Streptococcus pneumoniae is a bacterium responsible for Invasive pneumococcal disease (IPD), with bacteremic pneumonia, septicemia, and meningitis as the most common clinical presentations (1, 2). In Europe, the mean annual incidence of IPD in children under 2 years of age before the introduction of PCV7 was 44.4 per 100,000 population (3). In Latvia, the highest annual IPD incidence recorded during the PCV10 vaccination era (2012–2018) was 4.4 per 100,000 population in 2015, with infants and the older adult being the most affected groups (4).

The highest IPD burden is in infants, older adults, and those with certain comorbidities (5). Considering the IPD burden is important because pneumococcal conjugate vaccines are currently in almost all European countries’ national immunization programs (1).

The introduction of pneumococcal conjugate vaccines (PCV) into the National Immunization Programs (NIPs) across Europe, including Latvia, has significantly reduced the incidence of IPD caused by vaccine-included serotypes. However, the phenomenon of serotype replacement has been observed, with non-vaccine serotypes, such as 15B, 12F, 3, 17F, and 19A, becoming more prevalent (6–9). This serotype replacement presents a challenge to the continued effectiveness of current vaccination strategies.

Additionally, the introduction of PCVs has influenced S. pneumoniae antimicrobial resistance patterns (10). For instance, in Taiwan, following the introduction of PCV13, a significant reduction in penicillin resistance was observed among IPD patients, from 82% in 2010 to 47% in 2020 (8). However, in New Zealand, reverting from PCV13 to PCV10 in 2017 led to an increase in serotype 19A resistance to 65% (6). High resistance rates are most frequently observed against penicillin and erythromycin (8, 11–14). Globally, the highest resistance rates to penicillin and erythromycin have been reported in serotypes 6B, 6A, 9V, 14, 15A, 19F, 19A, and 23F (13). The early and rapid administration of antibiotics is crucial to increase survival in IPD cases and the choice should be based on the local epidemiology of antibiotic susceptibility, among other factors (10). These trends underscore the importance of local epidemiology in guiding antibiotic therapy for IPD cases.

In Latvia, vaccination against pneumococcal disease was introduced into the NIP in 2010 with PCV7, later transitioning to PCV10 in 2012 and to PCV15 in 2024. The current immunization schedule includes 2 + 1 doses administered at 2, 4, and 12–15 months, and the vaccine is provided free of charge for all children. Recommendations for adult vaccination against pneumococcal infection only began in 2019, with vaccination being self-funded, even for those in high-risk groups.

The objective of our study is to determine the changes in S. pneumoniae antimicrobial resistance and its association with PCV10 serotypes in Latvia during the period from 2012 to 2022 based on surveillance data and to describe the changes in invasive S. pneumoniae isolates detected during the period from 2012 to 2022.

The objective of the study was to determine the changes in S. pneumoniae antimicrobial resistance and its association with PCV10 serotypes in Latvia during the period from 2012 to 2022 using national surveillance data. Additionally, this study aims to describe the temporal trends in invasive S. pneumoniae isolates detected during the same period. Our findings demonstrate several key trends in antimicrobial resistance and provide important information about S. pneumoniae serotypes in Invasive pneumococcal disease cases.

Vaccination against pneumococcal infection was first introduced into the Latvian National Immunization Program in 2010 with the PCV7 vaccine. In 2012, PCV7 was replaced by PCV10, which remained in use until the end of 2023. Starting in early 2024, the vaccination program transitioned to the PCV15 vaccine. The introduction of PCV7, PCV10, and more recently PCV15 into the Latvian National Immunization Program has significantly influenced the S. pneumoniae serotype distribution in IPD cases. Our results indicate a decrease in the proportion of IPD cases caused by serotypes included in the PCV10 vaccine. However, our results show an increase in IPD cases caused by S. pneumoniae serotypes covered by PCV13, PCV15, and PPPV23 over the study period, suggesting possible serotype replacement. This is consistent with observations in other regions. In Canada where non-vaccine serotypes statistically significantly increased during the post-vaccination period (from 42% before vaccination to 73.3% during the PCV13 implementation period, p = 0.002) confirms that the introduction of PCV reduced the number of IPD cases caused by vaccine constituent S. pneumoniae serotypes. However, the increase in non-vaccine serotypes suggests serotype replacement (18). The same observations have been made in Spain after PCV13 introduction into the childhood immunization program. The number of IPD cases caused by PCV13 serotypes decreased by 88% (in children) and by 59% (in adults). However, the number of IPD cases caused by non-vaccine serotypes significantly increased (19). Austria also reports serotype 19A increasing from 3% to 6–7% in 2 years following PCV introduction (20) as well as Finland study indicates serotypes 19A (30%) and 3 (19%) as the most prevalent in IPD cases after PCV10 introduction (34). We observed in our study that introduction of PCV10 has reduced IPD cases caused by PCV10 vaccine serotypes, but PCV13nonPCV10 serotypes such as 3 and 19A become prevalent. This replacement has potential long-term implications such as severe IPD clinical presentation associated with 3 and 19A S. pneumoniae serotypes as well as serotype replacement possibly increasing the healthcare burden due to more severe clinical presentations and higher treatment costs for resistant infections. Latvia introduced PCV15 into the Latvian National Immunization Program which includes additional to PCV10 S. pneumoniae serotypes 3, 19A, 6A, 22F, 33F and could mitigate serotype replacement. To achieve this it is important to improve vaccine uptake rates in children and to prioritize for PCV vaccination high-risk groups, such as seniors and individuals with comorbidities.

Streptococcus pneumoniae serotype 3 was the most common serotype detected in IPD cases in Latvia during the study period. The same results were observed in the USA, where the most common S. pneumoniae serotypes identified in IPD patients were 3, 22F, 20, 35, 23A, 12.2%, 10.3%, 9.6, 9%, and 7.7%, respectively (21). Significant proportion of IPD cases (17.9%) were caused by serotypes not included in the vaccines. The emergence of non-vaccine serotypes (22F and 20) highlights the need for vaccines that cover a broader range of serotypes to reduce the burden of IPD (21, 33). As well Serbian study indicates serotype 3 (19.6%) as the most common in IPD cases (22).

The antibiotic consumption data in Latvia indicate one of the lowest reported in European Union (10.5 DDD per 1,000 inhabitants) (23) so our study results demonstrate relatively low antimicrobial resistance (7.5%) penicillin (3.8%), erythromycin (5.4%) and cefotaxime/ceftriaxone (1.2%) in IPD cases in comparison to other study results. Korean study results indicate that among IPD patients of all age groups, S. pneumoniae resistance to penicillin and ceftriaxone was 37.2% and 29.7%, respectively (24). Serbian study results shows high non-susceptibility percentage (40.4%) to erythromycin in IPD S. pneumoniae isolates (22). However World health organization reported penicillin resistance below 5% in 2020 in Austria, Czechia and the Netherlands while percentages equal to or above 25% were reported in Bosnia and Herzegovina, Cyprus, France, Iceland, Malta, Romania, Serbia and Turkey (25). In other countries, the rate of S. pneumoniae resistance to ceftriaxone among IPD patients was low: Japan (8.4%), South Africa (8.0%), and the USA (8.7%) (26, 27).

Our analysis shows that while penicillin and cefotaxime/ceftriaxone resistance trends did not demonstrate significant differences, there were significant differences in erythromycin resistance in IPD cases.

Multivariable logistic regression analysis revealed that S. pneumoniae PCV10 vaccine serotypes (particularly 14, 23F, 19F) detected in IPD patients and meningitis were strongly associated with an increased likelihood of penicillin resistance. Our findings indicate that patients with meningitis are over three times more likely to have penicillin resistant S. pneumoniae compared to other IPD cases. Other study results demonstrate that penicillin resistance in meningitis-causing S. pneumoniae strains has been noted as a critical concern due to the limited ability to achieve sufficient drug concentrations in the cerebrospinal fluid (28). Penicillin-resistant pneumococcal meningitis presents a significant clinical challenge. The study findings conducted in Spain demonstrate pneumococcal meningitis caused by penicillin-resistant strains significant association with mortality. Effective treatment is complicated by the blood–brain barrier, which limits antibiotic penetration into the cerebrospinal fluid. This is particularly problematic for resistant strains, requiring higher doses or combination therapies to achieve therapeutic levels. However, implementing high-dose cefotaxime requires careful monitoring for adverse effects, particularly in patients with comorbidities or in seniors (29). It is important to monitor not only meningitis caused by penicillin-resistant S. pneumoniae serotypes, but all reported IPD cases monitor for antimicrobial susceptibility and broader spectrum of antibiotics for susceptibility testing by enhancing IPD surveillance system. This surveillance helps in identifying emerging resistance trends, enabling timely updates to treatment guidelines. Meningitis and S. pneumoniae serotypes 19A (PCV13nonPCV10 vaccine constituent serotype), 14, 19F, and 15A (NonVacc serotype) also demonstrated a significant association with erythromycin resistance.

Further studies will cover comorbidities and other clinical factors for more comprehensive antimicrobial resistance analysis.

This indicates that vaccine serotype-specific resistance should be closely monitored to inform treatment guidelines and vaccine policy adjustments. Worldwide, the highest resistance rates to penicillin and erythromycin were found in serotypes 6B, 6A, 9V, 14, 15A, 19F, 19A, and 23F (12, 30), where 6B, 9V, 14, 19F, 23F are PCV10 vaccine serotypes.

Underreporting in a surveillance system and possible under diagnosis are likely to be study limitations. There are no clear guidelines for hospital laboratories regarding sample logistics. Some hospitals identify S. pneumoniae and test for antimicrobial susceptibility in their labs before sending the isolates to the National Reference Laboratory for further examination. There is a lack of information about the validation of identification and antimicrobial susceptibility tests in regional hospital laboratories. Moreover, PCR is not performed in these regional labs. Some hospitals directly send blood, CSF, or other sterile site samples to the NRL for S. pneumoniae identification, serotyping, and antimicrobial susceptibility detection, which prefers S. pneumoniae isolation over PCR. This approach may lead to an underestimation of cases.

Our study findings may have influenced by underreporting and under diagnosis described. This limitation possibly introduce bias, particularly in assessing the true burden of antimicrobial resistance. The selection of antibiotics for susceptibility testing reflects the limitations of the Latvian IPD surveillance system. Antimicrobial susceptibility data from Invasive pneumococcal disease patients reported to the surveillance system are collected in accordance with ECDC TESSy reporting requirements and submitted to the Centre for Disease Prevention and Control of Latvia (CDPC), which further disseminate surveillance data. TESSy mandates that countries report susceptibility to three antibiotics: penicillin, erythromycin, and cefotaxime/ceftriaxone. To mitigate these limitations in future studies we suggest following potential improvements to the IPD surveillance system: to incorporate routine PCR testing, standardize sample logistics, include all tested antimicrobial susceptibility notification in the case based surveillance and establish a centralized reporting platform to enhance case capture.

We suggest to conduct IPD surveillance system sensitivity analysis to detect possible underreporting rates and evaluate their potential effect on the IPD incidence and antimicrobial resistance findings. However our study reports an increase in IPD incidence in 2022. Similar increase in IPD incidence were observed in other countries following the easing of COVID-19 pandemic restrictions (31). It is important to continue monitor IPD incidence trends and describe potential factors contributing to these fluctuations.

Our findings are important for public health strategies, underlying the dynamic IPD and S. pneumoniae epidemiology. Surveillance of S. pneumoniae serotypes distribution and antimicrobial resistance patterns is important to vaccination programs. The introduction of the PCV15 into NIP in 2024 is an important step in the prevention of Invasive pneumococcal disease. PCV15 covers additional serotypes, including 22F and 33F, which are increasingly implicated in non-vaccine serotype replacements observed globally. A dynamic transmission model specific to Germany predicted that the introduction of PCV15 could lead to a reduction in IPD incidence by approximately 6% over 10 years compared to continued use of PCV13 (32). PCV15 introduction into NIP potentially will provide coverage against additional serotypes covered by this vaccine. Future studies should investigate the long-term PCV15 impact on S. pneumoniae serotype replacement dynamics and antimicrobial resistance. Additionally, compensation for vaccination against pneumococcal disease for high-risk group adults could further reduce the IPD burden and mitigate the spread of resistant S. pneumoniae.

This study provide national overview of S. pneumoniae serotypes identified in patients with IPD from 2012 to 2022, analyzing serotype replacement in relation to the pneumococcal vaccines available in the country, as well as antimicrobial resistance trends. Future studies will focus on analyzing changes in IPD incidence and regional stratification of IPD cases.

Overall, our study provides a comprehensive insight into the epidemiological diversity of S. pneumoniae isolates causing Invasive pneumococcal disease in Latvia in 11 year period. The most common serotypes were 3 and 19A. Our data demonstrate low S. pneumoniae antimicrobial resistance and resistance decreasing to erythromycin and penicillin in IPD cases over the years. Moreover, meningitis as IPD clinical presentation was significantly associated with penicillin and erythromycin resistance.

Further studies to monitor PCV15 impact on S. pneumoniae serotypes circulation are useful, as well as continuous S. pneumoniae serotypes antimicrobial resistance surveillance is needed to observe further trends in serotypes replacement.