Systemic Pneumococcal Infections Research Articles

Host-Mediated Copper Stress Is Not Protective against Streptococcus pneumoniae D39 Infection.

Metal ions are required by all organisms for the chemical processes that support life. However, in excess they can also exert toxicity within biological systems. During infection, bacterial pathogens such as Streptococcus pneumoniae are exposed to host-imposed metal intoxication, where the toxic properties of metals, such as copper, are exploited to aid in microbial clearance. However, previous studies investigating the antimicrobial efficacy of copper in vivo have reported variable findings. Here, we use a highly copper-sensitive strain of S. pneumoniae, lacking both copper efflux and intracellular copper buffering by glutathione, to investigate how copper stress is managed and where it is encountered during infection. We show that this strain exhibits highly dysregulated copper homeostasis, leading to the attenuation of growth and hyperaccumulation of copper in vitro. In a murine infection model, whole-tissue copper quantitation and elemental bioimaging of the murine lung revealed that infection with S. pneumoniae resulted in increased copper abundance in specific tissues, with the formation of spatially discrete copper hot spots throughout the lung. While the increased copper was able to reduce the viability of the highly copper-sensitive strain in a pneumonia model, copper levels in professional phagocytes and in a bacteremic model were insufficient to prosecute bacterial clearance. Collectively, this study reveals that host copper is redistributed to sites of infection and can impact bacterial viability in a hypersusceptible strain. However, in wild-type S. pneumoniae, the concerted actions of the copper homeostatic mechanisms are sufficient to facilitate continued viability and virulence of the pathogen. IMPORTANCE Streptococcus pneumoniae (the pneumococcus) is one of the world's foremost bacterial pathogens. Treatment of both localized and systemic pneumococcal infection is becoming complicated by increasing rates of multidrug resistance globally. Copper is a potent antimicrobial agent used by the mammalian immune system in the defense against bacterial pathogens. However, unlike other bacterial species, this copper stress is unable to prosecute pneumococcal clearance. This study determines how the mammalian host inflicts copper stress on S. pneumoniae and the bacterial copper tolerance mechanisms that contribute to maintenance of viability and virulence in vitro and in vivo. This work has provided insight into the chemical biology of the host-pneumococcal interaction and identified a potential avenue for novel antimicrobial development.

Proprotein convertase subtilisin/kexin type 9 regulates the production of acute-phase reactants from the liver.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) controls blood cholesterol levels by fostering the LDL receptor (LDLR) degradation in hepatocytes. Additionally, PCSK9 has been suggested to participate in immunoregulation by modulating cytokine production. We studied the immunological role of PCSK9 in Streptococcus pneumoniae bacteraemia in vivo and in a human hepatocyte cell line. CRISPR/Cas9 mutagenesis was utilized to create pcsk9 knock-out (KO) zebrafish, which were infected with S pneumoniae to assess the role of PCSK9 for the survival of the fish and in the transcriptomic response of the liver. The direct effects of PCSK9 on the expression of acute-phase reaction (APR) genes were studied in HepG2 cells. The pcsk9 KO zebrafish lines (pcsk9tpu-13 and pcsk9tpu-2,+15 ) did not show developmental defects or gross phenotypical differences. In the S pneumoniae infected zebrafish, the mortality of pcsk9 KOs was similar to the controls. A liver-specific gene expression analysis revealed that a pneumococcal challenge upregulated pcsk9, and that the pcsk9 deletion reduced the expression of APR genes, including hepcidin antimicrobial peptide (hamp) and complement component 7b (c7b). Accordingly, silencing PCSK9 in vitro in HepG2 cells using small interfering RNAs (siRNAs) decreased HAMP expression. We demonstrate that PCSK9 is not critical for zebrafish survival in a systemic pneumococcal infection. However, PCSK9 deficiency was associated with the lower expression of APR genes in zebrafish and altered the expression of innate immunity genes in a human hepatocyte cell line. Overall, our data suggest an evolutionarily conserved function for PCSK9 in APR in the liver.

Making sense of serotype-specific pneumococcal antibody measurements

In 2012, a specialist group of the American Academy of Allergy, Asthma & Immunology (AAAI) collaborated to produce guidelines on the use and interpretation of diagnostic vaccination in primary immunodeficiency. Within this document there is extensive evaluation of the use of serotype-specific pneumococcal serotype testing for diagnosis of immune deficiency. A titre of 1.3 mg/mL is reported to confer protection for each serotype. This concentration has generated much discussion: in the UK these tests are only available in a few centres and all use 0.35 mg/mL as a putative protective titre. In an attempt to help clarify this discrepancy, this article summarizes the literature describing the development of these assays. Although widely quoted, a ‘protective titre’ of 1.3 mg/mL may not have a sound evidence base. The evolution of assays to measure antibodies to serotype specific pneumococcus, particularly the unit of measurement conversions, has played a significant part in the confusion. A sensitive radioimmunoassay was developed by Schiffman et al. in 1980 which measured IgG antibodies to C polysaccharide generating antibodies in units of ng antibody nitrogen/mL. Later enzyme-linked immunosorbent assays (ELISAs) were developed which were more sensitive but also generated results in ng antibody nitrogen/mL. In 1995, the World Health Organisation (WHO) produced reference and calibration sera to standardize assays. The first ELISAs showed poor correlation of antibodies with vaccine efficacy studies. This was due to the presence of C polysaccharide and 22F. Antibodies to C polysaccharide, although naturally occurring in humans, are not opsonic and therefore do not protect against pneumococcal infection; antibodies to serotype 22F are cross reactive to a number of other serotypes. Reabsorbing sera with C polysaccharide and 22F led to the development of 2nd and 3rd generation assays respectively with increased specificity for measuring protective antibodies; these assays gave results in mg/ mL. From this point onwards there was a divergence in interpretation of assay results depending on special interests such as whether the assays were used to assess vaccination response from a public health perspective or to compare base line and postvaccination response to help diagnose T-cell independent antibody deficiency. The WHO approved the ELISA for monitoring response to newly produced vaccines. WHO published data showing that pneumococcal conjugated vaccines should induce titres of 0.35mg/mL or above four weeks after vaccination to confer protection against invasive pneumococcal disease. This putative protective level was based on a 2nd generation ELISA. When reassessed on a 3rd generation (more sensitive) ELISA only a small decline in putative protection level was found (0.32 mg/mL); this meta-analysis was based on three clinical efficacy trials with in excess of 60,000 control and vaccinated infants. A decision to stick to the original value (for ease) of 0.35mg/mL was made. Although derived from data in children, this level of protection has been extrapolated for adult use. Development and interpretation of ELISA results in the adult immune deficiency world took a different approach. Landesman and Schiffman used the radioimmunoassay to assess pneumococcal antibody concentration with systemic pneumococcal infection >250– 300 ng antibody nitrogen/mL for adults. This figure

Intranasal immunization with autolysin (LytA) in mice model induced protection against five prevalent Streptococcus pneumoniae serotypes in China

In order to evaluate immunogenicity and protective efficacy of LytA from Streptococcus pneumoniae, we subcloned the full-length lytA-encoded autolysin (LytA) from 5 major pathogenic serotype isolates in China and obtained purified rLytA. Bioinformatics analysis showed that sequences of LytA were highly conserved in all strains we used in this work, and western blot analysis demonstrated that rLytAs from heterogeneous serotypes were cross-recognized by serum of mice infected with 23F strain SH137. Mice were intranasally immunized with purified rLytA, and serum anti-rLytA IgG, IgA and secretory IgA were elicited. More importantly, rLytA intranasal-immunized mice showed a significantly higher survival rate and lower bacterial carriage in response to infection by Streptococcus pneumoniae. The fact that mice immunized with rLytA from strain SH137 also had a higher survival rate after intraperitoneal injection of other four serotype strains of living S. pneumoniae suggested that it possessed cross-protection effect. Our study revealed that intranasal immunization with rLytA may protect mice against mucosal and systemic pneumococcal infection; hence, it was an attractive vaccine candidate.

Mucosal Immunization with Polyamine Transport Protein D (PotD) Protects Mice Against Nasopharyngeal Colonization with Streptococcus pneumoniae

Streptococcus pneumoniae is an encapsulated pathogen that can cause invasive disease following colonization of the nasopharynx. Targeting colonization of mucosal surfaces may, therefore, be the best approach for vaccination to prevent pneumococcal invasive disease. Previous studies in our laboratory have shown that immunization with recombinant polyamine transport protein D (PotD) protects mice against systemic pneumococcal infections. In this study we investigated the efficacy of mucosal immunization with rPotD to protect against pneumococcal carriage and invasion in a murine model. Mice were intranasally immunized with either rPotD and cholera toxin B subunit (CTB) or CTB alone. Significantly less pneumococci were recovered from the nasopharynx of immunized mice compared to the control animals following intranasal challenge with either EF3030 (serotype 19F) (P < 0.05) or an invasive serotype 4 isolate (TIGR4) (P < 0.05). PotD immunized mice also had lesser bacteria in their sinus tissues (P < 0.05), brains (P < 0.05), lungs and olfactory bulbs following intranasal challenge with TIGR4. ELISA analysis demonstrated the presence of IgG antibodies to PotD in the serum and IgA antibodies in the saliva. These results indicate that mucosal immunization with PotD generates both mucosal and systemic immune responses and prevents establishment of nasopharyngeal carriage by multiple pneumococcal serotypes. Thus, PotD is a potentially important antigen for development of a pneumococcal protein vaccine.

Protection against systemic fatal pneumococcal infection by maternal intranasal immunization with pneumococcal surface protein A (PspA)

Streptococcus pneumoniae is a leading causative pathogen responsible for various types of bacterial infectious diseases in children. The aim of this study was to evaluate the protection conferred against fatal pneumococcal infections during infancy by maternal intranasal immunization with pneumococcal surface protein A (PspA). Four-week-old female BALB/c mice were immunized with PspA mixed with, or without, cholera toxin B (CTB) intranasally twice a week for 3 weeks. After the final immunization, they were mated with male mice to obtain offspring. Offspring at 10 days old were intraperitoneally inoculated with a pneumococcus strain, TIGR4, serotype 4. After the infections their survival periods were monitored. Anti-PspA-specific IgG antibody was induced in sera and breast milk at birth and maintained for 14 days during nursing periods in the PspA-immunized mother mice. At birth, offspring delivered from PspA-immunized mother mice had levels of anti-PspA-specific IgG antibody in sera same to those in their mothers on the day of birth. The survival times to death of offspring delivered from PspA-immunized mother mice after systemic fatal pneumococcal infections were significantly extended compared to those of controls. These findings suggest that maternal intranasal immunization with PspA could be an attractive procedure to employ against pneumococcal infections in early childhood.

Effect of high dose oral zinc in mice with severe infection with Streptococcus pneumoniae

Zinc is important for normal function of the immune system and inflammation increases the demand for zinc. We hypothesized that high doses of zinc given during acute pneumococcal illness would alter the severity of infection. 24 six-week-old BALB/c mice were anaesthetized and infected intranasally with Streptococcus pneumoniae. Zinc intake was controlled by administering zinc through an intragastric tube. One group was given normal doses (5 microg/d) and the other group high doses of zinc (225 microg/d). We counted the number of bacteria from venous blood at 24 and 48 h, and from heart puncture and nasal wash at 72 h after intranasal challenge. Mice given excess zinc had 2.65 micromol/l, i.e. 25% higher (p= 0.05) mean plasma zinc concentration compared to those given normal amounts. 75% of mice in both groups developed pneumococcal bacteraemia. There were no differences in the numbers of S. pneumoniae colony forming units (CFUs) in blood or nasal wash between the groups. Thus, high doses of zinc did not alter the severity of systemic pneumococcal infection in mice.

Recurrent Systemic Pneumococcal Disease in Children

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.

A Human Monoclonal Immunoglobulin M Reduces Bacteremia and Inflammation in a Mouse Model of Systemic Pneumococcal Infection

Antibody-based approaches to pneumococcal disease may hold promise for immunocompromised patients in whom vaccines are less immunogenic and/or in the context of antimicrobial resistance. Antibody-mediated protection against experimental pneumococcal pneumonia has been shown to depend on immunoregulation, but the relationship between antibody and protection against pneumococcal sepsis and immunoregulation has not been examined. Similarly, the requirement for B and T cells for antibody efficacy is not known. In this study, we determined the efficacy of the human pneumococcal capsular polysaccharide serotype 3-specific antibody, A7 (immunoglobulin M [IgM]), in secretory IgM (sIgM)(-/-), CD4(-/-), CD8(-/-), muMT(-/-), and SCID mice and investigated its effect on cytokine and chemokine expression in sera and spleens from mice with intact cellular immunity. A7 is known to be protective against systemic infection with serotype 3 and to require complement for efficacy. Compared to that of an isotype control antibody, A7 administration prolonged the survival of mice of each immunodeficient strain and was associated with a significant reduction in CFU in blood, lung, and spleen samples and a significantly reduced level of keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) expression in normal and sIgM(-/-) mice. Studies with mice treated with penicillin revealed similar reductions in CFU and similar levels of IL-6, KC, or MIP-2 expression in A7- and penicillin-treated mice. These findings demonstrate that natural IgM and B and T cells are dispensable for A7-mediated protection against experimental pneumococcal sepsis and suggest that the efficacy of antibody-mediated protection depends on immunomodulation. Taken together, our data extend the association between antibody-mediated protection and immunomodulation to protection against systemic pneumococcal infection and to a clinically important serotype often responsible for pneumococcal sepsis.

Streptococcus pneumoniae Bacteremia in Patients With Cancer

In the current era of multidrug-resistant organisms, the clinical spectrum of Streptococcus pneumoniae infection remains unclear, especially in immunosuppressed patients with cancer. We sought to define the characteristics of pneumococcal bacteremia in patients who were receiving care at a comprehensive cancer center. All consecutive episodes of S. pneumoniae bacteremia between January 1998 and December 2002 were evaluated retrospectively. One hundred thirty-five episodes of pneumococcal bacteremia occurred in 122 patients. Sixty-three (52%) of 122 patients had hematologic malignancies; the others had solid tumors. The median Acute Physiology and Chronic Health Evaluation II score was 14 +/- 5. Twenty-four episodes (18%) occurred during neutropenia (<500 cells/microL). Sixty-five patients (53%) were receiving antineoplastic therapy, and 36 (30%) were receiving systemic corticosteroids. Twelve (41%) of 29 hematopoietic stem cell transplant (HSCT) recipients had received transplantation within 12 months of the infection diagnosis; 11 patients had graft-versus-host disease (chronic in 10). In 27 episodes (22%), S. pneumoniae bacteremia was considered as a breakthrough infection. Nine (56%) of 16 hospital-acquired episodes of S. pneumoniae bloodstream infection occurred in patients with profound neutropenia, whereas 15 (13%) of 119 episodes of community-acquired infection occurred during neutropenia (p < 0.0002). In 91 episodes (67%), patients had radiographic evidence of pneumonia. Infected catheters were associated with 21 episodes (16%). Forty-eight (36%) of 135 isolates were not susceptible to penicillin (minimum inhibitory concentration [MIC] > or = 2 microg/mL); 9 (7%) showed intermediate susceptibility to ceftriaxone (MIC >0.5 and <2.0 microg/mL). Nineteen patients (16%) died within 2 weeks of diagnosis; 18 deaths were attributed to systemic pneumococcal infection. Univariate analysis showed no significant increase in the risk of short-term death in patients with infection due to penicillin non-susceptible organisms (OR [odds ratio], 1.47; 95% confidence intervals [CI], 0.53-4.05; p < 0.46), initially discordant treatment (OR, 1.0; 95% CI, 0.62-665.4; p < 0.16), presence of pneumonia (OR, 1.19; 95% CI, 0.39-3.62; p < 0.76), neutropenia (OR, 1.0; 95% CI, 0.28-4.09; p < 0.92), systemic corticosteroid use (OR, 1.96; 95% CI, 0.69-5.60; p < 0.21), or antineoplastic therapy (OR, 1.45; 95% CI, 1.52-4.05; p < 0.47). Similarly, patients with hematologic cancers compared to those with solid cancers (OR, 1.0; 95% CI, 0.49-3.70; p < 0.56) and recipients of HSCT compared to those with no history of transplantation (OR, 1.0; 95% CI 0.59-12.71; p < 0.20) did not have a less favorable outcome. In conclusion, most pneumococcal bloodstream infections were community acquired, although hospital-acquired infections were common in neutropenic patients. It is noteworthy that initially discordant therapy, penicillin non-susceptible S. pneumoniae, and other conventional predictors of unfavorable outcome were not associated with increased mortality rates in these high-risk patients with cancer.

Identification of a detrimental role for NK cells in pneumococcal pneumonia and sepsis in immunocompromised hosts

Gram-positive sepsis is a major disease problem. However, the contribution of various immune cell types to pathogenesis remains unclear. By infecting scid and wild type BALB/c mice with Streptococcus pneumoniae we have found a situation in which natural killer (NK) cells can play a detrimental role in the response to infection. scid mice were found to be significantly more susceptible to local and systemic pneumococcal infection than controls; they had significantly higher bacterial loads, elevated inflammatory responses and more widespread lung pathology. Interestingly, depletion of NK cells in scid mice resulted in significantly lower bacteraemia and inflammatory cytokine production. Infection with pneumococci deficient in pneumolysin revealed the toxin was involved in cytokine production. Overall results indicate that elevated NK cell activity during pneumococcal pneumonia amplifies pulmonary and systemic inflammation, increases bacteraemia and results in poor outcome.

Relationship between Surface Accessibility for PpmA, PsaA, and PspA and Antibody-Mediated Immunity to Systemic Infection by Streptococcus pneumoniae

Antibodies to capsular polysaccharide (PS) are protective against systemic infection by Streptococcus pneumoniae, but the large number of pneumococcal serogroups and the age-related immunogenicity of pure PS limit the utility of PS-based vaccines. In contrast, cell wall-associated proteins from different capsular serotypes can be cross-reactive and immunogenic in all age groups. Therefore, we evaluated three pneumococcal proteins with respect to relative accessibility to antibody, in the context of intact pneumococci, and their ability to elicit protection against systemic infection by encapsulated S. pneumoniae. Sequences encoding pneumococcal surface adhesin A (PsaA), putative protease maturation protein A (PpmA), and the N-terminal region of pneumococcal surface protein A (PspA) from S. pneumoniae strain A66.1 were cloned and expressed in Escherichia coli. The presence of genes encoding PsaA, PpmA, and PspA in 11 clinical isolates was examined by PCR, and the expression of these proteins by each strain was examined by Western blotting with antisera raised to the respective recombinant proteins. We used flow cytometry to demonstrate that PspA was readily detectable on the surface of the pneumococcal strains analyzed, whereas PsaA and PpmA were not. Consistent with these observations, mice with passively or actively acquired antibodies to PspA or type 3 PS were equivalently protected from homologous systemic challenge with type 3 pneumococci, whereas mice with passively or actively acquired antibodies to PsaA or PpmA were not effectively protected. These experiments support the hypothesis that the extent of protection against systemic pneumococcal infection is influenced by target antigen accessibility to circulating host antibodies.

Pr�vention von Pneumokokkeninfektionen

Die Morbidität systemischer Pneumokokkeninfektionen ist in den ersten Lebensjahren besonders hoch. Jahrzehntelang standen zur Prävention nur Polysaccharidimpfstoffe zur Verfügung, die erst ab dem Alter von 2 Jahren eine Schutzwirkung aufweisen.Mit der Entwicklung und Einführung eines Pneumokokkenimpfstoffs, bei dem die antigenen Polysaccharide an Trägerproteine gekoppelt sind, können nun auch Kinder unter 2 Jahren effektiv geschützt werden.Momentan wird der Pneumokokkenkonjugatimpfstoff für bestimmte Risikogruppen empfohlen.Epidemiologisch wirksam wäre aber nur die allgemeine Anwendung als Standardimpfung.Positive Erfahrungen seit der breiten Anwendung des Konjugatimpfstoffs in den USA sind viel versprechend und könnten schon in naher Zukunft zu einer Erweiterung der Impfempfehlungen in Deutschland führen. Dazu ist jedoch ein fachlicher und gesellschaftlicher Konsens erforderlich, denn die damit verbundenen Kosten und die ethischen Aspekte werden weiterhin kontrovers diskutiert.

PRIMARY STREPTOCOCCUS PNEUMONIAE APPENDICITIS IN A CHILD: CASE REPORT AND REVIEW

We describe an immunocompetent 12-year-old with pneumococcal appendicitis. The exact mechanism of the appendix seeding by Streptococcus pneumoniae is not known, and primary pneumococcal appendicitis has been described in only 6 children (of a total of 12 cases) in the English literature during the last 30 years. The actual incidence of this infection is thought to be ∼0.3% of all appendicitis cases.

The effect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections

PurposeTo evaluate the clinical relevance of cephalosporin (ceftriaxone/cefotaxime) resistance among patients with nonmeningeal systemic pneumococcal infection. Subjects and methodsFrom January 1994 to October 2000, we prospectively studied 522 episodes of nonmeningeal systemic pneumococcal infections (448 pneumonias) in 499 adults who were treated according to hospital guidelines. In vitro antibiotic susceptibility, as the minimum inhibitory concentration (MIC), was determined by microdilution method. The MIC methods and breakpoints (cutoffs) were established by the National Committee for Clinical Laboratory Standards. ResultsOf the 522 pneumococcal strains, 413 strains (79%) were susceptible to ceftriaxone/cefotaxime, MIC ≤0.5 μg/mL; 79 (15%) were intermediate, MIC = 1 μg/mL; and 30 (6%) were resistant, MIC = 2 μg/mL. After adjusting for several variables, including pneumococcal serogroups/serotypes, infections due to nonsusceptible (intermediate and resistant) pneumococcal strains were independently associated with prior antibiotic therapy, with an odds ratio of 5.9 (95% confidence interval: 2.6 to 13.6). Thirty-day mortality among the 185 patients who were treated with ceftriaxone (1 g/d) or cefotaxime (1.5 g every 8 hours) did not differ by cephalosporin susceptibility: 18% (26/148) among those with susceptible organisms, 13% (3/24) with intermediate organisms, and 15% (2/13) in resistant cases (P = 0.81). ConclusionCeftriaxone or cefotaxime were effective in treating patients with nonmeningeal systemic pneumococcal infections caused by strains with MIC ≤2 μg/mL. These results support the newly established ceftriaxone/cefotaxime MIC breakpoints (cutoffs) for nonmeningeal pneumococcal infections.

Occurrence and clinical presentation of systemic pneumococcal infections in an unselected population in Oslo, Norway, between 1993 and 1997.

In order to describe the clinical and microbiological manifestations of systemic pneumococcal infection in an unselected urban population, 147 cases that occurred in the period 1993-1997 were retrospectively reviewed. An unexpected finding was that gastrointestinal symptoms were remarkably common. All pneumococcal isolates were fully susceptible to penicillin. The 7-valent conjugated vaccine covered 71% of those under 2 years of age, but only 21% of those 15-65 years of age were covered. Although the case fatality rate was 17%, the rate of early fatality due to systemic pneumococcal infection was unchanged compared with data published in the era before antibiotics. This study emphasizes the importance of continuing efforts to prevent systemic pneumococcal infections.

Six year multicenter surveillance of invasive pneumococcal infections in children.

Monitor clinical and microbiologic features including antimicrobial susceptibility of invasive pneumococcal infections among children. A 6-year (September, 1993, through August, 1999) prospective surveillance study of all invasive pneumococcal infections in children. Infants and children cared for at eight children's hospitals in the United States with culture-proved invasive pneumococcal infection. During the 6-year period 2581 episodes of invasive pneumococcal infection occurred in 2498 children. Underlying conditions were present in 29% of the children. Of children without an underlying condition, 15% of the total infections occurred in those 25 to 60 months old. As the ages of the children advanced the proportion of cases classified as bacteremia declined, whereas the proportion classified as pneumonia increased. Also, as the ages of the children increased the proportion of isolates in serotypes/serogroups 1, 3 and 23 increased. whereas the proportion for serotype 14 diminished. During the 6 years of the study, there was a significant increase in the percentage of isolates intermediate or resistant to penicillin (P < 0.000001) or intermediate to ceftriaxone (P < 0.002). By the sixth year of the study, 37 and 11% of the isolates were nonsusceptible to penicillin or ceftriaxone, respectively. Antibiotic use in the 30 days before diagnosis of systemic pneumococcal infection occurred in 30 to 35% of the children for each of the 6 years. The overall case-fatality rate for children with systemic pneumococcal infection was 1.56%. Mortality was greatest in children >60 months old and in those with underlying conditions; mortality was not related to antibiotic susceptibility. The percentage of pneumococcal isolates recovered from children with systemic infection which were intermediate for penicillin or ceftriaxone or resistant to penicillin increased steadily during the 6-year period. There was also a trend toward increasing rates of resistance to ceftriaxone. The age and serogroup/serotype distributions of our patients support the recommendations to consider administration of the seven valent pneumococcal conjugate vaccine for all children 24 to 59 months old, with special consideration for selected groups.

Clinical study of 33 children with systemic pneumococcal infections

We retrospectively analyzed 33 cases of children with systemic pneumococcal infections, 22 bacteremia and 11 meningitis, diagnosed and treated in Asahi General Hospital between 1985 and 1999. The median age at diagnosis was 15 months old and the incidence peaked in infants between 7 and 24 months of age (57.6%). Two cases showed low serum IgG2 levels. Fever was a common symptom in all cases and 13 (39.4%) presented convulsions. Meningitis [median age: 10 months] tended to occur, if not significant, in younger children than bacteremia [16 months]. All cases of meningitis were diagnosed 12 hours or later after the onset of fever, though 54.5% of the cases of bacteremia were diagnosed within 12 hours. The cases of meningitis showed statistically lower white blood cell counts [median: 9,700/mm3] and higher CRP levels [median: 25.6 mg/dl] than those of bacteremia [23,900/mm3 and 4.2 mg/dl, respectively] at diagnosis. Although all cases of bacteremia were cured without any sequelae by antibiotic treatment, 3 cases (27.3%) of meningitis died and 4 (36.4%) developed severe neurological sequelae. Our findings suggest that the putative pathogenesis by which pneumococcal meningitis results from bacteremia and, taking in the account of the poor outcome of meningitis, may justify the early antibiotic intervention against pneumococcal bacteremia.

Antimicrobial Resistance with Streptococcus Pneumoniae in the United States

Among antimicrobial agents that have consistently been efficacious in treating infections due to specific bacteria over extended periods of time, there are few better examples than Streptococcus pneumoniae and penicillin. Until recently in the United States (U.S.), this combination had remained nearly uniformly effective. The sole issue mitigating for or against use of penicillin (or ampicillin) in the management of systemic pneumococcal infections, or oral ampicillin (or amoxicillin) in treating localized, nonlife-threatening pneumococcal infections, was the penicillin allergy status of the patient. In the nonallergic patient, penicillin or its congeners, have been the drugs of choice largely because resistance to these agents remained uncommon. All of that changed dramatically in the U.S. during the early part of the decade of the 1990s with the emergence of high rates of antimicrobial resistance with S. pneumoniae, and concomitantly, the recognition of diminished efficacy when certain other antimicrobials were used to treat pneumococcal infections. The intent of this discussion is to address a variety of specific issues that pertain to the problem of antimicrobial resistance with S. pneumoniae. The format chosen is a selection of the most asked questions regarding S. pneumoniae and antimicrobial resistance, and then answers are provided.

Characterization of Streptococcus pneumoniae strains isolated from systemic infections in children.

Twenty-three cases of systemic pneumococcal infection diagnosed from October 1988 to September 1998 were analyzed retrospectively in order to characterize the epidemiology of systemic pneumococcal infections. The clinical diagnosis of those cases were 8 pneumonia, 8 meningitis, 3 septicemia, 3 septic arthritis, and 1 peritonitis. The patients ranged in age from 6 months to 21 years old (mean +/- SD = 3 years, 6 months +/- 5 years, 2 months), and 61% of the patients were younger than 24 months. Resistance to penicillin G (PCG) was detected in 57% of all cases. Resistance to cefotaxime (CTX), imipenem (IPM), erythromycin (EM), and clindamycin (CLDM) was 33%, 9%, 70%, and 65%, respectively. Of the 13 isolates resistant to PCG, 2 were resistant to IPM, 11 to EM and 11 to CLDM. Serotyping was performed on 17 isolates. The identified serotypes were 19 (6 isolates), 6 (5 isolates), 23 (3 isolates), 14 (2 isolates), and 5 (1 isolate). Eleven isolates resistant to PCG were limited to serotypes 6, 19, or 23. One patient had a recurrent episode of bacteremic pneumonia 7 months after the first episode. Streptococcus pneumoniae isolates from both episodes were compared by serotyping and pulsed-field gel electrophoresis with restriction digestion, and were confirmed as the same strain.