25.3)

16.1 (12.0–20.2)

621

 Amoxicillin

3516

11.0 (9.2–12.9)

4.3 (3.2–5.4)

2322

 Ciprofloxacin

3484

10.9 (8.9–12.9)

6.0 (4.3–7.7)

1667

 Clindamycin

2750

8.6 (7.1–10.2)

11.8 (8.7–14.9)

847

 Cephalexin

2553

8.0 (6.2–9.8)

5.8 (4.2–7.4)

1714

 Amoxicillin/clavulanate

2289

7.2 (6.0–8.3)

4.8 (3.6–6.0)

2081

 Azithromycin

1674

5.2 (4.1–6.4)

1.6 (1.1–2.2)

6082

 Levofloxacin

1627

5.1 (4.2–6.0)

4.7 (3.3–6.1)

2127

 Doxycycline

1320

4.1 (3.3–5.0)

3.4 (2.5–4.4)

2918

 Metronidazole

1116

3.5 (2.5–4.5)

7.1 (5.2–9.0)

1404

 Moxifloxacin

1043

3.3 (2.0–4.5)

25.9 (12.1–39.7)

386

 Penicillin

966

3.0 (2.3–3.8)

6.9 (4.7–9.2)

1440

 Nitrofurantoin

743

2.3 (1.6–3.0)

4.4 (2.8–5.9)

2298

 Cefdinir

357

1.1 (0.7–1.6)

3.9 (2.2–5.6)

2545

 Other or unspecified oral antibiotics

2317

7.3 (5.4–9.1)

N/A

 Total for age group

31,924

N/A

N/A

Age ≥ 65

 Sulfamethoxazole/trimethoprim

5638

19.7 (17.6–21.8)

11.4 (8.4–14.4)

877

 Ciprofloxacin

3491

12.2 (9.7–14.7)

4.3 (2.9–5.7)

2315

 Levofloxacin

2494

8.7 (7.1–10.4)

5.1 (3.8–6.3)

1976

 Amoxicillin

2318

8.1 (6.2–10.0)

3.3 (2.3–4.3)

3054

 Cephalexin

2132

7.5 (5.9–9.0)

3.9 (2.6–5.1)

2596

 Clindamycin

1788

6.2 (4.7–7.8)

8.9 (6.0–11.8)

1125

 Nitrofurantoin

1474

5.2 (3.8–6.5)

4.6 (3.4–5.9)

2152

 Amoxicillin/clavulanate

1407

4.9 (3.7–6.2)

3.8 (2.6–5.0)

2628

 Azithromycin

1254

4.4 (3.4–5.3)

1.5 (1.0–2.0)

6641

 Moxifloxacin

1156

4.0 (2.7–5.4)

23.2 (13.7–32.8)

430

 Metronidazole

978

3.4 (2.4–4.5)

6.1 (3.8–8.4)

1634

 Doxycycline

946

3.3 (2.2–4.4)

2.6 (1.5–3.7)

3856

 Cefdinir

486

1.7 (0.9–2.5)

5.9 (2.4–9.4)

1687

 Penicillin

446

1.6 (0.7–2.4)

5.4 (2.1–8.8)

1845

 Cefuroxime

431

1.5 (0.6–2.4)

3.6 (1.2–6.1)

2747

 Clarithromycin

349

1.2 (0.7–1.8)

6.6 (3.0–10.2)

1516

 Other or unspecified oral antibiotics

2809

9.8 (8.2–11.4)

N/A

 Total for age group

28,617

N/A

N/A

Estimates of ED visits for antibiotic AEs are from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, CDC. Estimates of dispensed prescriptions (from retail and long-term care pharmacies) are from QuintilesIMS National Prescription Audit (2011–2015)

CI confidence interval, N/A not applicable, NNH number needed to harm

*Drug products shown if implicated in > 1% of estimated ED visits for oral antibiotic AEs within each age group. ED visits that involve two different drug products are included in estimates for each product

Number needed to harm calculated as 10,000 multiplied by the reciprocal of the ED visit rate

Coefficient of variation for ED visit estimate > 30%

Prescription-based estimated rates of ED visits for AEs from oral antibiotics generally decreased with increasing patient age group. For example, the estimated rate for oral sulfamethoxazole/trimethoprim was 29.7 (95% CI, 21.9–37.5) ED visits per 10,000 dispensed prescriptions among young adults aged 20–34 years, compared with 11.4 (95% CI, 8.4–14.4) per 10,000 dispensed prescriptions among older adults aged ≥ 65 years.

Moxifloxacin had the highest estimated rate of ED visits for AEs from oral antibiotics across all ages, at 30.1 ED visits per 10,000 dispensed prescriptions (95% CI, 20.2–40.0), a rate five to six times that of the oral fluoroquinolones ciprofloxacin and levofloxacin (5.8 and 5.7 ED visits per 10,000 dispensed prescriptions, respectively; 95% CI, 4.2–7.4 and 4.5–6.9). After moxifloxacin, oral antibiotics with the highest estimated rates were linezolid (19.9 ED visits per 10,000 dispensed prescriptions; 95% CI, 8.2–31.5), sulfamethoxazole/trimethoprim (19.1 ED visits per 10,000 dispensed prescriptions; 95% CI, 14.7–23.5), and clindamycin (13.2 ED visits per 10,000 dispensed prescriptions; 95% CI, 10.4–16.0).

Adverse Event Manifestations

Mild allergic reactions (e.g., rash, pruritus) were the most commonly documented adverse event manifestation across all oral antibiotic classes (Table 4), and accounted for over two thirds of estimated visits involving sulfonamides (69.3%). Moderate-to-severe allergic reactions (e.g., anaphylaxis, angioedema) occurred in approximately one quarter of estimated ED visits for AEs involving oral quinolones (26.2%), and allergic reactions of any severity accounted for 87.2% (95% CI, 84.7–89.7%) of estimated ED visits for AEs involving oral sulfonamides. Gastrointestinal disturbance (e.g., nausea, diarrhea, abdominal pain) was documented in approximately one quarter of estimated visits involving oral nitroimidazoles (metronidazole) (28.3%), macrolides (27.0%), and tetracyclines (25.4%).
Table 4

US Emergency Department (ED) Visits Among Adults for Adverse Events (AEs) from Oral Antibiotics, by Drug Class and AE Manifestation, 2011–2015

Oral antibiotic class*

Annualized national estimate

ED visits for AEs

Rate per 10,000 dispensed prescriptions

No.

% (95% CI)

Rate (95% CI)

NNH

Sulfonamides

 Mild allergic reaction

23,359

69.3 (65.5–73.0)

13.4 (10.0–16.8)

746

 Moderate-to-severe allergic reaction

6061

18.0 (14.5–21.4)

3.5 (2.6–4.3)

2873

 Gastrointestinal disturbance§

2915

8.6 (6.1–11.2)

1.7 (1.0–2.3)

5974

 Other or unspecified effect

868

2.6 (1.6–3.5)

0.5 (0.3–0.7)

20,060

 Neurological or psychiatric effect

522

1.5 (1.0–2.1)

0.3 (0.2–0.4)

33,363

Penicillins

 Mild allergic reaction

17,436

57.5 (52.5–62.6)

3.4 (2.7–4.0)

2958

 Moderate-to-severe allergic reaction

6982

23.0 (20.5–25.6)

1.4 (1.1–1.6)

7385

 Gastrointestinal disturbance§

4821

15.9 (11.6–20.2)

0.9 (0.5–1.3)

10,695

 Other or unspecified effect

878

2.9 (1.9–3.9)

0.2 (0.1–0.3)

58,737

 Neurological or psychiatric effect

Quinolones

 Mild allergic reaction

9847

43.2 (38.9–47.5)

2.9 (2.2–3.6)

3469

 Moderate-to-severe allergic reaction

5969

26.2 (21.6–30.8)

1.7 (1.3–2.1)

5723

 Gastrointestinal disturbance§

4474

19.6 (12.8–26.5)

1.3 (0.7–1.9)

7635

 Other or unspecified effect

1105

4.9 (3.7–6.0)

0.3 (0.2–0.4)

30,929

 Neurological or psychiatric effect

1376

6.0 (4.2–7.9)

0.4 (0.3–0.5)

24,834

Cephalosporins

 Mild allergic reaction

9265

59.3 (53.2–65.5)

3.9 (2.9–4.9)

2549

 Moderate-to-severe allergic reaction

3382

21.7 (17.7–25.7)

1.4 (1.1–1.8)

6983

 Gastrointestinal disturbance§

2296

14.7 (9.7–19.7)

1.0 (0.5–1.4)

10,286

 Other or unspecified effect

426

2.7 (1.5–4.0)

0.2 (0.1–0.3)

55,475

 Neurological or psychiatric effect

Lincomycins (clindamycin)

 Mild allergic reaction

6351

59.4 (55.1–63.8)

7.8 (6.2–9.5)

1275

 Moderate-to-severe allergic reaction

1862

17.4 (12.3–22.6)

2.3 (1.6–3.0)

4348

 Gastrointestinal disturbance§

1930

18.1 (12.4–23.7)

2.4 (1.3–3.5)

4196

 Other or unspecified effect

413

3.9 (2.2–5.5)

0.5 (0.3–0.7)

19,618

 Neurological or psychiatric effect

Macrolides

 Mild allergic reaction

4499

43.8 (38.3–49.2)

1.1 (0.8–1.5)

8709

 Moderate-to-severe allergic reaction

2353

22.9 (18.8–27.0)

0.6 (0.5–0.8)

16,650

 Gastrointestinal disturbance§

2775

27.0 (19.3–34.7)

0.7 (0.4–1.0)

14,116

 Other or unspecified effect

426

4.1 (2.1–6.2)

0.1 (0.1–0.2)

91,956

 Neurological or psychiatric effect

Tetracyclines

 Mild allergic reaction

3516

47.6 (39.8–55.4)

2.0 (1.4–2.7)

4885

 Moderate-to-severe allergic reaction

1164

15.8 (10.2–21.3)

0.7 (0.4–0.9)

14,752

 Gastrointestinal disturbance§

1874

25.4 (19.0–31.7)

1.1 (0.6–1.6)

9167

 Other or unspecified effect

561

7.6 (4.8–10.4)

0.3 (0.2–0.5)

30,621

 Neurological or psychiatric effect

Nitroimidazoles (metronidazole)

 Mild allergic reaction

2767

44.9 (37.6–52.2)

3.3 (2.4–4.2)

3016

 Moderate-to-severe allergic reaction

1219

19.8 (14.9–24.7)

1.5 (1.1–1.9)

6842

 Gastrointestinal disturbance§

1742

28.3 (20.9–35.7)

2.1 (1.2–3.0)

4789

 Other or unspecified effect

271

4.4 (2.0–6.8)

0.3 (0.2–0.5)

30,840

 Neurological or psychiatric effect

Nitrofurans (nitrofurantoin)

 Mild allergic reaction

2220

56.0 (48.6–63.5)

2.6 (1.9–3.3)

3825

 Moderate-to-severe allergic reaction

789

19.9 (14.5–25.4)

0.9 (0.6–1.2)

10,767

 Gastrointestinal disturbance§

767

19.4 (12.7–26.0)

0.9 (0.5–1.3)

11,066

 Other or unspecified effect

 Neurological or psychiatric effect

Estimates of ED visits for antibiotic AEs are from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, CDC. Estimates of dispensed prescriptions (from retail and long-term care pharmacies) are from QuintilesIMS National Prescription Audit (2011–2015). Unreliable estimates due to fewer than 20 surveillance cases are indicated by en dash (–) and not shown

CI confidence interval, N/A not applicable, NNH number needed to harm

*Adverse event manifestations were categorized in a mutually exclusive and hierarchical manner based on severity of presentation—for example, visits with both anaphylaxis and diarrhea would be classified as moderate-to-severe allergic reaction

Includes dermatitis, drug eruption, erythema, flushing, localized or peripheral edema, pruritus, rash, and urticaria

Includes anaphylaxis, angioedema, erythema multiforme, exfoliative dermatitis, facial-pharyngeal-genital edema, hyperhidrosis or chills, hypersensitivity vasculitis, allergy-related respiratory compromise (e.g., bronchospasm, dyspnea, hyperventilation, tachypnea, throat tightness, wheezing), serum sickness, and Stevens-Johnson syndrome

§Includes abdominal discomfort, appetite change, constipation, diarrhea, dyspepsia, gastrointestinal irritation (e.g., enteritis, colitis, pancreatitis), gastrointestinal bleeding (e.g., hematemesis, melena), and nausea/vomiting

Includes dizziness/syncope, headache, motor impairment (e.g., dystonia, movement disorders, muscle weakness), sensory impairment (e.g., balance/coordination disorders, paresthesia, visual disturbance), and mood disturbance (e.g., anxiety, insomnia, irritability)

Number needed to harm calculated as 10,000 multiplied by the reciprocal of the ED visit rate

Oral sulfonamides had the highest estimated rates of ED visits for mild allergic reactions (13.4 visits per 10,000 dispensed prescriptions; 95% CI, 10.0–16.8) and moderate-to-severe allergic reactions (3.5 visits per 10,000 dispensed prescriptions; 95% CI, 2.6–4.3). While the overall rate of ED visits for moderate-to-severe allergic reactions to oral quinolones (1.7 visits per 10,000 dispensed prescriptions; 95% CI, 1.3–2.1) was lower than that for sulfonamides, moxifloxacin had significantly higher estimated rates of ED visits for moderate-to-severe allergic reactions (9.7 visits per 10,000 dispensed prescriptions; 95% CI, 5.9–13.4) compared with sulfonamides. The estimated rate of ED visits for moderate-to-severe allergic reactions to moxifloxacin was significantly higher than rates for the other oral quinolones levofloxacin (1.7 per 10,000 dispensed prescriptions; 95% CI, 1.3–2.2) and ciprofloxacin (1.3 per 10,000 dispensed prescriptions; 95% CI, 1.0–1.6).

DISCUSSION

Using nationally representative public health surveillance data, an estimated 145,490 ED visits were made by adults for antibiotic AEs annually from 2011 through 2015, making antibiotics a leading cause of AEs, accounting for approximately 14% of all ED visits by adults for AEs from systemically administered medications. These findings are similar to those from a decade ago,21 highlighting the need for continued emphasis on avoiding acute adverse effects of antibiotics, in addition to the individual and community risks from antimicrobial resistance. Specific findings from this study include updated national estimates of the numbers and rates of ED visits for AEs from specific antibiotics stratified by patient age, which can be used by clinicians to optimize the risk-benefit assessment for patients.

The key to reducing the number of antibiotic AEs is avoiding unnecessarily prescribing antibiotics. Allergic reactions were the most common cause (74.3%) of ED visits by adults for antibiotic AEs, while supratherapeutic effects or excessive doses were the most common cause of AEs from other medications. Unlike supratherapeutic effects and overdoses which can be prevented by laboratory monitoring and appropriate dosing, most allergic reactions can only be prevented by avoiding exposure altogether.

Antibiotic adverse events are a particularly important issue for young adults. Young adults were involved in one third of antibiotic AE visits and had double the per-prescription rate of ED visits for antibiotic AEs compared with older adults (aged ≥ 65 years). Higher rates of antibiotic AEs among younger compared to older adults may be related to immune senescence decreasing the likelihood of allergic reactions as patients age.29 Lower proportions of antibiotic ED visits among older adults are likely due to higher use of other medications with high rates of ED visits for AEs such as anticoagulants, diabetes drugs, and chemotherapeutic agents,22 and drug-drug interactions potentiated by antibiotics may be attributed solely to the higher risk non-antibiotic agent. For example, overanticoagulation from interaction of sulfamethoxazole/trimethoprim and warfarin may be attributed only to warfarin in the ED setting.

Patient expectations for antibiotics, particularly expectations of young adults, might be tempered with specific information on antibiotic AEs. In a focus group evaluating knowledge and attitudes towards antibiotic AEs, most younger adults (age range, 23–53) reported that AEs were “not a significant issue” but also reported never having discussed the potential for AEs with their provider.30 When provided information about AEs, however, messages about AEs were found to resonate with younger parents, particularly mothers of young children.30 If specific data about acute harms from antibiotics can modify antibiotic safety assumptions of younger patients, targeting educational campaigns to these patients, who are more likely than older adults to be treated in the ED for antibiotic AEs and less likely to develop complications from infections,31,32 may be an efficient strategy to improve antibiotic prescribing and reduce AEs.

ED visits for antibiotic AEs were disproportionately made by women (71.8%); however, this finding is consistent with higher ED utilization in general by women33 and higher ED utilization by women for other types of adverse drug events,22 so it is uncertain if targeting antibiotic safety messages to women would be an effective approach to reducing antibiotic AEs.3437

Estimates of the number needed to harm (NNH) for individual antibiotics by patient age can also inform clinician decision-making when selecting among agents with similar activity. Among young adults, for example, the NNH for ED visits for AEs from oral antibiotics ranged more than 12-fold, from an estimated 1 in 200 moxifloxacin prescriptions to 1 in 2541 azithromycin prescriptions. Although the overall rates of ED visits for AEs from oral antibiotics were lower for older adults, the range in rates was greater, with more than 15-fold difference in rates between moxifloxacin and azithromycin.38,39

Efforts to improve antibiotic prescribing such as the Centers for Disease Control and Prevention’s Be Antibiotics Aware: Smart Use, Best Care educational program seek to bridge the communication and education gap with patients and clinicians.3 Engaging patients with data on rates of acute harms can help reinforce that there are downsides of antibiotic prescription, particularly for patients who may be unaware of or not understand the distinction between a viral and bacterial illness. However, for all patients, education on antibiotic use should include communicating the side effects and frequency of potential harms from antibiotic use.40 Providing clinicians with information on acute harms from antibiotics is also important, as clinicians are more likely to prescribe appropriately if they understand that the antibiotics can cause harm.41

Public health surveillance data have limitations. First, these data likely underestimate the total burden of antibiotic AEs because such events often can be managed outside the ED setting. ED-based surveillance is not the best method to detect antibiotic AEs with subacute onset, such as fluoroquinolone-associated disability syndromes, medication interactions, or indirect and long-term harms such as those resulting from antibiotic resistance. Second, adverse events were identified according to the data available at the time of the ED visit. Thus, Clostridium difficile infections were rarely identified since this diagnosis is not typically confirmed during the course of the ED visit. Third, because medical history and prior treatment information is limited in the ED medical record, the contribution of inappropriate prescribing (e.g., guideline-discordant prescription of antibiotics for acute bronchitis) could not be directly assessed. Fourth, specific types of reactions to specific antibiotics (e.g., admissions for moderate-to-severe allergic reactions to moxifloxacin) were not frequent enough to calculate reliable estimates. Fifth, these national data could not be stratified at the regional or state level, owing to surveillance system sampling design. Sixth, rate calculations were based on QuintilesIMS dispensed prescription data obtained from retail and long-term care pharmacies only and did not include mail order prescriptions; however, mail order was not likely a major source of systemically administered antibiotic prescriptions.

CONCLUSION

Antibiotic AEs are a common cause of ED visits by adults for adverse drug events and represent an important safety issue. Quantification of acute harms associated with taking specific antibiotics for specific patient populations, such as younger adults, can provide additional information to help clinicians weigh the risks versus benefits when making the decision to prescribe or not prescribe antibiotics. Quantification of AE rates is also important for facilitating clinician communication about the risks and benefits with patients and may modify patient preferences and expectations for antibiotics as well. Efforts to improve antibiotic prescribing are central to patient safety, to both avoid unnecessary adverse events and optimize treatment of infections.

Notes

Author Contributions

The authors thank Dr. Nina Weidle from Eagle Medical Services, LLC (contractor to CDC), Ms. Katie Rose, Ms. Sandra Goring, Ms. Arati Baral, and Mr. Alex Tocitu, from Northrop Grumman (contractor to CDC), for assistance with data coding and programming. The authors also thank Mr. Tom Schroeder, Ms. Elenore Sonski, Mr. Herman Burney, and data abstractors from the US Consumer Product Safety Commission, for their assistance with data acquisition.

Funding

This study was funded by the Federal government of the USA.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they do not have a conflict of interest.

Disclaimer

Federal government employees had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. However, the findings in and conclusions of this study are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.

Prior Presentations

None.

Supplementary material

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Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Andrew I. Geller
    • 1
    Email author
  • Maribeth C. Lovegrove
    • 1
  • Nadine Shehab
    • 1
  • Lauri A. Hicks
    • 1
  • Mathew R. P. Sapiano
    • 1
  • Daniel S. Budnitz
    • 1
  1. 1.Division of Healthcare Quality Promotion Centers for Disease Control and Prevention (CDC)AtlantaUSA

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