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Gross et al

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Serious antibiotic-related adverse effects following unnecessary

dental prophylaxis in the United States
Alan E. Gross PharmD, BCPS, BCIDP, FCCP1,2 , Katie J. Suda PharmD, MS, FCCP3,4, Jifang Zhou MD, MPH, PhD5,
Gregory S. Calip PharmD, MPH, PhD6, Susan A. Rowan DDS, MS7, Ronald C. Hershow MD8, Rose Perez BS9,
Charlesnika T. Evans MPH, PhD10,11 and Jessina C. McGregor PhD12
1
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States, 2Pharmacy Services, University of
Illinois Hospital and Health Sciences System, Chicago, Illinois, United States, 3Center for Health Equity Research and Promotion, Veterans’ Affairs Pittsburgh
Health Care System, Pittsburgh, Pennsylvania, United States, 4University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States, 5School of
International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China, 6Department of Pharmacy Systems, Outcomes and Policy,
College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States, 7Department of Restorative Dentistry, College of Dentistry, University of
Illinois at Chicago, Chicago, Illinois, United States, 8School of Public Health, University of Illinois at Chicago, Chicago, Illinois, United States, 9College of Medicine,
University of Illinois at Chicago, Chicago, Illinois, United States, 10Department of Preventive Medicine, Institute for Public Health and Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Illinois, United States, 11Center of Innovation for Complex Chronic Healthcare, Edward Hines, Jr VA Hospital,
Hines, Illinois, United States and 12College of Pharmacy, Oregon State University, Portland, Oregon, United States

Dentists prescribe 10% of outpatient antibiotics; a significant por-

Author for correspondence: Katie J. Suda, E-mail: ksuda@pitt.edu
PREVIOUS PRESENTATION. These data were presented in part as the SHEA featured
oral abstract # 1895 Presentation date, October 4, 2019, in Washington, DC.
Cite this article: Gross AE, et al. (2021). Serious antibiotic-related adverse effects
following unnecessary dental prophylaxis in the United States. Infection Control &
Hospital Epidemiology, 42: 110–112, https://doi.org/10.1017/ice.2020.1261
tion of these are for infection prophylaxis following dental proce-
dures.1,2 Current guidelines primarily recommend antibiotic
prophylaxis prior to dental procedures that manipulate the gingi-
val tissue or the periapical region of teeth or that perforate the oral
mucosa in patients at high risk of an adverse outcome should they
develop infective endocarditis.3 Recent data show that 80.9% of

© The Author(s), 2020. Published by Cambridge University Press on behalf of The Society for Healthcare Epidemiology of America.

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 Infection Control & Hospital Epidemiology 111

Table 1. Occurrence of Adverse Effects Within 14 Days of Unnecessary Antibiotic Prophylaxis

Total Follow-Up Time,a Person Incidence rate

Variable No. of Events Years Per 1,000 Person Days 95% CI
Overall
Any allergy 319 5,213.46 0.168 0.150–0.185
Anaphylaxis only 5 5,219.57 0.003 0.0003–0.005
C. difficile infection 14 5,219.43 0.007 0.004–0.011
ED visit 1,629 5,188.93 0.860 0.825–0.894
Visits associated with any 1,916 5,183.39 1.012 0.976–1.048
adverse effectb
By antibiotic agent

Total Follow-Up Incidence Rate Risk Difference

Time,2 Per 1,000 Per 1,000
No. of Adverse Events Person Years Person Days 95% CI Person Days 95% CI
Amoxicillin 1,220 3,486.74 0.958 0.915–1.001 Reference Reference
Clindamycin 356 835.06 1.167 1.075–1.259 0.209 0.108–0.311
Others 340 861.60 1.080 0.991–1.170 0.122 0.023–0.222

Note. CI, confidence interval; ED, emergency department.

a
Subjects were censored at the occurrence of event of interest, loss-to-follow-up and at end of enrollment.
b
Primary end point defined as 14 days after prescription (composite endpoint of allergy, anaphylaxis, C. difficile infection, or ED visit).

antibiotic prophylaxis was unnecessary prior to dental proce-
dures.2 The objective of this study was to assess the harms of
unnecessary antibiotic prophylaxis prior to dental procedures.
Methods
We conducted a retrospective cohort study of patients prescribed
unnecessary antibiotic prophylaxis for a dental visit between 2011
and 2015 using the IBM Watson Health Marketscan Commercial
Claims/Encounters, Medicare Supplemental, Coordination of
Benefits Research databases.2 Patients were included if they were
enrolled in commercial dental insurance and received unnecessary
antibiotic prophylaxis. Antibiotic prophylaxis was defined as a ≤2
day supply of antibiotics dispensed within 7 days prior to a dental
visit. Patients with a hospitalization or extra-oral infection 14 days
prior to antibiotic prophylaxis were excluded. Unnecessary antibi-
otic prophylaxis was defined as prophylaxis in patients who did not
undergo a procedure that manipulated the gingiva or tooth peri-
apex and did not have an appropriate cardiac diagnosis. Patients
with prosthetic joints were categorized as unnecessary (without
a cardiac condition).2 Patients with multiple eligible visits were
allowed to re-enter the cohort if visits were >7 days apart.
The primary end point was any antibiotic adverse effect (AAE)
within 14 days after prescription: composite of allergy, anaphy-
laxis, C. difficile infection (CDI), or emergency department (ED)
visit. Allergies and CDI were defined based on previously validated
International Classification of Disease, Ninth Revision (ICD-9) and
ICD-10 codes and ED visits were identified by provider and place
of service codes (Supplemental Table 1 online). Patients were cen-
sored at the occurrence of event, loss-to-follow-up, and end of
enrollment.
Statistical analysis
The primary end point of composite AAE incidence rate was mea-
sured as events per 1,000 patient days (PD) in the overall cohort and
stratified by amoxicillin and clindamycin; corresponding 95% con-
fidence intervals were calculated. Secondary end points included the
risk difference of the primary end point between amoxicillin and
clindamycin per 1,000 PD, the incidence of CDI 30 days after the
antibiotic, and the corresponding 95% CI for each. All analyses were
performed using SAS version 9.4 software (SAS Institute, Cary, NC)
and R version 3.3.1 (fmsb package) version 0.7.0 software
(R Foundation for Statistical Computing, Vienna, Austria).
Results
Of the 168,420 dental visits with antibiotic prophylaxis, 136,177
(80.9%) were unnecessary and were included for analysis (median
patient age, 62 years; interquartile range [IQR], 55–71; 58%
women). Antibiotics prescribed included amoxicillin (67.9%), clin-
damycin (15.5%), cephalexin (8.6%), azithromycin (2.8%), penicillin
(1.5%), and others (3%). For the primary endpoint, 1.4% of unnec-
essary prescriptions were associated with an AAE within 14 days; the
incidence of AAE was 1.01 per 1,000 PD, and ED visits (83%) and
allergies (16%) were the most frequent AAEs (Table 1).
Clostridioides difficile infection (CDI) incidence was 0.009 per
1,000 PD (95% CI, 0.006–0.012). Overall, AAEs were more common
with clindamycin (1.167 per 1,000 PD) than amoxicillin (0.958 per
1,000 PD; risk difference, 0.209 per 1,000 PD; 95% CI, 0.108–0.33),
including a higher risk of ED visit and allergy (Table 1 and
Supplemental Table 2 online).
Discussion
This study is the first to characterize adverse effects related to
unnecessary dental prophylaxis. Although the occurrence of an
AAE was rare (1.4%), serious AAEs (anaphylaxis, CDI) did occur.
A limited number of studies and case reports describe the adverse
effects of dental prophylaxis regardless of appropriateness.4-8 A
French database of voluntarily reported adverse effects contained
17 reports of anaphylaxis due to amoxicillin prophylaxis prior to

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 112
dental procedures.4 Another study using a UK database assessed
adverse reactions following single doses of amoxicillin or clinda-
mycin.5 Of 2.7 million amoxicillin prescriptions, 67 adverse reac-
tions were reported: 16 anaphylaxis and 38 other allergies. Of 1.2
million clindamycin prescriptions, 193 adverse reactions were
reported: 15 were fatal (12 due to CDI) and the remainder were
primarily gastrointestinal or allergy-related skin disorders. The
only study in the United States, outside the current report, was
an evaluation of community-acquired CDI cases in Minnesota
which reported that 136 of 1,626 CDI cases (8%) were related to
antibiotic prophylaxis for dental procedures.6 Consistent with
the study by Thornhill et al,5 we observed a significantly greater
rate of AAEs with clindamycin than with amoxicillin. Also consis-
tent with our findings, a previous study found that clindamycin
was associated with a greater rate of ED visits than amoxicillin.9
Collectively, these studies show that even short courses used for
antibiotic prophylaxis, regardless of appropriateness of use, are
associated with patient harm.
Our study has some limitations. Comparisons were not per-
formed with patients unexposed to antibiotics; thus, the risk asso-
ciated with inappropriate antibiotic prophylaxis could not be
ascertained. Only patients with commercial dental insurance
were included. ED visits could not be definitively attributed
to AAEs. Patients with adverse reactions but who did not seek
medical care were not captured in this study because our end
point was based on medical coding. However, our study did
not rely on voluntary reporting by medical professionals to
ascertain outcomes. Therefore, we may have been able to
identify and more comprehensively characterize AAE rates than
previous investigations.
In conclusion, the risk of harm with unnecessary antibiotic
prophylaxis is not trivial. Because most AAEs are diagnosed in
medical settings, dentists may not be aware of these adverse
effects. These data provide further impetus to optimize prescrib-
ing of antibiotic prophylaxis prior to dental procedures, and
improved prescribing may be facilitated via comprehensive,
multidisciplinary antimicrobial stewardship programs in dental
clinics.10
Supplementary material. To view supplementary material for this article,
please visit https://doi.org/10.1017/ice.2020.1261
Downloaded from https://www.cambridge.org/core, subject to the Cambridge Core terms of use.
Alan E. Gross et al
Acknowledgments. The opinions expressed are those of the authors and do
not represent those of AHRQ, the Department of Veterans’ Affairs or the
US government.
Financial support. Research was funded by Agency for Healthcare Research
and Quality (AHRQ no. R01 HS025177; principal investigator, Suda).
Conflicts of interest. No authors report potential conflicts of interest relevant
to this article.
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