Written by: Crystal McIntosh, DDS, MS, & Ronald S. Brown, DDS, MS
Penicillin, clindamycin (CM), and azithromycin (AZ) are the main broad-spectrum antibiotics utilized in dental practice.1,2 Drug toxicities include deleterious effects secondary to taking a drug, such as malignant transformation, GI distress, heart disease, cardiac conditions, fever, birth defects, predisposition to particular infections, drug allergy, and headache. Our concern with respect to this article are the more serious toxicities associated with penicillin, CM, and AZ.
What are the major toxicities of penicillin, CM, and AZ?
Recently, Lockhart et al1 published a superlative article in the Journal of the American Dental Association (JADA) on the topic of antibiotic stewardship. They reported that approximately 10% of US patients report a history of penicillin allergy. They noted that penicillin allergy represents the major penicillin toxicity with some of these allergic reactions resulting in anaphylaxis and death. The major toxicities for CM are Clostridium difficile (C. difficile) infections3 and for AZ are long QT cardiac issues.4
What are the concerns about the accuracy of patient histories of penicillin allergy?
Lockhart et al1 reported that approximately 90% of dental patient history information by patients reporting an allergy to penicillin were not accurate.
What are the actual statistics and study results for penicillin toxicity?
Agha et al5 reported that in a cohort of 10 million moderate- or high-risk people, penicillin antibiotic prophylaxis (AP) would prevent 19 cases of infectious endocarditis (IE) (which would result in approximately 2 to 4 deaths using either a 10% or 20% mortality rate) and causing 8 deaths due to anaphylaxis.
What were the reported comparative toxicities between penicillin and CM?
Thornhill et al3 reported that amoxicillin AP evaluations of close to 3 million prescriptions demonstrated zero fatal reactions and 22.62 non-fatal adverse reactions per one million prescriptions, while noting 13 fatal reactions to CM and 149 non-fatal reactions per million prescriptions. They noted that most CM reactions were secondary to C. difficile infections.
What are the risk factors pertaining to CM and C. difficile infections?
Risk factors for C. difficile secondary to CM utilization include age, the use of proton pump inhibitors, chronic renal failure, malignancy, and increased co-morbidity.
What are the current American Heart Association’s recommendations with respect to CM?
The American Heart Association and the ADA6 removed CM as the backup antibiotic to replace amoxicillin in patients reported to have a penicillin allergy regarding AP for IE.
What are the toxicity issues with related to AZ?
Cubeddu4 proposed that AZ and many other drugs promote long QT prolongation. Prolonged QT duration (a measure of heart rhythm) is associated with arrhythmias. However, he noted that even so, drug-induced, potentially lethal arrhythmia, Torsade de Pointes (TdP) was still rare. He reported a list of extenuating issues which increase the likelihood of such a potentially lethal arrhythmia. He noted such cardiovascular diseases such as: heart failure, structural cardiac disease, bradycardia, hypokalemia, and such pharmacogenomic variables as congenital long QT duration, sub-clinical ion-channel mutations, history of a relative with drug-induced long QT and/or TdP, and lastly such factors as high doses of other long QT inducing drugs, being female and/or elderly, metabolic inhibitors, and the combination (additive toxicity) of drugs known to induce long QT duration and/or TdP and ventricular tachycardia (hydroxy chloroquine, SSRIs, non-sedating antihistamines and other macrolides).7,8 With respect to additive toxicity, Funk and Bostwick7 advised against the utilization of the psychiatric SSRIs citalopram and escitalopram in patients taking other drugs such as AZ noted for QT prolongation.
What recommendations should practitioners follow?
Lockhart et al,1 suggest that oral healthcare clinicians are responsible for promoting antibiotic stewardship. It is incumbent upon prescribing oral healthcare clinicians to evaluate risk-benefit analysis through comprehensive investigation of dental patients’ penicillin antibiotic allergy histories and evaluation of dental patients’ vulnerabilities to the various toxicities of alternative penicillin drug therapies.
What are the major takeaway messages regarding dental clinicians prescribing broad-spectrum antibiotics?
There is concern with regard to prescribing CM to elderly and medically compromised patients. The AMA/ADA guidelines6 for antibiotic prophylaxis for infective endocarditis removed CM as a substitute antibiotic drug for dental patients allergic to penicillin and its derivatives. There is also limited concerns for the relatively rare long QT duration arrhythmias associated with AZ when combined with other drugs which increase promotion of such arrhythmias.
SUMMARY
In summary, the major toxicity with regard to penicillin is allergy and particularly anaphylaxis which although very rare, is lethal. Furthermore, penicillin allergy is over-reported by the public. The major toxicity issue with regard to CM is C. difficile infections. This is potentially lethal and particularly a problem with respect to the elderly and medically compromised dental patients. The major toxicity issue with AZ is the promotion of an arrhythmia which can be lethal but also very rare. Clinicians should be concerned when a patient is taking other drugs known to increase QT duration.
REFERENCES
1. Lockhart PB, Durkin MJ, Blumenthal KG, et al. Evaluation of patients labeled with a penicillin allergy to promote antimicrobial stewardship in dental practice. J Am Dent Assoc. 2024;155(7):565–73.e1. doi:10.1016/j.adaj.2024.03.003
2. Lafaurie GI, Noriega LA, Torres CC, et al. Impact of antibiotic prophylaxis on the incidence, nature, magnitude, and duration of bacteremia associated with dental procedures: A systematic review. J Am Dent Assoc. 2019;150(11):948–59.e4. doi:10.1016/j.adaj.2019.06.017
3. Thornhill MH, Dayer MJ, Prendergast B, et al. Incidence and nature of adverse reactions to antibiotics used as endocarditis prophylaxis. J Antimicrob Chemother. 2015;70(8):2382–8. doi:10.1093/jac/dkv115
4. Cubeddu LX. Drug-induced inhibition and trafficking disruption of ion channels: pathogenesis of QT abnormalities and drug-induced fatal arrhythmias. Curr Cardiol Rev. 2016;12(2):141–54. doi:10.2174/1573403×12666160301120217
5. Agha Z, Lofgren RP, VanRuiswyk JV. Is antibiotic prophylaxis for bacterial endocarditis cost-effective? Med Decis Making. 2005;25(3):308–20. doi:10.1177/0272989X05276852
6. Wilson WR, Gewitz M, Lockhart PB, et al. Prevention of viridans group streptococcal infective endocarditis: a scientific statement from the American Heart Association. Circulation. 2021;143(20):e963-e978. doi:10.1161/CIR.0000000000000969
7. Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann Pharmacother. 2013;47(10):1330–41. doi:10.1177/1060028013501994
8. Hussein H, Brown R. Hydroxychloroquine and the treatment of Sjogren syndrome, chronic ulcerative stomatitis, and oral lichen planus in the age of COVID-19. Oral Surg Oral Med Oral Pathol Oral Radiol. 2021;131(1):e9-e13. doi:10.1016/j.oooo.2020.06.011
ABOUT THE AUTHORS
Dr. McIntosh is an associate professor at the Howard University College of Dentistry (HUCD), department of comprehensive care, in the division of periodontology. She can be reached at [email protected].
Dr. Brown is a professor in the department of clinical dentistry at HUCD and a clinical associate professor in the department of otolaryngology at Georgetown University Medical Center in Washington, DC. He can be reached at [email protected].
Disclosures: The authors report no disclosures.
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