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Early clearance of inhaled Staphylococcus aureus is believed to be caused by phagocytosis by alveolar macrophages. In murine models inhaled pneumococci are cleared even more rapidly than S. aureus. Conventional opsonins appear to play no role in this clearance, and recently it has been shown that murine alveolar lining material contains free fatty acids and other soluble factors that are directly bactericidal for pneumococci. To determine whether non-phagocytic factors are involved in pneumococcal clearance, we compared the site of killing of inhaled pneumococci and S. aureus in rats using histologic methods and bronchoalveolar lavage. Spontaneous lysis of pneumococci was prevented by use of autolysin-defective pneumococci or by substitution of ethanolamine for choline in the cell wall. Histologic studies showed that the percent of inhaled staphylococci associated with alveolar macrophages always exceeded the percent of staphylococci cleared, whereas there was little association of pneumococci with macrophages during clearance. Analysis of the intracellular or extracellular location of iron 59 in bronchoalveolar lavage fluid of rats that had inhaled aerosols of 59Fe-labeled bacteria suggested that staphylococci were killed predominantly in macrophages and pneumococci in the extracellular space. When 59Fe-labeled pneumococci or staphylococci were ingested and killed by macrophages in vitro, the 59Fe remained with the macrophages, suggesting that the extracellular location of 59Fe during pneumococcal killing in vivo was not caused by rapid turnover of 59Fe in macrophages. Studies of the site of killing of inhaled type 25 pneumococci labeled exclusively in the cell wall with carbon 14-ethanolamine confirmed the results obtained with 59Fe-labeled pneumococci. Thus, early killing of inhaled pneumococci, unlike staphylococci, appears to take place outside of macrophages.
The purpose of this study was to compare the effect, both in vitro and in vivo, of cefepime with those of four other cephalosporins, namely ceftriaxone, cefotaxime, cefuroxime and cephalothin, against penicillin-resistant pneumococci. One hundred pneumococcal strains, 31 penicillin-susceptible, 30 penicillin-intermediate-resistant and 39 penicillin-resistant pneumococci, were used in MIC studies. Time-kill experiments were carried out for four strains. In the mouse peritonitis model, the dose that gave protection to 50% of mice challenged with a lethal dose of pneumococci (ED50) was determined for three pneumococci and five cephalosporins. The MICs of all five cephalosporins and penicillin correlated significantly with each other. In vitro, the most potent cephalosporins against pneumococci were cefotaxime, ceftriaxone and cefepime, followed by cefuroxime and cephalothin. In time-kill experiments, carried out for four pneumococci, no differences were found in the killing effect of these five cephalosporins in relation to MICs. In the mouse peritonitis model, there was no significant correlation between log(MIC) and log(ED50) for the five cephalosporins against three pneumococci (Spearman's rho = 0.39, P = 0.16). However, if the values for cefepime against the three pneumococci were excluded, there was a significant correlation for the remaining four cephalosporins (Spearman's rho = 0.62, P = 0.04). For all three pneumococci, the ED50s of cefepime were lower than expected from the MICs. It was not possible to explain this beneficial difference in the effect of cefepime in terms of in-vitro bactericidal activities, serum protein binding or pharmacodynamic parameters.
BACKGROUND: Nasopharyngeal carriage of pneumococci is prevalent among children in developing countries but little is known about the relationship of nasopharyngeal carriage to invasive disease or about the way in which pneumococci spread within households. OBJECTIVES: To determine the prevalence of nasopharyngeal carriage in healthy and sick Gambian children and to investigate transmission within households. METHODS: Nasopharyngeal swabs were obtained by the per nasal route and cultured for pneumococci on selective media. Pneumococci were serotyped with the use of latex particles coated with type-specific antisera. RESULTS: Pneumococci were isolated from the nasopharynx of 73 (90.1%) of 81 children with invasive pneumococcal disease, 86 (76.1%) of 113 healthy, age-matched control children and 911 (85.1%) of 1071 sick children. Pneumococci belonging to serotypes 1, 14 and 12 were isolated significantly more frequently from cases than from matched controls. In 43 (76.8%) of 56 children with invasive disease, pneumococci isolated from the nasopharynx and from the blood or other sterile site belonged to the same serotype. Pneumococci of the same serotype as the bacterium responsible for invasive disease in a child were obtained from 72 (8.5%) of 843 family members, most frequently from young siblings of the case patients. CONCLUSION: Nasopharyngeal carriage of pneumococci is more prevalent among young Gambian children than among adults and invasive infections are probably acquired more frequently from siblings than from parents. However, further studies are needed to confirm this hypothesis with more discriminating markers than polysaccharide serotyping.
Normal and splenectomized rats were challenged with Streptococcus pneumoniae type 1 via different administration routes. In experiment I, previously splenectomized or sham-operated rats received 4 X 10(3) colony-forming units (CFU) of pneumococci via (i) a peripheral vein, (ii) subcutaneously, or (iii) intraperitoneally. The results indicated an increased susceptibility of the splenectomized animal to pneumococci administered via all three routes. However, subcutaneously administered pneumococci gave a lower mortality than pneumococci given intravenously or intraperitoneally. In experiment II 40 splenectomized rats received 4 X 10(3) CFU of pneumococci via (i) peripheral, (ii) portal, or (iii) caval veins or the aorta. No differences in mortality were found. In experiment III, non-operated animals received 4 X 10(5) CFU of pneumococci either intravenously or intraperitoneally, resulting in mortality rates of 0/20 and 17/20, respectively. After 2 weeks the rats surviving intravenous challenge received 4 X 10(5) CFU of pneumococci intraperitoneally; all survived. The data indicate the the spleen and the subcutis have a greater capacity to protect against pneumococci in the absence of specific antibody than the peritoneum or the circulation outside the spleen.
Respiratory infections with penicillin resistant pneumococci constitute an increasing health care problem. This paper describes the nosocomial spread of penicillin resistant pneumococci (PRP) on a pulmonary ward. During an eight-month period, minimal inhibitory concentrations (MICs) for penicillin and several other antibiotics were performed on all Streptococcus pneumoniae isolates that were shown to be penicillin resistant by a screening assay. The personal data and case history of all patients with penicillin resistant pneumococci were evaluated. Penicillin Resistant Pneumococci were cultured from 18 patients, 16 men (mean age 74 +/- 8 yrs) and 2 women (aged 54 and 60 yrs). Chronic obstructive pulmonary disease was diagnosed in 16 patients, 10 of which had an additional underlying disease (2 diabetes mellitus, 2 heart failure, 2 malignancy). Prior to culture of Penicillin Resistant Pneumococci, 11 out of 18 patients were treated with antibiotics, a beta-lactam in most instances. Ten out of 18 patients died during or shortly after hospitalization. The death of one patient seems to be directly related to infection with Penicillin Resistant Pneumococci. The five Penicillin Resistant Pneumococci isolates available for serotyping were all type 9. The minimal inhibitory concentrations for penicillin varied from 0.5 to 2.0 mg.l-1. High minimal inhibitory concentrations were also noted for cefixime (all over 4.0 mg.l-1) and ceftriaxone (0.5-1.0 mg.l-1). It is concluded that penicillin resistant pneumococci can spread rapidly among old and debilitated patients. Thus, patients with this infection should be barrier nursed.
Penicillin-resistant and multi-resistant pneumococci have spread globally and reached high prevalence in many countries. Antimicrobial use is considered a major driving force for resistance, although the influence in the community has not been as clearly demonstrated. Other risk factors may be important, and only with a clear understanding of the risk factors can effective control measures be introduced. The main habitat of the pneumococcus is the nasopharynx of children. Carriage increases from birth and is maximal at pre-school age. Antimicrobial use in children is likely to have a significant influence on the susceptibility of pneumococci. Most studies looking for risk factors for resistance in pneumococci have identified antimicrobial use as a risk factor, especially the following aspects: ongoing, recent, repeated, frequent, and prophylactic antibiotic use. The effect of individual classes of antimicrobials has not been studied in detail but use of beta-lactam antibiotics and trimethoprim-sulpha has been associated with increased risk. Other risk factors are young age, nosocomial acquisition, prior hospitalization, and HIV infection. Day-care centers can facilitate the spread of resistant pneumococci and an Icelandic study showed that carriage of resistant pneumococci was associated with young age, domicile in an area with high antimicrobial consumption, recent antimicrobial use, frequent antimicrobial use, and use of trimethoprim-sulpha. The rapid increase of penicillin-resistant pneumococci in Iceland was met with propaganda against overuse of antimicrobials, which lead to reduction of antimicrobial use and subsequently a reduced incidence of penicillin-resistant pneumococci. This reduction may be related to reduced antimicrobial use. Reducing antimicrobial use should be considered important for programs aimed at reducing antimicrobial resistance.
We demonstrated that during colonization with Streptococcus pneumoniae the nasal mucosal tissues of mice support two populations of pneumococci. Transparent-phase pneumococci can be readily washed from the outer surface, while a second population composed of primarily opaque-phase pneumococci is released only by homogenization of the nasal tissue. The fact that the opaque phase has previously been associated with invasion and the fact that opaque-phase pneumococci were released by homogenization of previously washed nasal tissue suggest that the opaque-phase pneumococci may have invaded the nasal tissue. Consistent with this hypothesis was our observation that there was inflammation in portions of the nasal mucosa of the colonized mice but not in the mucosa of noncolonized mice, but this observation did not prove the hypothesis. If the opaque-phase pneumococci released from the nasal tissue were from within the tissue and/or if resistance of the opaque-phase subpopulation to antibody, complement, and phagocytes is essential for long-term carriage, it seems likely that the virulence factors of S. pneumoniae that are necessary for killing humans exist to facilitate carriage. Although this speculation is unproven, the observation that there are separate populations of pneumococci during colonization may help guide future attempts to understand the biology of nasal colonization by this pathogen.
OBJECTIVE: To study the correlation of antimicrobial consumption with the carriage rate of penicillin resistant and multiresistant pneumococci in children. DESIGN: Cross sectional and analytical prevalence study. SETTING: Five different communities in Iceland. MAIN OUTCOME MEASURE: Prevalence of nasopharyngeal carriage of penicillin resistant pneumococci in children aged under 7 years in relation to antibiotic use as determined by information from parents, patient's records, and total sales of antimicrobials from local pharmacies in four study areas. RESULTS: Total antimicrobial sales for children (6223 prescriptions) among the four areas for which data were available ranged from 9.6 to 23.2 defined daily doses per 1000 children daily (1.1 to 2.6 courses yearly per child). Children under 2 consumed twice as much as 2-6 year olds (20.5 v 10.9 defined daily doses per 1000 children daily). Nasopharyngeal specimens were obtained from 919 children, representing 15-38% of the peer population groups in the different areas. Pneumococci were carried by 484 (52.7%) of the children, 47 (9.7%) of the isolates being resistant to penicillin or multiresistant. By multivariate analysis age (< 2 years), area (highest antimicrobial consumption), and individual use of antimicrobials significantly influenced the odds of carrying penicillin resistant pneumococci. By univariate analysis, recent antimicrobial use (two to seven weeks) and use of co-trimoxazole were also significantly associated with carriage of penicillin resistant pneumococci. CONCLUSIONS: Antimicrobial use, with regard to both individual use and total antimicrobial consumption in the community, is strongly associated with nasopharyngeal carriage of penicillin resistant pneumococci in children. Control measures to reduce the prevalence of penicillin resistant pneumococci should include reducing the use of antimicrobials in community health care.
AIMS: To review the prevalence of antibiotic resistance and the distribution of capsular types among pneumococci from invasive disease in New Zealand from 1995 through 1997. METHOD: Pneumococci isolated from sterile sites that were referred to the Institute of Environmental Science and Research (ESR) were tested for antimicrobial susceptibility and capsular type. RESULTS: A total of 994 pneumococci were referred by 27 hospital and community laboratories. Almost 74% of the isolates were from patients aged < 15 years or > or = 60 years. The majority (88.2%) of the isolates were from blood cultures. In 1997, cefotaxime-resistant pneumococci were confirmed for the first time from invasive disease in New Zealand. Over the three years, 6.0% of the pneumococci were penicillin-nonsusceptible (MIC > or = 0.12 mg/L) and 3.7% were cefotaxime-nonsusceptible (MIC > or = 1 mg/L). Penicillin nonsusceptibility increased significantly from 1.9% in 1995 to 6.2% in 1996 and 9.9% in 1997. Similarly, cefotaxime nonsusceptibility increased from 0.6% in 1995 to 3.5% in 1996 and 6.9% in 1997. In descending order of frequency, the ten most common capsular types were 14, 19, 6, 9, 1, 4, 18, 7, 23, and 3. Eighty-three percent of the penicillin-nonsusceptible pneumococci belonged to serotypes 9V, 19A, 19F, 23F, 14 and 6B and 90% belonged to serotypes included in the 23-valent vaccine. CONCLUSIONS: The increasing prevalence of antimicrobial resistance among pneumococci highlights the need for continued surveillance and for effective measures to prevent pneumococcal infections.
Detailed studies in murine models show inhaled staphylococci are killed mainly by alveolar macrophages. Recently, using histology and lung lavage to determine the site of killing of inhaled 59Fe-labeled pneumococci in rats, we found unexpectedly that most of the organisms were killed extracellularly. In the present studies we compared clearance of inhaled 59Fe-pneumococci in rats, guinea pigs, and rabbits to determine if extracellular killing of pneumococci is species-dependent. Absolute clearance rates were measured using Andersen plates. lung lavage and differential centrifugation were used to measure leukocyte-associated and free 59Fe-pneumococci and nonsedimentable 59Fe. Clearance was rapid in all species but was fastest in rabbits, which killed pneumococci almost as quickly as they were deposited (p less than 0.025 versus rats and guinea pigs). At 1-1/2 hours after pneumococcal deposition in rats, when clearance had reached 92%, alveolar macrophages contained only 31% of the total 59Fe while 56% was in the nonsedimentable, extracellular fraction. At 1-1/2 hours in guinea pigs, when clearance was 96% complete, macrophages contained 51% of the 59Fe and 34% was nonsedimentable (p less than 0.002 versus rats). In rabbits at 1-1/2 hours, macrophages had 94% of the 59Fe and only 4% was nonsedimentable (p less than 0.001 versus the other species). In no species were opsonic antibodies detected in sera or concentrated lavage. In vitro, rabbit and guinea pig alveolar macrophages killed pneumococci opsonized with both specific antibody and fresh serum, while rat macrophages had little activity (p less than 0.001). We conclude that the role of alveolar macrophages in killing inhaled pneumococci varies in different species.
Pneumococci activate the alternative complement (C) pathway in the absence of demonstrable antibody in normal guinea pig serum. They also activate the classical C pathway in the presence of type-specific antibody and perhaps through other mechanisms as well. A quantitative examination was undertaken of the roles of these 2 pathways of C activation in the splanchnic sequestration of 125I-labeled pneumococci, using a-guinea pig model of pneumococcal bacteremia. Normal unimmunized guinea pigs (NIH-GP) localized more than 3 times as many pneumococci to the liver as the spleen during a period when exponential bloodstream clearance was occurring. C4-deficient guinea pigs (C4D-GP) and cobra venom factor-treated guinea pigs (CVF-GP) showed progressively fewer pneumococci cleared by the liver with concomitant increases in the extent of splenic uptake, demonstrating the important role of C in the clearance of bacteria in the unimmunized animal. Immunization of guinea pigs brought about an increase in pneumococcal sequestration by the liver in NIH and C4D-GP but did not affect the localization pattern of CVF-GP. A comparison of reticuloendothelial system (RES) localization patterns with the rate of removal of bacteria from the bloodstream showed a highly significant correlation between increases in splenic sequestration and persistence of bacteremia. Thus, opsonization by C is an important determinant of the RES clearance of pneumococci. Unlike RBC clearance, where C plus IgM leads to hepatic localization, and C plus IgG tends to produce splenic localization, C in the presence or absence of type-specific antibody tends to cause hepatic localization of pneumococci. When C-mediated opsonic activity is less than optimal, the slower clearance of bacteremia that results is accompanied by an increased dependence on splenic sequestration of pneumococci.
We investigated the mechanisms by which a serum activity, neither complement nor immunoglobulin, mediates killing of pneumococci by polymorphonuclear leukocytes (PMN). Electron microscopy revealed type 25 pneumococci to be within PMN when incubated in normal serum, in serum absorbed twice at 0 degrees C with type 25 pneumococci, or in absorbed plus heat-inactivated serum. Uptake of radiolabeled bacteria, and activation of oxygen consumption and of the hexose monophosphate shunt by PMN with pneumococci, were similar in normal serum, absorbed serum, or the combination of absorbed and heat-activated serum. Reduction of nitroblue tetrazolium (NBT) and of cytochrome c by PMN in the presence of type 25 pneumococci and absorbed serum, with or without heat-inactivated serum were one-third and one-half, respectively, of those in normal serum. Likewise, protein iodination was one-half that in normal serum. Reduction of cytochrome c by cytochalasin B-treated PMN was the same in normal, absorbed, or absorbed plus heat-inactivated serum. Furthermore, release of beta-glucuronidase from PMN after ingestion of pneumococci in 10% normal, absorbed, or absorbed plus heat-inactivated serum was identical. These data indicate that the "third" serum activity is not necessary for attachment of pneumococci to or ingestion by PMN, nor is it necessary for stimulation of the plasma membrane oxidase. Rather, it functions somehow in intracellular killing.
We prospectively examined the accuracy of Gram-stained sputum for identifying pneumococci in 42 patients with community-acquired pneumonia. We considered the Gram's stain positive if a preponderant flora or more than ten Gram-positive lancet-shaped diplococci were seen per oil immersion (x1,000) field. These criteria were met in 18 (62%) of 29 specimens that actually contained pneumococci as determined by a positive quellung reaction, or culture on plates or in mice. The Gram's stain was negative in 11 of 13 specimens that did not contain pneumococci. Of the 20 specimens yielding positive Gram's stains, 18 contained pneumococci. A positive Gram-stained smear of sputum strongly suggests the presence of pneumococci, but will miss 38% of specimens containing pneumococci. Deviation from these criteria substantially reduces the overall accuracy of the test.
In vitro susceptibility of eight antibiotics was compared using three groups of pneumococci and agar dilution method comprising 30 penicillin-susceptible, 30 intermediately penicillin-resistant, and 30 highly penicillin-resistant pneumococci. Decreased sensitivity to all beta-lactam agents of intermediately penicillin-resistant and highly penicillin-resistant pneumococci is shown. MIC50 and MIC90 was lower with amoxicillin with and without clavulanate by one dilution than with penicillin. Cephalosporin MIC90s were all significantly higher for intermediately resistant and fully resistant strains. Only imipenem was more active than penicillin with MIC90 of susceptible pneumococci 0.015 mg/L, intermediately resistant pneumococci 0.25 mg/L, resistant pneumococci 1 mg/L.
The efficacy of pneumococcal capsular polysaccharide vaccines after splenectomy to decrease the incidence of postsplenectomy pneumococcal sepsis is controversial. We examined the effect of pneumococcal vaccine on clearance of live pneumococci from lungs of splenectomized and sham-operated mice following an aerosol challenge of pneumococci. Splenectomy impaired clearance of pneumococci from mouse lungs and allowed for increased translocation of pneumococci to tracheobronchial lymph nodes compared to shams (P less than 0.01). Pneumococcal vaccine improved lung clearance in both splenectomized and sham-operated mice compared to saline controls (P less than 0.01), but the number of live pneumococci recovered from lung pairs was greater in splenectomized mice compared to shams (P less than 0.01). Pneumococcal vaccination facilitated earlier translocation of pneumococci to tracheobronchial lymph nodes, and probably promoted bactericidal activity in these nodes, in both splenectomized and sham-operated mice. Survival in splenectomized mice was improved by vaccination, but remained significantly less than that in saline-treated sham-operated mice (P less than 0.0009). The data show that pneumococcal vaccine can improve lung antipneumococcal defenses in splenectomized mice, but not to the same degree as in mice retaining their spleens. Pneumococcal vaccine should be given after splenectomy, but surgeons should caution patients that it may be less effective than when given to individuals with intact spleens or before elective surgery.
BACKGROUND: The aim of this project was to study the influence of pneumococci on nasopharyngeal epithelial integrity as a function of time and pneumococcal density. MATERIALS AND METHODS: Cell layers of an in vitro model of human nasopharyngeal epithelium were inoculated with different pneumococcal strains. The transepithelial electrical resistance (TEER), a measure of the integrity of the cell layers, and the pneumococcal concentration in the apical fluid on the epithelial cells were measured at different times after inoculation. RESULTS: Pneumococci caused a decrease in the TEER when a density of 1 x 107 CFU mL-1 was reached. The growth rate of pneumococci in our in vitro model differed between the strains tested and, for the same strain, between in vitro culture on the epithelial cells and broth culture. Differences in timing of the onset of decrease in the TEER between strains were the result of differences in growth rate on the epithelial cells. Antibiotic-induced lysis of pneumococci caused an immediate decrease in the TEER of the cell layers. CONCLUSION: Pneumococci cause a decrease in the TEER at a density of 1 x 107 CFU mL-1. Our hypothesis is that this decrease in the TEER is the result of quorum-induced lysis of the pneumococci.
An experimental model of pneumococcal bacteremia in guinea pigs has been developed. By use of this model, complement has been shown to play a critical role in clearance of Streptococcus pneumoniae from the bloodstream and in survival of guinea pigs after iv challenge with type 7 S. pneumoniae. In nonimmune animals, complement activation occurs primarily via the alternative pathway. However, anticapsular antibodies increase the rate of clearance of pneumococci primarily via activation of the classical complement pathway. Detailed studies of the reticuloendothelial localization of cleared radiolabeled pneumococci showed that clearance took place primarily in liver and spleen and that anticapsular antibody increased hepatic and decreased splenic sequestration. This effect could be blocked by depleting complement with cobra venom factor. Comparison of nonimmune animals injected with unencapsulated pneumococci or encapsulated types 7 or 12 pneumococci showed that the virulence of these organisms for guinea pigs correlated with the extent of splenic sequestration. Sensitization of encapsulated pneumococci with anticapsular antibodies led to an antibody dose-dependent increase in the rate of bloodstream clearance. Sensitization of encapsulated pneumococci with anticell wall antibodies had no effect on clearance rates despite the ability of these antibodies to bind to the bacteria and to activate and fix complement to the organisms. In vitro studies showed that C3b deposited by these opsonically ineffective antibodies interacted poorly with C3b receptors. Electron microscopic studies showed that C3b deposited by anticapsular antibodies bound to the pneumococcal capsule while C3b deposited by anti-cell wall antibodies did not. Thus, the localization of C3b deposition on the pneumococcus markedly affects its opsonic potential.