Older Age, Long-term Antibiotic Use Linked to Mortality Risk

Nancy A Melville

April 02, 2018

Older women who report longer-term use of antibiotics show increases in all-cause mortality and notably higher rates of cardiovascular mortality compared with those with no antibiotic use, after adjustment for illness and other risk factors, new research suggests.

The study included 37,516 women aged 60 years and older who reported their antibiotic use in the Nurses' Health Study from 2004 to 2012 and did not have heart disease or cancer at baseline.  

After adjustment for traditional risk factors, researchers found that women who used antibiotics for 2 months or longer were 27% more likely to die of all causes and were as much as 57% more likely to die of cardiovascular causes compared with those with no antibiotic use.

"To the best of our knowledge, no prospective cohort study has clarified how the duration of antibiotic use in different phases of adulthood is related to all-cause and cause-specific mortality in a population at usual risk," first author, Yoriko Heianza, PhD, a postdoctoral research fellow with the Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, told Medscape Medical News.

"Of note, many of the previous studies were conducted among patients with specific diseases, or with a limited follow-up period."

The research was presented at the American Heart Association's Epidemiology and Prevention | Lifestyle and Cardiometabolic Health Scientific Sessions 2018.

Antibiotic use has been linked with changes to the gut microbiome that can in fact last for years, while infections from antibiotic resistances remain an ever-increasing concern. However, no previous cohort studies have investigated how the duration of antibiotic use during adulthood affects mortality rates.

Over the course of the new study, which was a collaboration between Tulane University School of Public Health and Tropical Medicine and Harvard T.H. Chan School of Public Health, there were 4535 deaths from any cause among the 37,516 women, including 600 cardiovascular deaths and 1179 cancer deaths.

In looking at mortality rates, the authors categorized the women according to cause of death and total days of antibiotic use per year: none, less than 15 days, 15 days to less than 2 months, or 2 months or more.

A higher risk for death from any cause with antibiotic use for 2 months or longer was seen after a multivariate adjustment compared with women who didn't use antibiotics (hazard ratio [HR], 1.19; 95% CI, 1.04 - 1.36); the risk for cardiovascular mortality was also higher (HR, 1.57; 95% CI, 1.06 - 2.34).

The all-cause mortality risk was further increased among those who also used antibiotics for 2 months or more in middle adulthood, in addition to later adulthood (age 40 to 59 years; HR, 1.27).

The risk for cancer mortality was not increased in the highest antibiotic use group (HR, 0.83; 95% CI, 0.63 - 1.09); however, Heianza noted that further research is needed to evaluate the potential risk in specific cancer types.

The study adjust for such factors as previous disease status, indication for antibiotics, use during middle adulthood, demographic factors, body mass index, and lifestyle and dietary factors.

While women receiving longer-term antibiotics might logically be assumed to have been sicker, Heianza noted that the results were seen even after adjustment for extensive disease factors.

"We carefully adjusted for metabolic diseases, such as hypertension, hypercholesterolemia, diabetes, and also other diseases, including congestive heart failure, chronic renal failure, and emphysema/chronic bronchitis," she said.

"The elevated risk of long-term use remained significant after we adjusted for the disease status and traditional risk factors." 

While the observational study importantly did not show cause and effect, antibiotics have several mechanisms that could be linked to increased mortality, Heianza said.

"It is known that antibiotic treatment may induce a prolongation of QT interval and the [associated arrhythmia torsades de pointes] TdP, and may stimulate proliferation and activity of macrophages, which may induce atherosclerosis," she explained.

The adverse effects on gut microbiota could also play a role, she noted.

"Previous studies have suggested that antibiotic use may induce long-lasting (over 2 months) alterations in microbiota composition even after cessation of the treatment, and that gut microbe-dependent metabolites may increase platelet hyper-reactivity and propensity to thrombosis."

Information on the use of probiotics, often used to help counter the gut microbiome effects, was not available, but generally, lifestyle factors did appear to play a role in a reduced risk, Heianza said.

"We observed that women with long-term antibiotic use and unhealthy lifestyles had a particularly elevated risk of mortality compared to those with healthy lifestyles," she noted.

"Also, the increased risk of mortality among long-term antibiotic users was attenuated but not eliminated by healthy lifestyle factors, suggesting that women who took antibiotics for long-term during late adulthood may be a high-risk group to target for lifestyle modifications to reduce mortality in later life."

Previous studies that demonstrated cardiac risks with antibiotics include a meta-analysis of 33 studies involving a total of more than 20 million participants, published in the Journal of the American College of Cardiology in 2015.

The analysis did show an increased risk for sudden cardiac death or ventricular tachyarrhythmias associated with macrolide antibiotics, with an overall relative risk (RR) of 2.42 among those who took macrolides compared with those who did not, with an  RR of 3.40 for azithromycin, 2.16 for clarithromycin, 3.61 for erythromycin, and 1.48 for clarithromycin,  but no association with roxithromycin.

Some studies in the meta-analysis showed the risk to be associated only with current rather than former use, however, and the analysis did not include findings on short-term vs long-term antibiotic use.

The study received funding from National Institutes of Health grants from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Boston Obesity Nutrition Research Center. The authors had no disclosures to report.

American Heart Association's Epidemiology and Prevention | Lifestyle and Cardiometabolic Health Scientific Sessions 2018.

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