Abstract
Background
We aimed to estimate the burden of antibiotic-nonsusceptible nonbacteremic pneumonia and sinusitis due to Streptococcus pneumoniae (pneumococcus) in US adults (aged ≥18 years).
Methods
We 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).
Results
An 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.
Conclusions
We 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.
Keywords: antimicrobial resistance, pneumococcal, pneumonia, sinusitis, streptococcus pneumoniae
We estimated high antibiotic nonsusceptibility in pneumococcal acute respiratory infections in US adults: 16% of nonbacteremic pneumonia cases and 19% of sinusitis cases were nonsusceptible to ≥3 antibiotic classes. However, most cases were susceptible to at ≥1 first-line or alternative agent.
Graphical Abstract
Graphical Abstract.
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Antibiotic-nonsusceptible Streptococcus pneumoniae (pneumococcus) infections are recognized by the US Centers for Disease Control and Prevention (CDC) and the World Health Organization as important threats to human health [1, 2]. Acute respiratory infections (ARIs) account for most pneumococcal disease cases among adults [3] (nonbacteremic pneumonia, sinusitis) and children [4] (nonbacteremic pneumonia, acute otitis media [AOM]). Additionally, invasive pneumococcal disease (IPD; bacteremic pneumonia, sepsis, meningitis) causes substantial morbidity and mortality. In both IPD and ARIs, antibiotic nonsusceptibility may enhance the complexity of patients’ care needs. Meta-analyses of studies of IPD [5] and pneumococcal pneumonia [6] found that penicillin-nonsusceptibility was associated with 1.3-fold higher odds of 30-day mortality. In the United States, nonsusceptibility to penicillin, erythromycin, and fluoroquinolones in pneumococcal pneumonia was estimated to cause 32 000 excess outpatient visits, 19 000 excess hospitalizations, and $233 million in excess costs in 2012 [7]. Nonsusceptibility in pneumococcus is regularly considered in treatment guidelines for syndromes such as pneumonia [8] and sinusitis [9, 10].
There are >100 recognized pneumococcal serotypes [11], with a small proportion causing most disease. Antibiotic-nonsusceptibility varies widely across serotypes [12–14]. For instance, among IPD isolates from US Active Bacterial Core surveillance (ABCs) > 50% of isolates from serotypes 19A, 33F, 35B, and 15A were nonsusceptible to ≥1 antibiotic class, whereas nonsusceptibility was rare among serotypes 8, 20, and 38 [12]. Although studies of nonsusceptibility in pneumococcal ARIs are limited, serotypes generally show similar patterns of antibiotic susceptibility in studies of invasive and non-invasive isolates [14, 15]. Historically, 7-, 10-, and 13-valent pneumococcal conjugate vaccines ([PCVs] PCV7/10/13), targeting serotypes prevalent in IPD and often nonsusceptible to antibiotics, were associated with decreases in antibiotic-nonsusceptible pneumococcal infections [12, 16, 17] and colonization [18].
Newly licensed PCVs targeting 15, 20, and 21 serotypes (PCV15/20/21) are recommended for US adults meeting eligibility criteria [19]. While nonsusceptibility in IPD is well-characterized, the significant burden of pneumococcal ARIs underscores the importance of better understanding antibiotic-nonsusceptibility in these infections. We aimed to estimate the burden of nonbacteremic pneumonia and sinusitis associated with antibiotic-nonsusceptible S pneumoniae in US adults.
METHODS
Overview
We estimated the incidence of antibiotic-nonsusceptible (intermediate susceptibility or resistant) pneumococcal sinusitis and nonbacteremic pneumonia among adults using the following inputs (summarized in Supplementary Table 1): incidence rates for all-cause nonbacteremic pneumonia and sinusitis; proportions of cases for each of these syndromes attributable to pneumococcus; distributions of serotypes associated with non-bacteremic pneumococcal pneumonia and sinusitis among adults; and prevalence of antimicrobial nonsusceptibility, by serotype, from 2016–2019. We selected 2016–2019 to ensure multiple, continuous years of data without perturbations from COVID-19 pandemic-associated shifts in healthcare seeking and pneumococcal disease [20]. We estimated burdens within age-group strata (18–49, 50–64, and ≥65 years) for each syndrome and combined age-stratified estimates to obtain overall estimates for all adults. We derived incidence rates of nonbacteremic pneumonia (for cases managed across inpatient and outpatient settings) and sinusitis (outpatient settings only) from national healthcare utilization surveys and administrative datasets. We estimated pneumococcal-attributable fractions of cases and serotype distributions using published data. Last, we obtained serotype-specific antibiotic nonsusceptibility estimates from active population- and laboratory-based surveillance. We evaluated nonsusceptibility for all serotypes, serotypes targeted by PCVs (PCV15, PCV20, and PCV21), and nonvaccine type serotypes ([NVTs] not included in PCV20 or PCV21).
To propagate uncertainty from original data sources, we fit each age- and condition-specific inputs (point estimate and 95% confidence limits or standard error) to a beta distribution (for proportions) or gamma distribution (for counts). We sampled 4 900 000 draws from fitted distributions and multiplied vectors of sampled draws for each input to obtain estimates. A large number of draws was needed to ensure stability for all estimates derived via Markov chain Monte Carlo methods.
This activity was reviewed by the CDC, was deemed research not involving human subjects, and was conducted consistent with applicable federal law and CDC policy (see 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq.).
Incidence of Pneumococcal ARIs Among Adults
We estimated annual counts of all-cause pneumonia hospitalizations from the 2019 National Inpatient Sample [21] using International Classification of Disease, 10th revision, Clinical Modification, codes (Supplementary Table 2). The National Inpatient Sample provides national estimates of US hospitalizations, including associated diagnosis codes and procedures. We multiplied the resulting estimate by the proportion of hospitalized pneumonia cases attributable to pneumococcus from a study of adults hospitalized with pneumonia in 2 large regional hospital systems in the Southeastern United States (Pneumococcal pNeumonia Epidemology, Urine serotyping, and Mental Outcomes [PNEUMO] [3]; Supplementary Tables 3-4). From this estimate, we subtracted the number of bacteremic pneumococcal pneumonia cases among adults overall and by age group based on nationally projected counts derived from 2019 ABCs incidence data (Supplementary Table 4) [22], thus obtaining the total number of hospitalized nonbacteremic pneumococcal pneumonia cases. We divided case counts by corresponding 2019 population bridged-race population estimates [23] to generate incidence rates.
We estimated incidence rates of outpatient visits for all-cause pneumonia and sinusitis using data from the 2016 and 2019 National Ambulatory and National Hospital Ambulatory Medical Care Surveys (NAMCS/NHAMCS) [24] and 2016–2019 Meritage MarketScan Commercial and Medicaid datasets (MarketScan). Following previous studies [4, 25–27], we derived incidence rates for outpatient physician office and emergency department visits using NAMCS/NHAMCS, and visit incidence rates for all other outpatient settings (eg, retail health, urgent care) from MarketScan. Use of multiple data sources allowed us to generate estimates across all outpatient settings; NAMCS/NHAMCS provide national estimates of office and emergency department visits [24], whereas MarketScan contains data from a large convenience sample of individuals with commercial and Medicaid insurance. Total incidence rates were the sum of rate estimates for physician office and emergency department visits (from NAMCS/NHAMCS) and visits for all other settings (from MarketScan data) (Supplementary Table 5). Overall MarketScan incidence rates were derived as the weighted average of estimates from the Commercial and Medicaid datasets, with weights based on national estimates of private insurance versus other coverage among adults [28]. Incidence rates were estimated by age group: 18–49, 50–64, and ≥65 years. For each age group, we multiplied incidence rate estimates by previously published estimates of the proportions of sinusitis [4] and pneumonia [3] cases attributable to pneumococcus (Supplementary Table 3). We multiplied incidence rates by 2019 bridged-race census estimates [23] to obtain national counts. To evaluate the impact of varying the pneumococcal-attributable proportions on estimates of the burdens of antibiotic-resistant infections, we conducted sensitivity analyses incorporating alternative pneumococcal-attributable proportions of pneumonia from published studies [29, 30].
Pneumococcal Serotype Distribution
We estimated serotype distributions in adult nonbacteremic pneumococcal pneumonia and sinusitis using methods consistent with previous studies [27]. For both syndromes, we used data on serotype-specific frequencies from the PNEUMO study [3], which used a serotype-specific urinary antigen detection (SSUAD) assay to identify 30 pneumococcal serotypes. For additional serotypes not captured via the PNEUMO SSUAD, we extrapolated serotype-specific frequencies (based on a denominator of all cases involving non-SSUAD serotypes) from proportions observed in 2015–2019 ABCs data. We sampled from the distribution of serotype-specific proportions, defined as a Dirichlet distribution within each age group (18–49, 50–64, ≥65 years), via Markov chain Monte Carlo [27]. We assumed that serotype distributions were consistent for outpatient- and inpatient-managed nonbacteremic pneumonia.
As few data on serotype distribution in pneumococcal sinusitis are available, we additionally conducted a sensitivity analysis applying serotype distribution in pediatric ARIs (AOM and pneumonia) to adult sinusitis. Pediatric ARI serotype distribution was based on a meta-analysis of studies of serotype distribution in pediatric ARIs in high-income countries after PCV13 implementation [27].
Serotype-specific Antibiotic Nonsusceptibility
We estimated the proportion of antibiotic-nonsusceptible cases, by serotype, using ABCs data from 2016 to 2019. Although limited to IPD, ABCs data provided comprehensive estimates across a large number of serotypes and age groups not available via other data sources [29]. We defined nonsusceptible isolates as those with intermediate susceptibility or resistance based on Clinical and Laboratory Standards Institute breakpoints [31]. ABCs nonsusceptibility data were stratified by age groups 18–64 and ≥65 years.
We categorized nonsusceptibility by drug class (cephalosporins, lincosamides, antifolates, fluoroquinolones, linezolids, carbapenems, penicillins, tetracyclines, glycopeptides, macrolides) based on nonsusceptibility to specific agents within each class (Supplementary Table 6). To evaluate the potential for treatment failure, we also categorized antibiotic-nonsusceptibility based on nonsusceptibility to guideline-recommended antibiotic agents or classes for the management of pneumonia and sinusitis in adults, to >1 antibiotic class, and to ≥3 antibiotic classes (ie, multidrug-resistant). For pneumonia, we evaluated nonsusceptibility to guideline-recommended agents as nonsusceptibility to ≥1 outpatient first-line antibiotic agent, ≥2 first-line outpatient antibiotic agents, and ≥1 inpatient first-line antibiotic agent. We defined pneumonia outpatient first-line antibiotics as amoxicillin, doxycycline, and erythromycin (as a proxy for all macrolides), which are agents recommended for the outpatient management of pneumonia in patients without comorbidities or risk factors for complicated infections [8]. We defined pneumonia first-line inpatient antibiotics as agents recommended for inpatient management of pneumonia or outpatient management of complex cases: cephalosporins (cefotaxime, ceftriaxone, and cefuroxime) and levofloxacin (as a proxy for all respiratory fluoroquinolones) [8]. For sinusitis, we evaluated nonsusceptibility to the recommended first-line antibiotic agent (amoxicillin) and to recommended alternative agents (doxycycline, levofloxacin, clindamycin, and cephalosporins) [9, 10]. Although amoxicillin-clavulanate rather than amoxicillin is recommended as a first-line treatment for pneumonia and sinusitis, ABCs nonsusceptibility testing is limited to amoxicillin. We propagated uncertainty by defining the prevalence of nonsusceptibility within each age group and serotype stratum as a beta distribution, parameterized by counts of nonsusceptible and susceptible isolates.
Where serotype-specific nonsusceptibility proportions were available in only 1 age group, we applied that proportion across all ages. For serotypes without nonsusceptibility values (ie, serotypes not identified among ABCs isolates tested for nonsusceptibility), we imputed this value as the inverse variance-weighted mean proportion of nonsusceptible isolates across serotypes with known susceptibility, using the Metafor package for R (v 4.6–0) [32].
RESULTS
We estimated that US adults experience 58.1 (95% confidence interval [CI], 48.9–69.0) outpatient visits for nonbacteremic pneumococcal pneumonia, 380.9 (233.9–543.9) outpatient visits for pneumococcal sinusitis, and 2.5 (2.1–2.9) nonbacteremic pneumococcal pneumonia hospitalizations per 10 000 person-years (Supplementary Table 7).
Nonsusceptibility to ≥3 antibiotic classes was most common in serotypes 14 (94.5% [72.6–99.8%]), 35B (92.2% [89.6–94.4%]), 35D (89.2 [67.3–98.5%]), 9 V (89.2% [67.3–98.5%]), and 6B (73.1% [49.5–90.1%]) (Figure 1). Isolates were universally susceptible to linezolids and glycopeptides. Serotype-specific nonsusceptibility patterns are presented in Supplementary Table 8.
Figure 1.
Percent of isolates nonsusceptible to first-line recommended agents and ≥3 antibiotic classes by serotype. Only serotypes with known (nonimputed) nonsusceptibility data from Active Bacterial Core surveillance and those with >1% of isolates nonsusceptible for any category shown. Percent of isolates nonsusceptible to 1 first-line agent for pneumonia imputed for serotype 7B (all other categories not imputed). Outpatient first-line antibiotic agents for adult pneumonia defined as amoxicillin, doxycycline, and erythromycin (proxy for all macrolides) [9]. Inpatient first-line antibiotic agents for adult pneumonia defined as cephalosporins (cefotaxime, ceftriaxone, and cefuroxime) and levofloxacin (proxy for all respiratory fluoroquinolones) [9]. First-line antibiotic agent for adult sinusitis defined as amoxicillin [10, 11]. ALT TEXT: Graphs showing the percentage of Streptococcus pneumoniae isolates susceptible to at least 1 pneumonia outpatient first-line antibiotic agent, at least 1 pneumonia inpatient first-line antibiotic agent, the first-line sinusitis agent, and at least 3 antibiotic classes by serotype.
Almost one-third (31.2% [26.6–36.3%]) of nonbacteremic pneumococcal pneumonia cases were expected to be nonsusceptible to ≥1 outpatient first-line antibiotic agent, translating to 462 206 (366 292–581 045) outpatient visits annually, and 13.7% (10.7–17.9%) were nonsusceptible to ≥2 outpatient first-line antibiotics (Table 1). An estimated 13.4% (9.8–18.5%), or 8452 (5925–12 077) pneumococcal pneumonia hospitalizations annually, were nonsusceptible to ≥1 inpatient first-line antibiotic. In total, 16.4% (12.8–21.4%) of pneumococcal pneumonia cases were nonsusceptible to ≥3 antibiotic classes, translating to 243 521 (179 673–333 675) outpatient visits and 10 155 (7542–13 803) hospitalizations annually. We estimated that among nonbacteremic pneumococcal pneumonia cases, 28.0% (23.7–32.6%) were nonsusceptible to macrolides, 21.0% (17.2–25.7%) to antifolates, and 13.4% (9.7–18.5%) to cephalosporins, whereas only 0.1% (0.1–0.2%) were nonsusceptible to fluoroquinolones.
Table 1.
Proportion and Burdens of Antibiotic Nonsusceptible Non-bacteremic Pneumococcal Pneumonia
| Outpatient Visits | Hospitalizations | ||||
|---|---|---|---|---|---|
| Nonsusceptible toa | Percent of cases (95% CI)b | Incidence per 10 000 person-y (95% CI) | Annual no. in thousands (95% CI) | Incidence per 10 000 person-y (95% CI) | Annual no. in thousands (95% CI) |
| ≥1 outpatient first-line antibiotic agentc | 31.2 (26.6–36.3) | 18.1 (14.1–22.8) | 462.2 (366.3–581.0) | .8 (.6–1.0) | 19.7 (15.8–24.4) |
| ≥2 outpatient first-line antibiotic agentsc | 13.7 (10.7–17.9) | 8.0 (5.9–10.9) | 203.7 (150.6–278.3) | .3 (.2–.5) | 8.5 (6.3–11.5) |
| ≥1 inpatient first-line antibiotic agentd | 13.4 (9.8–18.5) | 7.8 (5.4–11.2) | 199.1 (139.0–286.5) | .3 (.2–.5) | 8.5 (5.9–12.1) |
| >1 antibiotic class | 21.6 (17.3–27.2) | 12.6 (9.5–16.7) | 320.5 (242.4–426.0) | .5 (4–.7) | 13.5 (10.3–17.8) |
| ≥3 antibiotic classes | 16.4 (12.8–21.4) | 9.5 (7.0–13.1) | 243.5 (179.7–333.7) | .4 (.3–.5) | 1.2 (7.5–13.8) |
| Macrolides | 28.0 (23.7–32.6) | 16.3 (12.8–20.5) | 415.0 (327.4–522.3) | .7 (.6–.9) | 17.7 (14.1–21.9) |
| Antifolates | 21.0 (17.2–25.7) | 12.2 (9.4–15.9) | 311.5 (239.1–406.8) | .5 (.4–.7) | 13.4 (10.4–17.3) |
| Cephalosporins | 13.4 (9.7–18.5) | 7.8 (5.4–11.2) | 198.3 (138.2–285.6) | .3 (.2–.5) | 8.4 (5.9–12.0) |
| Tetracyclines | 12.8 (10.2–16.4) | 7.4 (5.6–10.0) | 189.7 (143.1–255.9) | .3 (.2–.4) | 8.0 (6.1–10.8) |
| Carbapenems | 9.9 (6.5–14.8) | 5.7 (3.7–8.9) | 146.3 (93.9–226.8) | .2 (.2–.4) | 6.1 (3.9–9.4) |
| Penicillins | 8.6 (5.7–13.1) | 5.0 (3.2–7.8) | 127.9 (81.7–199.7) | .2 (.1–.3) | 5.2 (3.3–8.1) |
| Lincosamides | 8.6 (6.5–11.8) | 5.0 (3.6–7.1) | 127.3 (92.6–182.4) | .2 (.2–.3) | 5.3 (3.9–7.5) |
| Fluoroquinolones | .1 (.1–.2) | .1 (.0–.1) | 1.8 (.9–3.7) | .0 (.0–.0) | .1 (.0–.1) |
| Linezolidse | .0 (.0–.0) | .0 (.0–.0) | 0 (0–0) | .0 (.0–.0) | 0 (0–0) |
| Glycopeptidese | .0 (.0–.0) | .0 (.0–.0) | 0 (0–0) | .0 (.0–.0) | 0 (0–0) |
Abbreviations: CI, confidence interval; No, number.
aNonsusceptibility to antibiotic classes evaluated based on nonsusceptibility to specific agents within each class, as defined in Supplementary Table 6.
bEstimated as annual no. nonsusceptible pneumococcal outpatient visits for each nonsusceptibility category divided by annual no. total pneumococcal-attributable outpatient visits (N = 1 483 052 [95% CI, 1,248,097–1,760,694]).
cOutpatient first-line antibiotic agents for adult pneumonia defined as amoxicillin, doxycycline, and erythromycin (proxy for all macrolides) [8].
dInpatient first-line antibiotic agents for adult pneumonia defined as cephalosporins (cefotaxime, ceftriaxone, and cefuroxime) and levofloxacin (proxy for all respiratory fluoroquinolones) [8].
eAll pneumococcal isolates captured in ABCs were susceptible to linezolids and glycopeptides.
We estimated that 8.7% (5.1–14.1%) of pneumococcal sinusitis cases were nonsusceptible to recommended first-line antibiotics, respectively, translating to 833 697 (414 093–1 536 416) and 942 808 (540 819–1 519 744) outpatient visits each year (Table 2). An estimated 19.0% (14.8–24.9%) of pneumococcal sinusitis cases were nonsusceptible to ≥3 antibiotic classes, translating to 1 844 726 (1 070 763–2 904 089) outpatient visits annually. Nonsusceptibility in pneumococcal sinusitis was most common for macrolides (29.7% [25.1–34.8]), antifolates (21.9% [17.9–26.6%]), and cephalosporins (15.2% [10.9–21.1%]).
Table 2.
Proportion and Burdens of Antibiotic Nonsusceptible Pneumococcal Sinusitis
| Outpatient Visits | |||
|---|---|---|---|
| Nonsusceptible toa | Percent of cases (95% CI)b | Incidence per 10 000 person-y (95% CI) | Annual no. in thousands (95% CI) |
| First-line antibiotic agentc | 8.7 (5.1, 14.1) | 32.7 (16.2, 60.2) | 833.7 (414.1–1536.4) |
| ≥1 alternative antibiotic agentd | 9.7 (7.4, 13.2) | 36.9 (21.2, 59.5) | 942.8 (540.8–1519.7) |
| >1 antibiotic class | 23.9 (19.3–30.1) | 90.9 (53.6–139.5) | 2321.4 (1368.8–3561.4) |
| ≥3 antibiotic classes | 19.0 (14.8–24.9) | 72.3 (42.0–113.8) | 1844.7 (1070.8–2904.1) |
| Macrolides | 29.7 (25.1–34.8) | 112.9 (67.7–167.6) | 2881.3 (1728.8–4277.0) |
| Antifolates | 21.9 (17.9–26.6) | 83.2 (49.4–125.8) | 2122.7 (1259.7–3212.0) |
| Cephalosporins | 15.2 (10.9–21.1) | 57.4 (32.3–94.1) | 1466.2 (823.3–2400.9) |
| Tetracyclines | 13.5 (10.8–17.0) | 51.2 (30.1–78.8) | 1308.0 (769.3–2011.8) |
| Carbapenems | 12.1 (8.0–18.0) | 45.7 (24.5–78.7) | 1165.5 (624.6–2009.5) |
| Penicillins | 11.3 (7.7–16.7) | 42.7 (23.3–73.2) | 1090.7 (593.8–1867.3) |
| Lincosamides | 9.6 (7.3–13.1) | 36.5 (20.9–58.9) | 930.4 (534.4–1502.7) |
| Fluoroquinolones | .2 (.1–.4) | .6 (.2–1.5) | 15.9 (6.2–39.0) |
| Linezolidse | .0 (.0–.0) | .0 (.0–.0) | 0 (0–0) |
| Glycopeptidese | .0 (.0–.0) | .0 (.0–.0) | 0 (0–0) |
Abbreviations: CI—confidence interval; No.—number.
aNonsusceptibility to antibiotic classes evaluated based on nonsusceptibility to specific agents within each class, as defined in Supplementary Table 6.
bEstimated as annual no. nonsusceptible pneumococcal outpatient visits for each nonsusceptibility category divided by annual no. total pneumococcal-attributable outpatient visits (N = 9 722 028 [95% CI, 5,969,625–13,883,036]).
cFirst-line antibiotic agent for adult sinusitis defined as amoxicillin as a proxy for amoxicillin-clavulanate [9, 10].
dAlternative antibiotic agents for adult sinusitis defined as doxycycline, levofloxacin, clindamycin, and cephalosporins [9, 10].
eAll pneumococcal isolates captured in ABCs were susceptible to linezolids and glycopeptides.
Considering outpatient-managed pneumococcal sinusitis and non-bacteremic pneumonia together, an estimated 1 298 057 (836 840–2 050 628) ARIs were nonsusceptible to ≥1 outpatient first-line antibiotic agent annually. We estimated that, in a total of 2 089 275 (1 289 201–3 193 219) ARIs annually, were nonsusceptible to ≥3 antibiotic classes.
The estimated proportions of antibiotic-nonsusceptible cases of pneumococcal pneumonia and sinusitis were highest among adults aged 18–49 years compared with older age groups for all categories and classes (Supplementary Table 9-Supplementary Table 12). For instance, pneumococci nonsusceptible to ≥3 antibiotic classes accounted for 22.1% (16.6–29.5%) of nonbacteremic pneumococcal pneumonia and sinusitis among adults 18–49 years but 15.1% (11.2–20.4%) among those ≥65 years. However, given the higher overall incidence of pneumonia in older adults, the highest incidence rates and annual burdens of antibiotic nonsusceptible nonbacteremic pneumococcal pneumonia were observed among adults aged ≥65 years (Supplementary Tables 9-10). In pneumococcal sinusitis, where younger age groups account for higher incidence rates and annual case numbers compared with adults aged ≥65 years (Supplementary Table 7), the greatest incidence of nonsusceptible cases occurred among adults 18–49 years for most categories and classes (Supplementary Tables 11-12).
For nonbacteremic pneumococcal pneumonia, serotypes targeted by PCV15, PCV20, and PCV21 with nonsusceptibility 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 cases, respectively (Table 3). Nonsusceptible NVT serotypes contributed minimally across all measures. Divergent trends were observed by antibiotic class (Supplementary Table 13). Antibiotic nonsusceptible PCV-targeted serotypes accounted for smaller proportions of pneumococcal sinusitis compared with pneumonia (Table 4). As in pneumonia, NVT serotypes contributed minimally to antibiotic-nonsusceptible sinusitis burdens (Table 4, Supplementary Table 14).
Table 3.
Burdens of Antibiotic-nonsusceptible Non-bacteremic Pneumococcal Pneumonia by PCV-targeted Serotypes
| Outpatient Visits | Hospitalizations | |||||
|---|---|---|---|---|---|---|
| Nonsusceptible to | PCV-targeted serotypesa | Percent of cases (95% CI)b | Incidence per 10 000 person-y (95% CI) | Annual no. in thousands (95% CI) | Incidence per 10 000 person-y (95% CI) | Annual no. in thousands (95% CI) |
| ≥1 outpatient first-line antibiotic agentc | … | … | … | … | … | … |
| PCV15 | 16.0 (12.1–21.0) | 9.3 (6.7–12.8) | 237.2 (171.5–327.1) | .4 (.3–.5) | 10.2 (7.4–14.0) | |
| PCV20 | 19.2 (15.3–23.9) | 11.2 (8.4–14.8) | 284.8 (213.8–376.9) | .5 (.4–.6) | 12.4 (9.3–16.2) | |
| PCV21 | 24.8 (20.3–30.1) | 14.4 (11.1–18.6) | 367.1 (282.3–474.6) | .6 (.5–.8) | 15.6 (12.2–19.9) | |
| NVT | 1.8 (.9–5.1) | 1.0 (.5–3.0) | 26.7 (12.8–76.4) | .0 (.0–.1) | 1.1 (.5–3.2) | |
| ≥2 outpatient first-line antibiotic agentsc | … | … | … | … | … | … |
| PCV15 | 5.6 (3.6–8.7) | 3.3 (2.0–5.2) | 83.5 (51.9–132.9) | .1 (.1–.2) | 3.5 (2.2–5.6) | |
| PCV20 | 6.7 (4.6–9.6) | 3.9 (2.6–5.8) | 98.6 (65.1–148.3) | .2 (.1–.2) | 4.2 (2.8–6.3) | |
| PCV21 | 10.8 (8.0–14.9) | 6.3 (4.4–9.0) | 160.3 (113.0–229.3) | .3 (.2–.4) | 6.7 (4.7–9.5) | |
| NVT | .7 (.3–1.9) | .4 (.1–1.1) | 10.0 (3.7–27.5) | .0 (.0–.0) | .4 (.1, 1.2) | |
| ≥1 inpatient first-line antibiotic agentd | … | … | … | … | … | … |
| PCV15 | 8.0 (5.1–11.8) | 4.6 (2.9–7.1) | 118.3 (73.2–181.9) | .2 (.1–.3) | 5.1 (3.1–7.8) | |
| PCV20 | 8.3 (5.4–12.1) | 4.8 (3.0–7.3) | 122.5 (77.5–186.1) | .2 (.1–.3) | 5.3 (3.3–8.0) | |
| PCV21 | 10.8 (7.3–15.9) | 6.3 (4.1–9.5) | 159.9 (104.4–243.6) | .3 (.2–.4) | 6.8 (4.5–10.4) | |
| NVT | .4 (.2–1.6) | .3 (.1–.9) | 6.6 (2.4–23.3) | .0 (.0–.0) | .3 (.1–1.0) | |
| >1 antibiotic class | … | … | … | … | … | … |
| PCV15 | 11.1 (7.7–15.6) | 6.4 (4.3–9.5) | 164.4 (109.8–242.3) | .3 (.2–.4) | 7.1 (4.7–10.5) | |
| PCV20 | 12.4 (9.0–16.9) | 7.2 (5.0–10.3) | 183.8 (127.9–262.1) | .3 (.2–.4) | 8.0 (5.6–11.3) | |
| PCV21 | 16.3 (12.3–21.5) | 9.4 (6.8–13.1) | 240.9 (173.8–334.3) | .4 (.3–.5) | 10.2 (7.4–14.0) | |
| NVT | 1.0 (0.3–3.4) | .6 (.2–2.0) | 15.1 (4.9–50.5) | .0 (.0–.1) | .6 (.2–2.1) | |
| ≥3 antibiotic classes | … | … | … | … | … | … |
| PCV15 | 7.4 (4.7–11.1) | 4.3 (2.7–6.7) | 109.8 (68.2–170.9) | .2 (.1–.3) | 4.6 (2.8–7.2) | |
| PCV20 | 8.5 (5.8–12.1) | 4.9 (3.2–7.3) | 125.6 (82.6–187.3) | .2 (.1–.3) | 5.3 (3.5–7.9) | |
| PCV21 | 12.6 (9.2–17.5) | 7.3 (5.1–10.6) | 187.1 (130.2–269.8) | .3 (.2–.4) | 7.9 (5.5–11.3) | |
| NVT | .8 (.3–2.2) | .4 (.2–1.3) | 11.3 (4.2–33.2) | .0 (.0–.1) | .5 (.2–1.4) | |
Abbreviations: CI, confidence interval; No., number; NVT, nonvaccine type; PCV, pneumococcal conjugate vaccine.
aPCV15-targeted serotypes: 1, 3, 4, 5, 6A/C, 6B, 7F, 9 V, 14, 18C, 19F, 19A, 22F, 23F, 33F. PCV20-targeted serotypes 1, 3, 4, 5, 6A/C, 6B, 7F, 8, 9 V, 10A, 11A, 12F, 14, 15B, 18C, 19F, 19A, 22F, 23F, 33F. PCV21-targeted serotypes 3, 6A/C, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, 35B.
bEstimated as annual no. nonsusceptible pneumococcal outpatient visits for each nonsusceptibility category divided by annual no. total pneumococcal-attributable outpatient visits (N = 1 483 052 [95% CI, 1,248,097–1,760,694]).
cOutpatient first-line antibiotic agents for adult pneumonia defined as amoxicillin, doxycycline, and erythromycin (proxy for all macrolides) [8].
dInpatient first-line antibiotic agents for adult pneumonia defined as cephalosporins (cefotaxime, ceftriaxone, and cefuroxime) and levofloxacin (proxy for all respiratory fluoroquinolones) [8].
Table 4.
Burdens of Antibiotic-nonsusceptible Pneumococcal Sinusitis by PCV-targeted Serotypes
| Outpatient Visits | ||||
|---|---|---|---|---|
| Nonsusceptible to | PCV-targeted serotypesa | Percent of cases (95% CI)b | Incidence per 10 000 person-y (95% CI) | Annual no. in thousands (95% CI) |
| First-line antibiotic agentc | … | … | … | … |
| PCV15 | 3.0 (1.4–5.6) | 11.4 (4.6–23.8) | 290.2 (117.0–608.7) | |
| PCV20 | 3.1 (1.4–5.7) | 11.6 (4.7–24.1) | 295.5 (120.8–614.5) | |
| PCV21 | 8.3 (4.7–13.8) | 31.3 (15.3–58.6) | 800.0 (391.0–1496.0) | |
| NVT | .2 (.0–.8) | .6 (.1–3.1) | 14.4 (1.7–78.6) | |
| ≥1 alternative antibiotic agentd | … | … | … | … |
| PCV15 | 5.9 (3.7–9.2) | 22.4 (11.6–40.1) | 571.3 (295.7–1022.6) | |
| PCV20 | 6.2 (4.0–9.5) | 23.6 (12.5–41.4) | 601.7 (318.5–1057.4) | |
| PCV21 | 7.3 (5.2–10.4) | 27.8 (15.4–46.3) | 708.5 (394.3–1181.9) | |
| NVT | .7 (.3–1.8) | 2.5 (.9–7.3) | 62.9 (23.5–185.2) | |
| >1 antibiotic class | … | … | … | … |
| PCV15 | 11.4 (7.8–16.0) | 42.9 (23.5–71.3) | 1094.1 (599.9–1819.9) | |
| PCV20 | 12.5 (8.9–17.0) | 47.2 (26.5–76.5) | 1203.6 (675.9–1952.7) | |
| PCV21 | 18.4 (13.9–24.4) | 69.4 (39.9–110.5) | 1771.5 (1017.8–2819.9) | |
| NVT | 1.2 (.4–3.9) | 4.5 (1.4–15.3) | 114.0 (34.5–389.8) | |
| ≥3 antibiotic classes | … | … | … | … |
| PCV15 | 8.4 (5.3–12.5) | 31.7 (16.6–55.1) | 809.4 (424.7–1406.1) | |
| PCV20 | 9.4 (6.2–13.4) | 35.3 (19.1–59.6) | 900.2 (487.5–1521.2) | |
| PCV21 | 14.4 (10.4–20.0) | 54.5 (30.7–89.3) | 1391.0 (783.0–2280.2) | |
| NVT | .9 (.3–2.6) | 3.3 (1.2–10.0) | 84.5 (29.4–255.4) | |
Abbreviations: CI, confidence interval; No., number; PCV, pneumococcal conjugate vaccine.
aPCV15-targeted serotypes: 1, 3, 4, 5, 6A/C, 6B, 7F, 9 V, 14, 18C, 19F, 19A, 22F, 23F, 33F. PCV20-targeted serotypes 1, 3, 4, 5, 6A/C, 6B, 7F, 8, 9 V, 10A, 11A, 12F, 14, 15B, 18C, 19F, 19A, 22F, 23F, 33F. PCV21-targeted serotypes 3, 6A/C, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, 35B.
bEstimated as annual no. nonsusceptible pneumococcal outpatient visits for each nonsusceptibility category divided by annual no. total pneumococcal-attributable outpatient visits (N = 9 722 028 [95% CI, 5,969,625–13,883,036]).
In sensitivity analyses of etiologic inputs, we observed changes in estimated antibiotic nonsusceptible burdens. In scenarios assuming pneumococcal-attributable proportions of 9.9% and 5.1% of pneumonia cases, we estimated lower burdens of antibiotic nonsusceptible nonbacteremic pneumonia compared with primary analyses across categories (Supplementary Table 15). In sensitivity analyses applying serotype distribution from pediatric ARIs to adult sinusitis, the incidence of pneumococcal sinusitis nonsusceptible to ≥3 antibiotic classes increased to 104.1 (63.6–150.1) cases per 10 000 person years (Supplementary Table 16). Additionally, antibiotic-nonsusceptible NVT serotypes accounted for greater proportions of pneumococcal sinusitis cases compared with primary estimates (Supplementary Table 17).
DISCUSSION
We estimated that 16% of adult nonbacteremic pneumococcal pneumonia cases and 19% of pneumococcal sinusitis cases were multidrug resistant (ie, nonsusceptible to ≥3 antibiotic classes). These proportions translate to 244 000 outpatient visits and 10 000 hospitalizations for multidrug-resistant nonbacteremic pneumonia, and 1.8 million outpatient visits for multidrug-resistant sinusitis. An estimated 31% of nonbacteremic pneumococcal pneumonia cases were nonsusceptible to ≥1 outpatient first-line antibiotic whereas only 14% of cases were nonsusceptible to ≥2 outpatient first-line agents and 13% were nonsusceptible to ≥1 inpatient first-line agent. For sinusitis, only 9% of cases were nonsusceptible to the first-line agent. These findings suggest that most cases of pneumococcal ARIs among adults in the United States may be effectively managed with first-line or alternative agents, although initial treatment failure, which can lead to higher costs and more intensive care, is possible, especially in outpatient-managed pneumonia.
Across most nonsusceptibility measures, PCV21-targeted serotypes accounted for greater proportions of pneumococcal nonbacteremic pneumonia and sinusitis cases than PCV15- and PCV20-targeted serotypes, although CIs overlap across estimates, precluding definitive comparisons. Notably, NVT serotypes accounted for small proportions of nonsusceptible pneumococcal pneumonia and sinusitis. Thus, current PCVs target serotypes responsible for antibiotic-nonsusceptible infections and may mitigate antibiotic-nonsusceptible pneumococcal disease. Historically, implementation of PCV7 and PCV13 resulted in changes in serotype distribution [33] and reductions in vaccine-serotype antibiotic-nonsusceptible pneumococcal infection burdens, with some decreases offset by increases in NVT antibiotic-nonsusceptible disease [12, 16, 34].
Certain PCV-targeted serotypes contributed meaningfully to overall nonsusceptibility burdens. Serotype 35B, prevalent in both pneumococcal sinusitis and pneumonia, was nonsusceptible to almost all drug classes and 92.2% of 35B isolates were nonsusceptible to ≥3 agents. PCV21 is the only currently licensed pneumococcal vaccine targeting serotype 35B. Pipeline PCVs also target this serotype [27]. Serotype 19A—which is prevalent in adult pneumococcal ARIs and for which a majority of isolates are also nonsusceptible to most classes—was targeted by PCV13 and is included in the formulation of all PCVs currently recommended for use in adults. Its persistence in adult disease may reflect low PCV uptake in this group; in 2021, only 66% of US adults aged ≥65 years universally eligible for PCV vaccination and 22% of US adults 19–64 years eligible for risk-based PCV vaccination had ever received pneumococcal vaccination (including both PCVs and the 23-valent pneumococcal polysaccharide vaccine) [35]. Further uptake of PCVs in adults, potentially aided by the October 2024 expansion of universal vaccination recommendations to adults aged 50–64 years [19], may contribute to reducing the prevalence of this highly nonsusceptible serotype. Serotype 3, previously targeted by PCV13 and now targeted by PCV15/20/21, still accounted for the highest proportion (12%) of all serotypes in pneumococcal pneumonia. Despite low overall rates of nonsusceptibility in serotype 3, due to its overall prevalence, it wields outsize influence on susceptibility distributions in pneumococci at large. Ongoing surveillance of serotype distribution in noninvasive disease and antibiotic nonsusceptibility in nonvaccine-type serotypes will be important in informing future PCV formulations.
Antibiotic resistance is driven by antibiotic consumption, either for infections caused by S pneumoniae or due to exposure of pneumococcus to antibiotics used to treat other infections [36]. Thus, improving antibiotic prescribing practices and reducing antibiotic use through infection prevention remain important objectives. We found that antibiotic nonsusceptibility in pneumococcal ARIs was highest for macrolides compared with all other antibiotic classes. Macrolides are commonly prescribed for conditions for which they are not recommended (eg, sinusitis, AOM) and those for which no antibiotics are recommended (eg, viral upper respiratory infection, bronchitis) [4, 37]. A modeling study estimated that 93% of pneumococcal macrolide exposures occurred when antibiotics were consumed for infections caused by nonpneumococcal pathogens [36]. We also observed prevalent nonsusceptibility to antifolates in pneumonia. Antifolates are not indicated in adults for ARIs commonly caused by S pneumoniae but are recommended in the management of urinary tract infections [38, 39], a leading cause of antibiotic use among adults [40, 41]. We observed low proportions of fluoroquinolone nonsusceptibility in pneumococcal ARIs despite fluoroquinolones being frequently prescribed in adults: in 2013, 1440% of genitourinary and 15% of respiratory infections in adult outpatients were treated with fluoroquinolones [42]. Lack of fluoroquinolone resistance may be related to fitness tradeoffs for fluoroquinolone-specific resistance mechanisms [43] and that young children, important in pneumococcal colonization and transmission [44, 45], are infrequently prescribed fluoroquinolones [46].
Our study has limitations. First, to capture nonsusceptibility proportions for as many serotypes as possible, we used data from IPD isolates. Nonsusceptibility patterns in noninvasive disease may vary from those in invasive disease, although there is limited understanding of potential serotype-specific nonsusceptibility differences in adults. A study in children in Rochester, NY, found similar serotype-specific antibiotic nonsusceptibility patterns between AOM and IPD isolates for penicillins and macrolides but divergent patterns for cephalosporins and tetracyclines [15]. A meta-analysis of studies of antibiotic nonsusceptibility in S pneumoniae (adult and pediatric) found similar rates of nonsusceptibility to penicillin and macrolides in pneumococcal carriage and invasive disease isolates in high-income countries [16]. Overall nonsusceptibility was similar or lower in isolates from invasive sources compared with noninvasive sources in a study of US adults with pneumonia hospitalized at SENTRY Antimicrobial Surveillance Program sites from 2009 through 2017; however, serotype distribution was not considered [47]. As serotype is a major driver of resistance patterns, this approach offers enhanced clinical utility by predicting how resistance will change as vaccine-targeted serotypes decline and enabling more accurate estimates for populations with different serotype distributions [48]. For serotypes not identified in ABCs isolates, we imputed nonsusceptibility based on weighted averages for all identified serotypes. As serotypes not contained in ABCs data accounted for few ARI cases, this assumption is unlikely to have meaningfully affected our overall estimates. Second, serotype distribution was based on data from hospitalized adults in the Southeastern United States [3] and may not be representative of all US adults and those treated in outpatient settings. However, these data represent the most comprehensive assessment of serotypes in pneumococcal pneumonia—30 serotypes as compared with 20 in other recent studies. We supplemented these data with IPD serotype distribution. Third, data on post-PCV13 sinusitis etiology are limited. We relied on serotype distribution in adult pneumonia with sensitivity analyses using data from pediatric ARIs. In sensitivity analyses, NVT serotypes contributed markedly to antibiotic-nonsusceptible sinusitis burdens, emphasizing the importance of etiologic assumptions. Fourth, as no single data source provides nationally representative estimates of outpatient visits across all outpatient settings, we relied on multiple data sources. Fifth, for consistency in data sources, we used the proportion of pneumonia cases attributable to S pneumoniae observed in the PNEUMO study (9.9%–14.7%) [3]. This study used SSUAD to identify pneumococcal-attributable pneumonia cases. SSUAD provides a more reliable basis for determining pneumococcal etiology than microbiological methods based on nasopharyngeal and oropharyngeal samples, which are associated with low pneumococcal density in adults [49]. This pneumococcal-attributable proportion is slightly higher than that observed in a study of adults hospitalized with community-acquired pneumonia from 10 US cities from 2013 through 2016, in which S pneumoniae was identified in 9.9% of patients [30]. An earlier study (2010–2012) among community-acquired pneumonia patients in Nashville and Chicago detected S pneumoniae in only 5.1% of enrolled cases [29], likely because of sampling methodology. Randomized trails [50] and real-world effectiveness studies [51, 52] have estimated that PCV13 prevents 5% to 10% of all-cause community-acquired pneumonia, suggesting that pneumococci account for >10% of pneumonia cases. Sixth, we did not consider serotype cross-protection in estimating PCV-serotype-attributable burdens. Thus, our estimates of PCV-associated burdens are likely underestimates. Seventh, burden estimates were based on national surveys and administrative datasets and relied on International Classification of Disease, 10th revision, Clinical Modification, codes to identify diagnoses. Finally, in examining antibiotic-nonsusceptible infections by pneumococcal vaccines, we did not consider the 23-valent pneumococcal polysaccharide vaccine (PPSV23) given its limited effectiveness against nonbacteremic pneumococcal pneumonia [53].
In conclusion, we estimated high proportions of antibiotic nonsusceptibility in pneumococcal ARIs in US adults: 16% of nonbacteremic pneumonia cases and 19% of pneumococcal sinusitis cases were nonsusceptible to ≥3 antibiotic classes. However, most cases were susceptible to at least 1 first-line or alternative recommended agent. Serotypes targeted by PCV15, PCV20, and PCV21 accounted for sizeable burdens of antibiotic-nonsusceptible cases compared with NVT serotypes. Vaccine uptake and ongoing antibiotic stewardship may contribute to addressing antibiotic nonsusceptibility in pneumococcal disease.
Supplementary Material
Notes
Author Contributions. L.M.K.: Conceptualization, methodology, validation, formal analysis, investigation, data curation, writing—original draft. K.L.A.: Conceptualization, resources, writing—review & editing, supervision, project administration. M.K.: Conceptualization, methodology, resources, writing—review & editing. W.X.: Formal analysis, writing—review & editing. A.L.C.: Conceptualization, resources, writing—review & editing. J.A.L.: Conceptualization, methodology, writing—review & editing, supervision, resources, funding acquisition.
Disclaimer. The findings and conclusions in this report are those of the authors and do not represent the official position of the Centers for Disease Control and Prevention. Research reported in this publication was supported by the National Institutes of Health under Award Number F31AI174773. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The National Institutes of Health had no input into the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The Centers of Disease Control and Prevention was involved through coauthor participation the design and conduct of the study; analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health and the Centers for Disease Control and Prevention.
Financial support. This work was supported by the Centers for Disease Control and Prevention [21IPA2111845 to J.A.L.] and the National Institutes of Health [1F31AI174773 to L.M.K.].
Data availability. NAMCS, NHAMCS, and NIS datasets are publicly available. MarketScan data is proprietary. ABCs data is available by request to https://www.cdc.gov/abcs/isolates-and-data/isolate-and-data-requests.html.
Contributor Information
Laura M King, Division of Epidemiology, School of Public Health, University of California, Berkeley, California, USA.
Kristin L Andrejko, Pneumonia and Streptococcus Epidemiology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Miwako Kobayashi, Pneumonia and Streptococcus Epidemiology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Wei Xing, Pneumonia and Streptococcus Epidemiology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Adam L Cohen, Pneumonia and Streptococcus Epidemiology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Joseph A Lewnard, Division of Epidemiology, School of Public Health, University of California, Berkeley, California, USA.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
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