Streptococcus pneumoniae bacteremia: comparison of incidence, epidemiology, and clinical outcome in a pre- and post-COVID-19 period

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We aimed to evaluate the differences in clinical, epidemiological and outcome manifestations of patients admitted with S. pneumoniae bacteremia (SPB) in the pre- and post-COVID-19 period. Methods: The study analyzed all patients admitted in Province of Modena, Italy, during 2 time-periods: pre-COVID-19 (Jan 2018- Feb 2020) and post-COVID-19 (Mar 2018- Jun 2022) period. The data were compared using univariate and multivariate analysis. Results. A total of 150 patients with SPB were included, 109 and 41 patients in the pre- and post-COVID-19, respectively. We observed a decrease in SPB incidence from March 2020, after the implementation of the restrictive measures for the COVID-19 pandemic, and a new increase in 2022. SPB was associated with pneumonia in 128 patients (85.3%), meningitis in 25 (16.7%) and otitis-mastoiditis in 14 (9.3%). The proportion of patients presenting with multi-lobar pneumonia significantly increased during the post-COVID-19 period (39.0% vs. 16.5%, p = 0.008). Thirty-day mortality rate resulted higher in the post-COVID-19 period (24.4% vs. 11.9%, p = 0.075), and multivariate analysis identified an age≥80 years (OR 4.45, 95% CI 1.12–17.61, p=0.033), multi-lobar pneumonia (OR 4.34, 95% CI 1.56–12.07, p=0.005), and central nervous system disease (OR 3.63, 95% CI 1.08–12.20, p=0.036) as independent risk factors for 30-day mortality. The rate of pneumococcal vaccination in the at-risk population was low (9.3%), but in the pandemic period the rate increased by 26.7%, driven by the anti-SARS-CoV-2 vaccination campaign. Conclusions. The COVID-19 pandemic has impacted the epidemiology and clinical severity of SPB. In our study, less than 10% of the high-risk population was vaccinated, while the older population (age ≥80 years) had a significantly higher 30-day mortality risk. It would be necessary for Institutions to increase awareness campaigns for pneumococcal vaccination. Figures Figure 1 Figure 2 Introduction Streptococcus pneumoniae bacteremia ranks among the top 10 most common bloodstream infection (BSI) and is associated with high morbidity and mortality worldwide (1,2). S. pneumoniae is typically a cause of respiratory infections such as community-acquired pneumonia but can also cause non- respiratory infections such as peritonitis, infective endocarditis, and meningitis (3). Pneumococci usually colonize the human respiratory tract, especially during winter and early spring, spreading by air, via Flügge particles (4). During the COVID-19 pandemic, the implementation of non- pharmaceutical interventions (NPIs), such as mask wearing, stay-at-home orders and physical distancing were adopted as strategies of prevention of SARS-CoV-2 spreading. Introduction of NPIs has also been associated with a decreased diffusion of other respiratory pathogens, including influenza virus, respiratory syncytial virus (RSV), and S. pneumoniae (5–7). It has been proposed that a lower incidence of IPD may be due to reduced pneumococcal transmission (6,7). This study aims to compare the incidence, epidemiology, and clinical outcomes of S. pneumoniae bacteremia (SPB) before and after the onset of the COVID-19 pandemic. Materials and Methods A retrospective study was conducted with the aim of investigating the impact of the Sars-CoV-2 pandemic on the epidemiology, clinical manifestations, and outcome of patients hospitalized for Streptococcus pneumoniae bacteremia (SPB). We compared two time periods: pre-COVID-19 period (January 2018-February 2020) and post-COVID-19 period (March 2020-June 2022). We included all adult patients admitted in the Province of Modena with positive blood cultures for S. pneumoniae. Demographic and microbiological data, underlying diseases, clinical aspects, vaccination status were collected through hospital medical files. The cohort was divided into tertiles based on age (51 patients in 18-63 year-old group, 50 patients in 64-79 year-old, and 49 in the last group between 80 and 98 years). Underlying diseases were selected as those conditions affecting our study population at the time of hospital admission and identified as known risk factors for severe pneumococcal disease (cardiovascular disease, neurological disorders, splenectomy, chronic respiratory diseases, renal insufficiency, diabetes mellitus, solid-hematological neoplasms, chronic hepatopathy, immunodepression). Streptococcus pneumoniae was identified on blood samples through MALDI-TOF. Sites of infection were recorded and described. We included 'multiple sites of infection' as a dummy variable when more than one site was diagnosed. Antimicrobial susceptibility testing was performed through Vitek® 2, bioMérieux Italia, and pathogen MICs were interpreted according to EUCAST. The antimicrobials for which susceptibility testing was performed were: cefotaxime, ceftriaxone, imipenem, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, levofloxacin, moxifloxacin, rifampin, vancomycin and chloramphenicol. SARS-CoV-2 infection, during the post- COVID-19 era, was detected through antigenic testing of symptomatic patients, according to the protocols of the provincial hospitals of Modena. We compared the incidence, clinical course and mortality rates of SPB between the two designated time periods, investing also potential risk factors correlated to 30-day mortality. Ethics The study was approved by local ethics committee (Prot. AOU 0007576/24, 13 March 2024) and conducted in compliance with the Italian legislation and the principles of the Declaration of Helsinki. Statistical analyses Statistical analyses were performed with IBM SPSS V.28 software version and R Stats Package. We compared incidence rates of SPB between patients admitted during the study period using P per trend analysis (Mantel-Haenszel linear-by-linear association chi-squared test). Descriptive statistics were presented as frequency and percentages for categorical variables, and medians with interquartile range (IQR) for continuous variables. Categorical variables were compared using Chi-square test in parametric conditions. Student's t test and Mann Whitney U test were used in the comparison of continuous variables for normally distributed and non-normally distributed data, respectively. Univariate logistic regression analysis was performed to investigate unadjusted associated factors with 30-days and 60-days mortality. A p-value of ≤0.05 was considered statistically significant and different multivariable logistic regression models were conducted: goodness of fitness post-estimation tests were performed to evaluate best model for associated factors with mortality (only selected model was shown in Results section). Results Between January 2018 and June 2022, 150 episodes of SPB were observed in 150 patients (109 and 41 in the pre- and post-COVID-19, respectively). Ninety-one (60.7%) patients were male, and the median age was 71.5 years (IQR 58-83 years). The incidence of SPB was regular until February 2020 (Figure 1. A), with higher rates during the winter and spring months (Figure 1. B). Thereafter, the annual incidence decreased from 8.5 cases/100,000 population in 2018 to 3 and 2.5 cases/100,000 population in 2020 and 2021, respectively. Finally, a trend toward a new increase in incidence was observed from the first half of 2022 (Figure 2.A). SPB was associated with pneumonia in 128 patients (85.3%), meningitis in 25 (16.7%) and otitis-mastoiditis in 14 (9.3%). Among patients with pneumonia, multi-lobar involvement and pleural effusion were present in 34 (22.7%) and 48 (37.5%) patients, respectively. Three patients were affected by complex clinical syndromes, with multi-site involvement, comprehending both lung and CNS. At the onset of SPB, the patients were in an emergency department in 75 (50.0%) cases, medical wards in 53 (35.3%), intensive care unit in 13 (8.7%), and onco-hematological ward in 9 (5.8%). Urinary pneumococcal antigen test was performed in 68 patients (45.3%), proving positive in 46 (67.6%) patients. No significant differences were found between the site of infection (pneumonia, meningitis, otitis-mastoiditis, multiple-site of infection) and pneumococcal antigen positivity. The main comorbidities of the patients were cardiovascular diseases (n=64; 42.7%), arterial hypertension (n=59; 39.3%), chronic renal failure (n=32; 21.3%), oncological pathology (n=27; 16.7%), diabetes mellitus (n=26; 17.3%). In 148 cases (98.6%), pneumococcal bacteremia occurred within the first 24 hours of admission, representing the reason for hospitalization. Demographic and clinical characteristics of patients with SPB, according to pre- and post-COVID-19 onset period, are shown in Table 1. In comparison with the pre-pandemic era, during the post-pandemic period patients were older (71.1 vs 64.8 y, p=0.063), with a higher frequency of multi-lobular pneumonia (38.1% vs 8.7%; P=0.006) and diabetes mellitus (28.5% vs 13.1%; p=0.027). In addition, we observed a higher frequency of multi-lobar pneumonia in patients who had SPB and Sars CoV-2 co-infection (OR 5.075; 95% CI: 1.079-23.872; p=0.040). Anti-pneumococcal vaccination Considering or patients with age≥65 years, immunocompromised and splenectomized, there were 106 (70.6%) patients in our study who were candidates for pneumococcal vaccination. Despite this, only 14 (9.33%) received it (8 patients with at least PCV13, and 6 patients fully vaccinated with both PCV13 and PPSV23). Interesting, during the post-COVID period the percentage of vaccinated patients increased from 7.9 to 26.7% (p=0.022). Serotype distribution. The distribution of S. pneumoniae serotypes is reported in Figure 2, distinguishing pre- and post- COVID19. Of the 150 strains, serotyping was performed in only 112 (74.6%): in 36 (24.0%) cases the strain was not sent to the Hub Laboratory for serotyping, in 5 (3.3%) cases the strain was not viable, and in 3 (2.0%) the sample was contaminated. The 4 most commonly detected serotypes in our population were serotype 8 in 33.9%, serotype 3 in 8.9%, serotype 12F in 8.0%, and serotype 20 in 5.4%. Of the 14 vaccinated patients, none fully vaccinated developed SPB caused by a serotype that was included in the vaccine administered. Overall, no significant changes in the prevalence of the different serotypes were observed during the 2 study periods. We did not find any significant correlation between serotypes and severe clinical manifestations of pneumococcal disease, such as meningitis, septic shock, or multiple focus pneumonia (data not shown). Antimicrobial susceptibility Table 3. shows the MIC50 and MIC90 for the 11 antimicrobials tested and their resistance rates. It was not possible to test all antimicrobials on all isolates. Cefotaxime, ceftriaxone, imipenem, rifampin and vancomycin showed full activity towards the isolates (resistance rate 0.0%), and the MIC90 was ≤0.06, ≤0.06, 0.03 and 1 μg/ml, respectively. Only one (0.6%) isolate resulted resistant to levofloxacin, but 42 (26.9%) showed intermediate sensitivity (MIC=0.5 μg/ml) to this antibiotic. Resistance to erythromycin was found in 20/104 (16.1%) isolates, to trimethoprim-sulfamethoxazole in 7/129 (5.4%), to penicillin G in 12/155 (7.7%), to tetracycline in 18/128 (14.0%), to moxifloxacin in 1/129 (0.7%), and to chloramphenicol in 3/129 (2.3%). No differences in antimicrobial resistance were observed between the pre- and post-COVID-19 period. Mortality The 30 and 60-day mortality rate were 15.3% (23 patients) and 20% (30 patients), respectively. The first-one increased from 11.9 to 24.4% in the post COVID-19 period (p=0.0075); when we considered the 60-day mortality rate, the increase resulted statistically significant (from 15.6 to 31.7%, p=0.0039). Table 2 shows the univariate and multivariate analysis of risk factors related to 30-day mortality. At univariate analysis, an age ≥80 years (OR: 7.06; 95%CI: 1.89-26.29; p=0.004), SarsCoV-2 coinfection (OR:4.838; 95%CI: 1.00-23.23; p=0.049), multi-lobar pneumonia (OR: 5.21; 95%CI: 2.03-13.31; p=0. 001), renal failure (OR: 2.90; 95%CI: 1.12-7.52; p=0.028), and CNS diseases other than meningitis (OR: 4.19; 95%CI: 1.44-12.21; p=0.009) resulted associated with higher mortality rate. Multivariate analysis confirmed that an age ≥80 years (OR: 4.45; 95%CI: 1.12-17.61; p=0.033), multi-lobar pneumonia (OR: 4.34; 95%CI: 1.56-12.07; p=0. 005), and CNS diseases (OR: 3.63; 95%CI: 1.08-12.20; p=0.036) as independent factors associated to a higher mortality rate. We also evaluated the impact of antimicrobial resistance on the outcome of patients with SPB: it was observed that strains with resistance to erythromycin, trimethoprim-sulfamethoxazole, or tetracycline were not related to a higher 30-day mortality rate (Table 2), or a higher frequency of more severe clinical manifestations. Discussion In this retrospective study, we evaluated the epidemiological trend of SPB between January 2018 and June 2022. The progressive reduction in SPB incidence that we have observed since March 2020 can certainly be related to the stringent measures implemented in our country to contain the Sars Cov2 pandemic. In fact, the natural niche of S. pneumoniae is the human nasopharynx, and carriage is a prerequisite for human-to-human transmission and disease development (8). In our study, an increasing trend of SPB cases has been recorded since the first half of 2022 (Figure 2.A), specifically in the second quarter of 2022. The same trend was also observed by the National Surveillance System for Invasive Bacterial Diseases (9). Other authors demonstrated a reduction in pneumococcal respiratory infections and SPB cases after the implementation of the SARS-CoV-2 pandemic containment measures. Angela B. Brueggemann et al. observed a significant and sustained decline of invasive diseases due to S. pneumoniae , H. influenzae , and N. meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. The incidence of reported S. pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27– 0·37]) and 82% at 8 weeks (0·18 [0·14–0·23]) following the introduction of preventive strategies (6). Oster Y et al observed a decline in overall respiratory tests and positivity rate during the first months of the SARS-CoV-2 pandemic. Respiratory isolations of H. influenzae and S. pneumoniae were significantly affected and returned to their monthly average by November 2020, despite a parallel surge in COVID-19 activity, while Mycoplasma pneumoniae was almost erased from the respiratory pathogens’ scene (10). ML Nation et al. went further, attempting to quantify the impact of nonpharmaceutical interventions (NPIs) on the prevalence and density of pneumococcal carriage in 2,106 children over 24 months in Vietnam. The authors detected a decrease of pneumococcal carriage density up to 91.5% after the introduction of NPIs compared with pre-COVID-19, mainly due to capsular pneumococci. Only a minor effect on carriage prevalence was observed. Because respiratory viruses are known to increase pneumococcal carriage density, transmission, and disease, this study suggests that interventions targeting respiratory viruses may have the added benefit of reducing invasive pneumococcal disease, thus explaining the reductions observed after NPI implementation (11). Regarding the clinical manifestations of our study population, most SPB cases were associated with community acquired pneumonia, consistently with data from existing literature (12). Clinical pictures were comparable between the pre- and post-COVID- 19 period, excepting for multi-lobar pneumonia which occurred more frequently during post-COVID-19 era. This can only partly be explained by concomitant SARS-CoV-2 infection, because only 1 quarter of patients with a multi-lobar pattern were SARS-CoV-2 coinfected. Noteworthy, during post-COVID-19 era we observed a tendency towards elderly age; this aspect may have had an impact on clinical manifestations of pneumococcal pneumonia, explaining a higher percentage of multi-lobar lung involvement. The prevalent serotype in both the pre- and post-COVID-19 period was serotype 8. Since this serotype is included in the 20- and 23-valent polysaccharide vaccine, both of which are recommended for the adult population, this prevalence may indicate suboptimal adherence of the at-risk population to the pneumococcal vaccine campaign, in our area. Considering antimicrobial susceptibility testing, our study showed that the S. pneumoniae strains were fully susceptible to cefotaxime and ceftriaxone (100.0%), but less susceptible to erythromycin (85.9%) and tetracycline (86.0%). Despite this reduced susceptibility, the erythromycin data are encouraging: in fact, in comparison with the resistance rates in Emilia Romagna in 2019 (13), the resistance rate observed in our study is lower (45.4% vs. 14.1%, respectively), and probably indicates a more appropriate use of this class of antibiotics in our province. In addition, resistance to erythromycin, doxycycline and trimethoprim-sulfamethoxazole had no impact on 30-day mortality, in pour population. The reason for this may be related to the fact that in our province the empirical therapy for community-acquired pneumonia is the combination of a beta-lactam associated with a macrolide, but never a macrolide or doxycycline as monotherapy. In our study, no patients received monotherapy with macrolides, tetracyclines, or trimethoprim-sulfamethoxazole. In our study, we observed 30- and 60-day mortality rates of 15.3% and 20.0%, respectively. These results reflect the literature data: depending on the case series, the mortality rate of invasive pneumococcal disease varies from 10 to 20%., with higher rates among people aged ≥65 years (14). Moreover, in comparison with the pre-pandemic period, in the post-COVD-19 period, we observed an increase in mortality, both at 30 and 60 days. In particular, the 60-day mortality increased significantly from 24.4% to 31.7% (p=0.039). This finding indicates that patients with SPB had a worse prognosis in the pandemic period, and this could be related to Sars-CoV-2 co-infection. Other studies have also observed this increased mortality attributable to Sars CoV-2 co-infection (15,16). However, in our case series only 7 /41 (17%) patients were co-infected with SarsCov-2, so other hypotheses should be considered. Multivariate analysis confirmed that an age ≥80 years, multi-lobar pneumonia, and CNS diseases were independent factors associated with an increased 30-day mortality rate. Mannu et al , in their systematic review and metanalysis, showed how multi-lobar pneumonia resulted to be an independent risk factor for mortality in community acquired pneumonia (17). Although they did not undertake any specific sub-analysis of the microorganisms involved, the authors observed that S. pneumoniae was frequently present in the sputum of patients with multi-lobar pneumonia. Multi-lobar lung involvement was also found to be an independent risk factor for early death (within 48 hours of admission) in hospitalized patients with community-acquired pneumonia in a Spanish prospective study (18). Regarding advanced age, numerous studies have shown its correlation with poor prognosis in both pneumococcal pneumonia and invasive pneumococcal disease (2,12,19,20). This is one of the reasons why pneumococcal vaccination is recommended for individuals older than 65 years of age. Analyzing the data from our population, we can see that the target vaccination rate proposed for the at-risk population is still a long way off. In fact, only 13.2% of vaccination candidates in our study had been vaccinated against S. pneumoniae . In our country, the national vaccination plan 2017-2019 set the following goals: reaching a vaccine coverage of 95% in newborn infants and of 75% in citizens aged ≥65 years old (21). National surveillance data during the period 2019-2022 showed significantly higher percentages of anti-pneumococcal vaccine rate among newborn infants, ranging between 70 and 95% (22). Similar data are founded in the Pneumococcal Vaccination Atlas, which documents pneumococcal vaccination coverage and recommendations across Europe (23). It should be noted that only a minority of European countries recommend pneumococcal vaccine in all three risk groups listed above; moreover, not all national health systems provide it free of charge, especially for categories other than infants. These aspects might indicate low awareness among citizens, especially those of advanced age, about the risks associated with pneumococcal infection. In our study, the vaccination rate during the post-COVID 19 period increased to 26.7%, among vaccination candidate patients. This result could be a consequence of the massive commitment to the anti-SARS-CoV-2 vaccination campaign and in general to the prevention of other serious respiratory infectious diseases. Despite this increase, the adherence rate is still too low to ensure effective protection in the population. Our study has some limitations. The retrospective nature makes it difficult to draw definitive conclusions. Moreover, lacking data about all pneumococcal serotypes involved and precise timing and choice of antibiotic therapy limited our possibility of analyzing and interpreting the available data. Nonetheless, this is the first Italian study aimed at investigating the consequences of the COVID-19 pandemic on the epidemiology and outcomes of pneumococcal disease. Furthermore, S. pneumoniae remains one of the most frequent causes of community-acquired pneumonia to this day. Conclusions S. pneumoniae still represents a significant public health threat, affecting various age groups and vulnerable individuals. The SARS-CoV-2 pandemic has altered the circulation of respiratory pathogens: it is now clear that limiting the spread of respiratory viruses can help reduce the transmission of S. pneumoniae and its ability to cause severe infections. However, this is not feasible in everyday life, making vaccination the most effective prevention strategy. In our study, less than 10% of the high-risk population was vaccinated, while the older population (age ≥80 years) had a significantly higher 30-day mortality risk. We believe that Government Institutions should increase awareness campaigns for pneumococcal vaccination, as already recommended by the World Health Organization. Declarations Disclosure statement No potential conflict of interest was reported by the author(s). Funding No funds received Clinical trial number Not applicable Human Ethics and Consent to Participate declarations Not applicable. Given the retrospective nature of the study, it was not possible to obtain written informed consent from the subjects enrolled due to organizational reasons. References Diekema DJ, Hsueh PR, Mendes RE, Pfaller MA, Rolston KV, Sader HS, et al. 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Invasive Pneumococcal Disease and COVID-19 Coinfection: A Series of Cases Admitted to an Intensive Care Unit. Cureus. 2022 Nov;14(11):e31876. Mannu GS, Loke YK, Curtain JP, Pelpola KN, Myint PK. Prognosis of multi-lobar pneumonia in community-acquired pneumonia: A systematic review and meta-analysis. Eur J Intern Med. 2013 Dec 1;24(8):857–63. Garcia-Vidal C, Fernández-Sabé N, Carratalà J, Díaz V, Verdaguer R, Dorca J, et al. Early mortality in patients with community-acquired pneumonia: causes and risk factors. Eur Respir J. 2008 Sep;32(3):733–9. Chen H, Matsumoto H, Horita N, Hara Y, Kobayashi N, Kaneko T. Prognostic factors for mortality in invasive pneumococcal disease in adult: a system review and meta-analysis. Sci Rep. 2021 Jun 4;11(1):11865. Christensen JS, Jensen TG, Kolmos HJ, Pedersen C, Lassen A. Bacteremia with Streptococcus pneumoniae: sepsis and other risk factors for 30-day mortality--a hospital-based cohort study. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2012 Oct;31(10):2719–25. Piano Nazionale Prevenzione Vaccinale PNPV 2017-2019 [Internet]. Available from: https://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf EpiCentro. Copertura vaccinale in Italia [Internet]. [cited 2024 Nov 24]. Available from: https://www.epicentro.iss.it/vaccini/dati_Ita#pneumo Pneumococcal Vaccination Atlas - Homepage [Internet]. [cited 2024 Nov 24]. Available from: https://pneumoniaatlas.org/ Tables Table 1. Comparison of the main demographic and clinical characteristics of adult patients with S. pneumoniae infection according to pre- or post-COVID period of onset Variable All Episodes (n=150) pre-COVID period (n=109) post-COVID period (n=41) P Value Demographics Male sex, N (%) 91 (60.7) 65 (59.6) 26 (63.4) 0.711 Age, median (IQR), y 71.5 (58–83) 70 (54–82) 74 (63–84) 0.154 Age tertiles 18–63 64-79 80-98 51 (34) 50 (33.3) 49 (32.7) 40 (36.7) 33 (30.3) 36 (33.0) 11 (26.8) 17 (41.5) 13 (31.7) 0.383 Hospital wards stay at the time of bacteremia onset, N (%) Emergency department 75 (50) 55 (50.4) 20 (48.8) 0.349 Internal medicine ward 53 (35.3) 39 (35.8) 14 (34.1) Intensive care unit 13 (8.7) 7 (6.4) 6 (14.6) Onco-haematology unit 9 (6) 8 (7.3) 1 (2.4) LOS, median (IQR), days 15.7 (17.8) 14.9 (18.7) 17.0 (14.0) 0.115 Site of infection, N (%) Pneumonia 128 (85.3) 93 (85.3) 35 (85.4) 1.000 Multi-lobar pneumonia 34 (22.7) 18 (16.5) 16 (39.0) 0.008 Meningitis 25 (16.7) 18 (16.5) 7 (17.1) 1.000 Oto-mastoiditis 14 (9.3) 12 (11.0) 2 (4.9) 0.352 Multiple site of infection 17 (11.3) 14 (12.8) 3 (7.3) 0.404 Underlying conditions, N (%) Arterial hypertension 59 (39.3) 42 (38.5) 17 (41.4) 0.851 Cardiovascular disease 64 (42.7) 43 (39.4) 21 (51.2) 0.201 Hypercholesterolemia 16 (10.6) 10 (9.2) 6 (14.6) 0.377 Neurological disease 19 (12.7) 11 (10.1) 8 (19.5) 0.166 Gastrointestinal disease 21 (14.0) 15 (13.7) 6 (14.6) 1.000 Diabetes mellitus 26 (17.3) 14 (12.8) 12 (29.3) 0.028 Chronic lung disease 21 (14.0) 15 (13.7) 6 (14.6) 1.000 Chronic kidney failure 32 (21.3) 25 (22.9) 7 (17.1) 0.508 Chronic liver disease 11 (7.3) 9 (8.3) 2 (4.9) 0.728 Solid-hematological malignancy 27 (18.0) 19 (17.4) 8 (19.5) 0.813 Immunodepression 24 (16.0) 14 (12.8) 10 (24.4) 0.131 Splenectomy 2 (1.3) 1 (0.9) 1 (2.4) 0.473 Obesity 10 (6.7) 7 (6.4) 3 (7.3) 1.000 Smoke 25 (16.7) 18 (16.5) 7 (17.1) 1.000 Depression 16 (10.7) 15 (13.7) 1 (2.4) 0.071 Septic shock 11 (7.3) 9 (8.3) 2 (4.9) 0.728 Mortality, N (%) Death within 30 days 23 (15.3) 13 (11.9) 10 (24.4) 0.075 Death within 60 days 30 (20.0) 17 (15.6) 13 (31.7) 0.039 Abbreviations: BC, blood culture; SD, standard deviation. a. P values refer to pairwise comparisons based on Fisher exact test or Mann-Whitney U test, as appropriate. Table 2. Univariate and multivariate analysis of risk factors for death within 30 days from S. pneumoniae bacteremia. Definitive multivariable analysis was chosen according to goodness of fitness post-estimation . Risk factor, (N =150) Unadjusted cause-specific OR (95% CI) P Adjusted cause-specific OR (95% CI) P Sex male (91) 1.01 (0.41-2.51) 0.983 - - Age tertile 18–63 (51) 64-79 (50) 80-98 (49) 1 (ref.) 1.77 (0.40–7.87) 7.06 (1.89–26.29) - 0.449 0.004 1 (ref.) 1.40 (0.30–6.49) 4.45 (1.12–17.61) - 0.667 0.033 SARS-CoV-2 pneumonia (7) 4.838 (1.00-23.23) 0.049 2.00 (0.30-12.99) 0.467 Multiple site of infection (17) 0.71 (0.15–3.34) 0.666 - - Multi-lobar pneumonia (34) 5.21 (2.03–13.31) 0.001 4.34 (1.56–12.07) 0.005 Pneumonia (128) 1.96 (0.42–9.03) 0.387 - - Meningitis (25) 1.06 (0.33–3.44) 0.919 - - Otomastoiditis (14) 0.40 (0.05–3.20) 0.387 - - Immunodepression (24) 1.58 (0.52–4.76) 0.418 - - Hypertension (59) 1.22 (0.50-3.01) 0.659 - - Cardiovascular diseases (64) 1.28 (0.52–3.12) 0.587 - - Hypercholesterolemia (16) 0.76 (0.16–3.63) 0.740 - - Renal failure (32) 2.90 (1.12–7.52) 0.028 1.703 (0.556-5.212) 0.351 Solid/hematological cancer (27) 1.78 (0.63–5.05) 0.277 - - Diabetes (26) 1.40 (0.47–4.19) 0.546 - - Smoke (25) 0.19 (0.02–1.52) 0.119 - - COPD (21) 0.24 (0.03–1.91) 0.179 - - Gastro-intestinal disease (21) 0.91 (0.24–3.37) 0.886 - - CNS diseases (19) 4.19 (1.44–12.21) 0.009 3.63 (1.08–12.20) 0.036 Depression (16) 0.34 (0.04–2.70) 0.307 - - Resistance to erythromycin, SXT*, or tetracycline (21) 1.36 (0.41–4.49) 0.612 - - Covid period (41) 2.38 (0.95–5.97) 0.064 - - *SXT: trimethoprim-sulfamethoxazole Table. 3. In vitro susceptibility testing to 11 antimicrobials of S. pneumoniae isolates from blood cultures in patients hospitalized in the province of Modena, Italia (Jan-2018; Jun-2022). Antimicrobials (N) MIC50 (µg/ml) MIC90 (µg/ml) Resistance (%) Penicillin G (155) ≤0.06 1 7.7% Cefotaxime (155) ≤0.06 0.12 0.0% Ceftriaxone (101) ≤0.06 ≤0.06 0.0% Imipenem (118) ≤0.06 ≤0.06 0.0% Erythromycin (121) ≤0.12 >1 16.1% Tetracycline (127) ≤1 8 14.0% Trimethoprim-sulfamethoxazole* (128) ≤1 2 5.4% Levofloxacin (153) 1 1 0.6% Moxifloxacin (64) ≤0.125 ≤0.125 0.6% Vancomycin (62) ≤1 ≤1 0.0% Chloraphenicol (81) ≤2 4 2.3% *Trimethoprim:sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as the trimethoprim concentration. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6340086","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":466444265,"identity":"1889e956-c629-431c-89ae-d1dc7b8a7bb9","order_by":0,"name":"Andrea 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Ospedaliero-Universitaria Policlinico di Modena","correspondingAuthor":false,"prefix":"","firstName":"Mario","middleName":"","lastName":"Sarti","suffix":""},{"id":466444283,"identity":"12330bb8-e9e9-4424-b888-4f3de0c82533","order_by":11,"name":"Cristina Mussini","email":"","orcid":"","institution":"Infectious Diseases Unit, Azienda Ospedaliero-Universitaria Policlinico di Modena","correspondingAuthor":false,"prefix":"","firstName":"Cristina","middleName":"","lastName":"Mussini","suffix":""}],"badges":[],"createdAt":"2025-03-30 19:53:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6340086/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6340086/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10096-025-05267-6","type":"published","date":"2025-09-20T15:57:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84324962,"identity":"1e1dba6b-750e-465c-b461-9d6060d6c75b","added_by":"auto","created_at":"2025-06-10 14:58:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113701,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. Incidence of SPB cases in each semester - Province of Modena, Italy, (Jan 2018 - June 2022). B. Monthly distribution of SPB cases - Province of Modena, Italy (Jan 2018 - Jun 2022)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6340086/v1/682bd7932e66e930d04cc974.png"},{"id":84324963,"identity":"5049dc82-a44d-4412-92a5-0831043b3dc2","added_by":"auto","created_at":"2025-06-10 14:58:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64038,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of serotypes before (blue) and after (orange) COVID-19 pandemic.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6340086/v1/c733223a91048c7651c8a18b.png"},{"id":91889956,"identity":"1d6834b4-f340-499b-a5c1-48aba2bd2cb4","added_by":"auto","created_at":"2025-09-22 16:03:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1899576,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6340086/v1/f2e44fb2-fd4b-45d1-a81f-d09b2c1654fa.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e bacteremia: comparison of incidence, epidemiology, and clinical outcome in a pre- and post-COVID-19 period\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cem\u003eStreptococcus pneumoniae\u0026nbsp;\u003c/em\u003ebacteremia ranks among the top 10 most common bloodstream infection (BSI) and is associated with high morbidity and mortality worldwide (1,2). \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003eis typically a cause of respiratory infections such as community-acquired pneumonia but can also cause non- respiratory infections such as peritonitis, infective endocarditis, and meningitis (3). Pneumococci usually colonize the human respiratory tract, especially during winter and early spring, spreading by air, via Flügge particles (4). During the COVID-19 pandemic, the implementation of non- pharmaceutical interventions (NPIs), such as mask wearing, stay-at-home orders and physical distancing were adopted as strategies of prevention of SARS-CoV-2 spreading. Introduction of NPIs has also been associated with a decreased diffusion of other respiratory pathogens, including influenza virus, respiratory syncytial virus (RSV), and S. pneumoniae (5\u0026ndash;7). It has been proposed that a lower incidence of IPD may be due to reduced pneumococcal transmission (6,7). This study aims to compare the incidence, epidemiology, and clinical outcomes of \u003cem\u003eS. pneumoniae\u003c/em\u003e bacteremia (SPB) before and after the onset of the COVID-19 pandemic.\u003c/p\u003e"},{"header":"Materials and Methods ","content":"\u003cp\u003eA retrospective study was conducted with the aim of investigating the impact of the Sars-CoV-2 pandemic on the epidemiology, clinical manifestations, and outcome of patients hospitalized for Streptococcus pneumoniae bacteremia (SPB). We compared two time periods: pre-COVID-19 period (January 2018-February 2020) and post-COVID-19 period (March 2020-June 2022). We included all adult patients admitted in the Province of Modena with positive blood cultures for \u003cem\u003eS. pneumoniae.\u0026nbsp;\u003c/em\u003eDemographic and microbiological data, underlying diseases, clinical aspects, vaccination status were collected through hospital medical files. The cohort was divided into tertiles based on age (51 patients in 18-63 year-old group, 50 patients in 64-79 year-old, and 49 in the last group between 80 and 98 years). Underlying diseases were selected as those conditions affecting our study population at the time of hospital admission and identified as known risk factors for severe pneumococcal disease (cardiovascular disease, neurological disorders, splenectomy, chronic respiratory diseases, renal insufficiency, diabetes mellitus, solid-hematological neoplasms, chronic hepatopathy, immunodepression). \u003cem\u003eStreptococcus pneumoniae\u0026nbsp;\u003c/em\u003ewas identified on blood samples through MALDI-TOF. Sites of infection were recorded and described. We included \u0026apos;multiple sites of infection\u0026apos; as a dummy variable when more than one site was diagnosed. Antimicrobial susceptibility testing was performed through Vitek\u0026reg; 2, bioMérieux Italia, and pathogen MICs were interpreted according to EUCAST. The antimicrobials for which susceptibility testing was performed were: cefotaxime, ceftriaxone, imipenem, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, levofloxacin, moxifloxacin, rifampin, vancomycin and chloramphenicol. SARS-CoV-2 infection, during the post- COVID-19 era, was detected through antigenic testing of symptomatic patients, according to the protocols of the provincial hospitals of Modena. We compared the incidence, clinical course and mortality rates of SPB between the two designated time periods, investing also potential risk factors correlated to 30-day mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by local ethics committee (Prot. AOU 0007576/24, 13 March 2024) and conducted in compliance with the Italian legislation and the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analyses\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed with IBM SPSS V.28 software version and R Stats Package. We compared incidence rates of SPB between patients admitted during the study period using P per trend analysis (Mantel-Haenszel linear-by-linear association chi-squared test). Descriptive statistics were presented as frequency and percentages for categorical variables, and medians with interquartile range (IQR) for continuous variables. Categorical variables were compared using Chi-square test in parametric conditions. Student\u0026apos;s t test and Mann Whitney U test were used in the comparison of continuous variables for normally distributed and non-normally distributed data, respectively. Univariate logistic regression analysis was performed to investigate unadjusted associated factors with 30-days and 60-days mortality. A p-value of \u0026le;0.05 was considered statistically significant and different multivariable logistic regression models were conducted: goodness of fitness\u0026nbsp;\u003c/p\u003e\n\u003cp\u003epost-estimation tests were performed to evaluate best model for associated factors with mortality (only selected model was shown in Results section).\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween January 2018 and June 2022, 150 episodes of SPB were observed in 150 patients (109 and 41 in the pre- and post-COVID-19, respectively). Ninety-one (60.7%) patients were male, and the median age was 71.5 years (IQR 58-83 years). The incidence of SPB was regular until February 2020 (Figure 1. A), with higher rates during the winter and spring months (Figure 1. B). Thereafter, the annual incidence decreased from 8.5 cases/100,000 population in 2018 to 3 and 2.5 cases/100,000 population in 2020 and 2021, respectively. Finally, a trend toward a new increase in incidence was observed from the first half of 2022 (Figure 2.A).\u003c/p\u003e\n\u003cp\u003eSPB was associated with pneumonia in 128 patients (85.3%), meningitis in 25 (16.7%) and otitis-mastoiditis in 14 (9.3%). Among patients with pneumonia, multi-lobar involvement and pleural effusion were present in 34 (22.7%) and 48 (37.5%) patients, respectively. Three patients were affected by complex clinical syndromes, with multi-site involvement, comprehending both lung and CNS. At the onset of SPB, the patients were in an emergency department in 75 (50.0%) cases, medical wards in 53 (35.3%), intensive care unit in 13 (8.7%), and onco-hematological ward in 9 (5.8%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUrinary pneumococcal antigen test was performed in 68 patients (45.3%), proving positive in 46 (67.6%) patients. No significant differences were found between the site of infection (pneumonia, meningitis, otitis-mastoiditis, multiple-site of infection) and pneumococcal antigen positivity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe main comorbidities of the patients were cardiovascular diseases (n=64; 42.7%), arterial hypertension (n=59; 39.3%), chronic renal failure (n=32; 21.3%), oncological pathology (n=27; 16.7%), diabetes mellitus (n=26; 17.3%). In 148 cases (98.6%), pneumococcal bacteremia occurred within the first 24 hours of admission, representing the reason for hospitalization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDemographic and clinical characteristics of patients with SPB, according to pre- and post-COVID-19 onset period, are shown in Table 1. In comparison with the pre-pandemic era, during the post-pandemic period patients were older (71.1 vs 64.8 y, p=0.063), with a higher frequency of multi-lobular pneumonia (38.1% vs 8.7%; P=0.006) and diabetes mellitus (28.5% vs 13.1%; p=0.027). In addition, we observed a higher frequency of multi-lobar pneumonia in patients who had SPB and Sars CoV-2 co-infection (OR 5.075; 95% CI: 1.079-23.872; p=0.040).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnti-pneumococcal vaccination\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConsidering or patients with age\u0026ge;65 years, immunocompromised and splenectomized, there were 106 (70.6%) patients in our study who were candidates for pneumococcal vaccination. Despite this, only 14 (9.33%) received it (8 patients with at least PCV13, and 6 patients fully vaccinated with both PCV13 and PPSV23). Interesting, during the post-COVID period the percentage of vaccinated patients increased from 7.9 to 26.7% (p=0.022).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSerotype distribution.\u003cbr\u003e\u003c/em\u003eThe distribution of \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003eserotypes is reported in Figure 2, distinguishing pre- and post- COVID19. Of the 150 strains, serotyping was performed in only 112 (74.6%): in 36 (24.0%) cases\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ethe strain was not sent to the Hub Laboratory for serotyping, in 5 (3.3%) cases the strain was not viable, and in 3 (2.0%) the sample was contaminated. The 4 most commonly detected serotypes in our population were serotype 8 in 33.9%, serotype 3 in 8.9%, serotype 12F in 8.0%, and serotype 20 in 5.4%. Of the 14 vaccinated patients, none fully vaccinated developed SPB caused by a serotype that was included in the vaccine administered. Overall, no significant changes in the prevalence of the different serotypes were observed during the 2 study periods. We did not find any significant correlation between serotypes and severe clinical manifestations of pneumococcal disease, such as meningitis, septic shock, or multiple focus pneumonia (data not shown).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAntimicrobial susceptibility\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTable 3. shows the MIC50 and MIC90 for the 11 antimicrobials tested and their resistance rates. It was not possible to test all antimicrobials on all isolates. Cefotaxime, ceftriaxone, imipenem, rifampin and vancomycin showed full activity towards the isolates (resistance rate 0.0%), and the MIC90 was\u0026nbsp;\u0026le;0.06,\u0026nbsp;\u0026le;0.06, 0.03 and 1 \u0026mu;g/ml, respectively. Only one (0.6%) isolate resulted resistant to levofloxacin, but 42 (26.9%) showed intermediate sensitivity (MIC=0.5 \u0026mu;g/ml) to this antibiotic. Resistance to erythromycin was found in 20/104 (16.1%) isolates, to trimethoprim-sulfamethoxazole in 7/129 (5.4%), to penicillin G in 12/155 (7.7%), to tetracycline in 18/128 (14.0%), to moxifloxacin in 1/129 (0.7%), and to chloramphenicol in 3/129 (2.3%). No differences in antimicrobial resistance were observed between the pre- and post-COVID-19 period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMortality\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe 30 and 60-day mortality rate were 15.3% (23 patients) and 20% (30 patients), respectively. The first-one increased from 11.9 to 24.4% in the post COVID-19 period (p=0.0075); when we considered the 60-day mortality rate, the increase resulted statistically significant (from 15.6 to 31.7%, p=0.0039). Table 2 shows the univariate and multivariate analysis of risk factors related to 30-day mortality. At univariate analysis, an age \u0026ge;80 years (OR: 7.06; 95%CI: 1.89-26.29; p=0.004), SarsCoV-2 coinfection (OR:4.838; 95%CI: 1.00-23.23; p=0.049), multi-lobar pneumonia (OR: 5.21; 95%CI: 2.03-13.31; p=0. 001), renal failure (OR: 2.90; 95%CI: 1.12-7.52; p=0.028), and CNS diseases other than meningitis (OR: 4.19; 95%CI: 1.44-12.21; p=0.009) resulted associated with higher mortality rate. Multivariate analysis confirmed that an age \u0026ge;80 years (OR: 4.45; 95%CI: 1.12-17.61; p=0.033), multi-lobar pneumonia (OR: 4.34; 95%CI: 1.56-12.07; p=0. 005), and CNS diseases (OR: 3.63; 95%CI: 1.08-12.20; p=0.036) as independent factors associated to a higher mortality rate. We also evaluated the impact of antimicrobial resistance on the outcome of patients with SPB: it was observed that strains with resistance to erythromycin, trimethoprim-sulfamethoxazole, or tetracycline were not related to a higher 30-day mortality rate (Table 2), or a higher frequency of more severe clinical manifestations.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective study, we evaluated the epidemiological trend of SPB between January 2018 and June 2022. The progressive reduction in SPB incidence that we have observed since March 2020 can certainly be related to the stringent measures implemented in our country to contain the Sars Cov2 pandemic. In fact, the natural niche of \u003cem\u003eS. pneumoniae\u003c/em\u003e is the human nasopharynx, and carriage is a prerequisite for human-to-human transmission and disease development (8). In our study, an increasing trend of SPB cases has been recorded since the first half of 2022 (Figure 2.A), specifically in the second quarter of 2022. The same trend was also observed by the National Surveillance System for Invasive Bacterial Diseases (9). Other authors demonstrated a reduction in pneumococcal respiratory infections and SPB cases after the implementation of the SARS-CoV-2 pandemic containment measures. Angela B. Brueggemann \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003eobserved a significant and sustained decline of invasive diseases due to \u003cem\u003eS. pneumoniae\u003c/em\u003e, \u003cem\u003eH. influenzae\u003c/em\u003e, and \u003cem\u003eN. meningitidis\u0026nbsp;\u003c/em\u003ein early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. The incidence of reported \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003einfections decreased by 68% at 4 weeks (incidence rate ratio 0\u0026middot;32 [95% CI 0\u0026middot;27\u0026ndash; 0\u0026middot;37]) and 82% at 8 weeks (0\u0026middot;18 [0\u0026middot;14\u0026ndash;0\u0026middot;23]) following the introduction of preventive strategies (6). Oster Y \u003cem\u003eet al\u0026nbsp;\u003c/em\u003eobserved a decline in overall respiratory tests and positivity rate during the first months of the SARS-CoV-2 pandemic. Respiratory isolations of \u003cem\u003eH. influenzae\u0026nbsp;\u003c/em\u003eand \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003ewere significantly affected and returned to their monthly average by November 2020, despite a parallel surge in COVID-19 activity, while \u003cem\u003eMycoplasma pneumoniae\u0026nbsp;\u003c/em\u003ewas almost erased from the respiratory pathogens\u0026rsquo; scene (10). ML Nation \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003ewent further, attempting to quantify the impact of nonpharmaceutical interventions (NPIs) on the prevalence and density of pneumococcal carriage in 2,106 children over 24 months in Vietnam. The authors detected a decrease of pneumococcal carriage density up to 91.5% after the introduction of NPIs compared with pre-COVID-19, mainly due to capsular pneumococci. Only a minor effect on carriage prevalence was observed. Because respiratory viruses are known to increase pneumococcal carriage density, transmission, and disease, this study suggests that interventions targeting respiratory viruses may have the added benefit of reducing invasive pneumococcal disease, thus explaining the reductions observed after NPI implementation (11).\u003c/p\u003e\n\u003cp\u003eRegarding the clinical manifestations of our study population, most SPB cases were associated with community acquired pneumonia, consistently with data from existing literature (12). Clinical pictures were comparable between the pre- and post-COVID- 19 period, excepting for multi-lobar pneumonia which occurred more frequently during post-COVID-19 era. This can only partly be explained by concomitant SARS-CoV-2 infection, because only 1 quarter of patients with a multi-lobar pattern were SARS-CoV-2 coinfected. Noteworthy, during post-COVID-19 era we observed a tendency towards elderly age; this aspect may have had an impact on clinical manifestations of pneumococcal pneumonia, explaining a higher percentage of multi-lobar lung involvement.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prevalent serotype in both the pre- and post-COVID-19 period was serotype 8. Since this serotype is included in the 20- and 23-valent polysaccharide vaccine, both of which are recommended for the adult population, this prevalence may indicate suboptimal adherence of the at-risk population to the pneumococcal vaccine campaign, in our area.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsidering antimicrobial susceptibility testing, our study showed that the \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003estrains were fully susceptible to cefotaxime and ceftriaxone (100.0%), but less susceptible to erythromycin (85.9%) and tetracycline (86.0%). Despite this reduced susceptibility, the erythromycin data are encouraging: in fact, in comparison with the resistance rates in Emilia Romagna in 2019 (13), the resistance rate observed in our study is lower (45.4% vs. 14.1%, respectively), and probably indicates a more appropriate use of this class of antibiotics in our province. In addition, resistance to erythromycin, doxycycline and trimethoprim-sulfamethoxazole had no impact on 30-day mortality, in pour population. The reason for this may be related to the fact that in our province the empirical therapy for community-acquired pneumonia is the combination of a beta-lactam associated with a macrolide, but never a macrolide or doxycycline as monotherapy. In our study, no patients received monotherapy with macrolides, tetracyclines, or trimethoprim-sulfamethoxazole.\u003c/p\u003e\n\u003cp\u003eIn our study, we observed 30- and 60-day mortality rates of 15.3% and 20.0%, respectively. These results reflect the literature data: depending on the case series, the mortality rate of invasive pneumococcal disease varies from 10 to 20%., with higher rates among people aged \u0026ge;65 years (14). Moreover, in comparison with the pre-pandemic period, in the post-COVD-19 period, we observed an increase in mortality, both at 30 and 60 days. In particular, the 60-day mortality increased significantly from 24.4% to 31.7% (p=0.039). This finding indicates that patients with SPB had a worse prognosis in the pandemic period, and this could be related to Sars-CoV-2 co-infection. Other studies have also observed this increased mortality attributable to Sars CoV-2 co-infection (15,16).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, in our case series only 7 /41 (17%) patients were co-infected with SarsCov-2, so other hypotheses should be considered. Multivariate analysis confirmed that an age \u0026ge;80 years, multi-lobar pneumonia, and CNS diseases were independent factors associated with an increased 30-day mortality rate. Mannu \u003cem\u003eet al\u003c/em\u003e, in their systematic review and metanalysis, showed how multi-lobar pneumonia resulted to be an independent risk factor for mortality in community acquired pneumonia (17). Although they did not undertake any specific sub-analysis of the microorganisms involved, the authors observed that \u003cem\u003eS. pneumoniae\u003c/em\u003e was frequently present in the sputum of patients with multi-lobar pneumonia. Multi-lobar lung involvement was also found to be an independent risk factor for early death (within 48 hours of admission) in hospitalized patients with community-acquired pneumonia in a Spanish prospective study (18). Regarding advanced age, numerous studies have shown its correlation with poor prognosis in both pneumococcal pneumonia and invasive pneumococcal disease (2,12,19,20). This is one of the reasons why pneumococcal vaccination is recommended for individuals older than 65 years of age.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalyzing the data from our population, we can see that the target vaccination rate proposed for the at-risk population is still a long way off. In fact, only 13.2% of vaccination candidates in our study had been vaccinated against \u003cem\u003eS. pneumoniae\u003c/em\u003e. \u0026nbsp;In our country, the national vaccination plan 2017-2019 set the following goals: reaching a vaccine coverage of 95% in newborn infants and of 75% in citizens aged \u0026ge;65 years old (21). National surveillance data during the period 2019-2022 showed significantly higher percentages of anti-pneumococcal vaccine rate among newborn infants, ranging between 70 and 95% (22). Similar data are founded in the Pneumococcal Vaccination Atlas, which documents pneumococcal vaccination coverage and recommendations across Europe (23). It should be noted that only a minority of European countries recommend pneumococcal vaccine in all three risk groups listed above; moreover, not all national health systems provide it free of charge, especially for categories other than infants. These aspects might indicate low awareness among citizens, especially those of advanced age, about the risks associated with pneumococcal infection. In our study, the vaccination rate during the post-COVID 19 period increased to 26.7%, among vaccination candidate patients. This result could be a consequence of the massive commitment to the anti-SARS-CoV-2 vaccination campaign and in general to the prevention of other serious respiratory infectious diseases. Despite this increase, the adherence rate is still too low to ensure effective protection in the population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study has some limitations. The retrospective nature makes it difficult to draw definitive conclusions. Moreover, lacking data about all pneumococcal serotypes involved and precise timing and choice of antibiotic therapy limited our possibility of analyzing and interpreting the available data. Nonetheless, this is the first Italian study aimed at investigating the consequences of the COVID-19 pandemic on the epidemiology and outcomes of pneumococcal disease. Furthermore, \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003eremains one of the most frequent causes of community-acquired pneumonia to this day.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e\u003cem\u003eS. pneumoniae\u003c/em\u003e still represents a significant public health threat, affecting various age groups and vulnerable individuals. The SARS-CoV-2 pandemic has altered the circulation of respiratory pathogens: it is now clear that limiting the spread of respiratory viruses can help reduce the transmission of \u003cem\u003eS. pneumoniae\u003c/em\u003e and its ability to cause severe infections. However, this is not feasible in everyday life, making vaccination the most effective prevention strategy. In our study, less than 10% of the high-risk population was vaccinated, while the older population (age \u0026ge;80 years) had a significantly higher 30-day mortality risk. We believe that Government Institutions should increase awareness campaigns for pneumococcal vaccination, as already recommended by the World Health Organization.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflict of interest was reported by the author(s).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funds received\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Given the retrospective nature of the study, it was not possible to obtain written informed consent from the subjects enrolled due to organizational reasons.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDiekema DJ, Hsueh PR, Mendes RE, Pfaller MA, Rolston KV, Sader HS, et al. The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2019 Jul;63(7):e00355-19. \u003c/li\u003e\n\u003cli\u003eDemirdal T, Sen P, Emir B. Predictors of mortality in invasive pneumococcal disease: a meta- analysis. Expert Rev Anti Infect Ther. 2021 Jul;19(7):927\u0026ndash;44. \u003c/li\u003e\n\u003cli\u003eMetlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eWeiser JN, Ferreira DM, Paton JC. Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol. 2018 Jun;16(6):355\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eBaker RE, Park SW, Yang W, Vecchi GA, Metcalf CJE, Grenfell BT. The impact of COVID-19 nonpharmaceutical interventions on the future dynamics of endemic infections. Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30547\u0026ndash;53. \u003c/li\u003e\n\u003cli\u003eBrueggemann AB, Jansen van Rensburg MJ, Shaw D, McCarthy ND, Jolley KA, Maiden MCJ, et al. Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data. Lancet Digit Health. 2021 Jun;3(6):e360\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eMutnal MB, Arroliga AC, Walker K, Mohammad A, Brigmon MM, Beaver RM, et al. Early trends for SARS-CoV-2 infection in central and north Texas and impact on other circulating respiratory viruses. J Med Virol. 2020 Oct;92(10):2130\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eBogaert D, De Groot R, Hermans PWM. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004 Mar;4(3):144\u0026ndash;54. \u003c/li\u003e\n\u003cli\u003eFazio C, Camilli R, Giufré M, Urciuoli R, Boros S, Neri A, Del Grosso M, Vacca P, Giancristofaro S, Siddu A, Orioli R, Maraglino F, Pezzotti P, D\u0026rsquo;Ancona F, Palamara AT, Stefanelli P. Sorveglianza nazionale delle malattie batteriche invasive. Dati 2021-2023. Roma: Istituto Superiore di Sanità; 2024. (Rapporti ISS Sorveglianza RIS-2/2024) [Internet]. Available from: https://www.epicentro.iss.it/meningite/pdf/RIS%202-2024.pdf \u003c/li\u003e\n\u003cli\u003eOster Y, Abu Ahmad W, Michael-Gayego A, Rivkin M, Levinzon L, Wolf D, et al. Viral and Bacterial Respiratory Pathogens during the COVID-19 Pandemic in Israel. Microorganisms. 2023 Jan;11(1):166. \u003c/li\u003e\n\u003cli\u003eNation ML, Manna S, Tran HP, Nguyen CD, Vy LTT, Uyen DY, et al. Impact of COVID-19 Nonpharmaceutical Interventions on Pneumococcal Carriage Prevalence and Density in Vietnam. Microbiol Spectr. 11(1):e03615-22. \u003c/li\u003e\n\u003cli\u003eDrijkoningen JJC, Rohde GGU. Pneumococcal infection in adults: burden of disease. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2014 May;20 Suppl 5:45\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003ehttps://assr.regione.emilia-romagna.it/pubblicazioni/rapporti-documenti/antibioticoresistenza- rer-2019/@@download/publicationFile/antibioticoresistenza_2019.pdf \u003c/li\u003e\n\u003cli\u003eMonali R, De Vita E, Mariottini F, Privitera G, Lopalco PL, Tavoschi L. Impact of vaccination on invasive pneumococcal disease in Italy 2007\u0026ndash;2017: surveillance challenges and epidemiological changes. Epidemiol Infect. 148:e187. \u003c/li\u003e\n\u003cli\u003eAmin-Chowdhury Z, Aiano F, Mensah A, Sheppard CL, Litt D, Fry NK, et al. Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Invasive Pneumococcal Disease and Risk of Pneumococcal Coinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2): Prospective National Cohort Study, England. Clin Infect Dis Off Publ Infect Dis Soc Am. 2021 Mar 1;72(5):e65\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eAlmeida M, Lavado P, Cunha L, Cordeiro I, Baptista A. Invasive Pneumococcal Disease and COVID-19 Coinfection: A Series of Cases Admitted to an Intensive Care Unit. Cureus. 2022 Nov;14(11):e31876. \u003c/li\u003e\n\u003cli\u003eMannu GS, Loke YK, Curtain JP, Pelpola KN, Myint PK. Prognosis of multi-lobar pneumonia in community-acquired pneumonia: A systematic review and meta-analysis. Eur J Intern Med. 2013 Dec 1;24(8):857\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eGarcia-Vidal C, Fernández-Sabé N, Carratalà J, Díaz V, Verdaguer R, Dorca J, et al. Early mortality in patients with community-acquired pneumonia: causes and risk factors. Eur Respir J. 2008 Sep;32(3):733\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eChen H, Matsumoto H, Horita N, Hara Y, Kobayashi N, Kaneko T. Prognostic factors for mortality in invasive pneumococcal disease in adult: a system review and meta-analysis. Sci Rep. 2021 Jun 4;11(1):11865. \u003c/li\u003e\n\u003cli\u003eChristensen JS, Jensen TG, Kolmos HJ, Pedersen C, Lassen A. Bacteremia with Streptococcus pneumoniae: sepsis and other risk factors for 30-day mortality--a hospital-based cohort study. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2012 Oct;31(10):2719\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003ePiano Nazionale Prevenzione Vaccinale PNPV 2017-2019 [Internet]. Available from: https://www.salute.gov.it/imgs/C_17_pubblicazioni_2571_allegato.pdf \u003c/li\u003e\n\u003cli\u003eEpiCentro. Copertura vaccinale in Italia [Internet]. [cited 2024 Nov 24]. Available from: https://www.epicentro.iss.it/vaccini/dati_Ita#pneumo \u003c/li\u003e\n\u003cli\u003ePneumococcal Vaccination Atlas - Homepage [Internet]. [cited 2024 Nov 24]. Available from: https://pneumoniaatlas.org/ \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Comparison of the main demographic and clinical characteristics of adult patients with \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003einfection according to pre- or post-COVID period of onset\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"483\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Episodes (n=150)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epre-COVID period (n=109)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epost-COVID period (n=41)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eValue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 483px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale sex, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e91 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e65 (59.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e26 (63.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.711\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, median (IQR), y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e71.5 (58\u0026ndash;83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e70 (54\u0026ndash;82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e74 (63\u0026ndash;84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge tertiles\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e18\u0026ndash;63\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003cstrong\u003e64-79\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e80-98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51 (34)\u003c/p\u003e\n \u003cp\u003e50 (33.3)\u003c/p\u003e\n \u003cp\u003e49 (32.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 (36.7)\u003c/p\u003e\n \u003cp\u003e33 (30.3)\u003c/p\u003e\n \u003cp\u003e36 (33.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (26.8)\u003c/p\u003e\n \u003cp\u003e17 (41.5)\u003c/p\u003e\n \u003cp\u003e13 (31.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.383\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 483px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHospital wards stay at the time of bacteremia onset, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEmergency department\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e75 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e55 (50.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e20 (48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.349\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInternal medicine ward\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e53 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e39 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntensive care unit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e13 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e7 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOnco-haematology unit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e9 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e8 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLOS, median (IQR), days\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e15.7 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e14.9 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e17.0 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 483px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSite of infection, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePneumonia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e128 (85.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e93 (85.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e35 (85.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMulti-lobar pneumonia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e34 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16 (39.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeningitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e25 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOto-mastoiditis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e14 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e12 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.352\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultiple site of infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e17 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e14 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.404\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 483px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnderlying conditions, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArterial hypertension\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e59 (39.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e42 (38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e17 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.851\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCardiovascular disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e64 (42.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e43 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e21 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.201\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypercholesterolemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e16 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e10 (9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.377\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurological disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e19 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e11 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8 (19.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.166\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastrointestinal disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e21 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e15 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes mellitus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e26 (17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e14 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e12 (29.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic lung disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e21 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e15 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic kidney failure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e32 (21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e25 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.508\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic liver disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e11 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e9 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.728\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSolid-hematological malignancy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e27 (18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e19 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8 (19.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.813\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunodepression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e24 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e14 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e10 (24.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSplenectomy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.473\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObesity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e10 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e7 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoke\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e25 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDepression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e16 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e15 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeptic shock\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e11 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e9 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.728\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 483px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMortality, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath within 30 days\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e23 (15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e13 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e10 (24.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath within 60 days\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e30 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e17 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e13 (31.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.039\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: BC, blood culture; SD, standard deviation. a. P values refer to pairwise comparisons based on Fisher exact test or Mann-Whitney U test, as appropriate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2. Univariate and multivariate analysis of risk factors for death within 30 days from \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003ebacteremia. Definitive multivariable analysis was chosen according to goodness of fitness post-estimation\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eRisk factor, (N =150)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnadjusted cause-specific OR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted cause-specific OR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex male (91)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.01 (0.41-2.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.983\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge tertile\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;18\u0026ndash;63 (51)\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003cstrong\u003e64-79 (50)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e80-98 (49)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (ref.)\u003c/p\u003e\n \u003cp\u003e1.77 (0.40\u0026ndash;7.87)\u003c/p\u003e\n \u003cp\u003e7.06 (1.89\u0026ndash;26.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.449\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (ref.)\u003c/p\u003e\n \u003cp\u003e1.40 (0.30\u0026ndash;6.49)\u003c/p\u003e\n \u003cp\u003e4.45 (1.12\u0026ndash;17.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e0.667\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;SARS-CoV-2 pneumonia (7)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e4.838 (1.00-23.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.049\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e2.00 (0.30-12.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.467\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultiple site of infection (17)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.71 (0.15\u0026ndash;3.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.666\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMulti-lobar pneumonia (34)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e5.21 (2.03\u0026ndash;13.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e4.34 (1.56\u0026ndash;12.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePneumonia (128)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.96 (0.42\u0026ndash;9.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeningitis (25)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.06 (0.33\u0026ndash;3.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOtomastoiditis (14)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.40 (0.05\u0026ndash;3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunodepression (24)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.58 (0.52\u0026ndash;4.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.418\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension (59)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.22 (0.50-3.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.659\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCardiovascular diseases (64)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.28 (0.52\u0026ndash;3.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypercholesterolemia (16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.76 (0.16\u0026ndash;3.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRenal failure (32)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e2.90 (1.12\u0026ndash;7.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.703 (0.556-5.212)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.351\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSolid/hematological cancer (27) \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.78 (0.63\u0026ndash;5.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes (26)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.40 (0.47\u0026ndash;4.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoke (25)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.19 (0.02\u0026ndash;1.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCOPD (21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.24 (0.03\u0026ndash;1.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastro-intestinal disease (21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.91 (0.24\u0026ndash;3.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.886\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCNS diseases (19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e4.19 (1.44\u0026ndash;12.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e3.63 (1.08\u0026ndash;12.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.036\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDepression (16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.34 (0.04\u0026ndash;2.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResistance to erythromycin, SXT*, or tetracycline (21)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.36 (0.41\u0026ndash;4.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCovid period (41)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e2.38 (0.95\u0026ndash;5.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*SXT: trimethoprim-sulfamethoxazole\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable. 3. In vitro susceptibility testing to 11 antimicrobials of \u003cem\u003eS. pneumoniae\u0026nbsp;\u003c/em\u003eisolates from blood cultures in patients hospitalized in the province of Modena, Italia (Jan-2018; Jun-2022).\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntimicrobials (N)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMIC50 (\u0026micro;g/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMIC90\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u0026micro;g/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResistance (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePenicillin G (155)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCefotaxime (155)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCeftriaxone (101)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImipenem (118)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eErythromycin (121)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e16.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTetracycline (127)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e14.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrimethoprim-sulfamethoxazole* (128)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e5.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLevofloxacin (153)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMoxifloxacin (64)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVancomycin (62)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChloraphenicol (81)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026le;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Trimethoprim:sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as the trimethoprim concentration.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcm","sideBox":"Learn more about [European Journal of Clinical Microbiology \u0026 Infectious Diseases](https://www.springer.com/journal/10096)","snPcode":"10096","submissionUrl":"https://submission.nature.com/new-submission/10096/3","title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6340086/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6340086/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003e\u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e is a leading cause of severe bacterial infections, including pneumonia, meningitis, and bacteremia. We aimed to evaluate the differences in clinical, epidemiological and outcome manifestations of patients admitted with \u003cem\u003eS. pneumoniae\u003c/em\u003e bacteremia (SPB) in the pre- and post-COVID-19 period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe study analyzed all patients admitted in Province of Modena, Italy, during 2 time-periods: pre-COVID-19 (Jan 2018- Feb 2020) and post-COVID-19 (Mar 2018- Jun 2022) period. \u0026nbsp;The data were compared using univariate and multivariate analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults. \u003c/strong\u003eA total of 150 patients with SPB were included, 109 and 41 patients in the pre- and post-COVID-19, respectively. We observed a decrease in SPB incidence from March 2020, after the implementation of the restrictive measures for the COVID-19 pandemic, and a new increase in 2022. SPB was associated with pneumonia in 128 patients (85.3%), meningitis in 25 (16.7%) and otitis-mastoiditis in 14 (9.3%). The proportion of patients presenting with multi-lobar pneumonia significantly increased during the post-COVID-19 period (39.0% vs. 16.5%, p = 0.008). Thirty-day mortality rate resulted higher in the post-COVID-19 period (24.4% vs. 11.9%, p = 0.075), and multivariate analysis identified an age≥80 years (OR 4.45, 95% CI 1.12–17.61, p=0.033), multi-lobar pneumonia (OR 4.34, 95% CI 1.56–12.07, p=0.005), and central nervous system disease (OR 3.63, 95% CI 1.08–12.20, p=0.036) as independent risk factors for 30-day mortality. The rate of pneumococcal vaccination in the at-risk population was low (9.3%), but in the pandemic period the rate increased by 26.7%, driven by the anti-SARS-CoV-2 vaccination campaign.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions. \u003c/strong\u003eThe COVID-19 pandemic has impacted the epidemiology and clinical severity of SPB. In our study, less than 10% of the high-risk population was vaccinated, while the older population (age ≥80 years) had a significantly higher 30-day mortality risk. It would be necessary for Institutions to increase awareness campaigns for pneumococcal vaccination.\u003c/p\u003e","manuscriptTitle":"Streptococcus pneumoniae bacteremia: comparison of incidence, epidemiology, and clinical outcome in a pre- and post-COVID-19 period","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 14:58:47","doi":"10.21203/rs.3.rs-6340086/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-25T13:52:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T13:41:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37562166067409567260571929658790328673","date":"2025-08-11T20:32:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-04T12:24:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T00:49:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-01T00:48:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","date":"2025-03-30T19:39:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcm","sideBox":"Learn more about [European Journal of Clinical Microbiology \u0026 Infectious Diseases](https://www.springer.com/journal/10096)","snPcode":"10096","submissionUrl":"https://submission.nature.com/new-submission/10096/3","title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"136cdd65-9055-4020-b118-7949b72280ba","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T16:02:18+00:00","versionOfRecord":{"articleIdentity":"rs-6340086","link":"https://doi.org/10.1007/s10096-025-05267-6","journal":{"identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isVorOnly":false,"title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases"},"publishedOn":"2025-09-20 15:57:03","publishedOnDateReadable":"September 20th, 2025"},"versionCreatedAt":"2025-06-10 14:58:47","video":"","vorDoi":"10.1007/s10096-025-05267-6","vorDoiUrl":"https://doi.org/10.1007/s10096-025-05267-6","workflowStages":[]},"version":"v1","identity":"rs-6340086","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6340086","identity":"rs-6340086","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}