Macrolide antibiotics alter brain functions through the gut-brain axis, leading to shifts in mood and behavior [1-3], altering neuroplasticity through anti-inflammation, and priming the brain for increased behavior changes [4].

Bacterial infections’ limited treatments, antibiotic overprescription, and subsequent resistance is a current concern in US healthcare [5, 6]. Anxiety’s global burden is the estimated sixth leading cause of disability across income levels [7], complicated by recognition, stigma, and treatment [8].

Anxiety and stress are prevalent in the military and directly affect medical readiness [9, 10], especially in SOF [11, 12]. While SOF SM have elite training and support [13, 14], prescription side-effects may be attributed to situational factors [15, 16]. We examine macrolide prescriptions’ relationship to four common behavior disorders within SOF.

Population: 171,058 active-duty U.S. SOF SM from 2011-2022. Career and medical history captured from the Military Data Repository and Defence Manpower Data Center [17], analysed in the Medical Active Readiness System (MARS). 

Diagnoses: ICD-10 diagnostic categories defined as (1) anxiety (n=176,004), (2) trauma-related stress (n=384,058), (3) depression (n=150,802), and (4) bipolar (n=11,088). Those with psychosis excluded. 

Prescriptions: 80,145 macrolide prescriptions including azithromycin (n=75,832), clarithromycin (n=3,458), and erythromycin (n=855). Non oral forms and those for ulcers and H. pylori excluded. Aggregated monthly to match military records.

Dose Effect Window: Four-month rolling effect window. Prescription doses normalized to a WHO standard Defined Daily Dose (DDD) [18]. Mood and cognition are affected from one week to one year [20-24]. One-, four-, and twelve-month windows were considered using AIC and z-score. 

Survival Analysis: Time-series regression models estimating each individual diagnosis category employing a Weibull distribution and 95% confidence intervals. Results displayed in adjusted Hazard Ratios (aHR). 

Model Variables: Prescription affect windows (azithromycin, clarithromycin, erythromycin), military controls (operator status, service, pay grade), medical controls (BMI, healthcare utilization, tobacco use, alcohol use), and demographics (gender, age, race, education, marital status). 

Military clinicians should consider anxiety and trauma when prescribing clarithromycin, and observe mood for several months following prescription. 

Macrolide affect differences between product highlight the importance of treatment type in stressful military settings. 

Socio-economic factors shown by differences in gender, race, and pay grade highlight disparity in recognition, treatment, and diagnosis. 

The opinions and assertions expressed herein are those of the authors and do not reflect the official policy or position of the Uniformed Services University or the Department of Defense.

The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

The authors have no financial interests or relationships to disclose.

DataVation, LLC in collaboration with CHAMP for Award No HU0001-19-2-0060, sponsored by the Uniformed Services University of the Health Sciences.

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