Omega-3 fatty acids in contrast to omega-6 protect against pneumococcal pneumonia.

PURPOSE: The aim of this study was to assess if long-term supplementation of omega-3 fatty acids or a diet rich in omega-6 fatty acids ameliorates disease severity in a murine model of pneumococcal pneumonia. We hypothesize that long-term dietary supplementation of omega-3 fatty acids will reduce inflammation, disease severity and improve survival compared to omega-6 fatty acids. METHODS: Mice receiving diets supplemented with Omega-3 or Omega-6 for two months were intranasally infected with Streptococcus pneumoniae. We analyzed survival, bacterial burden, histopathology and inflammatory biomarkers. RESULTS: Our results showed that Omega-3 supplementation had increased survival (p = 0.005), less bacteremia (p = 0.0001) and lower bacterial burden in the lungs (p = 0.0002) when compared to the Omega-6 supplementation. Overall, Omega-3 reduced lung pathology, in particular peribronchial inflammation and cell death. Analyses of lung homogenates showed the Omega-3 cohort had decreased levels of the inflammatory cytokine interleukin-6 and an increase in anti-inflammatory cytokine interleukin-10. CONCLUSIONS: Supplementation of mouse diets with Omega-3 fatty acids improved survival, bacterial invasion in the blood and lungs as well as decreased overall lung tissue inflammation and cell death when compared to the Omega-6 supplemented diets. Translation of these findings in humans may improve outcomes of patients at risk for pneumonia.

Effectiveness of the 10-Valent Pneumococcal Conjugate Vaccine (PCV-10) in Children in Chile: A Nested Case-Control Study Using Nationwide Pneumonia Morbidity and Mortality Surveillance Data.

BACKGROUND: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Chilean National Immunization Program (NIP) in January 2011 with a 3+1 schedule (2, 4, 6 and 12 months) without catch-up vaccination. We evaluated the effectiveness of PCV10 on pneumonia morbidity and mortality among infants during the first two years after vaccine introduction. METHODS: This is a population-based nested case-control study using four merged nationwide case-based electronic health data registries: live birth, vaccination, hospitalization and mortality. Children born in 2010 and 2011 were followed from two moths of age for a period of two years. Using four different case definitions of pneumonia hospitalization and/or mortality (all-cause and pneumonia related deaths), all cases and four randomly selected matched controls per case were selected. Controls were matched to cases on analysis time. Vaccination status was then assessed. Vaccine effectiveness (VE) was estimated using conditional logistic regression. RESULTS: There were a total of 497,996 children in the 2010 and 2011 Chilean live-birth cohorts. PCV10 VE was 11.2% (95%CI 8.5-13.6) when all pneumonia hospitalizations and deaths were used to define cases. VE increased to 20.7 (95%CI 17.3-23.8) when ICD10 codes used to denote viral pneumonia were excluded from the case definition. VE estimates on pneumonia deaths and all-cause deaths were 71.5 (95%CI 9.0-91.8) and 34.8 (95% CI 23.7-44.4), respectively. CONCLUSION: PCV10 vaccination substantially reduced the number of hospitalizations due to pneumonia and deaths due to pneumonia and to all-causes over this study period. Our findings also reinforce the importance of having quality health information systems for measuring VE.

Penicillin resistance not a factor in outcome from invasive Streptococcus pneumoniae community-acquired pneumonia in adults when appropriate empiric therapy is started.

BACKGROUND: Invasive Streptococcus pneumoniae pneumonia among adults due to penicillin-resistant or intermediate resistant strains was investigated to determine whether these patients responded poorly to common antibiotic regimens compared to pneumonia due to susceptible strains. METHODS: During a 21-year period (1983-2003), clinical outcome was analyzed among 3 groups of adults, 19 with resistant, 33 with intermediate, and 133 with susceptible invasive S pneumoniae pneumonia admitted to hospitals in Huntington, West Virginia. Adults with resistant and intermediate infections were matched by age and month of admission to a group of 133 adults with penicillin-susceptible infections. All isolates of resistant and intermediate infections were capsular serotypes/serogroups 6, 9, 14, 19, and 23, and isolates of susceptible infections included 24 different serotypes/serogroups. Case fatality rates were calculated for deaths that occurred during the first 7, first 14, and first 21 days of hospitalization. Minimal inhibitory concentration (MIC) was determined by E-test and capsular serotype by Quellung procedures. RESULTS: The resistant and susceptible groups did not differ in several measures of severity of illness, including admission vital signs, duration of fever, mean total leukocyte count, number of lobes involved, preexisting underlying diseases, and antibiotic treatment regimens. There were no significant differences in case fatality rates between the 3 groups of pneumonia by days in hospital, age, severity of illness, and empiric antibiotic treatment regimen with a cephalosporin and a macrolide, the most common antibiotic regimen. CONCLUSIONS: These findings provide evidence that combination antibiotic regimens effective in the treatment of invasive susceptible S pneumoniae pneumonia are equally effective in the treatment of invasive resistant (MIC = 2-4 microg/mL) and of intermediate (MIC = 0.1-1 microg/mL) S pneumoniae pneumonia.

Risk factors and clinical outcomes of penicillin resistant S. pneumoniae community-acquired pneumonia in Khon Kaen, Thailand.

To determine the prevalence, risk factors and clinical outcomes of penicillin-resistant S. pneumoniae (PRSP) in community-acquired pneumonia (CAP), a cross-sectional study was conducted between January 1995 and December 2004 at Srinagarind Hospital, Khon Kaen, Thailand. Patients hospitalized with CAP and culture proved to be S. pneumoniae were included. PRSP was found in 22 of 64 (34.4%) patients. The MIC levels of penicillin non-susceptible strains ranged between 0.25 and 0.75 microg/ml. Resistance to other antibiotics ranked: cotrimoxazole (51.6%), tetracycline (26.6%), erythromycin (20.6%), lincomycin (18.7%), chloramphenicol (12.5%) and ampicillin (1.6%). None of the isolates was resistant to cephalothin. The significant risk factors for PRSP infection were previous antibiotic use within 3 months (Adjusted OR 40.83, 95% CI 3.71 to 449.41) and alcoholism (Adjusted OR 8.82, 95% 1.25 to 62.46). Bacteremia and empyema thoracis were found more commonly in PRSP than PSSP infection, but not statistically significant. Pneumonia-related mortality was nearly the same, PRSP 9.1% vs PSSP 9.5% (p = 0.96). The reason why the clinical outcomes of these two groups were not different may be the patients were infected with mildly resistant organisms. Thus, pneumonia caused by intermediate-level penicillin resistant S. pneumoniae appears to be adequately treated with beta-lactams or aminopenicillin antibiotics. The MIC levels of penicillin resistance should be monitored further. The need for antibiotics active against drug-resistant S. pneumoniae was required if high-level penicillin resistance was detected.

Short-course therapy of gemifloxacin effective against pneumococcal pneumonia in mice.

Standard 7-14 day (d) courses of antimicrobial therapy for community-acquired pneumonia (CAP) are thought to have contributed to the emergence of resistant pneumoccoci. Consequently, short-course fluoroquinolone regimens have been proposed to minimize resistance. To test this, we examined 2-day versus 5-day regimens of gemifloxacin and levofloxacin for treatment of pneumonia in a murine model. In doing so, we also investigated whether the enhanced potency of gemifloxacin would influence outcomes. CD1 Swiss mice were infected intratracheally with 10(5)-CFU of a virulent Streptococcus pneumoniae strain. Drugs were administered every 8 h for 2 d and 5 d, starting at 24 h postinfection. Temperature was used to assess disease progression. Gemifloxacin remained effective for 2 d and 5 d, with survival rates of 100%-83% compared with 40%-58% for levofloxacin. Eighty-nine to 100% of gemifloxacin-treated mice were clear of pulmonary bacteria compared with only 0%-20% for levofloxacin. For levofloxacin-treated mice, 2 of 7 (29%) isolates with a levofloxacin minimum inhibitory concentration (MIC) 4 times that of the infecting parent strain had ParC mutations. By contrast, no isolates recovered from gemifloxacin-treated mice were reduced in susceptibility. Gemifloxacin could be effective in shortening duration of therapy for CAP treatment as well as minimize resistance development.

Pharmacodynamics and bactericidal activity of gatifloxacin in experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae.

BACKGROUND: Antimicrobial resistance rates for Streptococcus pneumoniae continue to increase worldwide, and resistance to nearly every major class of antimicrobials used to treat pneumococcal infections has been reported. Gatifloxacin (GFLX) is one of the quinolones that have strong activity against S. pneumoniae. METHODS: We compared the bacteriological, pharmacological and histopathological effects of orally administered GFLX with those of levofloxacin (LVFX) and ciprofloxacin (CPFX) in a murine model of pneumonia caused by penicillin-resistant S. pneumoniae (PRSP). RESULTS: Treatment with GFLX resulted in a significant decrease in the number of viable bacteria (control, CPFX, LVFX, and GFLX: 6.48 +/- 0.36, 6.44 +/- 0.27, 5.51 +/- 0.15, and 4.89 +/- 0.28 log10 CFU/lung, respectively, mean +/- SD). A significant decrease in mortality was observed in the GFLX-treated group in comparison with the other groups. Histopathological examination revealed that inflammatory changes in GFLX-treated mice were less marked than in the other mice. CONCLUSION: Our results suggest that orally administered GFLX is effective in PRSP pneumonia. The pharmacokinetic profiles also reflected the effectiveness of GFLX.

Influence of penicillin resistance on outcome in adult patients with invasive pneumococcal pneumonia: is penicillin useful against intermediately resistant strains?

OBJECTIVES: To compare outcome between patients with pneumonia due to penicillin-susceptible S. pneumoniae and patients with pneumonia due to penicillin intermediately resistant strains and to study the outcome of patients with pneumococcal pneumonia caused by strains with MICs of 0.12-1 mg/L treated empirically during the first 48 h with beta-lactam antibiotics. MATERIALS AND METHODS: We studied 247 adult patients with invasive pneumococcal pneumonia occurring from 1997 to 2001. The following data were recorded from each patient: socio-demographic characteristics, underlying diseases, clinical presentation, initial severity of pneumonia, initial and subsequent antimicrobial therapy, in-hospital complications, hospital mortality and length of hospital stay. Multivariate analysis was done to identify variables associated with the development of pneumonia caused by a non-susceptible strain. RESULTS: The overall presence of penicillin non-susceptibility was 26.7%; no strain had an MIC >2 mg/L. Overall mortality was 23.5% in patients with pneumonia caused by intermediately resistant pneumococci and 12.7% in those with pneumonia caused by susceptible strains (P=0.075). Mortality during the first 7 days of admission, considered to be pneumonia-related deaths (13.7% versus 9.9%; P=0.448) was similar in both groups. The multivariate analysis showed that serotype 14 (OR, 140.18; 95% CI, 16.95-1159.20), serotype 19 (OR, 7.53; 95% CI, 1.98-28.7), haematological malignancy or splenectomy (OR, 4.46; 95% CI, 1.5-13.23) and HIV infection (OR, 4.54; 95% CI, 1.54-13.44) were the only independent factors associated with pneumonia caused by penicillin intermediately resistant pneumococci. In patients with strains having MICs of 0.1-1 mg/L, overall mortality was similar in the group of penicillin-treated patients (22.2%) to those treated with broad-spectrum beta-lactams (23.5%). CONCLUSIONS: There is a non-significant trend to higher mortality in patients with pneumococcal pneumonia caused by intermediately resistant strains; however, they do not have a poorer outcome when they are treated with amoxicillin.

Prospective observational study of bacteremic pneumococcal pneumonia: Effect of discordant therapy on mortality.

STUDY OBJECTIVE: To evaluate the effect of discordant empirical therapy on outcome in bacteremic pneumococcal community-acquired pneumonia. DESIGN: Prospective observational study. SETTING: A 600-bed teaching hospital with a reference area of 400,000 inhabitants. PATIENTS: All patients aged > or =18 yrs with a diagnosis of community-acquired pneumonia whose blood cultures, obtained within the first 48 hrs of hospitalization, demonstrated growth of Streptococcus pneumoniae were included in the study. METHODS: Discordant therapy was defined as failure to administer an antibiotic with in vitro activity against the isolated strain within 24 hrs of hospital admission. The 2002 breakpoints recommended for respiratory infections by the National Committee for Clinical Laboratory Standards were used to classify therapy. RESULTS: A total of 100 patients with bacteremic pneumococcal pneumonia were identified. Penicillin- and macrolide-resistant strains were identified in 29 and 18 cases, respectively. Only two strains had minimum inhibitory concentrations of >2 microg/mL for cephalosporins. Discordant therapy was documented in ten patients, five of whom died. Mortality in patients receiving concordant therapy was 14% (13 of 90). Nursing home residence (odds ratio [OR] = 14.8) and immunocompromise (OR = 11.5) were independently (p <.05) associated with discordant therapy. Risk of discordant therapy was significantly higher (p <.05) when empirical therapy did not include cefotaxime or ceftriaxone (OR = 10.4). Discordant therapy (OR = 27.3), multilobar involvement (OR = 14.2), underlying chronic obstructive pulmonary disease (OR = 9.1), and hospitalization during the previous 12 wks (OR = 7.9) were independently associated (p <.05) with death. The excess mortality for initial discordant therapy was estimated to be 35.6% (95% confidence interval, 3.73-67.4). CONCLUSIONS: Survival in patients with bacteremic community-acquired pneumococcal pneumonia can be improved by avoiding suboptimal therapy. Using the 2002 breakpoints, it is very unlikely that discordant therapy would be given with ceftriaxone or cefotaxime. Clinical outcome is worse in those patients receiving antimicrobial therapy that in vitro testing suggests would be ineffective.

Effect of dexamethasone and pentoxifylline in combination with amoxicillin in the treatment of penicillin-insensitive pneumococcal pneumonia in guinea pigs.

A fatal guinea pig model of pneumococcal pneumonia was developed in order to evaluate the efficacy of amoxicillin combined with either pentoxifylline or dexamethasone. Parameters assessed were survival time and lung changes (alterations, bacterial colony counts, inducible nitric oxide synthase [iNOS] and cyclooxygenase-2 [COX-2] protein expression). Animals receiving pentoxifylline (50 mg/kg) showed higher survival rates than controls (p < 0.05). Animals which received amoxicillin (50 mg/kg), alone or combined, showed significantly higher survival rates than controls (p < 0.05). Animals dying in spite of receiving amoxicillin alone or combined had lung colony counts significantly lower than those that did not receive the antibiotic (p < 0.001), but their lungs showed identical changes. The correlation between COX-2 protein expression and mortality was rather high (r = 0.75). The addition of either dexamethasone or pentoxifylline to amoxicillin improved neither survival rates nor lung pathology when compared with the antibiotic alone.

Aetiology, outcome, and risk factors for mortality among adults with acute pneumonia in Kenya.

BACKGROUND: Despite a substantial disease burden, there is little descriptive epidemiology of acute pneumonia in sub-Saharan Africa. We did this study to define the aetiology of acute pneumonia, to estimate mortality at convalescence, and to analyse mortality risk-factors. METHODS: We studied 281 Kenyan adults who presented to two public hospitals (one urban and one rural) with acute radiologically confirmed pneumonia during 1994-96. We did blood and lung-aspirate cultures, mycobacterial cultures, serotype-specific pneumococcal antigen detection, and serology for viral and atypical agents. FINDINGS: Aetiology was defined in 182 (65%) patients. Streptococcus pneumoniae was the most common causative agent, being found in 129 (46%) cases; Mycobacterium tuberculosis was found in 26 (9%). Of 255 patients followed up for at least 3 weeks, 25 (10%) died at a median age of 33 years. In multivariate analyses, risk or protective factors for mortality were age (odds ratio 1.51 per decade [95% CI 1.04-2.19]), unemployment (4.42 [1.21-16.1]), visiting a traditional healer (5.26 [1.67-16.5]), visiting a pharmacy (0.30 [0.10-0.91]), heart rate (1.64 per 10 beats [1.24-2.16]), and herpes labialis (15.4 [2.22-107]). HIV-1 seropositivity, found in 52%, was not associated with mortality. Death or failure to recover after 3 weeks was more common in patients with pneumococci of intermediate resistance to benzylpenicillin, which comprised 28% of pneumococcal isolates, than in those infected with susceptible pneumococci (5.60 [1.33-23.6]). INTERPRETATION: We suggest that tuberculosis is a sufficiently common cause of acute pneumonia in Kenyan adults to justify routine sputum culture, and that treatment with benzylpenicillin remains appropriate for clinical failure due to M. tuberculosis, intermediate-resistant pneumococci, and other bacterial pathogens. However, interventions restricted to hospital management will fail to decrease mortality associated with socioeconomic, educational, and behavioural factors.

Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia.

The impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia was evaluated in a retrospective cohort study conducted during population-based surveillance for invasive pneumococcal disease in the greater Atlanta region during 1994. Of the 192 study patients, 44 (23%) were infected with pneumococcal strains that demonstrated some degree of penicillin nonsusceptibility. Compared with patients infected with penicillin-susceptible pneumococcal strains, patients whose isolates were nonsusceptible had a significantly greater risk of in-hospital death due to pneumonia (relative risk [RR], 2.1; 95% confidence interval [CI], 1-4.3) and suppurative complications of infection (RR, 4.5; 95% CI, 1-19.3), although only risk of suppurative complications remained statistically significant after adjustment for baseline differences in severity of illness. Among adults with bacteremic pneumococcal pneumonia, infection with penicillin-nonsusceptible pneumococci is associated with an increased risk of adverse outcome.

Increased rate of survival in Streptococcus pneumoniae-infected rats treated with the new immunomodulator Pidotimod.

Wistar rats infected with Streptococcus pneumoniae (type III ATCC) rapidly develop an acute form of experimental lobar pneumonia (ELP) with death of 80-90% of the animals by 6 days after the infection. Prophylactic treatment of these animals with the novel immunomodulator Pidotimod, at the dose of 25 mg/kg bw, significantly increased their rate of survival as compared to the control group (50 vs. 90% respectively). Recovery from the infection appeared definitive since all the Pidotimod-treated survivors were alive and in good condition at the end of the observation period (45 days post infection). Prophylactic treatment with higher or lower doses of the drug was ineffective. Therapy with Pidotimod was not effective. This preliminary study suggests that Pidotimod may have contributed to activation of specific and non-specific immune effectors involved in the host response to S. pneumoniae infection.

Ascorbate modulates antibacterial mechanisms in experimental pneumococcal pneumonia.

To evaluate the influence of vitamin C on pulmonary antibacterial mechanisms, normal CD-1 mice were administered sodium ascorbate (200 mg/kg/24 h) and challenged intratracheally with type 3 Streptococcus pneumoniae. Survival rates were similar in ascorbate-treated and control animals. When infected with a high inoculum (1 X 10(6) cfu), animals given vitamin C demonstrated a significant enhancement in their capacity to clear viable pneumococci from the lungs at 24 h after challenge; the augmented pulmonary clearance was associated with an increased influx of granulocytes at 6 and 24 h. After infection with a lower inoculum (1 X 10(5) cfu), animals treated with the vitamin exhibited a significant advantage in pulmonary clearance and granulocyte recruitment but at 6 h only. After a very low inoculum challenge (1 X 10(4) cfu), the clearance of viable pneumococci was retarded in ascorbate-treated mice. In vitro, the pneumococcidal capacity of resident alveolar macrophages from animals given vitamin C was significantly reduced, but the ability of these cells to generate leukocyte chemoattractant activity after stimulation with the calcium ionophore A23187 remained unaltered. We conclude that in the mouse, large doses of vitamin C alter pulmonary defense mechanisms against S. pneumoniae; however, these changes do not appear to convey a substantial advantage to the host.