By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: A case-control study found that receipt of an oral antibiotic in the preceding three to 12 months was associated with nephrolithiasis. The risk persisted up to five years, and younger patients were at increased risk.

SOURCE: Tasian GE, Jemielita T, Goldfarb DS, et al. Oral antibiotic exposure and kidney stone disease. J Am Soc Nephrol 2018;29:1731-1740.

Despite the miraculous benefits of antibiotics, they carry risks and can produce side effects, some of which can be quite detrimental. It is well established that antibiotics disrupt the human microbiome. There also is evidence that patients with nephrolithiasis have an altered gut microbiome compared to those without nephrolithiasis. Therefore, Tasian et al sought to determine whether receiving oral antibiotics increases a patient’s risk for developing nephrolithiasis.

The investigators conducted a case-control study that used The Health Improvement Network (THIN), a database from more than 13 million patients who received care from general practitioners in the United Kingdom between 1994 and 2015. Individuals < 90 years of age with a diagnosis code for nephrolithiasis were included. Those with codes for infectious calculi, such as calculous pyelonephritis, were excluded. The primary exposure was receiving an oral antibiotic as an outpatient within three to 12 months of the index date (i.e., the date of nephrolithiasis diagnosis). Any antibiotic prescription of any dosage and duration within the exposure window was included.

The most common reasons for antibiotic use were chest infection, cough, upper respiratory infection, tonsillitis, and urinary tract infection (UTI). Prescriptions for all classes of oral antibiotics except lincosamides (e.g., clindamycin) were greater among patients with nephrolithiasis compared to controls. The oral antibiotics with the highest association for nephrolithiasis with no adjustment for other antibiotic use were sulfa drugs (odds ratio [OR], 2.37; 95% confidence interval [CI], 2.23-2.52), cephalosporins (OR, 1.93; 95% CI, 1.81-2.07), fluoroquinolones (OR, 1.84; 95% CI, 1.7-1.99), nitrofurantoin (OR, 1.84; 95% CI, 1.67-2.02), and broad-spectrum penicillins (OR, 1.37; 95% CI, 1.28-1.47). Treatment with antibiotics for H. pylori was not significantly associated with nephrolithiasis risk. The risk was greatest within three to six months from the index date for antibiotics in all five classes and remained significant for three to five years for all classes except broad-spectrum penicillins.

Furthermore, the odds ratios were greatest for antibiotic exposures at younger ages, which were seen with all five antibiotic classes. When investigators conducted a sensitivity analysis, they found that when patients with a prior UTI were excluded, the magnitude of the association increased for sulfa and nitrofurantoin, decreased for broad-spectrum penicillins, and stayed the same for the other antibiotic classes.

COMMENTARY

During the past 30 years, the prevalence of nephrolithiasis in the United States has risen by 70%. The reasons for this spike are uncertain. One hypothesis is that it might be caused by antibiotic use. Because correlation does not always equal causality, the study by Tasian et al is important because it elucidates the association between oral antibiotics and nephrolithiasis. Exposure to five common classes of oral antibiotics increased the risk for nephrolithiasis, even after adjustment for multiple confounding factors, the rate of healthcare encounters, and exclusion of patients with prior UTI. Moreover, the magnitude of the associations was strongest in younger patients. This is an important finding because children receive more antibiotics than any other age group and the incidence of nephrolithiasis has been rising fastest among children and young women. Thus, the results of this study are another reason to promote judicious antibiotic use in the outpatient setting.

How could antibiotics increase the risk for developing nephrolithiasis? One proposed mechanism is that changes in the gut microbiota alter macronutrient metabolism, leading to increased calcium stone formation. Indeed, children might be more susceptible because antibiotic exposure at a younger age produces more profound effects on their microbiome than exposure later in life. Another potential mechanism is that antibiotics select for multidrug-resistant (MDR) pathogens that promote kidney stone formation. Prior studies have shown that up to 70% of bacteria cultured from calcium stones are MDR, and their role in stone formation needs further investigation.

There are a few limitations to the study that should be mentioned. First, the results could have been influenced by unmeasured confounding variables, such as unreported comorbid illnesses. Second, some patients may have had unrecognized, asymptomatic kidney stones before receiving their course of antibiotics. Third, only outpatient data on oral antibiotics were available, so no conclusions about the association of parenteral antibiotics and nephrolithiasis can be reached. Finally, it was presumed that patients prescribed antibiotics took them and no attempt was made to verify medication compliance.

The report by Tasian et al suggests that oral antibiotics from five common classes are a novel risk factor for the development of nephrolithiasis. These findings carry important implications for both the pathogenesis of nephrolithiasis and for promoting better antibiotic stewardship in the outpatient setting.