We aimed to estimate the burden of antibiotic-nonsusceptible nonbacteremic pneumonia and sinusitis due to Streptococcus pneumoniae (pneumococcus) in US adults (aged ≥18 years).MethodsWe estimated antibiotic-nonsusceptible pneumococcal sinusitis and nonbacteremic pneumonia incidence as products of pneumococcal pneumonia and sinusitis incidence rates, serotype distribution, and serotype-specific antimicrobial nonsusceptibility prevalences from 2016 through 2019. Nonsusceptibility was considered by antibiotic class and guideline-recommended agents. We estimated pneumonia and sinusitis incidence rates from national surveys and administrative datasets and derived pneumococcal-attributable percents and serotype distributions from published data. Serotype-specific nonsusceptibility estimates were from Active Bacterial Core surveillance data. We evaluated nonsusceptibility for all serotypes and those targeted by 15-, 20-, and 21-valent pneumococcal conjugate vaccines (PCV15/20/21).ResultsAn estimated 16.4% (95% confidence interval, 12.8–21.4) of nonbacteremic pneumococcal pneumonia and 19.0% (14.8–24.9%) of sinusitis cases were nonsusceptible to ≥ 3 antibiotic classes, translating to 243 521 (179 673–333 675) and 1 844 726 (1 070 763–2 904 089) outpatient visits for pneumonia and sinusitis, respectively, and 10 155 (7542–13 803) pneumonia hospitalizations annually. An estimated 31.2% (26.6%–36.3%) of nonbacteremic pneumococcal pneumonia and 10.5% (9.4%–12.0%) of pneumococcal sinusitis cases were nonsusceptible to ≥ 1 outpatient first-line antibiotic agent. Cases attributable to serotypes targeted by PCV15, PCV20, and PCV21 that were nonsusceptible to ≥3 antibiotic classes accounted for 7.4% (4.7%–11.1%), 8.5% (5.8–12.1%), and 12.6% (9.2–17.5%) of nonbacteremic pneumococcal pneumonia, and 8.4% (5.3–12.5%), 9.4% (6.2–13.4), and 14.4% (10.4–20.0%) of pneumococcal sinusitis.ConclusionsWe estimated high proportions of antibiotic-nonsusceptibility in nonbacteremic pneumococcal pneumonia and sinusitis in US adults. Use of PCVs and antibiotic stewardship may mitigate the burden of antibiotic-nonsusceptible pneumococcal disease.