ro13-9904 and Pneumonia--Pneumococcal

Ceftaroline fosamil resulted in higher cure rates than ceftriaxone in patients with community-acquired bacterial pneumonia in 2 randomized trials (FOCUS 1 and FOCUS 2). The present analysis examines the subgroup of patients with Streptococcus pneumoniae infection to determine whether the apparent difference in cure rates persists after adjusting for potential covariates. We retrospectively pooled subjects with S. pneumoniae isolated at baseline in the original studies and employed logistic regression to evaluate the independent relationship between clinical cure and treatment with ceftaroline. Covariates evaluated included demographics, severity of illness, bacteremia, and pathogen characteristics. The final cohort included 139 subjects (69 ceftaroline, 70 ceftriaxone). Unadjusted cure rates were 85.5% and 68.6% (P = 0.009) in the ceftaroline and ceftriaxone groups, respectively. After logistic regression, ceftaroline remained associated with higher cure rates. Our findings indicate that ceftaroline may result in improved outcomes of S. pneumoniae pneumonia. Formal clinical trials are warranted to confirm this hypothesis.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Female; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Odds Ratio; Pneumonia, Pneumococcal; Retrospective Studies; Treatment Outcome

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.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftriaxone; Cytokines; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukins; Levofloxacin; Male; Middle Aged; Ofloxacin; Pneumonia, Pneumococcal; Prospective Studies; Time Factors; Tumor Necrosis Factor-alpha

The suitability of ceftriaxone for penicillin-resistant Streptococcus pneumoniae (PRSP) and ampicillin-resistant Haemophilus influenzae (especially beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae) and the relationship between in vitro antimicrobial activities and pharmacokinetic parameters were evaluated. The values for percentage of time above the MIC (%T>MIC) for ceftriaxone, cefotiam, flomoxef, sulbactam/cefoperazone, sulbactam/ampicillin, and meropenem, using 400 S. pneumoniae isolates and 430 H. influenzae isolates from patients with community-acquired pneumonia (CAP) from more than 100 geographically diverse medical centers during January to July of 2005, were calculated by measuring the MIC for each isolate and by using patameters of pharmacokinetics. A broth microdilution method was used to determine the MIC, using the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Meropenem showed the lowest MIC against penicillin-susceptible S. pneumoniae, followed by sulbactam/cefoperazone and ceftriaxone. Ceftriaxone had the best activity against penicillin-resistant S. pneumoniae and beta-lactamase-negative and beta-lactamase-producing ampicillin-resistant H. influenzae. Ceftriaxone was unique, showing a long elimination half-life and low MIC values where its serum level duration time was above the MIC for longer than other cephalosporins. Accordingly, the %T>MIC of ceftriaxone for a once-daily administration greatly exceeded the efficacy levels of those for the other antibacterial agents tested. Ceftriaxone has an excellent balance between in vitro antimicrobial activities and pharmacokinetic profiles; and therefore remains effective as a therapeutic agent against PRSP and BLNAR H. influenzae in CAP.

Topics: Ampicillin Resistance; Anti-Bacterial Agents; beta-Lactamases; Ceftriaxone; Community-Acquired Infections; Drug Resistance, Bacterial; Haemophilus Infections; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Streptococcus pneumoniae

To compare the efficacy and safety of ertapenem, 1 g once a day, with ceftriaxone, 1 g once a day, for treatment of the subgroup of patients aged 65 and older with community-acquired pneumonia (CAP) requiring parenteral therapy.. Combined data from patients aged 65 and older in two randomized, double-blind clinical trials.. Eighty international centers.. Eight hundred fifty-seven treated patients, of whom 351 were aged 65 and older.. Intravenous or intramuscular ertapenem or ceftriaxone with the option to switch to oral amoxicillin-clavulanate after at least 3 days of parenteral therapy.. Clinical efficacy was assessed at completion of parenteral therapy and 7 to 14 days after all therapy had been completed (test of cure (TOC) assessment). Bacterial eradication was assessed at the TOC visit. Safety was assessed daily during study therapy and for 14 days thereafter.. One hundred forty-eight clinically evaluable patients aged 65 and older were treated with ertapenem and 125 with ceftriaxone. Pathogens were identified in 157 (57.5%) patients (the most common being Streptococcus pneumoniae), most of which were penicillin-susceptible. Clinical cure rates were 95.9% for patients in the ertapenem group and 92.7% for patients in the ceftriaxone group at completion of parenteral therapy and 93.9% and 90.4%, respectively, at the TOC assessment. Overall bacterial eradication rates were 92.8% (77 of 83) for patients treated with ertapenem and 93.2% (69 of 74) for those treated with ceftriaxone. The most common drug-related adverse experiences in both treatment groups were diarrhea and mild to moderate elevation of serum aminotransferase levels.. Ertapenem 1 g once a day was highly effective for treatment of elderly patients with CAP requiring parenteral therapy and was as effective as ceftriaxone. Ertapenem was generally well tolerated, with an overall safety profile similar to ceftriaxone.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Community-Acquired Infections; Double-Blind Method; Ertapenem; Female; Humans; Lactams; Logistic Models; Male; Odds Ratio; Pneumonia, Pneumococcal; Retrospective Studies; Statistics, Nonparametric; Streptococcus pneumoniae; Treatment Outcome

Intravenous (i.v.) to oral linezolid (600 mg twice daily for both, with optional aztreonam) and a cephalosporin regimen (i.v. ceftriaxone 1 g twice daily followed by oral cefpodoxime 200 mg twice daily) were compared for the treatment of community-acquired pneumonia (CAP), with emphasis on patients with Streptococcus pneumoniae. This multicenter, randomized, open-label trial was conducted in 27 countries in 6 continents. Efficacy was assessed 12-28 d following treatment. Clinical and laboratory safety assessments were evaluated; isolates for microbiologic assessments were identified primarily by sputum or blood culture. In all treated patients (linezolid, n = 381; ceftriaxone/cefpodoxime, n = 366), linezolid had a higher clinical cure rate than ceftriaxone/cefpodoxime (83.0% vs. 76.4%, respectively; p = 0.040). S. pneumoniae was isolated in 73.2% (186/254) of patients at baseline, with similar eradication rates in the linezolid and ceftriaxone/cefpodoxime groups (88.7% vs. 89.9%, respectively; p = 0.830). Linezolid had a superior clinical cure rate (93.1% vs. 68.2%; p = 0.021) in patients with S. pneumoniae bacteremia. Logistic regression analyses revealed that linezolid-treated patients with bacteremia, pleural effusion, cardiac comorbidities, diabetes or abnormal white blood cell counts had significantly better outcomes than cephalosporin-treated patients. Both regimens were well tolerated, although the incidence of drug-related adverse events was higher in the linezolid group than in the ceftriaxone/cefpodoxime group (21.3% vs. 11.2%, respectively; p = 0.0002). In summary, empiric i.v./oral linezolid was more effective than ceftriaxone/cefpodoxime in patients hospitalized with CAP, with comparable cure rates in S. pneumoniae pneumonia and higher cure rates in pneumonia complicated by bacteremia.

Topics: Acetamides; Administration, Oral; Adolescent; Adult; Aged; Cefpodoxime; Ceftizoxime; Ceftriaxone; Community-Acquired Infections; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Infusions, Intravenous; Italy; Linezolid; Logistic Models; Male; Middle Aged; Oxazolidinones; Pneumonia, Pneumococcal; Probability; Streptococcus pneumoniae; Treatment Outcome

Ertapenem is a once-daily parenteral beta-lactam licensed in the United States in November 2001 and in Europe in May 2002.. This study compared the efficacy and safety profiles of ertapenem with those of ceftriaxone for the treatment of hospitalized adult patients with serious community-acquired pneumonia (CAP) requiring parenteral therapy.. In this prospective, double-blind (with sponsor blinding), multicenter study, adult patients with CAP were stratified by Pneumonia Severity Index (< or = 3 or > 3) and age (< or = 65 or > 65 years) and randomized (2:1) to receive IV or intramuscular (IM) ertapenem 1 g once daily or IV or IM ceftriaxone 1 g once daily. Investigators could switch patients to an oral antimicrobial agent if clinical improvement was shown after at least 3 days of parenteral therapy.. A total of 364 patients were randomized to treatment: 239 to the ertapenem group and 125 to the ceftriaxone group. Three patients in the ertapenem group and 2 in the ceftriaxone group did not receive study therapy. Of the treated patients, 77.1% (182/236) of patients in the ertapenem group and 75.6% (93/123) in the ceftriaxone group were clinically evaluable. Among clinically evaluable patients, the mean (SD) durations of parenteral and total (parenteral plus optional oral) therapy were 5.5 (2.6) and 11.5 (2.7) days for ertapenem and 5.6 (2.8) and 11.7 (3.0) days for ceftriaxone, respectively. Streptococcus pneumoniae was the most frequently isolated pathogen in both treatment groups. Cure rates were 92.2% for clinically evaluable patients in the ertapenem group and 93.6% for those in the ceftriaxone group (95% CI for the difference, adjusted for stratum, -8.6 to 5.7), fulfilling the criteria for statistical equivalence. At completion of parenteral therapy, 94.7% of patients in the ertapenem group and 95.8% in the ceftriaxone group showed clinical improvement. Infused vein complications (ertapenem, 3.4% [8/236]; ceftriaxone, 7.3% [9/123]) and elevated transaminase levels (ertapenem, 6.3% [13/207]; ceftriaxone, 7.1% [8/113]) were the most common adverse events in both groups.. In this study of hospitalized adult patients, ertapenem therapy, with an oral switch option, was as effective as ceftriaxone with the same oral switch option for treatment of CAP requiring initial parenteral therapy. The overall safety profiles of the 2 drugs were comparable.

Topics: Aged; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Community-Acquired Infections; Double-Blind Method; Ertapenem; Europe; Female; Hospitalization; Humans; Injections, Intramuscular; Injections, Intravenous; Lactams; Latin America; Male; Middle Aged; Pneumonia, Pneumococcal; Prospective Studies; Severity of Illness Index; Streptococcus pneumoniae; Treatment Outcome; United States

This study aimed to compare the efficacy and safety of oral gemifloxacin, an enhanced-affinity quinolone, with sequential therapy with IV ceftriaxone followed by oral cefuroxime (with or without a macrolide) in patients hospitalized for community-acquired pneumonia (CAP).. A randomized, open-label, multicenter study comprised adults hospitalized with a clinical and radiologic diagnosis of CAP. Patients were randomized 1:1 to receive either (1) oral gemifloxacin 320 mg once daily (7-14 days); or (2) IV ceftriaxone 2 g once daily (1-7 days) followed by oral cefuroxime 500 mg twice daily (1-13 days) for a total of < or = 14 days. Patients receiving ceftriaxone/cefuroxime were allowed concomitant macrolide treatment.. A total of 345 patients were randomized, of whom 341 received at least 1 dose of study medication (gemifloxacin, 169/172; ceftriaxone/cefuroxime, 172/173). Clinical success rates in the clinically evaluable (CE) population at follow-up (day 21-28 post-therapy), the primary end point, were 92.2% (107/116) for gemifloxacin and 93.4% (113/121) for ceftriaxone/cefuroxime (treatment difference, -1.15; 95% CI, -7.73 to 5.43). In patients in Fine risk classes IV and V, the clinical success rate was 87.0% (20/23) for gemifloxacin versus 83.3% (20/24) for ceftriaxone/cefuroxime. No difference in clinical response at follow-up was noted based on macrolide use. Bacteriologic success rates at follow-up in the bacteriologically evaluable (BE) population were 90.6% (58/64) for gemifloxacin and 87.3% (55/63) for ceftriaxone/cefuroxime (treatment difference 3.32; 95% CI, -7.57 to 14.21). The clinical success rate in bacteremic patients at follow-up (BE population) was 100.0%. Both treatments were generally well tolerated. The frequency and types of adverse events were similar between the 2 groups. The most common treatment-related adverse events with gemifloxacin were diarrhea, liver-function adverse events, and rash; with ceftriaxone/cefuroxime, they were diarrhea, elevated hepatic-enzyme activity, and moniliasis.. The clinical efficacy and tolerability of oral gemifloxacin 320 mg once daily were similar to those of IV ceftriaxone followed by oral cefuroxime (with or without a macrolide) in the treatment of adult patients hospitalized with moderate to severe CAP. Both treatments were effective in bacteremic patients and those at increased risk of mortality.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Infective Agents; Ceftriaxone; Cefuroxime; Community-Acquired Infections; Drug Therapy, Combination; Female; Fluoroquinolones; Follow-Up Studies; Gemifloxacin; Hospitalization; Humans; Injections, Intravenous; Length of Stay; Macrolides; Male; Middle Aged; Naphthyridines; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Treatment Outcome

Levofloxacin is a new fluoroquinolone active against S. pneumoniae. Oral and intravenous administration is available. The aim of this study was to determine its efficacy in community-acquired pneumonia.. Five clinical trials included 1989 patients eligible for analysis. The dosage was 500 mg once or twice a day depending on the studies. Levofloxacin was compared with amoxicillin (3 g/d), amoxicillin/clavulanic acid (1500 mg/d), ceftriaxone (1-4 g/d combined or not with a macrolide and/or relay cefuroxime axetil).. In these studies and among the patients eligible for analysis, microbiologically proven S. pneumoniae pneumonia occurred in 170 of the patients treated with levofloxacine and in 140 treated with the comparator. Bacteriemia was evidenced in 51/170 of the levofloxacin-treated patients (30%) and in 45/140 (32%) of the comparator-treated patients. At treatment end, clinical success rate was 93.5% (159/170) for levofloxacin and 90.7% (127/140) for comparators. S. pneumoniae eradication rate was comparable for levofloxacin (94.9%) and comparators (95.3%). In patients with bacteriemia, the clinical success rate was 86.2% (44/51) for levofloxacin and 84.4% (38/45) for comparators.. These findings establish the efficacy of levofloxcin for the treatment of pneumococcal pneumonia, a major treatment challenge in community-acquired pneumonia. This compound has its place in the context of good use of antibiotics. Levofloxacin should be used in priority for patients with risk factors for complications with rapidly unfavorable course or as second intention treatment when re-evaluating insufficient therapeutic response.

Topics: Adult; Aged; Amoxicillin; Anti-Infective Agents; Ceftriaxone; Cefuroxime; Clavulanic Acid; Community-Acquired Infections; Drug Therapy, Combination; Humans; Levofloxacin; Middle Aged; Ofloxacin; Pneumonia, Pneumococcal

Preliminary results have recently shown that an early switch from parenteral antimicrobials to an oral substitute provides an effective means of treating pneumonia in pediatric patients. In a controlled randomized study, 62 children with community-acquired lobar/segmental pneumonia were selected to receive 8 days of cefixime or amoxicillin-clavulanate after an initial therapy of two doses of parenteral ceftriaxone. Enrollment criteria included: age 6 months to 5 years, fever > 38.5 degrees C, white blood cell (WBC) count > or = 15,000/ mm3, and lobar/segmental pneumonia on chest radiograph. Twenty-nine patients were randomized to receive oral cefixime and 33 to oral amoxicillin-clavulanate. The two groups were comparable in the following pretreatment parameters: age, duration of illness, temperature, mean WBC count, erythrocyte sedimentation rate, C-reactive protein, and need for hospitalization. Days of resolution of high fever, tachypnea, cough, grunting, and laboratory test abnormalities were similar in the two groups. Clinical response at the end of treatment showed cure, improvement, and failure in 97%, 3%, and 0%, respectively, in the cefixime group and in 88%, 6%, and 6%, respectively in the amoxicillin-clavulanate group (P = NS). We conclude that young children with community-acquired lobar/segmental pneumonia can be successfully treated with 2 days of parenteral ceftriaxone followed by 8 days of oral cefixime or amoxicillin-clavulanate.

Topics: Administration, Oral; Amoxicillin; Cefixime; Cefotaxime; Ceftriaxone; Cephalosporins; Child, Preschool; Clavulanic Acids; Drug Therapy, Combination; Female; Humans; Infant; Male; Penicillins; Pneumonia, Pneumococcal; Radiography

In phase I of a 2-phase study, 56 evaluable children (0.8 to 5 years) with lobar or segmental pneumonia received intravenous or intramuscular ceftriaxone 50 mg/kg/day for 2 days followed by oral cefetamet pivoxil 20 mg/kg/day in 2 divided doses to complete 7 days of treatment. All patients achieved a clinical cure. In phase II, a randomised open multicentre study, 62 children with pneumonia received an identical regimen to phase I (arm A), and 59 children received ceftriaxone 50 mg/kg/day for 1 day followed by 6 days' treatment with cefetamet pivoxil 20 mg/kg/day (arm B). Patients from phase I and arm A were combined giving a total of 118 evaluable patients in arm A. At the end of treatment, 100% of patients in arm A and 96% in arm B achieved a clinical cure; cure was maintained in 99 and 98% of patients, respectively. Two (4%) patients in arm B failed therapy; in both cases, factors other than treatment failure may have accounted for the poor response. 11 and 12% of patients in treatment arms A and B, respectively, experienced adverse events; gastrointestinal events (nausea and/or vomiting) were reported in 9 and 8% of patients, respectively. In conclusion, 1 or 2 days' treatment with parenteral ceftriaxone before switching to oral cefetamet pivoxil was safe and effective in the treatment of childhood pneumonia. Therefore, parenteral-oral switch is a feasible treatment option in the treatment of serious paediatric community-acquired pneumonia.

Topics: Administration, Oral; Biological Availability; Blood Sedimentation; C-Reactive Protein; Ceftizoxime; Ceftriaxone; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Half-Life; Humans; Infant; Injections, Intramuscular; Injections, Intravenous; Leukocyte Count; Male; Pneumonia, Pneumococcal; Prospective Studies; Treatment Outcome

Objectives The multi-center clinical microbiological study in Taiwan aimed to evaluate the impact of childhood PCV13 immunization on pneumococcal disease, and the magnitude of serotype replacement in invasive and non-invasive pneumococcal disease among all age groups. Methods The study of culture-confirmed pneumococcal disease (CCPD) was conducted at four hospitals across Taiwan in 2015-2018. Pneumococcal pneumonia was defined as clinical diagnosis with positive sputum or bronchoalveolar lavage culture. Serotyping, multi-locus sequence typing, and antimicrobial susceptibility testing for penicillin and ceftriaxone were performed. Results A total of 1413 CCPD cases were identified. Invasive pneumococcal disease (IPD) accounted for 13.4% (190/1413) of CCPD. PCV7-type CCPD incidence declined among all age groups between 2015 and 2018. In adults aged 50-64 years, PCV7-type pneumococcal pneumonia incidence in 2018 was 72% lower than that in 2015, and all pneumococcal pneumonia incidence was 35% lower than that in 2015. In children, CCPD incidence was higher in 2018 than in 2015 (IRR 1.75 for age < 5 years, IRR 1.56 for age 5-17 years). Incidence of CCPD caused by non-PCV13-types, mainly 15A and 23A, increased significantly in those younger than 50 years. Serotypes 19A and 19F constituted the largest clonal complex, CC236/320 (n = 280, 19.8%). The rates of penicillin and ceftriaxone non-susceptibility were higher in PCV13-type isolates. Conclusions Childhood PCV13 immunization exerted an indirect protection to vaccine serotype clinically defined non-bacteremic pneumococcal pneumonia among adults, especially those between 50 and 64 years of age. Emerging non-PCV13 serotypes mainly caused non-invasive mucosal disease among children.

Topics: Adolescent; Adult; Anti-Infective Agents; Ceftriaxone; Child; Child, Preschool; Genotype; Humans; Incidence; Middle Aged; Multilocus Sequence Typing; Penicillins; Pneumococcal Infections; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Serogroup; Serotyping; Streptococcus pneumoniae; Taiwan

Serogroup 6 remains common in the pneumococcal-conjugated vaccine era in Bulgaria; therefore, we investigated its clonal and serotype dynamics. The antibiotic susceptibilities were assessed by broth microdilution. Strains identified as serogroup 6 with latex agglutination method were subjected to serotype-specific PCRs. Erythromycin-resistant strains were analyzed by PCR for presence of ermB and mefE genes. MLST was performed to define clonal composition of the sequence types (STs). Serogroup 6 was represented by 40 (13.3%) from 301 invasive and non-invasive Streptococcus pneumoniae isolates. Molecular serotyping revealed new emerging serotype 6C (6.6%), not detected in pre-vaccine era. Among unvaccinated patients, mostly we observed serotypes 6А (57.1%) and 6В (28.6%). Serotype 6C was distinctive for vaccinated children (64%), followed by 6A (24%). Penicillin and ceftriaxone non-susceptible serogroup 6 strains were 65% and 5%, respectively; erythromycin- and clindamycin-resistant were 70.0% and 52.5%, respectively. Multidrug-resistant strains were 57.5%. Prevalent genetic determinant for macrolide resistance was ermB gene (75%). MLST revealed 17 STs into 5 clonal complexes and 7 singletons. Predominant genetic lineage was CC386, represented by MDR-6C non-invasive strains. Serotype 6B, principally responsible for invasive diseases in the pre-vaccine era, retreated this position to serotype 6A.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bulgaria; Ceftriaxone; Child; Child, Preschool; Clindamycin; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Infant; Infant, Newborn; Methyltransferases; Microbial Sensitivity Tests; Middle Aged; Multilocus Sequence Typing; Penicillins; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Serotyping; Streptococcus pneumoniae; Young Adult

To investigate drug resistance features and homology among penicillin-intermediate. Fifty-one penicillin-intermediate. Transmission of penicillin-intermediate

Topics: Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Child, Preschool; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Molecular Typing; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Polymerase Chain Reaction; Retrospective Studies; Sequence Homology, Nucleic Acid; Streptococcus pneumoniae; Vancomycin

Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key signaling protein controlling the activation of various immune cells, including macrophages and neutrophils. The aim of this study was to determine whether ibrutinib treatment ameliorates acute lung inflammation during pneumococcal pneumonia.. Mice were treated orally with ibrutinib and the effect on acute pulmonary inflammation elicited by the gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during ceftriaxone-treated pneumococcal pneumonia was assessed.. Treatment with ibrutinib prior to and after intranasal LTA instillation reduced alveolar macrophage activation, neutrophil influx, cytokine release and plasma leakage into the lung. Postponed treatment with ibrutinib supplementing antibiotic therapy during ongoing pneumococcal pneumonia did not impair bacterial killing in lung, blood and spleen. In this setting, ibrutinib reduced alveolar macrophage and systemic neutrophil activation and substantially diminished further monocyte and neutrophil influx in the lung. In vitro, ibrutinib inhibited macrophage TNF secretion and neutrophil activation upon LTA and pneumococcal stimulation.. Taken together, these data indicate that the Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses during acute pulmonary inflammation evoked by LTA and antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Ceftriaxone; Lipopolysaccharides; Lung; Male; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Piperidines; Pneumonia, Pneumococcal; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Teichoic Acids

Invasive S. pyogenes diseases are uncommon, serious infections with high case fatality rates (CFR). There are few publications on this subject in the field of pediatrics. This study aimed at characterizing clinical and laboratory aspects of this disease in Chinese children.. A retrospective study was conducted and pediatric in-patients with S. pyogenes infection identified by cultures from normally sterile sites were included, who were diagnosed and treated in 9 tertiary hospitals during 2010-2017.. A total of 66 cases were identified, in which 37 (56.1%) were male. The median age of these patients, including 11 neonates, was 3.0 y. Fifty-nine (89.4%) isolates were determined from blood. Fever was the major symptom (60/66, 90.9%) and sepsis was the most frequent presentation (64/66, 97.0%, including 42.4% with skin or soft tissue infections and 25.8% with pneumonia. The mean duration of the chief complaint was (3.8 ± 3.2) d. Only 18 (27.3%) patients had been given antibiotics prior to the hospitalization. Among all patients, 15 (22.7%) developed streptococcal toxin shock syndrome (STSS). No S. pyogenes strain was resistant to penicillin, ceftriaxone, or vancomycin, while 88.9% (56/63) and 81.4% (48/59) of the tested isolates were resistant to clindamycin and erythromycin respectively. Most of the patients were treated with β-lactams antibiotics and 36.4% had been treated with meropenem or imipenem. Thirteen (19.7%) cases died from infection, in which 9 (13.6%) had complication with STSS.. Invasive S. pyogenes infections often developed from skin or soft tissue infection and STSS was the main cause of death in Chinese children. Ongoing surveillance is required to gain a greater understanding of this disease.

Topics: Ceftriaxone; Child, Preschool; China; Clindamycin; Drug Resistance, Bacterial; Erythromycin; Female; Fever; Humans; Infant; Infant, Newborn; Male; Penicillins; Pneumonia, Pneumococcal; Retrospective Studies; Sepsis; Shock, Septic; Skin Diseases, Bacterial; Soft Tissue Infections; Streptococcal Infections; Streptococcus pyogenes; Tertiary Care Centers; Vancomycin

A 34-year-old HIV-positive man with a history of chronic substance abuse was admitted with dual infection of Streptococcus pneumoniae and Listeria monocytogenes. Combined bacteraemia with S. pneumoniae and L. monocytogenes is very rare. To the best of our knowledge, this is the first such case documented at our institution and in South Africa. Ampicillin should be added to antibiotic regimens to improve patient outcome if L. monocytogenes infection is suspected. Co-infections that occur with L. monocytogenes may have conflicting antibiotic treatment options. This case report emphasises the need for a good relationship between the local microbiology pathologist and physician to select appropriate antibiotic treatment before definitive results are available.

Topics: Adult; Ampicillin; Anemia; Anti-Bacterial Agents; Blood Transfusion; CD4 Lymphocyte Count; Ceftriaxone; Coinfection; Fatal Outcome; HIV; HIV Seropositivity; Humans; Listeria monocytogenes; Listeriosis; Male; Multiple Organ Failure; Pneumonia, Pneumococcal; Respiration, Artificial; Streptococcus pneumoniae

Bacteremic pneumococcal pneumonia (BPP) is a preventable disease with high morbimortality.. To evaluate clinical aspects and mortality on BPP patients admitted to a Chilean regional hospital.. We looked for adult patients with Streptococcus pneumoniae isolated from blood cultures between 2010 and 2014 years and reviewed clinical records of those who were admitted with pneumonia.. We identified 70 BPP patients: 58% were men, mean age was 56 years, 30% were > 65 years, 70% with basic public health insurance, 26% were alcoholics, 86% had comorbidities. Only two patients were vaccinated against S. pneumoniae. CURB-65 severity index for community acquired pneumonia was > 3 in 37% of patients. Twenty-four patients were admitted to ICU, twenty required mechanical ventilation and twenty-four died (34%). Mortality was associated with an age over 65 years, presence of comorbidities and complications of pneumonia. A total of 22 serotypes of S. pneumoniae were identified, five of them (1,3,7F,14 y 9V) were present in 57% of cases.. Elevated mortality of our BNN patients was associated with comorbidities and possibly with socio economic factors, which conditioned a late access to medical care.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Ceftriaxone; Chile; Community-Acquired Infections; Comorbidity; Female; Hospital Mortality; Humans; Male; Middle Aged; Pneumonia, Pneumococcal; Risk Factors; Severity of Illness Index; Socioeconomic Factors; Streptococcus pneumoniae

Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases.

Topics: Animals; Annexin A1; Anti-Bacterial Agents; Ceftriaxone; Cyclic Nucleotide Phosphodiesterases, Type 4; Lung; Lung Injury; Macrophages; Male; Mice, Inbred BALB C; Phagocytosis; Phosphodiesterase 4 Inhibitors; Pneumonia; Pneumonia, Pneumococcal; Respiratory Function Tests; Rolipram; Streptococcus pneumoniae

Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although β-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of β-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone-treated group. Notably, the analysis of cell surface markers in the ceftriaxone-plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b(+) CD11c(+)) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxone-plus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; B7-2 Antigen; Bacterial Load; CD11b Antigen; CD11c Antigen; Ceftriaxone; Community-Acquired Infections; Dendritic Cells; Disease Models, Animal; Drug Therapy, Combination; Female; Gene Expression; Histocompatibility Antigens Class II; Humans; Macrophages, Alveolar; Mice; Mice, Inbred CBA; Neutrophils; Pneumonia, Pneumococcal; Programmed Cell Death 1 Receptor; Streptococcus pneumoniae; Survival Analysis; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer

Fever is a common clinical symptom in children attending hospital outpatient clinics in rural Tanzania, yet there is still a paucity of data on the burden of bloodstream bacterial infection among these patients.. The present study was conducted at Korogwe District Hospital in north-eastern Tanzania. Patients aged between 2 and 59 months with a history of fever or measured axillary temperature ≥37.5°C attending the outpatient clinic were screened for enrolment into the study. Blood culturing was performed using the BACTEC 9050® system. A biochemical analytical profile index and serological tests were used for identification and confirmation of bacterial isolates. In-vitro antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion method. The identification of Plasmodium falciparum malaria was performed by microscopy with Giemsa stained blood films.. A total of 808 blood cultures were collected between January and October 2013. Bacterial growth was observed in 62/808 (7.7%) of the cultured samples. Pathogenic bacteria were identified in 26/808 (3.2%) cultures and the remaining 36/62 (58.1%) were classified as contaminants. Salmonella typhi was the predominant bacterial isolate detected in 17/26 (65.4%) patients of which 16/17 (94.1%) were from patients above 12 months of age. Streptococcus pneumoniae was the second leading bacterial isolate detected in 4/26 (15.4%) patients. A high proportion of S. typhi 11/17 (64.7%) was isolated during the rainy season. S. typhi isolates were susceptible to ciprofloxacin (n = 17/17, 100%) and ceftriaxone (n = 13/17, 76.5%) but resistant to chloramphenicol (n = 15/17, 88.2%). P. falciparum malaria was identified in 69/808 (8.5%) patients, none of whom had bacterial infection.. Bloodstream bacterial infection was not found to be a common cause of fever in outpatient children; and S. typhi was the predominant isolate. This study highlights the need for rational use of antimicrobial prescription in febrile paediatric outpatients presenting at healthcare facilities in rural Tanzania.

Topics: Acute Disease; Anti-Bacterial Agents; Bacteremia; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Ciprofloxacin; Drug Resistance, Bacterial; Female; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Microbial Sensitivity Tests; Microscopy; Outpatients; Plasmodium falciparum; Pneumonia, Pneumococcal; Rural Population; Salmonella typhi; Streptococcus pneumoniae; Tanzania; Typhoid Fever

In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10(6) CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Levofloxacin; Male; Mice; Mice, Inbred BALB C; N-Acetylmuramoyl-L-alanine Amidase; Pneumococcal Infections; Pneumonia; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Streptolysins; Virulence; Virulence Factors

Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 μg/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 23 μg/ml, T(1/2) = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 10(7) CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥ 3 log(10) CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤ 0.008, 0.25, 0.25, and 0.5 μg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 μg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, -5.49 log(10) CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, -2.03 log(10) CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [-5.91 log(10) CFU/ml, P ≤ 0.002], SP 90 [-5.26 log(10) CFU/ml, P ≤ 0.008], and SP1466 [-5.14 log(10) CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Community-Acquired Infections; Culture Media; Half-Life; Humans; Microbial Sensitivity Tests; Models, Biological; Pneumonia, Pneumococcal; Streptococcus pneumoniae

To assess the effectiveness of guidelines and education on empirical therapy for community-acquired pneumonia.. Administrative records for children with a primary diagnosis of pneumonia from January 2007 to September 2009 were reviewed. Antimicrobial use was measured monthly over 3 periods: (1) before creation of an antimicrobial stewardship task force (ASTF), (2) after ASTF formation but before release of guidelines for antimicrobial use, and (3) after guideline release. Antimicrobial use over time was assessed by using quasi-binomial logistic regression models that incorporated interrupted events, seasonality, and autocorrelation. Allowing calculation of immediate changes due to specific interventions and trends in use over each time period. The primary outcome was use of ampicillin as recommended in the guidelines versus ceftriaxone, the historical standard. Secondary outcomes included other antimicrobial use, length of stay, mortality, and readmission.. One thousand two hundred forty-six children met study criteria. Ampicillin use increased from 2% at baseline to 6% after ASTF formation and 44% after guideline release. Ceftriaxone use increased slightly (from 56% to 59%) after ASTF formation but decreased to 28% after guideline release. An immediate change in prescription occurred in the month after guideline publication and remained stable over the following year.. Guidelines and education can have an impact on antimicrobial use in the pediatric setting. Although the optimal strategies for pediatric antimicrobial stewardship programs still are being determined, we believe that our approach offers an inexpensive and low-risk step in the right direction.

Topics: Ampicillin; Anti-Bacterial Agents; Azithromycin; Ceftriaxone; Child; Child, Preschool; Clindamycin; Community-Acquired Infections; Consensus; Drug Substitution; Drug Utilization; Evidence-Based Medicine; Female; Guideline Adherence; Hospitals, Pediatric; Humans; Infant; Inservice Training; Kentucky; Length of Stay; Logistic Models; Male; Patient Readmission; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Practice Patterns, Physicians'; Survival Analysis; Treatment Outcome; Vancomycin

Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh-TFPI) attenuates sepsis-induced coagulation and has been evaluated in clinical trials involving patients with sepsis and community-acquired pneumonia.. To examine the effect of rh-TFPI on coagulation, inflammation and bacterial outgrowth in S. pneumoniae pneumonia in mice, with or without concurrent antibiotic treatment.. Pneumonia was induced by intranasal inoculation with S. pneumoniae. Mice were treated with placebo, rh-TFPI, ceftriaxone or rh-TFPI combined with ceftriaxone. Early (8 h) and late (24 h) initiated treatments were evaluated. Samples were obtained 24 or 48 h after infection, for early and late initiated treatment, respectively. In vitro, placebo or rh-TFPI was added to a suspension of S. pneumoniae.. Rh-TFPI reduced pneumonia-induced coagulation; rh-TFPI with ceftriaxone further attenuated coagulation relative to ceftriaxone alone. Rh-TFPI inhibited accumulation of neutrophils in lung tissue and reduced the levels of several cytokines and chemokines in lungs and plasma in mice not treated with antibiotics; in these animals, rh-TFPI initiated 24 h after infection decreased pulmonary bacterial loads. In vitro, rh-TFPI also inhibited growth of S. pneumoniae.. Therapeutic rh-TFPI attenuates coagulation, inflammation and bacterial growth during pneumococcal pneumonia, whereby the latter two effects only become apparent in the absence of concurrent antibiotic treatment.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Inflammation Mediators; Injections, Intraperitoneal; Lipoproteins; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Recombinant Proteins; Streptococcus pneumoniae; Time Factors

See also van den Boogaard FE, Brands X, Schultz MJ, Levi M, Roelofs JJTH, van 't Veer C, van der Poll T. Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inflammatory and antimicrobial effects in murine pneumococcal pneumonia. This issue, pp 122-32.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Ceftriaxone; Drug Therapy, Combination; Humans; Inflammation Mediators; Lipoproteins; Pneumonia, Pneumococcal; Recombinant Proteins; Streptococcus pneumoniae

Ceftaroline (CPT) is a new cephalosporin exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), as well as common Gram-negative pathogens. This study investigated the in vivo efficacy of a 48-hour simulated human dose regimen of CPT compared with ceftriaxone (CRO) against isolates of S. pneumoniae with different susceptibilities to penicillin in a rabbit pneumonia model. Three S. pneumoniae strains were used: CRO-susceptible penicillin-susceptible S. pneumoniae (CRO-S PSSP), CRO-susceptible penicillin-intermediate S. pneumoniae (CRO-S PISP), and CRO-resistant penicillin-resistant S. pneumoniae (CRO-R PRSP). Animals were randomized to the control group (no treatment) (n = 22) or to a group given intravenous (IV) CPT human equivalent (HE) dosage (600 mg/12 h; n = 19) or IV CRO HE dosage (1 g/24 h; n = 19). The total doses needed to achieve the HE dosage were 71 and 82 mg/kg of body weight/24 h for CRO and CPT, respectively. One group of rabbits infected with the CRO-R PRSP strain received intramuscular (IM) administration of CPT (5 or 20 mg/kg twice daily; n = 5 for each). Evaluation of efficacy was based on bacterial counts in the lungs and spleen. For IV CPT and IV CRO, the mean areas under the concentration-time curves from 0 to 24 h (AUC(0-24)s) were 155 and 938 mg · h/liter, respectively, the maximum concentrations in serum (C(max)s) were 20 and 158 mg/liter, respectively, and the minimum concentrations in serum (C(min)s) were 1.3 and 6 mg/liter, respectively. Both agents effectively treated pulmonary infections caused by CRO-S PSSP or CRO-S PISP with complete bacterial eradication in the lungs and spleen after 2 days of treatment. Against PRSP, CPT demonstrated excellent bactericidal activity, reducing bacterial counts in the lungs and spleen by approximately 8 and 4 log units, respectively (P < 0.001); CRO treatment resulted in a 2-log-unit reduction in the bacterial counts in lungs that did not reach statistical significance. Twice-daily IM CPT (5 mg/kg) reduced the bacterial burden by approximately 6 log units in the lungs and 3 log units in the spleen, and the 20-mg/kg dosage effectively eradicated PRSP infection. These findings further validate the in vivo bactericidal activity of CPT against pneumococci.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Humans; Male; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Pneumococcal; Rabbits; Streptococcus pneumoniae

Purulent pericarditis is an extremely rare complication of invasive Streptococcus pneumoniae infection among children in the antibiotic era, and its mortality remains high if left untreated. This report involves a 4½-year-old girl who presented to our emergency department with productive cough, shortness of breath, and left-sided chest pain with a diagnosis of pneumococcal pneumonia. She subsequently developed life-threatening conditions including bilateral empyema with respiratory failure, purulent pericarditis, and multiple organ failure leading to death. The case highlights that purulent pericarditis is a rare yet possible disorder complicating pneumococcal disease in the antibiotic era. The increase in strains resistant to penicillin should alert emergency physicians to the potential for reemergence of pneumococcal pericarditis in children.

Topics: Anti-Bacterial Agents; Ceftriaxone; Child, Preschool; Empyema, Pleural; Fatal Outcome; Female; Humans; Pericarditis; Pleural Effusion; Pneumonia, Pneumococcal; Respiration, Artificial; Thoracostomy; Ultrasonography; Vancomycin

Daptomycin is a novel lipopeptide antibiotic with excellent activity against Gram-positive bacterial pathogens, but its therapeutic value for the treatment of invasive pneumococcal disease compared to that for the treatment of pneumococcal pneumonia is incompletely defined. We investigated the efficacy of daptomycin in two models of Streptococcus pneumoniae-induced lung infection, i.e., pneumococcal pneumonia and septic pneumococcal disease. Mice were infected with a bioluminescent, invasive serotype 2 S. pneumoniae strain or a less virulent serotype 19 S. pneumoniae strain and were then given semitherapeutic or therapeutic daptomycin or ceftriaxone. Readouts included survival; bacterial loads; and septic disease progression, as determined by biophotonic imaging. Semitherapeutic daptomycin treatment fully protected the mice against the progression of septic disease induced by serotype 2 S. pneumoniae, while therapeutic treatment of the mice with daptomycin or ceftriaxone led to approximately 70% or approximately 60% survival, respectively. In contrast, mice infected with serotype 19 S. pneumoniae developed severe pneumonia and lung leakage even in the presence of increased intra-alveolar daptomycin levels, resulting in only 40% survival, whereas the ceftriaxone-treated mice had 100% survival. Together, although daptomycin demonstrates little efficacy in the treatment of pneumococcal pneumonia, daptomycin is highly effective in preventing S. pneumoniae-induced septic death, thus possibly offering a therapeutic option for patients with life-threatening septic pneumococcal disease.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Daptomycin; Disease Models, Animal; Mice; Mice, Inbred C57BL; Pneumococcal Infections; Pneumonia, Pneumococcal; Sepsis; Streptococcus pneumoniae

Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The factor V Leiden (FVL) mutation results in resistance of activated FV to inactivation by activated protein C and thereby in a prothrombotic phenotype. Human heterozygous FVL carriers have been reported to be relatively protected against sepsis-related mortality. We here determined the effect of the FVL mutation on coagulation, inflammation, bacterial outgrowth and outcome in murine pneumococcal pneumonia.. Wild-type mice and mice heterozygous or homozygous for the FVL mutation were infected intranasally with 2*106 colony forming units of viable S. pneumoniae. Mice were euthanized after 24 or 48 hours or observed in a survival study. In separate experiments mice were treated with ceftriaxone intraperitoneally 24 hours after infection and euthanized after 48 hours or observed in a survival study.. The FVL mutation had no consistent effect on activation of coagulation in either the presence or absence of ceftriaxone therapy, as reflected by comparable lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products. Moreover, the FVL mutation had no effect on lung histopathology, neutrophil influx, cytokine and chemokine levels or bacterial outgrowth. Remarkably, homozygous FVL mice were strongly protected against death due to pneumococcal pneumonia when treated with ceftriaxone, which was associated with more pronounced FXIII depletion; this protective effect was not observed in the absence of antibiotic therapy.. Homozygosity for the FVL mutation protects against lethality due to pneumococcal pneumonia in mice treated with antibiotics.

Topics: Activated Protein C Resistance; Animals; Anti-Bacterial Agents; Blood Coagulation Tests; Ceftriaxone; Factor V; Female; Homozygote; Lung; Male; Mice; Pneumonia, Pneumococcal; Point Mutation

Recombinant human activated protein C (APC) improves survival of patients with severe sepsis; this beneficial effect is especially apparent in patients with pneumococcal pneumonia. The aim of this study was to determine the effect of APC treatment initiated after induction of pneumococcal pneumonia on pulmonary coagulation, inflammation, and survival, with or without concurrent antibiotic therapy.. Mice were infected intranasally with viable Streptococcus pneumoniae and were treated intraperitoneally after 24 h of infection with vehicle, recombinant mouse (rm) APC (125 μg), ceftriaxone (500 μg), or rm-APC plus ceftriaxone. Treatment with rm-APC or vehicle was repeated every 8 h for a maximum of 96 h. Animals were either killed 48 h after infection or were monitored in a survival study (with an extra dose of ceftriaxone given after 72 h).. Rm-APC treatment inhibited pulmonary activation of coagulation, as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Rm-APC did not affect the pulmonary levels of 55 inflammatory mediators in the context of antibiotic therapy. Rm-APC added to ceftriaxone markedly improved survival, compared with ceftriaxone treatment alone.. Rm-APC inhibits pulmonary activation of coagulation and, when added to antibiotic therapy, improves survival in murine pneumococcal pneumonia.

Topics: Animals; Anti-Bacterial Agents; Blood Coagulation Factors; Ceftriaxone; Coagulation Protein Disorders; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Protein C; Recombinant Proteins

A case of Streptococcus pneumoniae meningitis in a possibly immune-compromised child with a ventriculoatrial shunt is described. The infection was successfully eradicated by treatment with intravenous ceftriaxone and rifampicin, without removal of the shunt.

Topics: Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid Shunts; Drug Therapy, Combination; Female; Humans; Infant; Meningitis, Pneumococcal; Pneumonia, Pneumococcal; Prosthesis-Related Infections; Rifampin

Topics: Adult; Aged; Ambulatory Care; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Male; Middle Aged; Patient Admission; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Pneumonia, Viral; Risk Factors; Systemic Inflammatory Response Syndrome

Recurrent systemic pneumococcal infection usually occurs in immunocompromised patients and patients with underlying conditions.. Between 1993 and 2006, investigators at 8 pediatric hospitals prospectively identified cases of invasive pneumococcal disease (IPD) and retrospectively documented demographics and clinical information. Antibiotic susceptibility was determined for penicillin and ceftriaxone by microbroth dilution. Isolates were serotyped and molecular relatedness determined using pulse field gel electrophoresis (PFGE).. Four thousand sixty-seven children were diagnosed with IPD over 12.3 years. One hundred and 8 episodes of recurrent disease were seen in 90 children (2.6%); 75 experienced 2 infections, 12 experienced 3 infections and 3 experienced 4 infections. Fourteen of the 15 children with >2 episodes of infection had underlying conditions. The mean duration between 1st and 2nd infection was 22.9 weeks for children with no known underlying condition and 43.0 weeks for children with an underlying condition (P = 0.001). Seventy episodes of IPD among the 90 patients were caused by a different serotype or a different genotype as demonstrated by the PFGE. Sixteen children had intervals <30 days between infections; 7 were caused by different strains.. Approximately 80% of the children with recurrent invasive pneumococcal disease had underlying conditions. Seven of 16 children with recurrent infection <30 days apart were caused by acquisition of a new strain. Relapse of infection requires documentation that the pneumococcal isolates are not only the same serotype but also have the same PFGE patterns.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftriaxone; Cellulitis; Child; Child, Preschool; DNA Fingerprinting; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Genotype; Humans; Immunocompromised Host; Infant; Male; Microbial Sensitivity Tests; Penicillins; Pneumococcal Infections; Pneumonia, Pneumococcal; Recurrence; Serotyping; Streptococcus pneumoniae

Streptococcus pneumoniae ( S. pneumoniae ) has been associated with hemolytic uremic syndrome (HUS), which is an unusual but serious disease in childhood. We conducted a retrospective review of children aged less than 18 years with S. pneumoniae -associated HUS in northern Taiwan from January 2000 to June 2005. The demographic characters, clinical courses, and outcomes were analyzed. Seven children (three girls, four boys) with S. pneumoniae -associated HUS were studied. The median age at onset of HUS was 40 months (range: 25-60 months). The median duration of hospital stay was 36 days (range: 15-50 days). The interval between the onset of illness attributable to S. pneumoniae and the development of HUS was around 1-2 weeks. The onset of oliguria developed within 2 weeks after illness. Six patients required dialysis with median duration of 16 days. Three patients had leukopenia as the initial presentation. All seven patients had pneumococcal pneumonia complicating with empyema, and two of them received decortication via video-assisted thoracoscopic surgery. Between patients who needed dialysis or not, there was no significant difference in age, sex, duration of thrombocytopenia, incidence of extra-renal complications, such as hepatitis, pancreatitis, and hypertension, and length of hospital stay. The seven patients survived with normal renal function. HUS is a potentially fatal complication of S. pneumoniae infection. Clinicians managing patients with pneumococcal pneumonia with empyema accompanied by leukopenia should beware of the development of HUS. The long-term prognosis for recovery of renal function appears to be good in these patients in northern Taiwan.

Topics: Anti-Bacterial Agents; Ceftriaxone; Child, Preschool; Empyema, Pleural; Erythrocyte Transfusion; Female; Hemolytic-Uremic Syndrome; Humans; Length of Stay; Leukopenia; Male; Oliguria; Platelet Transfusion; Pneumonia, Pneumococcal; Renal Dialysis; Respiration, Artificial; Retrospective Studies; Taiwan; Thoracostomy; Thrombocytopenia

Novel rifamycins such as ABI-0043, ABI-0369, and ABI-0699 had comparable in vivo bactericidal activity with ceftriaxone against a penicillin-G-resistant, mefA-positive Streptococcus pneumoniae in a murine pneumonia model. ABI-0043 demonstrated a dose-dependent response with a high correlation to bacterial kill (+0.1 to -3.7 log 10CFU).

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred ICR; Penicillin Resistance; Pneumonia, Pneumococcal; Rifamycins

A rat model was used to study the effects of cirrhosis on antibiotic therapy of pneumococcal pneumonia. Cirrhotic and control male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae. Treatment began 18 h later with phosphate-buffered saline (PBS), azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic concentrations were measured by high-performance liquid chromatography. Azithromycin, trovafloxacin, and ceftriaxone were all equally effective at preventing mortality in both cirrhotic and normal rats. Free fraction area under the curve to minimum inhibitory concentration ratio (AUC/MIC) and maximum calculated serum concentration to MIC ratio (C(max)/MIC) and percent time that the serum concentration exceeded the MIC (%T > MIC) were greater for ceftriaxone compared with azithromycin or trovafloxacin. Azithromycin achieved higher concentrations in bronchoalveolar lavage fluid (BALF), epithelial lining fluid (ELF), and BAL white blood cells than ceftriaxone or trovafloxacin in cirrhotic rats. Macrolide, beta-lactam, or fluoroquinolone antibiotic efficacy in a pneumococcal pneumonia model does not appear to be affected by hepatic cirrhosis.

Topics: Animals; Azithromycin; Biological Availability; Blood Chemical Analysis; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Fluoroquinolones; Injections, Subcutaneous; Liver Cirrhosis; Male; Naphthyridines; Pneumonia, Pneumococcal; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Risk Assessment; Sensitivity and Specificity; Survival Rate

Anti-inflammatory therapy with interleukin-10 (IL-10) was previously reported to reduce pulmonary inflammation and to prevent septicaemia in murine pneumococcal pneumonia treated with ceftriaxone. In the present report, we investigated the influence of pulmonary infection and IL-10 administration on the pharmacokinetics of ceftriaxone.. CD1 mice were infected with 10(7) cfu of Streptococcus pneumoniae. Treatments (intraperitoneal) with IL-10 (1 microg per mouse), ceftriaxone (20 mg/kg) or the combination of IL-10 + ceftriaxone were initiated 18 h after infection. Groups of mice were sacrificed at several time points from 5 min to 24 h after initiation of therapy. Ceftriaxone was quantified in blood and lungs using a microbiological assay. Additional groups of mice received a second dose of IL-10 at 36 h post-infection. Survival rates were recorded over 14 days.. The clearance of ceftriaxone was significantly reduced in infected mice compared with that in non-infected animals (P < 0.01), whereas AUC, mean residence time, t(1/2) and AUC(lung)/AUC(serum) were significantly enhanced (P < 0.01, 0.01, 0.05, 0.05). Co-administration of IL-10 with ceftriaxone in infected animals further retained ceftriaxone in the bloodstream and reduced its volume of distribution at steady state and the ratio of AUC(lung)/AUC(serum). IL-10 alone did not modify significantly the pharmacokinetics of ceftriaxone in blood and lungs of non-infected animals.. The results suggest that pulmonary infection, and therapy with IL-10, both affect the pharmacokinetics of ceftriaxone. Indeed, administration of IL-10 + ceftriaxone improved the survival rate of mice (P < 0.001 compared with therapy with ceftriaxone alone). IL-10 should be considered as an adjunctive therapy to antibiotics against severe infections.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Drug Therapy, Combination; Female; Inflammation; Interleukin-10; Lung; Mice; Pneumonia, Pneumococcal; Streptococcus pneumoniae

BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.

Topics: Animals; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Female; Injections, Subcutaneous; Leukopenia; Lung; Mice; Microbial Sensitivity Tests; Pneumonia, Pneumococcal; Prodrugs; Streptococcus pneumoniae; Survival Analysis

Topics: Anti-Bacterial Agents; Ceftriaxone; Culture; Humans; Language; Penicillins; Pneumonia, Pneumococcal; Terminology as Topic

Encapsulation of ciprofloxacin in sterically stabilized liposomes results in a prolonged circulation time and improved pharmacokinetics. Liposome-encapsulated ciprofloxacin was compared with conventional ciprofloxacin and ceftriaxone in a rat model of pneumococcal pneumonia. Male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae and then treated with intravenous ceftriaxone (100 mg/kg), ciprofloxacin (40 or 80 mg/kg) or liposomal ciprofloxacin (40 or 80 mg/kg) administered once or twice daily for 3 days. White blood counts, development of bacteraemia and mortality were measured for 10 days. Antibiotic concentrations in serum, lung lavage fluid and white blood cells recovered from lung lavage fluid were determined. Liposomal ciprofloxacin concentrations were significantly higher in serum and lavage fluid compared with conventional ciprofloxacin, resulting in greater area under the serum concentration-time curve and maximum serum concentration. Despite these higher concentrations, survival rates were similar between groups treated with equivalent doses of liposomal ciprofloxacin versus ciprofloxacin. When antibiotics were given once daily, ceftriaxone was more effective than either form of ciprofloxacin.

Topics: Animals; Bronchoalveolar Lavage Fluid; Ceftriaxone; Ciprofloxacin; Colony Count, Microbial; Disease Models, Animal; Leukocyte Count; Liposomes; Male; Neutrophils; Pneumonia, Pneumococcal; Rats; Rats, Sprague-Dawley; Survival Rate

The study aimed to evaluate the prevalence, clinical significance and outcome of community-acquired penicillin-resistant Streptococcus pneumoniae (PRSP) pneumonia in Thailand.. We conducted a prospective study in culture-proven pneumococcal pneumonia. Pneumococci were defined as susceptible, intermediate resistance and high resistance according to the definitions of the United States National Committee for Clinical Laboratory Standards (NCCLS).. Forty-six consecutive patients were enrolled. Of the S. pneumoniae isolates collected, 41.3% were resistant to penicillin (37% intermediate resistance and 4.3% high resistance). Resistance to other antibiotics was 13% to ceftriaxone (8.7% intermediate resistance and 4.3% high resistance), 34.8% to erythromycin, 39.1% to tetracycline, 26.1% to chloramphenicol, and 43.5% to trimethoprim -sulfamethoxazole. Prior antibiotic use within 3 months was significantly associated with resistance to penicillin. The overall mortality of pneumococcal pneumonia was 26.1%. Multilobar involvement and requirement for mechanical ventilation proved to be associated with mortality. However, resistance to penicillin or ceftriaxone was not associated with death.. According to the US NCCLS guidelines, we found a high prevalence of drug-resistant S. pneumoniae in Thai patients with community-acquired pneumonia. Prior antibiotic use was significantly associated with penicillin resistance. However, the outcome was not related to in vitro penicillin susceptibility of S. pneumoniae isolated from the patients.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftriaxone; Community-Acquired Infections; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Penicillin Resistance; Pneumonia, Pneumococcal; Prospective Studies; Thailand

Treatments aimed at inhibition of tumor necrosis factor (TNF) in patients with sepsis have been unsuccessful. Up to 50% of such patients suffer from pneumonia. To determine the effect that treatment with anti-TNF has on pneumococcal pneumonia, mice were intranasally inoculated with Streptococcus pneumoniae and, 25 h later, treated with 1 of the following: (1) control antibody, (2) anti-TNF, (3) ceftriaxone (CEF) with control antibody, or (4) CEF with anti-TNF. In the absence of treatment with CEF, mice displayed high bacterial loads in lungs, and all of these mice died within 5 days after inoculation. Anti-TNF did not influence these outcomes. In contrast, 60% of mice treated with CEF alone survived. Anti-TNF administered together with CEF reduced survival to 40% and was associated with enhanced bacterial outgrowth. These data suggest that treatment with anti-TNF impairs the therapeutic efficacy of CEF during pneumococcal pneumonia.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Ceftriaxone; Disease Models, Animal; Lung; Mice; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Topics: Adult; Anti-Bacterial Agents; Antigens, Bacterial; Bioterrorism; Cefotaxime; Ceftriaxone; Chlamydophila pneumoniae; Community-Acquired Infections; Humans; Legionnaires' Disease; Macrolides; Microbial Sensitivity Tests; Pneumonia; Pneumonia, Pneumococcal; Severe Acute Respiratory Syndrome; Streptococcus pneumoniae

We report the case of a 51-year-old man with an allergy to amoxicillin/acid clavulanique who presented with Streptococcus pneumoniae meningitis. Initial treatment consisted of an association of antibiotics including ceftriaxone. Six days after treatment was initiated the patient developed skin reaction and the diagnosis of allergy to ceftriaxone was established by the dosage of specific IgE. Typically Streptococcus pneumoniae meningitis is treated with vancomycin and a third-generation cephalosporin. This association had to be modified because cross allergy to cephalosporins could have developed in this patient who had previously reacted to penicillins.

Topics: Ceftriaxone; Cephalosporins; Humans; Male; Meningitis, Bacterial; Middle Aged; Pneumonia, Pneumococcal; Streptococcus pneumoniae

To determine the outcome of children treated primarily with beta-lactam antibiotics for a systemic infection outside the central nervous system (CNS) caused by isolates of Streptococcus pneumoniae nonsusceptible to ceftriaxone (MIC > or = 1.0 microg/ml).. Retrospective review of the medical records of children identified prospectively with invasive infections outside of the CNS caused by isolates of S. pneumoniae that were not susceptible to ceftriaxone between September, 1993, and August, 1999. A subset of this group treated primarily with beta-lactam antibiotics was analyzed for outcome.. Infants and children with pneumococcal infections cared for at eight children's hospitals.. Among 2,100 patients with invasive infections outside the CNS caused by S. pneumoniae, 166 had isolates not susceptible to ceftriaxone. One hundred patients treated primarily with beta-lactam antibiotics were identified. From this group 71 and 14 children had bacteremia alone or with pneumonia, respectively, caused by strains with an MIC of 1.0 microg/ml. Bacteremia or pneumonia caused by isolates with a ceftriaxone MIC > or = 2.0 microg/ml occurred in 6 and 5 children, respectively. Three children with septic arthritis and 1 with cellulitis had infections caused by strains with an MIC to ceftriaxone of 1.0 microg/ml. Most were treated with parenteral ceftriaxone, cefotaxime or cefuroxime for one or more doses followed by an oral antibiotic. All but one child were successfully treated. The failure occurred in a child with severe combined immune deficiency and bacteremia (MIC = 1.0 microg/ml) who remained febrile after a single dose of ceftriaxone followed by 12 days of cefprozil.. Ceftriaxone, cefotaxime or cefuroxime are adequate to treat invasive infections outside the CNS caused by pneumococcal isolates with MICs up to 2.0 microg/ml, a concentration currently considered resistant for these antibiotics by National Committee for Clinical Laboratory Standards breakpoints.

Topics: Anti-Bacterial Agents; Bacteremia; Cefotaxime; Ceftriaxone; Cefuroxime; Cephalosporin Resistance; Cephalosporins; Child; Child, Preschool; Humans; Infant; Pneumococcal Infections; Pneumonia, Pneumococcal; Retrospective Studies; Streptococcus pneumoniae

Topics: Bronchitis, Chronic; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Humans; Male; Middle Aged; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Treatment Failure

Efficacy of panipenem/betamipron (PAPM/BP) against experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae (PRSP: MIC of benzylpenicillin, > or = 1.56 micrograms/ml) in mice was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), cefozopran (CZOP), ceftriaxone (CTRX), ampicillin (ABPC), and vancomycin (VCM). The infection was induced by inoculating a PRSP clinical isolate, 9601 (serotype 6) or 10,693 (serotype 19), into ddY male mice intranasally. Drugs were administered subcutaneously at doses of 0.4, 2, and 10 mg/kg, 18, 26, 42, and 50 hours post-infection. Viable cell counts in the lungs were determined 66 hours post-infection. PAPM/BP showed the greatest efficacy against the infections among tested drugs. MICs of PAPM against PRSP 9601 and 10,693 were both 0.125 microgram/ml, which were superior to those of IPM (0.25 and 0.5 microgram/ml, respectively), MEPM (0.5 and 1 microgram/ml, respectively), CZOP (2 and 1 microgram/ml, respectively), CTRX (both 1 microgram/ml), ABPC (both 4 micrograms/ml), and VCM (0.5 and 0.25 microgram/ml, respectively). These results suggest that the potent in vivo activity of PAPM/BP reflects the potent in vitro activity of PAPM. MICs of PAPM, IPM, MEPM, and CZOP against clinical isolates, penicillin-susceptible S. pneumoniae (PSSP: MIC of benzylpenicillin, < or = 0.05 microgram/ml), penicillin-intermediate S. pneumoniae (PISP: MIC of benzylpenicillin, 0.1-0.78 microgram/ml), and PRSP, were tested by an agar dilution method. MIC90s of the drugs against the PSSP, PISP, and PRSP were as follows: PAPM, 0.012, 0.05, and 0.39 microgram/ml; IPM, < or = 0.006, 0.1, and 0.78 microgram/ml; MEPM, 0.05, 0.39, and 1.56 micrograms/ml; and CZOP, 0.2, 0.78, and 6.25 micrograms/ml, respectively. Thus, PAPM showed the most potent activity among tested drugs against clinical isolates of PISP and PRSP.

Topics: Ampicillin; Animals; beta-Alanine; Cefozopran; Ceftriaxone; Cephalosporins; Cilastatin; Cilastatin, Imipenem Drug Combination; Disease Models, Animal; Drug Combinations; Drug Resistance; Imipenem; Male; Meropenem; Mice; Mice, Inbred Strains; Penicillin Resistance; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thienamycins; Vancomycin

The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Female; Leukopenia; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Pneumococcal; Serum Bactericidal Test; Streptococcus pneumoniae; Survival Analysis; Vancomycin

Interleukin (IL)-10 is a biologically active anti-inflammatory and immunomodulatory cytokine. The respective effects or combined effect of ceftriaxone (Ctri) and IL-10 on host response was studied in a mouse model of lethal pneumococcal pneumonia. A once daily intraperitoneal (ip) injection of IL-10 (1 microg/mouse) for 2 days did not affect inflammation but accelerated bacterial dissemination to the bloodstream. Of mice treated with 1 ip 20 mg/kg Ctri injection, 40% developed septicemia, and only 52% survived. However, the addition of IL-10 to Ctri enhanced bacterial clearance, prevented septicemia, and yielded a 95% survival rate (P<.001). This approach also significantly (P<.05) decreased IL-1beta, IL-6, macrophage inflammatory protein-2, and myeloperoxidase levels in lungs and the production of nitric oxide in bronchoalveolar lavage fluid. Furthermore, Ctri plus IL-10 significantly (P<.05) reduced pulmonary vascular leakage and the appearance of red blood cells in alveoli. These data indicate a beneficial role for IL-10 as an adjunctive therapy to antibiotics against pneumococcal pneumonia.

Topics: Animals; Capillary Permeability; Ceftriaxone; Chemokines; Cytokines; Female; Inflammation; Interleukin-10; Lung; Mice; Pneumonia, Pneumococcal; Pulmonary Circulation; Sepsis; Survival Rate

A rat model of ethanol feeding was used to study the effects of ethanol on antibiotic therapy of pneumococcal pneumonia. Male Sprague-Dawley rats (150 g) received a liquid diet containing 36% of total calories as ethanol. Controls were pair-fed a liquid diet without ethanol or received rat chow. Diets began 7 days pre- and continued postinfection. Rats were infected transtracheally with type 3 Streptococcus pneumoniae and then treated with azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic levels in serum, lung cells, and lavage fluid were measured by HPLC. Ethanol- and pair-fed rats had depressed baseline peripheral neutrophil counts but were able to generate adequate numbers of peripheral and pulmonary polymorphonuclear leukocytes early in the course of their infection. Ethanol feeding did not alter the pharmacokinetics of azithromycin, trovafloxacin, or ceftriaxone. All three antibiotics were equally effective in curing experimental pneumococcal pneumonia, and survival rates were similar in treated ethanol-fed and control rats.

Topics: Animals; Anti-Infective Agents; Azithromycin; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Ethanol; Feeding Behavior; Fluoroquinolones; Leukocyte Count; Male; Naphthyridines; Neutrophils; Pneumonia, Pneumococcal; Rats; Rats, Sprague-Dawley

We report a case of a cyst of maxillary in a patient suffering from sickle-cell anemia. A review of literature and therapeutic management is exposed.

Topics: Anemia, Sickle Cell; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Child; Drug Therapy, Combination; Female; Humans; Incisor; Maxillary Diseases; Odontogenic Cysts; Pneumonia, Pneumococcal; Postoperative Complications; Root Canal Therapy; Tooth Fractures; Vancomycin

To compare the clinical characteristics, treatment, and outcome of pediatric patients with pneumonia attributable to isolates of Streptococcus pneumoniae that were either susceptible or nonsusceptible to penicillin.. Multicenter, retrospective study.. Eight children's hospitals in the United States.. Two hundred fifty-four children with pneumococcal pneumonia identified from patients enrolled in the United States Pediatric Multicenter Pneumococcal Surveillance Study during the 3-year period from September 1, 1993 to August 31, 1996.. Demographic and clinical variables including necessity for and duration of hospitalization, frequency of chest tube placement, antimicrobial therapy, susceptibility of isolates, and clinical outcome.. There were 257 episodes of pneumococcal pneumonia that occurred in 254 patients. Of the 257 isolates, 22 (9%) were intermediate and 14 (6%) were resistant to penicillin; 7 (3%) were intermediate to ceftriaxone and 5 (2%) were resistant to ceftriaxone. There were no differences noted in the clinical presentation of the patients with susceptible versus nonsusceptible isolates. Twenty-nine percent of the patients had a pleural effusion. The 189 (74%) hospitalized patients were more likely to have an underlying illness, multiple lung lobe involvement, and the presence of a pleural effusion than nonhospitalized patients. Fifty-two of 72 hospitalized patients with pleural effusions had a chest tube placed, and 27 subsequently underwent a decortication drainage procedure. Eighty percent of the patients treated as outpatients and 48% of the inpatients received a parenteral second or third generation cephalosporin followed by a course of an oral antimicrobial agent. Two hundred forty-eight of the patients (97.6%) had a good response to therapy. Six patients died; however, only 1 of the deaths was related to the pneumococcal infection.. The clinical presentation and outcome of therapy did not differ significantly between patients with penicillin-susceptible versus those with nonsusceptible isolates of S pneumoniae. Hospitalized patients were more likely to have underlying illnesses, multiple lobe involvement, and the presence of pleural effusions than patients who did not require hospitalization. In otherwise normal patients with pneumonia attributable to penicillin-resistant pneumococcal isolates, therapy with standard beta-lactam agents is effective.

Topics: Adolescent; Adult; Ambulatory Care; Anti-Bacterial Agents; Ceftriaxone; Cefuroxime; Cephalosporins; Child; Child, Preschool; Empyema, Pleural; Female; Hospitalization; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pleural Effusion; Pneumonia, Pneumococcal; Retrospective Studies; Streptococcus pneumoniae; Treatment Outcome

The clinical course for a patient hospitalized with pneumonia and meningitis due to penicillin-, ceftriaxone-, and cefotaxime-resistant Streptococcus pneumoniae is described. The pneumonia and meningitis responded to antimicrobial therapy, but the patient died following rupture of an infected abdominal aortic aneurysm; gram-positive cocci resembling S. pneumoniae were detected within the aneurysm.

Topics: Aortic Aneurysm, Abdominal; Cefotaxime; Ceftriaxone; Cephalosporins; Drug Resistance, Microbial; Humans; Male; Meningitis, Bacterial; Middle Aged; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftriaxone; Cefuroxime; Cephalosporin Resistance; Cephalosporins; Clarithromycin; Drug Therapy, Combination; Female; Humans; Penicillin Resistance; Pneumonia, Pneumococcal; Streptococcus pneumoniae

We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.

Topics: Amoxicillin; Animals; Cefotaxime; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Disease Models, Animal; Female; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Penicillin-resistant strains of Streptococcus pneumoniae are now found worldwide, and strains with resistance to cephalosporin are being reported. The appropriate antibiotic therapy for pneumococcal pneumonia due to resistant strains remains controversial.. To examine the effect of resistance to penicillin and cephalosporin on mortality, we conducted a 10-year, prospective study in Barcelona of 504 adults with culture-proved pneumococcal pneumonia.. Among the 504 patients, 145 (29 percent) had penicillin-resistant strains of S. pneumoniae (minimal inhibitory concentration [MIC] of penicillin G, 0.12 to 4.0 micrograms per milliliter), and 31 patients (6 percent) had cephalosporin-resistant strains (MIC of ceftriaxone or cefotaxime, 1.0 to 4.0 micrograms per milliliter). Mortality was 38 percent in patients with penicillin-resistant strains, as compared with 24 percent in patients with penicillin-sensitive strains (P = 0.001). However, after the exclusion of patients with polymicrobial pneumonia and adjustment for other predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strains was 1.0 (95 percent confidence interval, 0.5 to 1.9; P = 0.84). Among patients treated with penicillin G or ampicillin, the mortality was 25 percent in the 24 with penicillin-resistant strains and 19 percent in the 126 with penicillin-sensitive strains (P = 0.51). Among patients treated with ceftriaxone or cefotaxime, the mortality was 22 percent in the 59 with penicillin-resistant strains and 25 percent in the 127 with penicillin-sensitive strains (P = 0.64) The frequency of resistance to cephalosporin increased from 2 percent in 1984-1988 to 9 percent in 1989-1993 (P = 0.002). Mortality was 26 percent in patients with cephalosporin-resistant S. pneumoniae and 28 percent in patients with susceptible organisms (P = 0.89). Among patients treated with ceftriaxone or cefotaxime, mortality was 22 percent in the 18 with cephalosporin-resistant strains and 24 percent in the 168 with cephalosporin-sensitive organisms (P = 0.64).. Current levels of resistance to penicillin and cephalosporin by S. pneumoniae are not associated with increased mortality in patients with pneumococcal pneumonia. Hence, these antibiotics remain the therapy of choice for this disease.

Topics: Adult; Aged; Bacteremia; Cefotaxime; Ceftriaxone; Cephalosporin Resistance; Community-Acquired Infections; Female; Humans; Incidence; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Penicillin G; Penicillin Resistance; Pneumonia, Pneumococcal; Prospective Studies; Spain; Streptococcus pneumoniae

The increasing emergence of penicillin-resistant (Pr) strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against Pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (Ps) strain (MICs of < 0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a Pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the Ps strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the Pr strain, whereas 20- and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the Ps strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly Pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [delta t MIC], > or less than 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: delta t MIC, <2; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

Topics: Amoxicillin; Animals; Ceftriaxone; Disease Models, Animal; Female; Injections, Subcutaneous; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Pneumococcal Infections; Pneumonia, Pneumococcal; Streptococcus pneumoniae