| Summary: | Antibiotic resistance patterns of the major human periodontal pathogen <i>Porphyromonas gingivalis</i> were assessed over a 20-year period in the United States. Subgingival <i>P. gingivalis</i> was cultured pre-treatment from 2193 severe periodontitis patients during three time periods: 1999–2000 (936 patients), 2009–2010 (685 patients), and 2019–2020 (572 patients). The clinical isolates were tested for in vitro resistance to 4 mg/L for clindamycin and doxycycline, 8 mg/L for amoxicillin, and 16 mg/L for metronidazole, with a post hoc combination of data for metronidazole plus amoxicillin. Clindamycin-resistant <i>P. gingivalis</i> was significantly more prevalent in 2009–2010 (9.1% of patients) and 2019–2020 (9.3%; 15-fold increase) as compared to 1999–2000 (0.6%). <i>P. gingivalis</i> resistance to amoxicillin also significantly increased from 0.1% of patients in 1999–2000 to 1.3% in 2009–2010 and 2.8% (28-fold increase) in 2019–2020. <i>P. gingivalis</i> resistance to metronidazole, metronidazole plus amoxicillin, and doxycycline was low (≤0.5% prevalence), and statistically unchanged, over the 20-year period. These findings are the first to reveal marked increases over 20 years in clindamycin-resistant and amoxicillin-resistant <i>P. gingivalis</i> in United States periodontitis patients. Increased antibiotic resistance of <i>P. gingivalis</i> and other periodontitis-associated bacteria threatens the efficacy of periodontal antimicrobial chemotherapy.
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