Study reveals antibiotics lead to severe skin reactions

Commonly prescribed oral antibiotics may be associated with potentially life-threatening cutaneous adverse drug reactions (cADRs), according to a large, population-based, nested case-control study of older adults spanning 20 years.

According to the survey results, Published Online JAMA “The study highlights the importance of judicious prescribing, with lower-risk antibiotics being used preferentially when clinically appropriate,” the senior author noted Aug. 8. David Juerling, MDProfessor in the Departments of Pediatrics, Faculty of Medicine, and Department of Health Policy, Management and Evaluation at the University of Toronto and Chief of the Division of Clinical Pharmacology and Toxicology at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and co-authors.

“We hope that our study will raise awareness about the importance of drug allergies and garner support for future research to improve drug allergy treatment,” said lead author Erica Lee, MD, lecturer in clinical immunology and allergy at the University of Toronto Drug Allergy Clinic and Sunnybrook Health Sciences Centre. Medscape Medical News“It is important to recognize the symptoms and signs of a severe drug rash and to immediately discontinue the offending medication to prevent a worsening of the reaction.”

Serious cADRs are “a group of rare but potentially life-threatening drug hypersensitivity reactions that affect the skin and, frequently, internal organs,” the authors write. “Typically of delayed onset, these reactions include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), and the most severe cADR, toxic epidermal necrolysis (TEN), which has a reported mortality rate of 20% to 40%.”

Guessing without data

It has been speculated that some oral antibiotics may be more likely to be associated with serious cADRs than others, but no population-based studies have been conducted to examine this, the researchers added.

This study included adults aged 66 years or older and used administrative health care databases from April 1, 2002 to March 31, 2022 in Ontario, Canada. Data on antibiotic use were obtained from the Ontario Drug Benefits Database. The Canadian Institute for Health Information (CIHI) National Ambulatory Care Reporting System was used to obtain data on emergency department (ED) visits for cADRs, and the CIHI Hospital Discharge Abstract Database was used to identify hospitalizations for cADRs. Finally, demographic information and outpatient health care utilization data were obtained from the Enrollee Database and the Ontario Health Insurance Plan Database, respectively.

A cohort of 21,758 older adults (median age 75 years, 64.1% women) who visited the emergency department or were hospitalized for a serious cADR within 60 days of receiving antibiotic therapy were matched by age and sex to 87,025 antibiotic-treated controls who did not have a skin reaction.

The median duration of antibiotic prescription in the case and control groups was 7 days, and in the case group the median latency period from antibiotic prescription to hospital visit for cADR was 14 days. The majority of patients in the case group (86.9%) only visited the emergency department, and the remainder were hospitalized.

The most commonly prescribed antibiotics were penicillins (28.9%), followed by cephalosporins (18.2%), fluoroquinolones (16.5%), macrolides (14.8%), nitrofurantoin (8.6%), and sulfonamides (6.2%). Less commonly used antibiotics (“other” antibiotics) accounted for 6.9%.

Macrolide antibiotics were used as the benchmark because they are rarely associated with serious cADRs, the authors noted, and in multivariate analyses, they adjusted for risk factors associated with serious cADRs, including malignancy, chronic liver disease, chronic kidney disease, and HIV.

After multivariate adjustment, sulfonamides were most strongly associated with serious cADRs compared with macrolides (adjusted odds ratio [aOR]2.9), but so were all other antibiotic classes, including cephalosporins (aOR, 2.6), “other” antibiotics (aOR, 2.3), nitrofurantoin (aOR, 2.2), penicillins (aOR, 1.4), and fluoroquinolones (aOR, 1.3).

In a secondary analysis, the crude rate of emergency department visits or hospitalizations due to cADRs was highest for cephalosporins (4.92 per 1000 prescriptions), followed by sulfonamides (3.22 per 1000 prescriptions). The mean length of stay for hospitalized patients was 6 days, with 9.6% requiring transfer to intensive care, and 5.3% dying in the hospital.

Hospitalizations and emergency department visits have not been investigated previously.

“Of note, the rate at which antibiotic-associated serious cADRs result in emergency department visits or hospitalizations has not been studied previously,” the authors note. “We found that at least two serious cADR hospitalizations occurred per 1,000 antibiotic prescriptions, a rate that is substantially higher than suggested by studies that looked only at SJS/TEN and drug reactions with eosinophilia and systemic symptoms.”

Lee also highlighted a previously unreported finding about nitrofurantoin: “It is surprising that nitrofurantoin, an antibiotic commonly prescribed for urinary tract infections, is also associated with an increased risk of severe drug rash,” she said. Medscape Medical News“This finding highlights a potential new risk at the population level and warrants further investigation in other populations to validate this association,” the authors write.

Dr. Amesh AdaljaHe is a senior fellow at the Johns Hopkins Center for Health Security. IDSAHe was not involved in the study and agreed that the nitrofurantoin finding was a surprise, but he wasn't surprised that sulfonamides were so high on the list.

“This study reaffirms that antibiotics are not harmless drugs that should be administered indiscriminately,” he said. Medscape Medical News“Antibiotics carry risks, including severe skin reactions and promoting antibiotic resistance. Clinicians should always first ask themselves whether a patient really needs an antibiotic, and then assess what is the safest antibiotic for that purpose, keeping in mind, however, that certain antibiotics are more likely to cause side effects than others.”

The study was supported by the Canadian Institutes of Health Research. The study was conducted at ICES, which is funded in part by an annual grant from the Ontario Ministry of Health and Long-Term Care. British Journal of Dermatology As a reviewer and section editor, American Academy of Dermatology As the creator of the guidelines, Canadian Academy of Dermatology He reports consulting with the National Eczema Society and the Canadian Drugs and Technology Agency, and that his institution has received research grants from the National Eczema Society, the Canadian Eczema Association, the Canadian Dermatology Foundation, the Canadian Institutes of Health Research, the US National Institutes of Health, and the PSI Foundation. The other co-author (Piguet) reports receiving grants from AbbVie, Bausch Health, Celgene, Lilly, Incyte, Janssen, LEO Pharma, L'Oreal, Novartis, Organon, Pfizer, Sandoz, Amgen, and Boehringer Ingelheim, receiving speaking fees or honoraria from Sanofi China, serving on advisory boards for LEO Pharma, Novartis, Sanofi, and Union Therapeutics, and receiving equipment donations from L'Oreal. No other disclosures reported. Adalja reports no relevant disclosures.