Severe Pneumococcal Pneumonia Research Articles

Hyperglycemia in diabetics and non-diabetics: Effect on the risk for and severity of pneumococcal pneumonia

We sought to determine whether poor glucose control among diabetics is associated with increased risk for pneumococcal pneumonia and whether elevated admitting plasma glucose (APG) levels are associated with increased severity of this infection in diabetic and non-diabetic patients. We compared hemoglobin A(1c) (HbA(1c)) in diabetics who had pneumococcal pneumonia with diabetic case-controls who did not have pneumonia. In patients with pneumococcal pneumonia, we related APG to disease severity as determined by SMART-COP score, need for ICU admission, and mortality at 7 and 30 days. Fifty-three of 233 patients with pneumococcal pneumonia (22.7%) were diabetic. Diabetics with pneumonia had poorer glycemic control than diabetic case-controls (HbA(1c) 8.2% vs. 7.2%, respectively, P<0.01). In pneumococcal pneumonia patients, SMART-COP scores, need for ICU admission, and mortality increased in proportion to the APG. These findings were attributable to the significant association between hyperglycemia and severity in non-diabetics. Poor glycemic control predisposes diabetics to pneumococcal pneumonia but, among diabetics, the degree of hyperglycemia at admission is not associated with increased disease severity. In contrast, among non-diabetics with pneumococcal pneumonia, hyperglycemia is a marker for severe disease and increased mortality, perhaps reflecting massive release of cytokines and glucocorticosteroids in overwhelming infection.

Severe Invasive Pneumococcal Sepsis Associated with Influenza a Infection

We present two patients admitted to the intensive care unit with sepsis secondary to severe community-acquired pneumococcal pneumonia who had, in addition, influenza A positive serology. Both Streptococcus pneumoniae and influenza A are known to be responsible for significant morbidity and mortality in their own right during the winter months. This report highlights the need, in cases of confirmed pneumococcal pneumonia, to test for other organisms at an early stage, in particular influenza A and other respiratory viruses, as this synergistic combination is known to carry a very high mortality. The early detection of the influenza A virus in addition to pneumococcus and early treatment with oseltamivir could potentially improve clinical outcomes in this condition.

The impact of time on the systemic inflammatory response in pneumococcal pneumonia

The aim of our study was to analyse the impact of time from onset of symptoms on the systemic cytokine concentrations in patients with pneumococcal pneumonia. Adults with severe pneumococcal pneumonia were prospectively included. At admission, vital signs, time from onset of pneumonia symptoms and circulating levels of C-reactive protein (CRP), serum amyloid A (SAA), tumour necrosis factor (TNF)-alpha, and interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-1ra were recorded. 32 patients were included; 13 patients had <48 h of evolution and 19 patients had been sick for >48 h. The group with a longer time of evolution presented higher plasmatic levels of TNF-alpha (19.1+/-8.5 versus 35.5+/-26 pg.mL(-1)), fibrinogen (6+/-1.8 versus 9+/-2); CRP (130+/-85 versus 327+/-131) and SAA (678+/-509 versus 984+/-391). Concentrations of TNF-alpha were associated with the presence of bacteraemia, initial blood pressure <90 mmHg and with a lower oxygen saturation at admission. Likewise, TNF-alpha levels were correlated with concentrations of IL-1beta (r = 0.49), IL-6 (r = 0.41) and IL-8 (r = 0.40). In pneumococcal pneumonia, patients with a longer time of evolution presented with higher levels of pro-inflammatory cytokines and a higher expression of acute phase proteins, suggesting a sustained release of pneumococcal antigens over time.

Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia*

Severe pneumococcal pneumonia frequently causes respiratory failure. Both pathogen factors and an uncontrolled host response may contribute to acute lung injury by impairing microvascular barrier function. Phosphodiesterase 2 (PDE2) was examined as a potential target in pneumonia-induced lung microvascular hyperpermeability. Controlled, in vitro, ex vivo, and in vivo laboratory study. Female Balb/C and C57Bl/6 mice, 8-12 weeks old. Human umbilical vein endothelial cells and isolated mouse lungs were challenged with the pneumococcal exotoxin pneumolysin in the presence or absence of the selective PDE2 inhibitors 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6one (PDP) or hydroxy-PDP. Transcellular electrical resistance or human serum albumin leakage in bronchoalveolar lavage fluid was determined, respectively. In addition, we induced pneumococcal pneumonia in mice and treated with hydroxy-PDP via continuous subcutaneous application by osmotic pumps. Human serum albumin leakage in bronchoalveolar lavage fluid was measured 48 hours after transnasal infection, and lung specimens were analyzed by TaqMan real-time polymerase chain reaction and Western blot for PDE2 gene and protein expression. In isolated perfused mouse lungs and in human umbilical vein endothelial cell monolayers, selective inhibition of PDE2 markedly decreased pneumolysin-induced hyperpermeability. Furthermore, in murine pneumococcal pneumonia, pulmonary PDE2-mRNA and -protein expression was significantly increased, and pneumonia-induced vascular permeability was distinctively reduced by PDE2 inhibition. PDE2 inhibition diminished microvascular leakage in pneumococcal pneumonia, and pulmonary PDE2 upregulation may play a crucial role in this respect. Selective PDE2 inhibitors thus may offer a promising therapeutic approach in severe pneumococcal pneumonia.

Infection with Human Metapneumovirus Predisposes Mice to Severe Pneumococcal Pneumonia

Human metapneumovirus (hMPV) is a recently described paramyxovirus that causes respiratory tract infections. Prior clinical studies have highlighted the importance of respiratory viruses, such as influenza virus, in facilitating secondary bacterial infections and increasing host immunopathology. The objective of the present work was to evaluate the effects of initial viral infection with hMPV or influenza A virus followed by Streptococcus pneumoniae superinfection 5 days later in a murine model. Both groups of superinfected mice demonstrated significant weight loss (mean of 15%) and higher levels of airway obstruction (mean enhanced pause value of 2.7) compared to those of mice infected with hMPV, influenza virus, or pneumococcus alone. Bacterial counts increased from 5 x 10(2) CFU/lung in mice infected with pneumococcus only to 10(7) and 10(9) CFU/lung in mice with prior infections with hMPV and influenza A virus, respectively. A more pronounced interstitial and alveolar inflammation correlated with higher levels of inflammatory cytokines and chemokines such as interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, IL-12, monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, KC, and granulocyte colony-stimulating factor, as well as greater expression of Toll-like receptor 2 (TLR2), TLR6, TLR7, and TLR13 in the lungs of superinfected animals compared to results for single infections, with similar immunological effects seen in both coinfection models. Prior infection with either hMPV or influenza A virus predisposes mice to severe pneumococcus infection.

Immunostimulation with Macrophage-Activating Lipopeptide-2 Increased Survival in Murine Pneumonia

Community-acquired pneumonia (CAP) is associated with high morbidity and mortality, and Streptococcus pneumoniae is the most prevalent causal pathogen identified in CAP. Impaired pulmonary host defense increases susceptibility to pneumococcal pneumonia. S. pneumoniae may up-regulate Toll-like receptor (TLR)-2 expression and activate TLR-2, contributing to pneumococcus-induced immune responses. In the current study, the course of severe murine pneumococcal pneumonia after pulmonary TLR-2-mediated immunostimulation with synthetic macrophage-activating lipopeptide-2 (MALP-2) was examined. Intratracheal MALP-2 application evoked enhanced proinflammatory cytokine and chemokine release, resulting in recruitment of polymorphonuclear neutrophils (PMN), macrophages, and lymphocytes into the alveolar space in WT, but not in TLR-2-deficient mice. In murine lungs as well as in human alveolar epithelial cells (A549), MALP-2 increased TLR-2 expression at both mRNA and protein level. Blood leukocyte numbers and populations remained unchanged. MALP-2 application 24 hours before intranasal pneumococcal infection resulted in increased levels of CCL5 associated with augmented leukocyte recruitment, and decreased levels of anti-inflammatory IL-10 in bronchoalveolar lavage fluid. Clinically, MALP-2-treated as compared with untreated mice showed increased survival, reduced hypothermia, and increased body weight. MALP-2 also reduced bacteremia and improved bacterial clearance in lung parenchyma, as examined by immunohistochemistry. In conclusion, pulmonary immunostimulation with MALP-2 before infection with S. pneumoniae improved local host defense and increased survival in murine pneumococcal pneumonia.

Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

Bacterial alveolar invasion is followed by an inflammatory response. A systemic extension of the compartmentalized immune response has been described in patients with severe pneumonia. The data suggest that some antimicrobials may induce a differential release of cytokines. We conducted a prospective, randomized study in adult patients with severe pneumococcal pneumonia to measure the effects of ceftriaxone and levofloxacin in the systemic cytokine expression over time. Demographic, clinical characteristics, and severity scores were recorded. The serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-8, IL-10, and IL-1 receptor agonist were measured at 0, 24, 72, and 120 h. A total of 32 patients were included in the study. Both groups were homogeneous in terms of age, comorbidities, severity of disease, and corticosteroid or statin use. With the single exception of IL-1beta, all cytokines were detected in venous blood. All of the cytokines studied showed a similar pattern of progressive decrease over time. No significant differences in the concentrations of any of the cytokines studied were found, with the exception of TNF-alpha, for which lower concentrations were obtained at 120 h in the levofloxacin group (P = 0.014). Basal oxygen saturation (P = 0.034) and heart rate (P = 0.029) returned to normal values earlier in the levofloxacin arm. We demonstrated that in patients with severe pneumococcal pneumonia pro- and anti-inflammatory responses could be detected in venous blood, representing a systemic extension of the compartmentalized response. Treatment with a beta-lactam agent or a fluoroquinolone has different effects on cytokine production and its systemic expression, impacting the clinical course of the disease.

Role of platelet-activating factor in pneumolysin-induced acute lung injury

Acute respiratory failure is a major complication of severe pneumococcal pneumonia, characterized by impairment of pulmonary microvascular barrier function and pulmonary hypertension. Both features can be evoked by pneumolysin (PLY), an important virulence factor of Streptococcus pneumoniae. We hypothesized that platelet-activating factor (PAF) and associated downstream signaling pathways play a role in the PLY-induced development of acute lung injury. Controlled, ex vivo laboratory study. Female Balb/C mice, 8-12 wks old. Ventilated and blood-free-perfused lungs of wild-type and PAF receptor-deficient mice were challenged with recombinant PLY. Intravascular PLY, but not the pneumolysoid Pd-B (PLY with a Trp-Phe substitution at position 433), caused an impressive dose-dependent increase in pulmonary vascular resistance and increased PAF in lung homogenates, as detected by reversed-phase high-performance liquid chromatography coupled to tandem mass spectrometry. The pressor response was reduced in lungs of PAF receptor-deficient mice and after PAF receptor blockade by BN 50730. PLY and exogenous PAF increased thromboxane B2 in lung effluate, and thromboxane receptor inhibition by BM 13505 diminished the pressor response to PLY. Differential inhibition of intracellular signaling steps suggested significant contribution of phosphatidylcholine-specific phospholipase C and protein kinase C and of the Rho/Rho-kinase pathway to PLY-induced pulmonary vasoconstriction. Unrelated to the pulmonary arterial pressor response, microvascular leakage of PLY was diminished in lungs of PAF receptor-deficient mice as well. PAF significantly contributed to PLY-induced acute injury in murine lungs. The PAF-mediated pressor response to PLY depends on thromboxane and on the downstream effectors phosphatidylcholine-specific phospholipase C, protein kinase C, and Rho-kinase.

P1193 Systemic infiammatory response and time from onset to hospital admission in severe pneumococcal pneumonia

P1193 Systemic infiammatory response and time from onset to hospital admission in severe pneumococcal pneumonia

P1192 Systemic TNF-α production and severity of disease in severe pneumococcal pneumonia

P1192 Systemic TNF-α production and severity of disease in severe pneumococcal pneumonia

Severe pneumococcal pneumonia: new strategies for management

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia worldwide and is the most likely causative pathogen in patients with community-acquired pneumonia admitted to the intensive care unit. Bacteremic pneumococcal pneumonia is an advanced stage of severe pneumococcal pneumonia. Improvement in the management of bacteremic pneumococcal pneumonia has the potential for improving the survival for severe pneumococcal pneumonia. Non-culture methods, especially the Binax urinary antigen test, can increase the diagnostic yield for pneumococcal pneumonia, allowing targeted antimicrobial therapy (specifically penicillin). In-vitro resistance to penicillin has increased over the past decade; however, it has not led to clinical failure when used for pneumococcal pneumonia. Hospitalized patients with community-acquired pneumonia should have blood cultures obtained to confirm the possibility of bacteremic pneumococcal pneumonia. Based on pharmacodynamic properties, parenteral penicillin remains the drug of choice to treat pneumococcal pneumonia regardless of in-vitro resistance. Combination antimicrobial therapy will likely improve survival of patients with bacteremic pneumococcal pneumonia among the subset of critically ill patients.

Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia

Acute respiratory failure is a significant complication of severe pneumococcal pneumonia. In a mouse model, we observed early-onset lung microvascular leakage after pulmonary infection with Streptococcus pneumoniae, and we hypothesized that the important virulence factor pneumolysin may be the direct causative agent. Controlled, in vivo, ex vivo, and in vitro laboratory study. Laboratory. Female mice, 8-12 wks old. Ventilated and blood-free perfused murine lungs were challenged with recombinant pneumolysin via the airways as well as via the vascular bed. In addition, we analyzed the impact of pneumolysin on electrical cell impedance and hydraulic conductivity of human umbilical vein endothelial cell (HUVEC) and alveolar epithelial cell (A549) monolayers. Aerosolized pneumolysin dose-dependently increased capillary permeability with formation of severe lung edema but did not affect pulmonary vascular resistance. Intravascular pneumolysin caused an impressive dose-dependent increase in pulmonary vascular resistance and in lung microvascular permeability. By immunohistochemistry, pneumolysin was detected mainly in endothelial cells of pulmonary arterial vessels, which concomitantly displayed strong vasoconstriction. Moreover, pneumolysin increased permeability of HUVEC and A549 monolayers. Interestingly, immunofluorescence of endothelial cell monolayers exposed to pneumolysin showed gap formation and moderate stress fiber generation. Pneumolysin may play a central role for early-onset acute lung injury due to severe pneumococcal pneumonia by causing impairment of pulmonary microvascular barrier function and severe pulmonary hypertension.

Optimal therapy for severe pneumococcal community-acquired pneumonia

Streptococcus pneumoniae is responsible for two-thirds of ICU admissions due to community-acquired pneumonia (CAP) and is the leading cause of CAP-related death. Early death is principally due to cardiovascular collapse, whereas late death is associated with hypoxemic respiratory failure. Outcome depends on interactions between non-modifiable factors of predisposition (age, comorbidities, host defences, genetic predisposition) or infection (toxins, virulence, bacterial burden) and modifiable factors (organ-failure support, surgical drainage for empyema, adjuvant therapies and antibiotics). Excess mortality has been reported when initial therapy is discordant, but more than 95% of isolates have minimum inhibitory concentration (MIC) <4 microg/ml. Therefore, cefotaxime, ceftriaxone and high doses of amoxicillin remain successful for non-meningeal infections. Recent studies suggest that initial combination therapy improves survival in the subset of bacteremic episodes with highest severity, conceivably due to the immunomodulatory effects of macrolides. Prospective, randomized clinical trials of pneumonia patients with a pneumonia severity index score above 90 are warranted to define optimal antibiotic regimens.

Pneumococcal serogroups and serotypes in severe pneumococcal pneumonia in Belgian children: Theoretical coverage of the 7-valent and 9-valent pneumococcal conjugate vaccines

Although the causative pneumococcal serotypes of invasive diseases are already extensively studied, few data are available about the pneumococcal serotypes additionally isolated from broncho-alveolar lavage samples in childhood pneumonia. To identify the causative pneumococcal serotypes in culture proven childhood community acquired pneumonia (CAP) and to calculate the effectiveness of the heptavalent and nonavalent pneumococcal vaccine (7- and 9-valent PnV) in severe pneumococcal pneumonia. All pneumococcal isolates stored from broncho-alveolar lavage, blood culture and pleural fluid in healthy children with CAP were characterized. Seventy children (median age 2 years 3.5 months) could be included. The most prevalent serotypes were: SGT1 (21.4%), SGT6 (20.0%), SGT19 (12.8%), SGT23 (10.0%), and SGT14 (7.1%). SGT1 was especially prevalent in complicated cases and children >5 years. This first ranking of SGT1 is not reported in invasive pneumococcal disease studies. The overall theoretical coverage of the 7-valent PnV and the 9-valent PnV for pneumococcal pneumonia was 45.7% and 72.8%. The theoretical coverage of both vaccines was equal for non-invasive pneumonia (64%) but the theoretical coverage of the 9-valent PnV for invasive pneumonia was much higher (79% vs. 37.2%). Antibiotic susceptibility to penicillin was 84%, 70% to tetracycline and 61% to erythromycin; however only one strain (MIC = 4 mg/L) was highly resistant to penicillin. Based on this serotyping, the theoretical coverage of the 7-valent PnV for proven pneumococcal pneumonia is good but decreases with age. A 9-valent PnV containing SGT1 could significantly increase the coverage, especially for invasive pneumonia. According to these data, penicillin remains the first choice antibiotic treatment for childhood CAP in Belgium.

Optimal antibiotic treatment in severe pneumococcal pneumonia — time for real answers

Optimal antibiotic treatment in severe pneumococcal pneumonia — time for real answers

Telithromycin: A Ketolide Antibiotic for Treatment of Respiratory Tract Infections

Telithromycin, a recently approved ketolide antibiotic derived from 14-membered macrolides, is active against erythromycin-resistant pneumococci. Telithromycin has enhanced activity in vitro because it binds not only to domain V of ribosomal RNA (like macrolides do) but also to domain II. However, it is not active against streptococci and staphylococci with constitutive macrolide, lincosamide, and streptogramin B resistance. Telithromycin, available in an oral formulation, is approved by the US Food and Drug Administration for use in adults for treatment of (1) community-acquired pneumonia due to Streptococcus pneumoniae (including multidrug-resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae; (2) acute exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, or M. catarrhalis; or (3) acute bacterial sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, or methicillin- and erythromycin-susceptible Streptococcus aureus. It is not approved for treatment of tonsillitis, pharyngitis, or severe pneumococcal pneumonia. Unique visual adverse effects occurred in 0.27%-2.1% of patients receiving telithromycin therapy. Its enhanced activity against some common respiratory pathogens makes it a valuable addition to the available macrolides.

Monotherapy versus combination antimicrobial therapy for pneumococcal pneumonia

In the past 5 years a number of studies have suggested that combination antibiotic therapy may be superior to monotherapy for pneumococcal pneumonia. This review outlines the major findings for and against combination therapy. The evidence for a benefit of multiple antibiotics is strongest in patients with severe, bacteremic pneumococcal disease. All of these studies have limitations due to their retrospective or uncontrolled design. Unfortunately prospective, randomized, double-blind, controlled studies have not been performed in an appropriately severe disease cohort and are therefore urgently needed. Several viable mechanisms for a benefit of combination therapy have been proposed, especially related to non-antibiotic effects of macrolides. There is also some evidence that third-generation cephalosporins may be superior to penicillins as the non-macrolide component of combination therapy. Although based on retrospective and observational data, there is substantial evidence to support combination antibiotic therapy, at least in patients with severe bacteremic pneumococcal pneumonia. What evidence is available supports a cephalosporin/macrolide combination as being associated with the highest survival, but proper prospective studies in patients with severe pneumonia are urgently required to clarify this issue.

Severe pneumonia and a second antibiotic

Streptococcus pneumoniae is the most common cause of community acquired pneumonia (CAP) and the pathogen causing most deaths. CAP management guidelines in North America and the UK recommended that patients with severe pneumonia be given initially a combination antibiotic therapy. According to a recent retrospective study adults with severe bacteremic pneumococcal pneumonia have significantly greater risk of death if they receive a single antibiotics rather than combination antibiotics on the first day of admission. Although some patients died shortly after admission half of the deaths occurred after 5 days and mortality rates continued to increase throughout the 15-day study suggesting that subsequent antibiotic therapy might be an important determinant of outcome. Hence the investigators recommended a double-blind trial of single versus combination therapy for patients with severe CAP and suspected bacteremic pneumococcal pneumonia. The need to cover this pathogen effectively in any empirical antibiotic regimen for CAP remains a priority.

Two antibacterials better than one in severe pneumococcal pneumonia?

Two antibacterials better than one in severe pneumococcal pneumonia?