Evolution of invasive pneumococcal disease by serotype 3 in adults: a Spanish three-decade retrospective study.

Background: Invasive pneumococcal disease due to serotype 3 (S3-IPD) is associated with high mortality rates and long-term adverse effects. The introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the Spanish paediatric immunisation programme has not led to a decrease in the adult S3-IPD. We aimed to analyse the incidence, clinical characteristics and genomics of S3-IPD in adults in Spain. Methods: Adult IPD episodes hospitalized in a Southern Barcelona hospital were prospectively collected (1994-2020). For genomic comparison, S3-IPD isolates from six Spanish hospitals (2008-2020) and historical isolates (1989-1993) were analysed by WGS (Illumina and/or MinION). Findings: From 1994 to 2020, 270 S3-IPD episodes were detected. When comparing pre-PCV (1994-2001) and late-PCV13 (2016-2020) periods, only modest changes in S3-IPD were observed (from 1.58 to 1.28 episodes per 100,000 inhabitants year). In this period, the incidence of the two main lineages shifted from 0.38 to 0.67 (CC180-GPSC12) and from 1.18 to 0.55 (CC260-GPSC83). The overall 30-day mortality remained high (24.1%), though a decrease was observed between the pre-PCV (32.4%; 95.0% CI, 22.0-45.0) and the late-PCV13 period (16.7%; 95.0% CI, 7.5-32.0) (p = 0.06). At the same time, comorbidities increased from 77.3% (95.0% CI, 65.0-86.0) to 85.7% (95.0% CI, 71.0-94.0) (p = 0.69). There were no differences in clinical characteristics or 30-day mortality between the two S3 lineages. Although both lineages were genetically homogeneous, the CC180-GPSC12 lineage presented a higher SNP density, a more open pan-genome, and a major presence of prophages and mobile genetic elements carrying resistance genes. Interpretation: Adult S3-IPD remained stable in our area over the study period despite PCV13 introduction in children. However, a clonal shift was observed. The decrease in mortality rates and the increase in comorbidities suggest a change in clinical management and overall population characteristics. The low genetic variability and absence of clinical differences between lineages highlight the role of the S3 capsule in the disease severity. Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) "PI18/00339", "PI21/01000", "INT22/00096", "FI22/00279", CIBER "CIBERES-CB06/06/0037", "CIBERINFEC-CB21/13/00009" and MSD grant "IISP 60168".

Respiratory Syncytial Virus Vaccination Recommendations for Adults Aged 60 Years and Older: The NeumoExperts Prevention Group Position Paper / Recomendaciones de vacunación contra el virus sincitial respiratorio para adultos de 60 años o más: documento de posición del grupo de prevención NeumoExperts

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in adults, particularly older adults and those with underlying medical conditions. Vaccination has emerged as a potential key strategy to prevent RSV-related morbidity and mortality. This Neumoexperts Prevention (NEP) Group scientific paper aims to provide an evidence-based positioning and RSV vaccination recommendations for adult patients. We review the current literature on RSV burden and vaccine development and availability, emphasising the importance of vaccination in the adult population. According to our interpretation of the data, RSV vaccines should be part of the adult immunisation programme, and an age-based strategy should be preferred over targeting high-risk groups. The effectiveness and efficiency of this practice will depend on the duration of protection and the need for annual or more spaced doses. Our recommendations should help healthcare professionals formulate guidelines and implement effective vaccination programmes for adult patients at risk of RSV infection now that specific vaccines are available.(AU)

Invasive disease caused simultaneously by two different serotypes of Streptococcus pneumoniae: a microbiological appreciation.

We report a clinical case of a child with an invasive pneumococcal disease caused by two different pneumococcal serotypes that belonged to different sequence types. She was a 15-month-old girl with pneumonia and pleural effusion in which S. pneumoniae colonies with different morphologies grew, one from the blood culture (characteristic greyish appearance) and the other from the pleural fluid (mucoid appearance). The isolate from blood was serotype 22 F (ST698/CC698/GPSC61), while the isolate from the pleural fluid was serotype 3 (ST180/CC180/GPSC12). The patient fully recovered after treatment with intravenous ampicillin followed by oral amoxicillin.

Respiratory Syncytial Virus Vaccination Recommendations for Adults Aged 60 Years and Older: The NeumoExperts Prevention Group Position Paper.

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in adults, particularly older adults and those with underlying medical conditions. Vaccination has emerged as a potential key strategy to prevent RSV-related morbidity and mortality. This Neumoexperts Prevention (NEP) Group scientific paper aims to provide an evidence-based positioning and RSV vaccination recommendations for adult patients. We review the current literature on RSV burden and vaccine development and availability, emphasising the importance of vaccination in the adult population. According to our interpretation of the data, RSV vaccines should be part of the adult immunisation programme, and an age-based strategy should be preferred over targeting high-risk groups. The effectiveness and efficiency of this practice will depend on the duration of protection and the need for annual or more spaced doses. Our recommendations should help healthcare professionals formulate guidelines and implement effective vaccination programmes for adult patients at risk of RSV infection now that specific vaccines are available.

Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Comparison of next generation technologies and bioinformatics pipelines for capsular typing of Streptococcus pneumoniae.

Whole genome sequencing (WGS)-based approaches for pneumococcal capsular typing have become an alternative to serological methods. In silico serotyping from WGS has not yet been applied to long-read sequences produced by third-generation technologies. The objective of the study was to determine the capsular types of pneumococci causing invasive disease in Catalonia (Spain) using serological typing and WGS and to compare the performance of different bioinformatics pipelines using short- and long-read data from WGS. All invasive pneumococcal pediatric isolates collected in Hospital Sant Joan de Déu (Barcelona) from 2013 to 2019 were included. Isolates were assigned a capsular type by serological testing based on anticapsular antisera and by different WGS-based pipelines: Illumina sequencing followed by serotyping with PneumoCaT, SeroBA, and Pathogenwatch vs MinION-ONT sequencing coupled with serotyping by Pathogenwatch from pneumococcal assembled genomes. A total of 119 out of 121 pneumococcal isolates were available for sequencing. Twenty-nine different serotypes were identified by serological typing, with 24F (n = 17; 14.3%), 14 (n = 10; 8.4%), and 15B/C (n = 8; 6.7%) being the most common serotypes. WGS-based pipelines showed initial concordance with serological typing (>91% of accuracy). The main discrepant results were found at the serotype level within a serogroup: 6A/B, 6C/D, 9A/V, 11A/D, and 18B/C. Only one discrepancy at the serogroup level was observed: serotype 29 by serological testing and serotype 35B/D by all WGS-based pipelines. Thus, bioinformatics WGS-based pipelines, including those using third-generation sequencing, are useful for pneumococcal capsular assignment. Possible discrepancies between serological typing and WGS-based approaches should be considered in pneumococcal capsular-type surveillance studies.

Clinical Impact of Rapid Bacterial Microbiological Identification with the MALDI-TOF MS.

Rapid microbiological reports to clinicians are related to improved clinical outcomes. We conducted a 3-year quasi-experimental design, specifically a pretest-posttest single group design in a university medical center, to evaluate the clinical impact of rapid microbiological identification information using MALDI-TOF MS on optimizing antibiotic prescription. A total of 363 consecutive hospitalized patients with bacterial infections were evaluated comparing a historical control group (CG) (n = 183), in which the microbiological information (bacterial identification and antibiotic susceptibility) was reported jointly to the clinician between 18:00 h and 22:00 h of the same day and a prospective intervention group (IG) (n = 180); the bacterial identification information was informed to the clinician as soon as it was available between 12:00 h and 14:00 h and the antibiotic susceptibility between 18:00 h and 22:00 h). We observed, in favor of IG, a statistically significant decrease in the information time (11.44 h CG vs. 4.48 h IG (p < 0.01)) from the detection of bacterial growth in the culture medium to the communication of identification. Consequently, the therapeutic optimization was improved by introducing new antibiotics in the 10-24 h time window (p = 0.05) and conversion to oral route (p = 0.01). Additionally, we observed a non-statistically significant decrease in inpatient mortality (global, p = 0.15; infection-related, p = 0.21) without impact on hospital length of stay. In conclusion, the rapid communication of microbiological identification to clinicians reduced reporting time and was associated with early optimization of antibiotic prescribing without worsening clinical outcomes.

Mid-Regional Pro-Adrenomedullin Can Predict Organ Failure and Prognosis in Sepsis?

Sepsis causes immune dysregulation and endotheliitis, with an increase in mid-regional pro-adrenomedullin (MR-proADM). The aim of the study is to determine an MR-proADM value that, in addition to clinical diagnosis, can identify patients with localized infection or those with sepsis/septic shock, with specific organ damage or with the need for intensive care unit (ICU) transfer and prognosis. The secondary aim is to correlate the MR-proADM value with the length of stay (LOS). In total, 301 subjects with sepsis (124/301 with septic shock) and 126 with localized infection were retrospectively included. In sepsis, MR-proADM ≥ 3.39 ng/mL identified acute kidney injury (AKI); ≥2.99 ng/mL acute respiratory distress syndrome (ARDS); ≥2.28 ng/mL acute heart failure (AHF); ≥2.55 ng/mL Glascow Coma Scale (GCS) < 15; ≥3.38 multi-organ involvement; ≥3.33 need for ICU transfer; ≥2.0 Sequential Organ Failure Assessment (SOFA) score ≥ 2; and ≥3.15 ng/mL non-survivors. The multivariate analysis showed that MR-proADM ≥ 2 ng/mL correlates with AKI, anemia and SOFA score ≥ 2, and MR-proADM ≥ 3 ng/mL correlates with AKI, GCS < 15 and SOFA score ≥ 2. A correlation between mortality and AKI, GCS < 15, ICU transfer and cathecolamine administration was found. In localized infection, MR-proADM at admission ≥ 1.44 ng/mL identified patients with AKI; ≥1.0 ng/mL with AHF; and ≥1.44 ng/mL with anemia and SOFA score ≥ 2. In the multivariate analysis, MR-proADM ≥ 1.44 ng/mL correlated with AKI, anemia, SOFA score ≥ 2 and AHF. MR-proADM is a marker of oxidative stress due to an infection, reflecting severity proportionally to organ damage.

NMR Spectroscopic Identification of Urolithin G, a Novel Trihydroxy Urolithin Produced by Human Intestinal Enterocloster Species.

Urolithins are gut microbiota metabolites of ellagic acid. Here, we have identified and chemically characterized a novel urolithin produced from urolithin D (3,4,8,9-tetrahydroxy urolithin) by in vitro incubation with different human gut Enterocloster species under anaerobic conditions. Urolithin G (3,4,8-trihydroxy urolithin) was identified by 1H NMR, 13C NMR, UV, HRMS, and 2D NMR. For the identification, NMR spectra of other known urolithins were also recorded and compared. Urolithin G was present in the feces of 12% of volunteers in an overweight-obese group after consuming an ellagitannin-rich pomegranate extract. The production of urolithin G required a bacterial 9-dehydroxylase activity and was not specific to the known human urolithin metabotypes A and B. The ability to produce urolithin G could be considered an additional metabolic feature for volunteer stratification and bioactivity studies. This is the first urolithin with a catechol group in ring A while having only one hydroxyl in ring B, a unique feature not found in human and animal samples so far.

Evolution of Antimicrobial Susceptibility to Penicillin in Invasive Strains of Streptococcus pneumoniae during 2007-2021 in Madrid, Spain.

The use of pneumococcal conjugate vaccines has affected the epidemiology and distribution of Streptococcus pneumoniae serotypes causing Invasive Pneumococcal Disease (IPD). The aim of this study was to analyze the evolution of the phenotypical profiles of antimicrobial susceptibility to penicillin (PEN) in all IPD strains isolated in Madrid, Spain, during 2007-2021. In total, 7133 invasive clinical isolates were characterized between 2007 and 2021. Levels of PENR and PNSSDR were 2.0% and 24.2%, respectively. In addition, 94.4% of all the PENR belonged to four serotypes, including 11A (33.6%), 19A (30.8%), 14 (20.3%) and 9V (9.8%). All the strains of serotype 11A, which is a non-PCV13 serotype, were detected after the year 2011. Serotypes 6C, 15A, 23B, 24F, 35B, 19F, 16F, 6B, 23F, 24B, 24A, 15F and a limited number of strains of serogroups 16 and 24 (non-typed at serotype level) were associated with PNSSDR (p < 0.05). PNSSDR strains of non-PCV13 serotypes 11A, 24F, 23B, 24B, 23A and 16F were more frequent from 2014 to 2021. The changes in S. pneumoniae serotype distribution associated with the use of conjugate vaccines had caused in our region the emergence of non-PCV13 pneumococcal strains with different PENR or PNSSDR patterns. The emergence of serotype 11A resistant to penicillin as the most important non-PCV13 serotype is a worrisome event with marked relevance from the clinical and epidemiological perspective.

Distribution of Multidrug-Resistant Invasive Serotypes of Streptococcus pneumoniae during the Period 2007-2021 in Madrid, Spain.

After the systematic use of conjugate vaccines, the invasive pneumococcal disease (IPD) was included into the Madrid Notifiable Diseases Surveillance System through an Epidemiological Surveillance Network. Furthermore, Streptococcus pneumoniae was included in the Spanish Plan of Antibiotic Resistance. The aim of this study was to analyse the multidrug-resistant (MDR) phenotype distribution among invasive strains of Streptococcus pneumoniae isolated during 2007-2021 from usually sterile clinical samples in Madrid, Spain. A total number of 7133 invasive pneumococcal isolates were studied during the period from February 2007 to December 2021. Serotyping was characterised using the Pneumotest-Latex and by the Quellung reaction. Antibiotic susceptibility testing to penicillin (PEN), erythromycin (ERY), and levofloxacin (LVX) was performed using the E-test according to the EUCAST guidelines and breakpoints. Combination of non-susceptibility to PEN at standard dosing regimen (PNSSDR), resistance to ERY (ERYR) and to LVX (LVXR) was considered to be multidrug-resistant at standard dosing regimen of penicillin (MRPSDR), whereas the combination of resistance to PEN (PENR), ERYR, and LVXR was considered multidrug-resistant (MDR). The number of MDRPSDR and or MDR strains in the entire population (n = 7133) during the complete period (2007-2021) were 51 (0.7%) and 6 (0.1%), respectively. All MDRPSDR and/or MDR strains belonged to nine serotypes: 19A (n = 13), 15A (n = 12), 9V (n = 12), 14 (n = 7), 24F (n = 3), 15F (n = 1), 19F (n = 1), 6B (n = 1) and 6C (n = 1). Only two serotypes (9V and 19A) were found among MDR strains, and most of them (5/6) belonged to serotype 9V. Only 12.4% of the strains typified as serotype 9V were MDRPSDR and only 5.2% as MDR. The levels of pneumococcal MDRPSDR and/or MDR in this study were low and all six MDR strains were isolated between 2014 and 2018. These results reinforce the importance of monitoring the evolution of non-susceptible serotypes including those with MDR in the coming years, especially after the introduction of new conjugate vaccines of a broader spectrum.

Vaccination against Community-Acquired Pneumonia in Spanish Adults: Practical Recommendations by the NeumoExperts Prevention Group.

In the adult population, community-acquired pneumonia (CAP) is a serious disease that is responsible for high morbidity and mortality rates, being frequently associated with multidrug resistant pathogens. The aim of this review is to update a practical immunization prevention guideline for CAP in Spain caused by prevalent respiratory pathogens, based on the available scientific evidence through extensive bibliographic review and expert opinion. The emergence of COVID-19 as an additional etiological cause of CAP, together with the rapid changes in the availability of vaccines and recommendations against SARS-CoV-2, justifies the need for an update. In addition, new conjugate vaccines of broader spectrum against pneumococcus, existing vaccines targeting influenza and pertussis or upcoming vaccines against respiratory syncytial virus (RSV) will be very useful prophylactic tools to diminish the burden of CAP and all of its derived complications. In this manuscript, we provide practical recommendations for adult vaccination against the pathogens mentioned above, including their contribution against antibiotic resistance. This guide is intended for the individual perspective of protection and not for vaccination policies, as we do not pretend to interfere with the official recommendations of any country. The use of vaccines is a realistic approach to fight these infections and ameliorate the impact of antimicrobial resistance. All of the recently available scientific evidence included in this review gives support to the indications established in this practical guide to reinforce the dissemination and implementation of these recommendations in routine clinical practice.

Combination of Cefditoren and N-acetyl-l-Cysteine Shows a Synergistic Effect against Multidrug-Resistant Streptococcus pneumoniae Biofilms.

Biofilm formation by Streptococcus pneumoniae is associated with colonization of the upper respiratory tract, including the carrier state, and with chronic respiratory infections in patients suffering from chronic obstructive pulmonary disease (COPD). The use of antibiotics alone to treat recalcitrant infections caused by biofilms is insufficient in many cases, requiring novel strategies based on a combination of antibiotics with other agents, including antibodies, enzybiotics, and antioxidants. In this work, we demonstrate that the third-generation oral cephalosporin cefditoren (CDN) and the antioxidant N-acetyl-l-cysteine (NAC) are synergistic against pneumococcal biofilms. Additionally, the combination of CDN and NAC resulted in the inhibition of bacterial growth (planktonic and biofilm cells) and destruction of the biofilm biomass. This marked antimicrobial effect was also observed in terms of viability in both inhibition (prevention) and disaggregation (treatment) assays. Moreover, the use of CDN and NAC reduced bacterial adhesion to human lung epithelial cells, confirming that this strategy of combining these two compounds is effective against resistant pneumococcal strains colonizing the lung epithelium. Finally, administration of CDN and NAC in mice suffering acute pneumococcal pneumonia caused by a multidrug-resistant strain was effective in clearing the bacteria from the respiratory tract in comparison to treatment with either compound alone. Overall, these results demonstrate that the combination of oral cephalosporins and antioxidants, such as CDN and NAC, respectively, is a promising strategy against respiratory biofilms caused by S. pneumoniae. IMPORTANCE Streptococcus pneumoniae is one of the deadliest bacterial pathogens, accounting for up to 2 million deaths annually prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccines have decreased the burden of diseases produced by S. pneumoniae, but the rise of antibiotic-resistant strains and nonvaccine serotypes is worrisome. Pneumococcal biofilms are associated with chronic respiratory infections, and treatment is challenging, making the search for new antibiofilm therapies a priority as biofilms become resistant to traditional antibiotics. In this work, we used the combination of an antibiotic (CDN) and an antioxidant (NAC) to treat the pneumococcal biofilms of relevant clinical isolates. We demonstrated a synergy between CDN and NAC that inhibited and treated pneumococcal biofilms, impaired pneumococcal adherence to the lung epithelium, and treated pneumonia in a mouse pneumonia model. We propose the widely used cephalosporin CDN and the repurposed drug NAC as a new antibiofilm therapy against S. pneumoniae biofilms, including those formed by antibiotic-resistant clinical isolates.

Improvement of the Antibacterial Activity of Phage Lysin-Derived Peptide P87 through Maximization of Physicochemical Properties and Assessment of Its Therapeutic Potential.

Phage lysins are a promising alternative to common antibiotic chemotherapy. However, they have been regarded as less effective against Gram-negative pathogens unless engineered, e.g., by fusing them to antimicrobial peptides (AMPs). AMPs themselves pose an alternative to antibiotics. In this work, AMP P87, previously derived from a phage lysin (Pae87) with a presumed nonenzymatic mode-of-action, was investigated to improve its antibacterial activity. Five modifications were designed to maximize the hydrophobic moment and net charge, producing the modified peptide P88, which was evaluated in terms of bactericidal activity, cytotoxicity, MICs or synergy with antibiotics. P88 had a better bactericidal performance than P87 (an average of 6.0 vs. 1.5 log-killing activity on Pseudomonas aeruginosa strains treated with 10 µM). This did not correlate with a dramatic increase in cytotoxicity as assayed on A549 cell cultures. P88 was active against a range of P. aeruginosa isolates, with no intrinsic resistance factors identified. Synergy with some antibiotics was observed in vitro, in complex media, and in a respiratory infection mouse model. Therefore, P88 can be a new addition to the therapeutic toolbox of alternative antimicrobials against Gram-negative pathogens as a sole therapeutic, a complement to antibiotics, or a part to engineer proteinaceous antimicrobials.

C5a elevation in convalescents from severe COVID-19 is not associated with early complement activation markers C3bBbP or C4d.

Numerous publications have underlined the link between complement C5a and the clinical course of COVID-19. We previously reported that levels of C5a remain high in the group of severely ill patients up to 90 days after hospital discharge. We have now evaluated which complement pathway fuels the elevated levels of C5a during hospitalization and follow-up. The alternative pathway (AP) activation marker C3bBbP and the soluble fraction of C4d, a footprint of the classical/lectin (CP/LP) pathway, were assessed by immunoenzymatic assay in a total of 188 serial samples from 49 patients infected with SARS-CoV-2. Unlike C5a, neither C3bBbP nor C4d readouts rose proportionally to the severity of the disease. Detailed correlation analyses in hospitalization and follow-up samples collected from patients of different disease severity showed significant positive correlations of AP and CP/LP markers with C5a in certain groups, except for the follow-up samples of the patients who suffered from highly severe COVID-19 and presented the highest C5a readouts. In conclusion, there is not a clear link between persistently high levels of C5a after hospital discharge and markers of upstream complement activation, suggesting the existence of a non-canonical source of C5a in patients with a severe course of COVID-19.

Effect of pneumococcal conjugate vaccines and SARS-CoV-2 on antimicrobial resistance and the emergence of Streptococcus pneumoniae serotypes with reduced susceptibility in Spain, 2004-20: a national surveillance study.

BACKGROUND: Epidemiological studies are necessary to explore the effect of current pneumococcal conjugate vaccines (PCVs) against antibiotic resistance, including the rise of non-vaccine serotypes that are resistant to antibiotics. Hence, epidemiological changes in the antimicrobial pattern of Streptococcus pneumoniae before and during the first year of the COVID-19 pandemic were studied. METHODS: In this national surveillance study, we characterised the antimicrobial susceptibility to a panel of antibiotics in 3017 pneumococcal clinical isolates with reduced susceptibility to penicillin during 2004-20 in Spain. This study covered the early and late PCV7 periods; the early, middle, and late PCV13 periods; and the first year of the COVID-19 pandemic, to evaluate the contribution of PCVs and the pandemic to the emergence of non-vaccine serotypes associated with antibiotic resistance. FINDINGS: Serotypes included in PCV7 and PCV13 showed a decline after the introduction of PCVs in Spain. However, an increase in non-PCV13 serotypes (mainly 11A, 24F, and 23B) that were not susceptible to penicillin promptly appeared. A rise in the proportion of pneumococcal strains with reduced susceptibility to ß-lactams and erythromycin was observed in 2020, coinciding with the emergence of SARS-CoV-2. Cefditoren was the ß-lactam with the lowest minimum inhibitory concentration (MIC)50 or MIC90 values, and had the highest proportion of susceptible strains throughout 2004-20. INTERPRETATION: The increase in non-PCV13 serotypes associated with antibiotic resistance is concerning, especially the increase of penicillin resistance linked to serotypes 11A and 24F. The future use of PCVs with an increasingly broad spectrum (such as PCV20, which includes serotype 11A) could reduce the impact of antibiotic resistance for non-PCV13 serotypes. The use of antibiotics to prevent co-infections in patients with COVID-19 might have affected the increased proportion of pneumococcal-resistant strains. Cefotaxime as a parenteral option, and cefditoren as an oral choice, were the antibiotics with the highest activity against non-PCV20 serotypes. FUNDING: The Spanish Ministry of Science and Innovation and Meiji-Pharma Spain. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Genomic features of predominant non-PCV13 serotypes responsible for adult invasive pneumococcal disease in Spain.

BACKGROUND: Although pneumococcal conjugate vaccines (PCVs) effectively prevent invasive pneumococcal disease (IPD), serotype replacement has occurred. OBJECTIVES: We studied the pangenome, antibiotic resistance mechanisms and presence of mobile elements in predominant non-PCV13 serotypes causing adult IPD after PCV13 vaccine introduction in Spain. METHODS: We conducted a multicentre study comparing three periods in six Spanish hospitals and analysed through whole genome sequencing representative strains collected in the pre-PCV13, early-PCV13 and late-PCV13 periods. RESULTS: Among 2197 cases of adult IPD identified, 110 pneumococci expressing non-PCV13 capsules were sequenced. Seven predominant serotypes accounted for 42.6% of IPD episodes in the late-PCV13 period: serotypes 8 (14.4%), 12F (7.5%), 9N (5.2%), 11A (4.1%), 22F (3.9%), 24F (3.9%) and 16F (3.6%). All predominant non-PCV13 serotypes were highly clonal, comprising one or two clonal complexes (CC). In general, CC538, CC4048, CC3016F, CC43322F and CC669N, related to predominant non-PCV13 serotypes, were antibiotic susceptible. CC15611A was associated with resistance to co-trimoxazole, penicillin and amoxicillin. CC23024F was non-susceptible to penicillin and resistant to erythromycin, clindamycin, and tetracycline. Six composite transposon structures of the Tn5252-family were found in CC23024F, CC98912F and CC3016F carrying different combinations of erm(B), tet(M), and cat. Pangenome analysis revealed differences in accessory genomes among the different CC, with most variety in CC3016F (23.9%) and more conservation in CC15611A (8.5%). CONCLUSIONS: We identified highly clonal predominant serotypes responsible for IPD in adults. The detection of not only conjugative elements carrying resistance determinants but also clones previously associated with vaccine serotypes (CC15611A and CC23024F) highlights the importance of the accessory genome.

Impact of Infectious Diseases training in the perception of antibiotic resistance and rational use of antibiotics among Spanish medical students - a cross-sectional study.

BACKGROUND: Antibiotic resistance is one of the main public health problems worldwide. One key tool to optimize antibiotic prescription is medical training. The aim of this study is to compare the impact of training in infectious diseases on students' knowledge of the antibiotic resistance problem and the rational use of antibiotics. METHODS: We performed a cross-sectional study in the medical school of the University of Navarra. We conducted an anonymous in situ survey of students in each year of training. Data were analyzed grouping the students as follows: GROUP 1: first three years of education, no training in Clinical Microbiology (CM) or in Infectious Diseases (ID); GROUP 2: fourth-year students, training in CM but not ID; GROUP 3: Fifth and sixth-year students who have completed the training in CM and ID. Chi-square test (or Fisher's exact test when appropriate) was performed to evaluate potential associations. Wilcoxon's test was used to compare the median correct answers between groups. We used Spearman's test for correlation between year of training and performance in questionnaire. RESULTS: A total of 994 students respond to the survey, 80.4% of the eligible students. Almost all students who had completed infectious diseases training perceive antibiotic resistance as an important problem in comparison with students who had not completed the formation (99.5% in group 3 vs 94.5% in group 1, p = 0.02). Knowledge of antibiotic stewardship underwent a statistically significant change after training in infectious diseases (from 9.2% in group 1 to 52.2% in group 3, p < 0.001). In the training questions block we also found an increase in the average number of correct answers (21.4% in group 1 vs 44.7% in group 3, p < 0.001). When comparing the results of subgroups 3A and 3B we found a significant loss of knowledge as we moved away from training (49% vs 40.9%, p < 0.001). CONCLUSIONS: The training of medical students is the key to improving both perception and knowledge of infectious diseases. However, we have an opportunity for educational improvement as far as infectious diseases are concerned, regarding both the acquisition of knowledge and its loss as time lapses after training.