The use of pneumococcal conjugate vaccines (PCVs) in children and adults has proven to be an effective intervention for controlling the burden of both invasive and non-invasive pneumococcal disease (Bertran et al., 2024; Pérez-García et al., 2024; Sempere et al., 2024; Pérez-García et al., 2025), in addition to being a key measure in reducing the impact of antimicrobial resistance (AMR). In Spain, the effectiveness of PCVs (PCV7 and PCV13) in controlling the spread of resistant pneumococcal isolates has been demonstrated, and it is suggested that incorporating these vaccines into national immunization schedules is a cost-effective strategy to counteract antibiotic resistance (Sempere et al., 2022; Calvo-Silveria et al., 2025). Before the introduction of PCVs in Spain, most cases of invasive pneumococcal disease (IPD) associated with antimicrobial resistance were caused by serotypes included in conjugate vaccines (Fenoll et al., 2015). Following the implementation of PCV7 for a brief period and later PCV13, there was a drastic decline in IPD cases caused by vaccine serotypes associated with resistance (Sempere et al., 2022). However, the emergence of non-vaccine serotypes harboring antibiotic resistance has also been observed. These serotypes have been increasing in recent years, and some are associated with hypervirulence, such as the ST6521 clone in serotype 11A (Aguinagalde et al., 2015; González-Díaz et al., 2020) and the GPSC10 genetic lineage in serotype 24F (Lo et al., 2022), which is linked to severe meningitis episodes.

In the United States, PCVs have also shown an impact in reducing the burden of IPD caused by antibiotic-resistant serotypes (Bajema et al., 2022). Among children under 5 years old, the incidence of resistance-associated IPD decreased across all antibiotic classes from 2009 to 2018, dropping from 8.8 to 2.3 per 100,000 inhabitants for macrolides, from 5.9 to 0.4 per 100,000 for cephalosporins, and from 5.2 to 0.4 per 100,000 for penicillins (Bajema et al., 2022). Among adults over 65 years old during the same period, the incidence decreased from 10.4 to 7.3 per 100,000 for macrolides, from 6.2 to 2.4 per 100,000 for cephalosporins, and from 3.6 to 1.6 per 100,000 for penicillins (Bajema et al., 2022). Nearly two decades after the introduction of PCVs in the U.S., their impact on reducing IPD by AMR resistant isolates remains significant.

However, recently approved and implemented vaccines, such as PCV15 and PCV20, along with PCV21—an adult-targeted vaccine already approved by the FDA and EMA—are expected to expand coverage against non-vaccine serotypes associated with antibiotic resistance. To ensure their effectiveness, these vaccines must be administered with high coverage rates. Another problem with AMR and IPD is the possibility of increased resistant rates during the first pandemic year due to the extensive use of azithromycin and other antibiotics to prevent complications related to bacterial coinfections in patients with COVID-19 (Meschiari et al., 2022). Several authors have warned that antibiotic resistance has expanded because of the careless use of antibiotics in the medical field, the food industry, agriculture, and other industries (Singh, 2024). In addition, other studies have stated that antimicrobial resistance has emerged as a hidden pandemic following COVID-19 (Singh and Sodhi, 2023). A recent report from United States confirmed that multidrug resistant infections in hospitals increased during the pandemic due to antibiotic exposure (Yek et al., 2025).

In this study, we show the evolution of antimicrobial resistance to different β-lactam antibiotics including oral cephalosporins, intravenous cephalosporins, and penicillins, in pneumococcal isolates causing disease in adults. We compared data from 2019 to 2020, coinciding with the years before and after the COVID-19 pandemic, to assess the impact of the pandemic in the antibiotic susceptibility of Streptococcus pneumoniae.

A key breakthrough in combating pneumococcal disease was the development of antibiotic chemotherapy, which emerged in the 1930s and led to the discontinuation of serum therapy. Nevertheless, the effectiveness of antibiotic chemotherapy was soon threatened by the emergence of resistant clinical isolates, which appeared shortly after the widespread use of antibiotics (Spagnolo et al., 2021). The prevalence of antibiotic resistance in pneumococcus increased globally in the pre-PCV era, and despite the current use of vaccines with high coverage rates in pediatric population, the rise of serotypes associated with antibiotic resistance remains as a concerning phenomenon (Cassiolato et al., 2018; Sempere et al., 2022). Resistance patterns vary depending on serotype and geographic region, as several factors contribute to the emergence and spread of resistant isolates, including low vaccination rates specially in adult population, serotype replacement by non-vaccine serotypes, and inappropriate antibiotic use (Reinert, 2009; Song et al., 2012; Chávez et al., 2021). However, prophylactic strategies based on immunization appear to be the best approach for controlling the development of IPD and pneumonia, as well as reducing the impact of antibiotic resistance (Atkins et al., 2018).

Our results showed a rise in antibiotic resistance during the first year of the COVID-19 pandemic. During 2020, the generic use of antibiotics to avoid co-infections with bacterial pathogens was extended (Langford et al., 2021) and antibiotic sales correlated positively with COVID-19 cases globally (Nandi et al., 2023). Moreover, a recent United States study confirmed that AMR infections in hospitalized patients during the pandemic increased due to antibiotic exposure (Yek et al., 2025), which is in line with our observations. This makes antimicrobial stewardship essential, even in the context of a global health crisis (Langford et al., 2021), as inadequate use of antibiotics may exacerbate the antimicrobial resistance problem (Group, 2021).

In this study we showed that cefditoren was the β-lactam antibiotic with the highest proportion of susceptible isolates, achieving the lowest MIC₅₀ and MIC₉₀ values among all antibiotics tested, including other oral and intravenous cephalosporins. Since its introduction in 2004 and despite its widespread use in clinical practice, the emergence of non-susceptible isolates to this antibiotic has remained very low. In contrast, cefixime, cefpodoxime and cefuroxime, two third-generation and one second-generation oral cephalosporins, had the lowest proportion of susceptible isolates throughout the study period. It had already been demonstrated that cefditoren maintains good activity against penicillin-non-susceptible isolates due to its high affinity for PBP2x, enhancing its antimicrobial activity, which explains the consistently low and stable MIC₅₀ and MIC₉₀ values (0.5 and 1 μg/mL in most of the clinical isolates analyzed) (Yamada et al., 2007; Yang et al., 2012).

Lower respiratory tract infections (LRTIs) are associated with high morbidity and mortality rates worldwide. Before the COVID-19 pandemic, nearly 2.4 million deaths were caused by infections affecting the LRT being S. pneumoniae the major etiologic agent of these cases, affecting largely to high-risk groups such as the pediatric and elderly population (children under 5 years old and adults over 65 years old) (GBD, 2018). In this sense, our findings demonstrated that cefditoren as oral option and cefotaxime as iv choice, exhibited the highest antimicrobial activities regardless of the serotype or source of the clinical isolate. This is important from the LRTIs perspective as both cephalosporins are indicated for the treatment of community-acquired pneumonia (Granizo et al., 2006; Di Marco et al., 2014). We observed higher MIC values for iv cephalosporins and penicillins in non-invasive isolates than in invasive isolates (both with or without respiratory origin). Other studies have also described a higher proportion of resistance in non-invasive isolates compared with IPD isolates (Mohanty et al., 2023). Our results demonstrated that cefditoren maintained the same antimicrobial activity regardless of the source of the clinical isolate. Cefditoren can be used as oral treatment following parenteral administration of third-generation cephalosporins such as cefotaxime or ceftriaxone (Monmaturapoj et al., 2012). This is particularly relevant because early switching from intravenous to oral antibiotic therapy in patients with severe community-acquired pneumonia has been shown to be safe and to reduce hospitalization time (Mandell et al., 2007). It is also recommended by various organizations, including the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS). In this context, cefditoren has been recommended as the most suitable option for the early switch from intravenous third-generation cephalosporins to oral therapy, as it has a similar spectrum of activity but greater intrinsic efficacy (Blasi et al., 2016). This transition benefits not only patients but also healthcare systems by reducing hospitalization time and costs, as well as the risk of hospital-acquired infections—one of the major healthcare challenges today. This concept agrees with a recent study evaluating the hospital burden of pneumococcal disease in Spain showing that the annual cost of pneumococcal hospitalizations for the national health system exceeded EUR 383 million (Gil-Prieto et al., 2025).

Although the introduction of conjugate vaccines significantly reduced IPD cases caused by vaccine serotypes and helped control the spread of multidrug-resistant isolates, many countries have reported serotype replacement, including the emergence of multidrug-resistant serotypes (Cassiolato et al., 2018; Ladhani et al., 2018; de Miguel et al., 2021; Ouldali et al., 2021). Especially, serotypes associated with hypervirulent lineages, such as 11A and 24F, are of great concern (Aguinagalde et al., 2015; Lo et al., 2022). Recently, new conjugate vaccines PCV15 and PCV20 have been approved and introduced in Spain and PCV21 has been recently approved by FDA and EMA. This will be very useful from the public health perspective because the use of broader vaccines would increase the potential coverage against resistant isolates. For instance, PCV20 and PCV21 include serotype 11A, that showed high MIC₉₀ values for most antibiotics tested, although cefditoren and cefotaxime still maintained a good antimicrobial activity profile against this serotype. Moreover, PCV21, a vaccine targeting specifically the adult population, has been just approved by FDA and EMA, and includes non-PCV20 serotypes such as 15A, 23B and 24F, and could be a potential candidate to ameliorate the emergence of these multidrug-resistant serotypes (Sempere et al., 2022). However, PCV21 excluded PCV20 serotypes such as 14, 19F and 9V that diminished after PCV13 introduction but are still an important cause of IPD in Spain (Pérez-García et al., 2024).

To summarize, we evaluated the evolution of antimicrobial resistance to different β-lactam antibiotics by comparing the years before and after the COVID-19 pandemic, in order to assess its impact on the antibiotic susceptibility of S. pneumoniae. The main limitations of the manuscript are the lack of results covering recent years although this will be address in future studies, and the lack of information on patients’ clinical characteristics.

Overall, we found that cefditoren as oral cephalosporin, and cefotaxime as iv option, are good candidates for the treatment of pneumococcal disease in Spain, even when it is associated with reduced susceptibility to β-lactams. Moreover, the high antimicrobial activity of cefditoren might reinforce its use as an oral option after pneumococcal hospitalization. From the prevention perspective, the use of higher valency conjugate vaccines in Spain might tackle the emergence of non-PCV13 serotypes associated with antibiotic resistance.