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The immune response against the infecting group A streptococcus (GAS) extracellular products (EP) was determined in acute- and convalescent-phase sera from 75 patients with different clinical manifestations of GAS infection. All EP elicited a high proliferative response in human peripheral blood mononuclear cells. In patients with bacteremia, low neutralization in acute-phase sera was associated with development of streptococcal toxic shock syndrome. Lack of neutralization in acute-phase sera was more common in patients infected with the T1emm1 serotype. The majority of patients did not develop the ability to neutralize the mitogenic activity of their infecting isolate despite a significant increase in enzyme-linked immunosorbent assay titer in early convalescent-phase sera. In patients with the ability to neutralize GAS EP, the immune response remained high over at least 3 years. In contrast, the neutralization capacity conferred by intravenous immunoglobulin and/or plasma treatment disappeared within 3 months.

Objective: To study the effect of recolonisation with alpha streptococci with the ability to inhibit the growth of otopathogens ("interfering" activity) on the recurrence of acute otitis media in susceptible children and the effect on the frequency of secretory otitis media., Design: Double blind, randomised, placebo controlled study., Setting: Ear, nose, and throat clinic with three doctors., Participants: 130 children prone to otitis media aged between 6 months and 6 years, 108 of whom were eligible and followed for 3 months., Main Outcome Measures: Recurrence of otitis media during follow up and a normal tympanic membrane at the last valid visit., Interventions: Children with no recurrences during the last month received phenoxymethylpenicillin (n=22), and those with a recurrence within 1 month received amoxicillin clavulanic acid (n=86), both twice daily for 10 days. These were followed by a streptococcal or placebo solution sprayed into the nose for a further 10 days. At day 60 the same spray was started for another 10 days., Results: At 3 months 22 children (42%) given the streptococcal spray were healthy and had a normal tympanic membrane compared with 12 (22%) of those given placebo. This difference was shown separately for recurrences of both acute otitis media and secretory otitis media., Conclusions: Selected bacteria with the ability to inhibit the growth of common otopathogens can be used to protect against recurrent acute otitis media and secretory otitis media in children.

The present study was undertaken to elucidate the inhibitory activity of the normal nasopharyngeal flora against the three most common otitis media (OM) pathogens in healthy children, children with secretory otitis media (SOM) and children with recurrent otitis media (rAOM). Isolates of alpha-hemolytic streptococci (AHS) and OM pathogens were recovered from the tubal orifice in each child. The samples were taken from 20 healthy children under general anesthesia, from 19 children with SOM and 20 children with rAOM. The method used to test the bacterial interference in vitro was a modified agar overlay method. The AHS sampled from the tubal orifice of the healthy children were able to inhibit 92% of the S. peumoniae isolates, 74% of the non-typable H. influenzae isolates and 89% of the M. catarrhalis isolates. The corresponding figures for children with SOM and children with rAOM were: 73% of the S. pneumoniae isolates, 58 and 54% of the non-typable H. influenzae isolates and 86 and 89% of the M. catarrhalis isolates. The AHS from children with SOM and children with rAOM were significantly less capable of inhibiting the S. peumoniae and the H. influenzae isolates (P<0.001). There was no significant difference between the three groups of children regarding inhibitory activity against M. catarrhalis. The results suggest that the inhibitory activity of the normal bacterial flora at the tubal orifice against pneumococci and H. influenzae may be reduced in children with SOM and rAOM.

The present study aimed to investigate the inhibitory activity of the normal epipharyngeal flora against the three most common acute otitis media (AOM) pathogens in healthy children, and to study if the inhibitory activity differs between alpha-hemolytic streptococci (AHS) sampled from the tubal orifice and from those sampled from the adenoid. A total number of ten isolates of AHS were collected from the tubal orifice and the adenoid, respectively, in ten children undergoing adenoidectomy or tonsillectomy. None of the children had a history of otitis media, neither secretory otitis media (SOM) nor AOM. The method used to test the bacterial interference in vitro was a modified agar overlay method. The results showed that the AHS from nasopharynx were able to inhibit the majority of the S. pneumoniae, nontypable Haemophilus influenzae and Moraxella catharralis isolates tested. The AHS isolates from the tubal orifice inhibited growth of 93% of S. pneumoniae, 79% of H. influenzae and 84% of M. catharralis isolates. The corresponding figures among isolates from the adenoid were 76, 48 and 62%. This difference in the inhibitory capacity between the AHS isolates collected from the adenoid, compared with the AHS collected from the tubal orifice, is statistically significant (P<0.01) and implies that it is important to know the exact sampling locality before conclusions are made concerning the significance of bacterial interference in the upper airways.

A total of 342 patients with clinical signs of tonsillitis and suspected group A beta-haemolytic streptococci (GAS) aetiology, verified with rapid test and GAS culture, were enrolled in a randomized, placebo-controlled, double-blind, multicentre study. They received antibiotic treatment for 10 days, followed by 10 days of alpha-streptococcal or placebo spray treatment in the ratio of 2 : 1. Pharyngeal status, throat culture and adverse events were investigated up to 75 days after treatment. The frequency of bacteriologically verified clinical recurrence was 13% in the alpha-streptococcal group and 15% in the placebo group at the follow-up on day 22. The corresponding figures at the last valid visit after 45-75 days were 19% and 30%, respectively, a statistically significant difference (p = 0.037). Furthermore, at the last valid visit 5% of subjects in the alpha-streptococcal and 12% in the placebo group were healthy carriers, bacteriological treatment failures, of GAS (p = 0.029). Treatment with alpha-streptococci and placebo spray were equally well tolerated. Thus, re-colonization with alpha-streptococci seem to hinder late recurrences of GAS pharyngotonsillitis.

On the basis of the presented results and those published by other investigators it can be stated that in the throat (i) bacterial interference is a multifaceted phenomenon; (ii) bacterial interference not only varies individually but also fluctuates in the individual by time and the epidemiological situation; (iii) bacterial interference among the microbes in the normal flora apparently helps the individual to combat the invading microorganisms; (iv) bacteriocins, if present, in the invading bacteria represent an important virulence factor; (v) bacterial interference as a factor of the host resistance to infection can be influenced negatively by antibiotic therapy; (vi) bacterial interference can act synergistically with antibiotics given in optimal doses saving the normal flora.

In sera from 4 of 25,000 individuals tested for antibodies against streptococci, extremely high antideoxyribonuclease B titers ( > 10(6) U/ml) were found. Two of the cases were diagnosed as monoclonal gammopathies. The M-components were shown to possess the anti-deoxyribonuclease B activity. The other two cases were diagnosed as relapsing erysipelas. The high serum titers of deoxyribonuclease B antibodies were accompanied by a very inflammatory reactivity in the patients' sera and by an oligopolyclonal pattern of immunoglobulin G. In routine diagnoses of streptococcal infections with the anti-deoxyribonuclease B test, patients with extremely high serum titers should be examined for the possible occurrence of gammopathies.

A factor from Streptococcus azgazardah (Lancefield's group C) capable of reacting with the Fc fragment of human IgG was partially purified and characterized. The bacteria were lysed by infection with phage, and the IgG Fc-reactive factor was purified from the crude lysate by affinity chromatography on a IgG-coupled Sepharose 4B column. The column was eluted with 3 M KSCN and the eluate gel-filtered on a Sephadex G 75 column. A 30-fold purification was obtained. The molecular weight of the IgG Fc-reactive factor was estimated to be 60,000. The factor was sensitive to trypsin treatment and to heating 95 degrees C, 10 min at pH 2.0. On polyacrylamide electrophoresis only one band was obtained. The trypsin-and heat-sensitivity, and the estimated molecular weight of the factor was similar to an IgG Fc-reactive factor preparation obtained from group A, type M 56 streptococci by heat treatment at 120 degrees C for 30 min.

Out of 169 patients with streptococcal tonsillitis treated with phenoxymethylpenicillin, 13 (8%) developed a new clinical infection with the same streptococcal strain within 2 weeks of completing the therapy (clinical treatment failure) and 24 (14%) were clinically healthy but harboured the same streptococcal strain after treatment (bacterial treatment failure). Patients with clinical treatment failure showed beta-lactamase activity in their saliva pellet significantly more often than patients with bacterial treatment failure, healed streptococcal tonsillitis or non-streptococcal tonsillitis as well as healthy controls. In an interference study, clinical treatment failures were compared with healthy streptococcal carriers, i.e. persons living in the same household and harbouring the same beta-streptococcal strain. 11/12 healthy carriers had alpha-streptococci with interfering activity against their own beta-streptococcal strain, while the corresponding figure for the clinical treatment failures was 2/13. Furthermore, 6/12 healthy carriers had beta-streptococci inhibiting their own alpha-strains, while the streptococci in 11/13 clinical treatment failures had this ability. The beta-lactamase activity and the interference between alpha- and beta-streptococci may be a contributory cause to treatment failure in streptococcal tonsillitis.

The study was designed to analyse the effect of penicillin on interference between alfa-streptococci and group A streptococci in vivo. Tissue cages were implanted subcutaneously in 9 rabbits and inoculated with 10(5) cfu of alfa- and beta-streptococci together as well as separately. Both streptococci were recovered 96 h after the inoculation in the untreated rabbits. Alfa-streptococci inhibiting the growth of beta-streptococci in vitro retained this capacity under the experimental in vivo conditions. Higher penicillin concentration did not increase the killing rate of beta-streptococci grown separately while a faster killing was observed with low penicillin levels in the presence of inhibiting alfa-streptococci, indicating synergistic effect.

The interference between alpha-streptococcal strains obtained from patients with repeated tonsillitis and a collection of group A streptococcal strains were studied. For this purpose three in vitro methods were designed and compared. The results obtained by a simple plating technique suitable for screening purposes were found to correlate well with those using more laborious techniques. In a limited scale some of the alpha- and beta-streptococcal combinations were tested under in vivo conditions using a tissue cage model allowing repeated sampling. In most instances agreement between the results of the in vitro and in vivo methods was registered. Several alpha-strains having inhibitory capacity to the majority of a collection of group A streptococci belonging to different serotypes were found, but also alpha-strains with an inhibitory activity restricted to few group A isolates within a certain serotype. Also beta-streptococcal strains with growth inhibiting activity towards some alpha-strains were found. As the methods were chosen to eliminate many of the unspecific inhibitory factors and the beta-hemolytic test strains showed a pattern of inhibition that varied for each of the reference alpha-strains the activity is most likely attributed to bacteriocin-like substances.

Studies on the streptococcal epidemiology of impetigo in children below 12 years of age in Addis Ababa indicated that most streptococci isolated belonged to the classic serological impetigo strains. Streptococcal type 9 seemed to be a new impetigo strain. Several cases of severe acute glomerulonephritis on impetigo basis were observed during the study.

Beta-streptococci isolated from patients with acute tonsillitis were tested for penicillin tolerance defined as an MBC/MIC ratio greater than or equal to 16. 11/18 strains recovered from patients with clinical treatment failure were tolerant to penicillin in comparison with 0/15 strains from successfully treated patients. The MBC/MIC ratio was less than 16 for all strains versus cefadroxil but above that ratio for many strains versus clindamycin, doxycycline and erythromycin. We suggest that penicillin tolerance may be one reason to treatment failures in individuals with streptococcal tonsillitis and that other antibiotics could be used to treat these patients since penicillin tolerance is not correlated to a general increase in antibiotic resistance.

The aim of the investigation was to study the influence of various penicillin levels on the interference between alfa- and beta-streptococci based on antibiotic levels registered after oral intake of penicillin tablets. It was found that penicillin was released from ordinary sugar coated tablets already in the mouth resulting in concentrations in saliva above the MIC of most penicillin sensitive microorganisms during the first 2 min. This was followed by a decrease of the alfa-streptococcal flora. It was also shown that penicillin levels above the MIC of alfa-streptococci resulted in prolonged survival of beta-streptococci as compared to that noted at penicillin levels above the MIC of beta-streptococci but below that of the alfa-strains. At this latter level a synergistic effect between penicillin and interfering alfa-streptococcal strains could be demonstrated.

Isolates of Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes and Branhamella catarrhalis were collected from five laboratories in different geographical areas in Sweden. Nine hundred and fortyfour strains were tested by the agar dilution method for susceptibility to seven oral antibiotics: phenoximethylpenicillin, ampicillin, cefaclor, erythromycin, doxycycline, trimethoprim-sulfamethoxazole and chloramphenicol. The H. influenzae and B. catarrhalis strains were also tested for beta-lactamase production. Of the H. influenzae strains, 8% were beta-lactamase-producing, while 35% of B. catarrhalis strains produced beta-lactamase. The latter value is higher than has earlier been reported in Sweden. Five S. pneumoniae strains showed decreased sensitivity to penicillin, and 9.5% of the S. pneumoniae strains showed a decreased sensitivity to one or more of the seven antibiotics tested. The S. pyogenes strains were sensitive to all the antibiotics tested with the exception of 4% of the strains, which showed a decreased sensitivity to doxycycline.

Comparison of the serum titers obtained with the Streptozyme, the antistreptolysin O, the antideoxyribonuclease B, and the antistreptohyaluronidase tests suggested that the Streptozyme test had failed to detect antibodies against streptococcal deoxyribonuclease B and hyaluronidase. Moreover, sera that were negative in the Streptozyme test could be shown by immunodiffusion to possess significant numbers of precipitins against extracellular factors produced by group A streptococci. Follow-up studies on patients with diagnosed streptococcal infections revealed elevated antideoxyribonuclease and streptohyaluronidase titers and increased numbers of precipitation lines without simultaneous increased titers by the Streptozyme test. There is thus a need for stricter control of possible batch-to-batch variations and more careful standardization of the antigen content of the Streptozyme test.

The streptococcal erythromycin resistance plasmid pSM9 was used to study the problem of how the transforming activity of mixtures of two unique linear products of restriction enzyme digestion depends on the distance between the cleavage sites. In transformation of the Challis strain of S. sanguis, the transforming activity of mixed digests increased with increasing relative distances (x) between the restriction sites, where 0 less than or equal to X less than or equal to 0.5. To explain the experimental results, a mathematical model was proposed according to which the overall probability (p) of transformation resulting in a functional replicon is the product of the partial probabilities of initial single-strand pairing, circularization, and stability of the paired intermediate, all of which were assumed to depend on x. A linear relationship found between transformation frequency and p was taken to support the model. Transformation of Challis by mixtures of two linearized plasmid molecules with regions of internal nonhomology resulting in paired intermediates with insertion or substitution loops allowed either donor molecule to contribute to the transformation yield.

The significance of various microorganisms as pathogens in septicemia has been changing over the years. This has been amply demonstrated by several authors especially in the interesting survey from Boston by Maxwell Finland covering a 30 years' period from 1935-1965. Dramatic changes were noted among the Gram-positives and this seemed to coincide with the introduction of antibiotics. However, since that time a continuous variation of microflora isolated from patients with bacteremia has been reported, which indicates the significance of a through analysis of isolated pathogens presently and in the future. The difference in etiology in various age groups has been strengthened and microorganisms, which were seldom found ten years ago, are now of major clinical importance in septicemia. There is no simple explanation to this phenomenon but rather reflects a summary of influences including changes of the host-microorganism interaction induced by different treatment procedures, survival of patients with diseases with a negative effect on the infectious response, new and better microbiological diagnostic procedures, etc. The possibility that the increased frequency of e.g. group B streptococcal infections reflects a change in 'Status epidemicus' must also be born in mind. The clinical significance of changes in the etiology of septicemia is obvious since the microorganisms have different virulence factors, influencing in various ways upon the host. These microorganisms may also have a different or changing antibiotic sensitivity pattern. It should be added, however, that the changes in antibiotic sensitivity pattern is a multifacetted problem involving factors like types of patients in a hospital, treatment regime, antibiotic use.