Pharmacokinetics of Long‐Acting Ampicillin and Its Impact on the Gut Microbiome and Resistome in Rhesus Macaques ( Macaca mulatta )

Injectable antimicrobials with documented prolonged dosing intervals (> 48 h) for use in rhesus macaques are sparse. The objective of our study was to assess the pharmacokinetics, urine excretion, and effects on gut microbiome and resistome of intramuscular administered long-acting formulation of ampicillin (Albipen LA) in macaques. Four female rhesus macaques (Macaca mulatta) were administered intramuscularly 25 mg/kg anhydrous ampicillin (AMP-LA). Serial plasma samples were collected over a 72 h period and urine samples were collected over a 150 h period. Rectal swabs were collected over a 180-day period for microbiome and resistome analysis. Both plasma and urine samples were analyzed with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters for AMP-LA ranged as follows: Cmax 1.3-10.3 μg/mL, T1/2 5.5-10.6 h, AUC0-∞ 52.5-135.4 μg h/mL. Post-administration, alpha diversity significantly decreased on Day 2 and maintained reduced up till Day 14. Sequence depth of beta-lactam resistance genes significantly increased on Day 2 after administration and then declined until Day 90. A dose of 25 mg/kg AMP-LA administered intramuscularly maintains a plasma concentration ≥ 0.25 μg/mL for up to 48 h. Therefore, administration of AMP-LA could be an effective treatment with a prolonged treatment interval for relevant organisms with short lasting effects on the intestinal microbiome and resistome.