Catching the Culprit: Benzylpenicillin Neurotoxicity Confirmed by Therapeutic Drug Monitoring in a Critically Ill Patient With Continuous Venovenous Hemofiltration.

ABSTRACT: We present the case of a 65-year-old patient who was treated with high-dose benzylpenicillin for severe invasive pneumococcal pneumonia, complicated by acute renal failure managed with continuous venovenous hemofiltration. After cessation of continuous venovenous hemofiltration, the patient experienced multiple tonic-clonic seizures. Therapeutic drug monitoring revealed high total serum concentrations of benzylpenicillin, identifying it as the likely cause of the neurotoxicity. This case study presents the first documented total serum benzylpenicillin concentration associated with neurotoxicity.

Unveiling the role of preceding seasonal influenza in the development of bacteremic pneumococcal pneumonia in older adults before the COVID-19 pandemic in Japan.

OBJECTIVE: We aimed to investigate the impact of preceding seasonal influenza on the clinical characteristics of adult patients with invasive pneumococcal disease (IPD) in Japan. METHODS: Data for 1722 adult patients with IPD were analyzed before (2017-2019) and during the COVID-19 pandemic (2020-2022). RESULTS: The seasonal influenza epidemic disappeared soon after the emergence of the pandemic. Compared with that before the pandemic (66.7%), we observed a lower bacteremic pneumonia proportion in patients with IPD during the pandemic (55.6%). The clinical presentations of IPD cases significantly differed between those with and without preceding influenza. The proportion of bacteremic pneumonia was higher in IPD patients with preceding influenza than in those without in both younger (44.9% vs 84.2%) and older adults (65.5% vs 87.0%) before the pandemic. The case fatality rate was significantly higher in IPD patients with preceding influenza (28.3%) than in those without (15.3%) in older adults before the pandemic (P = 0.020). Male and aging are high risk factors for death in older patients with IPD who had preceding influenza. CONCLUSION: Our study reveals that preceding seasonal influenza plays a role in the development of bacteremic pneumococcal pneumonia, increasing the risk of death in older adults.

Triad of Terror: Rapidly Progressive Austrian Syndrome in a 62-Year-Old Female.

We report a case of a 62-year-old female presenting with shortness of breath, who was subsequently diagnosed with Austrian syndrome. The patient had a complicated clinical course, including invasive central nervous system pneumococcal disease, pneumococcal bacteremia, and mitral valve vegetation with possible leaflet perforation. Despite aggressive treatment, her condition continued to worsen. We will discuss the clinical features of this disease, approaches to diagnosis and treatment, and outcomes in light of this rare condition.

The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy.

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

Memory Th17 cell-mediated protection against lethal secondary pneumococcal pneumonia following influenza infection.

Streptococcus pneumoniae (Sp) frequently causes secondary pneumonia after influenza A virus (IAV) infection, leading to high morbidity and mortality worldwide. Concomitant pneumococcal and influenza vaccination improves protection against coinfection but does not always yield complete protection. Impaired innate and adaptive immune responses have been associated with attenuated bacterial clearance in influenza virus-infected hosts. In this study, we showed that preceding low-dose IAV infection caused persistent Sp infection and suppression of bacteria-specific T-helper type 17 (Th17) responses in mice. Prior Sp infection protected against subsequent IAV/Sp coinfection by improving bacterial clearance and rescuing bacteria-specific Th17 responses in the lungs. Furthermore, blockade of IL-17A by anti-IL-17A antibodies abrogated the protective effect of Sp preinfection. Importantly, memory Th17 responses induced by Sp preinfection overcame viral-driven Th17 inhibition and provided cross-protection against different Sp serotypes following coinfection with IAV. These results indicate that bacteria-specific Th17 memory cells play a key role in providing protection against IAV/Sp coinfection in a serotype-independent manner and suggest that a Th17-based vaccine would have excellent potential to mitigate disease caused by coinfection. IMPORTANCE Streptococcus pneumoniae (Sp) frequently causes secondary bacterial pneumonia after influenza A virus (IAV) infection, leading to increased morbidity and mortality worldwide. Current pneumococcal vaccines induce highly strain-specific antibody responses and provide limited protection against IAV/Sp coinfection. Th17 responses are broadly protective against Sp single infection, but whether the Th17 response, which is dramatically impaired by IAV infection in naïve mice, might be effective in immunization-induced protection against pneumonia caused by coinfection is not known. In this study, we have revealed that Sp-specific memory Th17 cells rescue IAV-driven inhibition and provide cross-protection against subsequent lethal coinfection with IAV and different Sp serotypes. These results indicate that a Th17-based vaccine would have excellent potential to mitigate disease caused by IAV/Sp coinfection.

Impact of severe lymphopenia on the early prediction of clinical outcome in hospitalized patients with pneumococcal community-acquired pneumonia.

PURPOSE: To evaluate the impact of an optimal and reproducible cutoff value set according to a predefined lymphopenia scale as an early predictor of in-hospital mortality and other outcomes in patients hospitalized with pneumococcal pneumonia and positive urinary antigen at admission to the emergency department. METHODS: An observational cohort study was conducted based on analysis of a prospective registry of consecutive immunocompetent adults hospitalized for pneumococcal pneumonia in two tertiary hospitals. Generalized additive models were constructed to assess the smooth relationship between in-hospital mortality and lymphopenia. RESULTS: We included 1173 patients. Lymphopenia on admission was documented in 686 (58.4%). No significant differences were observed between groups regarding the presence of comorbidities. Overall, 299 (25.5%) patients were admitted to intensive care and 90 (7.6%) required invasive mechanical ventilation. Fifty-nine (5%) patients died, among them 23 (38.9%) in the first 72 h after admission. A lymphocyte count < 500/µL, documented in 282 (24%) patients, was the predefined cutoff point that best predicted in-hospital mortality. After adjustment, these patients had higher rates of intensive care admission (OR 2.9; 95% CI 1.9-4.3), invasive mechanical ventilation (OR 2.2; 95% CI 1.2-3.9), septic shock (OR 1.8; 95% CI 1.1-2.9), treatment failure (OR 2.1; 95% CI 1.2-3.5), and in-hospital mortality (OR 2.2; 95% 1.1-4.9). Severe lymphopenia outperformed PSI score in predicting early and 30-day mortality in patients classified in the higher-risk classes. CONCLUSION: Lymphocyte count < 500/µL could be used as a reproducible predictor of complicated clinical course in patients with an early diagnosis of pneumococcal pneumonia.

Estimating the risk of bacteraemia in hospitalised patients with pneumococcal pneumonia.

OBJECTIVE: To construct a prediction model for bacteraemia in patients with pneumococcal community-acquired pneumonia (P-CAP) based on variables easily obtained at hospital admission. METHODS: This prospective observational multicentre derivation-validation study was conducted in patients hospitalised with P-CAP between 2000 and 2020. All cases were diagnosed based on positive urinary antigen tests in the emergency department and had blood cultures taken on admission. A risk score to predict bacteraemia was developed. RESULTS: We included 1783 patients with P-CAP (1195 in the derivation and 588 in the validation cohort). A third (33.3%) of the patients had bacteraemia. In the multivariate analysis, the following were identified as independent factors associated with bacteraemia: no influenza vaccination the last year, no pneumococcal vaccination in the last 5 years, blood urea nitrogen (BUN) ≥30 mg/dL, sodium <130 mmol/L, lymphocyte count <800/µl, C-reactive protein ≥200 mg/L, respiratory failure, pleural effusion and no antibiotic treatment before admission. The score yielded good discrimination (AUC 0.732; 95% CI: 0.695-0.769) and calibration (Hosmer-Lemeshow p-value 0.801), with similar performance in the validation cohort (AUC 0.764; 95% CI:0.719-0.809). CONCLUSIONS: We found nine predictive factors easily obtained on hospital admission that could help achieve early identification of bacteraemia. The prediction model provides a useful tool to guide diagnostic decisions.

Surfactant for a Patient with Refractory Pyopneumothorax and Acute Respiratory Distress Syndrome Due to Pneumococcal Necrotizing Pneumonia Complicated by a Bronchopleural Fistula.

Background: Necrotizing pneumonia rarely occurs in children, but when it does it can be complicated by bronchopleural fistula, empyema, pneumothorax, sepsis, and acute respiratory distress syndrome (ARDS). Antimicrobial therapy is the cornerstone of its management; however, surgery is necessary in some cases. Ideally, surgical interventions are kept to a minimum, but this is not always possible if there is a mass effect from air and fluid in the pleural space, pulmonary necrosis leading to massive hemoptysis, uncontrolled sepsis, or difficulties with assisted ventilation. Case Presentation: Herein we present a patient with refractory pyopneumothorax and ARDS due to pneumococcal necrotizing pneumonia complicated by a bronchopleural fistula. The patient's clinical condition deteriorated despite antibiotics, surgical drainage, and assisted ventilation. Owing to pneumothorax with a high percentage of air leakage, bilateral diffuse collapse of the lungs, and insufficient oxygenation, surgical treatment was considered, but because of the patient's lack of tolerance for surgery due to hemodynamic reasons and the complications associated with surgery, medical treatment was determined to be more appropriate. Surfactant treatment was administered to the patient, resulting in significant clinical improvement. Conclusion: To the best of our knowledge, this is the first report of the use of surfactant to treat ARDS due to necrotizing pneumonia. Based on the presented case, we think surfactant can be considered as a salvage treatment for such patients.

Radiological patterns and prognosis in elderly patients with acute Klebsiella pneumoniae pneumonia: A retrospective study.

Although Klebsiella pneumoniae pneumonia is an insidious threat among the elderly, the role of radiological features has not been elucidated. We aimed to evaluate thin-section chest computed tomography (CT) features and assess its associations with disease prognosis in elderly patients with acute K. pneumoniae pneumonia. We retrospectively included elderly patients, admitted for acute K. pneumoniae pneumonia, and investigated thin-section CT findings to determine whether bronchopneumonia or lobar pneumonia was present. The association between the radiological pattern of pneumonia and in-hospital mortality was analyzed. Eighty-six patients with acute K. pneumoniae pneumonia were included, and among them, the bronchopneumonia pattern was observed in 70 (81%) patients. Twenty-five (29%) patients died in hospital, and they had a greater incidence of lobar pneumonia pattern (40% in nonsurvivors vs 10% in survivors; P = .008), low albumin level (2.7 g/dL, range, 1.6-3.8 in nonsurvivors vs 3.0 g/dL, range, 1.7-4.2 in survivors; P = .026) and higher levels of aspartate aminotransferase (30 U/L, range, 11-186 in nonsurvivors vs 23 U/L, range, 11-102 in survivors, P = .017) and C-reactive protein (8.0 mg/dL, range, 0.9-26.5 in nonsurvivors vs 4.7 mg/dL, range, 0.0-24.0 in survivors; P = .047) on admission. Multivariate analysis showed that lobar pneumonia pattern was independently associated with increased in-hospital mortality (adjusted hazard ratio, 3.906; 95% CI, 1.513-10.079; P = .005). In elderly patients with acute K. pneumoniae pneumonia, the lobar pneumonia pattern may be less commonly observed, and this pattern could relate to poor prognosis.

Acetylsalicylic acid use is associated with improved survival in bacteremic pneumococcal pneumonia: A long-term nationwide study.

BACKGROUND: Pneumonia is commonly caused by Streptococcus pneumoniae (pneumococcus) and associated with subsequent cardiovascular complications and increased mortality. Potential short-term survival benefits conferred by acetylsalicylic acid (ASA) use in pneumonia remain controversial, and long-term outcomes have not been studied. OBJECTIVES: To evaluate the association between ASA use and survival for up to 1 year following bacteremic pneumococcal pneumonia. METHODS: All bacteremic pneumococcal episodes in Iceland from 1975 to 2019 were reviewed. The study cohort consisted of individuals at least 18 years of age with symptoms and imaging results consistent with pneumonia. Differences in survival were assessed at 30 days, 90 days and 1 year using propensity score weighting (inverse probability weighting). Splitting and stratifying on survival at 7 days was done for the 30-day survival, because of nonproportionality. RESULTS: In total, 815 bacteremic pneumococcal pneumonia episodes (median age 67 years, females 48%) were identified. Cox regression using propensity score weighting on the association of ASA with survival at 30 days showed an average hazard ratio (HR) of 0.60 (95% confidence interval [CI] 0.34-1.05). A significantly improved survival was observed within 7 days (HR = 0.42, 95% CI 0.19-0.92) but not during days 7-30 (HR = 1.08, 95% CI 0.46-2.55). ASA was associated with survival at 90 days (HR = 0.53, 95% CI 0.32-0.87) and 1 year (HR = 0.48, 95% CI 0.31-0.75). CONCLUSION: Use of ASA upon admission for bacteremic pneumococcal pneumonia is associated with significantly reduced mortality for up to 1 year after diagnosis. ASA therapy in patients with pneumonia and other infectious syndromes warrants further study.

Glucocorticoid-Induced Leucine Zipper Alleviates Lung Inflammation and Enhances Bacterial Clearance during Pneumococcal Pneumonia.

Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and proresolving bioactions, yet the therapeutical role of GILZ in infectious diseases remains unexplored. Herein, we investigate the role and effects of GILZ during acute lung injury (ALI) induced by LPS and Streptococcus pneumoniae infection. GILZ deficient mice (GILZ-/-) presented more severe ALI, characterized by increased inflammation, decreased macrophage efferocytosis and pronounced lung damage. In contrast, pulmonary inflammation, and damage were attenuated in WT mice treated with TAT-GILZ fusion protein. During pneumococcal pneumonia, TAT-GILZ reduced neutrophilic inflammation and prevented the associated lung damage. There was also enhanced macrophage efferocytosis and bacterial clearance in TAT-GILZ-treated mice. Mechanistically, TAT-GILZ enhanced macrophage phagocytosis of pneumococcus, which was lower in GILZ-/- macrophages. Noteworthy, early treatment with TAT-GILZ rescued 30% of S. pneumoniae-infected mice from lethal pneumonia. Altogether, we present evidence that TAT-GILZ enhances host resilience and resistance to pneumococcal pneumonia by controlling pulmonary inflammation and bacterial loads leading to decreased lethality. Exploiting GILZ pathways holds promise for the treatment of severe respiratory infections.

Pneumococcal Pneumonia Co-infection with Mycobacterium avium and Nocardia cyriacigeorgica in an Immunocompetent Patient.

A 61-year-old woman was transferred with a complaint of a fever and productive cough. She had tested positive for Mycobacterium avium and Nocardia cyriacigeorgica at least twice, and Streptococcus pneumonia (PISP) was isolated (3+) from her purulent sputum. As radiological findings, a lower lung field-dominant infiltration shadow and nodular shadow with cavity were recognized in the bilateral lung fields. We diagnosed her with pneumococcal pneumonia co-infection with M. avium and N. cyriacigeorgica. She was treated with MEPM for pneumococcal pneumonia, a standard regimen containing clarithromycin for pulmonary M. avium complex (MAC) disease, and sulfamethoxazole/trimethoprim for pulmonary nocardiosis. She improved with appropriate treatment.

Bacteraemic pneumococcal pneumonia and SARS-CoV-2 pneumonia: differences and similarities.

OBJECTIVE: To analyse differences in clinical presentation and outcome between bacteraemic pneumococcal community-acquired pneumonia (B-PCAP) and sSvere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pneumonia. METHODS: This observational multi-centre study was conducted on patients hospitalized with B-PCAP between 2000 and 2020 and SARS-CoV-2 pneumonia in 2020. Thirty-day survival, predictors of mortality, and intensive care unit (ICU) admission were compared. RESULTS: In total, 663 patients with B-PCAP and 1561 patients with SARS-CoV-2 pneumonia were included in this study. Patients with B-PCAP had more severe disease, a higher ICU admission rate and more complications. Patients with SARS-CoV-2 pneumonia had higher in-hospital mortality (10.8% vs 6.8%; P=0.004). Among patients admitted to the ICU, the need for invasive mechanical ventilation (69.7% vs 36.2%; P<0.001) and mortality were higher in patients with SARS-CoV-2 pneumonia. In patients with B-PCAP, the predictive model found associations between mortality and systemic complications (hyponatraemia, septic shock and neurological complications), lower respiratory reserve and tachypnoea; chest pain and purulent sputum were protective factors in these patients. In patients with SARS-CoV-2 pneumonia, mortality was associated with previous liver and cardiac disease, advanced age, altered mental status, tachypnoea, hypoxaemia, bilateral involvement, pleural effusion, septic shock, neutrophilia and high blood urea nitrogen; in contrast, ≥7 days of symptoms was a protective factor in these patients. In-hospital mortality occurred earlier in patients with B-PCAP. CONCLUSIONS: Although B-PCAP was associated with more severe disease and a higher ICU admission rate, the mortality rate was higher for SARS-CoV-2 pneumonia and deaths occurred later. New prognostic scales and more effective treatments are needed for patients with SARS-CoV-2 pneumonia.

High Prevalence of Vaccine-Type Infections Among Children with Pneumococcal Pneumonia and Effusion After 13-Valent Pneumococcal Conjugate Vaccine Introduction in the Dominican Republic.

BACKGROUND: In 2013, the Dominican Republic introduced 13-valent pneumococcal conjugate vaccine (PCV13) using a 3-dose schedule (at 2, 4 and 12 months of age). We evaluated the impact of PCV13 on serotypes causing pneumococcal pneumonia with pleural effusion. METHODS: Surveillance data after PCV13 introduction (July 2014 to June 2016) were compared with data before PCV13 introduction (July 2009 to June 2011). Cases were defined as radiologic evidence of pneumonia with pleural effusion in a child aged <15 years. Pneumococcus was detected in pleural fluid by either culture or polymerase chain reaction, and serotyping was performed. The Ministry of Health's PCV13 uptake data for 2014-2016 were obtained. RESULTS: The prevalence of pneumococcus among cases was similar before and after PCV13 introduction (56.4% and 52.8%, respectively). The proportion of pneumococcal cases caused by vaccine serotypes was 86% for children <2 years old both before and PCV13 introduction. Compared with before PCV13, serotype 14 accounted for a smaller (28% vs 13%, respectively; P = .02) and serotype 1 for a larger (23% vs 37%; P = .09) proportion of pneumococcal cases after PCV13 introduction. National uptake for the first, second, and third PCV13 doses was 94%, 81%, and 28%, respectively, in 2014 and 75%, 61%, and 26% in 2015. DISCUSSION: While the decrease in pneumococcal pneumonia with pleural effusion caused by serotype 14 may reflect an early effect of PCV13 implementation, other vaccine serotypes, including serotype 1, are not well controlled. Better PCV13 coverage for all 3 doses is needed.

C-reactive protein to rule out complicated pneumococcal disease manifestations: a retrospective cohort study in adults with pneumococcal bacteraemia.

OBJECTIVES: To explore the negative predictive value (NPV) of C-reactive protein (CRP) at admission to exclude complicated disease manifestations of pneumococcal disease. METHODS: A Dutch multicentre retrospective cohort study was conducted between 01-01-2012 and 30-06-2020. Adults with positive blood cultures for Streptococcus pneumoniae, whose CRP was measured at admission and whose infection focus was known, were included. Electronic medical and microbiological records were reviewed. RESULTS: Of the 832 bacteraemic patients enrolled, 30% had complicated manifestations of pneumococcal disease; most frequent were pleural effusion (8.9%), pleural empyema (5.4%) and meningitis (7.5%). Compared to solitary pneumonia, patients with pleural effusion and empyema presented with higher CRP levels. Although low CRP levels did not exclude complicated disease in general, a CRP level < 114 mg/L at admission could reliably exclude empyema among adult pneumonia patients with an NPV of 93% and a specificity of 26%. However, in cases where pleural fluid was present, CRP levels were mostly > 114 mg/L, such that suspicion of empyema could only be ruled out in a minority of cases (10%). CONCLUSIONS: Complicated manifestations are prevalent in adult pneumococcal bacteraemia. Low blood CRP levels can reliably exclude the development of pulmonary empyema. Practical value may be largest in settings without thoracic imaging at hand.

Inhibition of the lipoxin A4 and resolvin D1 receptor impairs host response to acute lung injury caused by pneumococcal pneumonia in mice.

Resolution of the acute respiratory distress syndrome (ARDS) from pneumonia requires repair of the injured lung endothelium and alveolar epithelium, removal of neutrophils from the distal airspaces of the lung, and clearance of the pathogen. Previous studies have demonstrated the importance of specialized proresolving mediators (SPMs) in the regulation of host responses during inflammation. Although ARDS is commonly caused by Streptococcus pneumoniae, the role of lipoxin A4 (LXA4) and resolvin D1 (RvD1) in pneumococcal pneumonia is not well understood. In the present experimental study, we tested the hypothesis that endogenous SPMs play a role in the resolution of lung injury in a clinically relevant model of bacterial pneumonia. Blockade of formyl peptide receptor 2 (ALX/FPR2), the receptor for LXA4 and RvD1, with the peptide WRW4 resulted in more pulmonary edema, greater protein accumulation in the air spaces, and increased bacteria accumulation in the air spaces and the blood. Inhibition of this receptor was also associated with decreased levels of proinflammatory cytokines. Even in the presence of antibiotic treatment, WRW4 inhibited the resolution of lung injury. In summary, these experiments demonstrated two novel findings: LXA4 and RvD1 contribute to the resolution of lung injury due to pneumococcal pneumonia, and the mechanism of their benefit likely includes augmenting bacterial clearance and reducing pulmonary edema via the restoration of lung alveolar-capillary barrier permeability.