Stig E. Holm

Effect of recolonisation with "interfering" alpha streptococci on recurrences of acute and secretory otitis media in children: randomised placebo controlled trial.

Abstract Objective: To study the effect of recolonisation with α 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 natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study.

This prospective, multicentre, randomized, double-blind and placebo controlled study was performed to describe the natural course of uncomplicated lower urinary tract infection (UTI). A total of 1143 women 18 y and above, consulting at 18 primary health care centres in northern Sweden for symptoms suggestive of UTI were included. The symptoms urgency, dysuria, suprapubic pain and loin pain were registered, and urine cultures performed at inclusion and follow-up visits 8–10 d and 5–7 weeks later. Associations between all symptoms and bacteriuria or bacterial counts were unpredictable. Eradication of symptoms and bacteriuria and combinations of them were studied in 288 patients placebo treated for 7 d, of whom 39% dropped out after the first follow-up visit. The spontaneous cure rate of symptoms was 28% after the first week, and 37% had neither symptoms nor bacteriuria after 5–7 weeks. Considering the high dropout rate after the first follow-up visit, the spontaneous cure rate of symptoms and bacteriuria was calculated to 24% at the end of study. We conclude that patient near-laboratory tests are required to establish the diagnosis of lower UTI, and the guidelines for diagnosis of UTI need to be revised.

Invasive Group A Streptococcal Infections: T1M1 Isolates Expressing Pyrogenic Exotoxins A and B in Combination with Selective Lack of Toxin-Neutralizing Antibodies Are Associated with Increased Risk of Streptococcal Toxic Shock Syndrome

Analysis of 132 group A streptococcal (GAS) isolates from 151 invasive episodes, including streptococcal toxic shock syndrome (STSS), from 1983 to 1995 showed great genetic variation by use of T serotyping in combination with restriction fragment length polymorphism. In contrast, genetically homogenous T1M1 isolates appeared in epidemic patterns with significantly increased risk of STSS. The speA gene, with the allelic variants speA2 and speA3 carried by the T1M1 and T3M3 serotypes, respectively, was strongly associated with STSS. Infection with a GAS isolate carrying speA, alcohol abuse, and malignancy recently treated with cytostatic drugs were factors independently related to STSS. Neutralization of SpeA lymphocyte mitogenicity was totally absent in sera from patients with STSS and low in sera from persons with uncomplicated bacteremia compared with levels in sera from uncomplicated erysipelas. Neutralization of SpeB was significantly lower in sera of patients with STSS than in sera from persons with bacteremia or erysipelas.

Septic Shock Induced by Group a Streptococcal Infection: Clinical and Therapeutic Aspects

During 1988 and 1989 > 500 cases of serious group A streptococcal infections were reported in Sweden, many with a fatal outcome. We report here on 11 consecutive patients with septic preshock/shock and multiorgan failure, including acute renal failure. 10 had verified group A streptococci (GAS) serotype T1M1 infections while 1 patient was culture negative but with clinical signs of severe infection and serological evidence of GAS infection. Presenting symptoms were high fever, relative bradycardia, edema and renal failure. In all patients the condition deteriorated despite conventional treatment including volume substitution and antibiotics. Systolic blood pressure was transiently < 80 mmHg in 10 patients and 9 of them needed infusion of inotropic agents to avoid fatal circulatory shock. In 9 patients respiratory aid was instituted and 7 were dialysed. Plasma exchange was performed in 7, while the remaining 4 received transfusions with blood and plasma without plasma exchange. 10 patients improved and were discharged within 8 weeks. One woman died within 2 days after admission to the hospital. Renal function recovered in all survivors, with a follow-up serum creatinine < 80 mumol/l. The complicated clinical picture in these patients with many simultaneous therapeutic events confounds the interpretation of the effect of single actions. The favourable outcome in these severely ill patients suggests that potent inotropic agents, immunoglobulin therapy and plasma exchange might be beneficial in severe streptococcal disease when conventional treatment fails.

Evaluation of Beta-lactamase Activity and Microbial Interference in Treatment Failures of Acute Streptococcal Tonsillitis

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.

Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: The LUTIW project

Objective. To analyse associations between symptoms and bacteriuria in uncomplicated lower urinary tract infection in women (LUTIW) and to evaluate outcome of therapy with three different regimens of pivmecillinam or placebo. Design. Prospective, multicentre, randomized, double-blind, and placebo-controlled therapy study. Symptoms registered at inclusion, during therapy and at follow-up visits after 8–10 and 35–49 days. Significant bacteriuria defined according to current European guidelines. Setting. A total of 18 primary healthcare centres in northern Sweden. Subjects. Women aged 18 years and above with symptoms of urgency, dysuria, supra pubic or loin pain. Main outcome measures. Symptoms and bacteriuria at inclusion and course of symptoms, bacteriuria, and their combinations during and post-therapy. Results. At inclusion, no associations or significant differences were found between symptom scores and bacteriuria, bacterial counts, or species. The 884 patients (77%) with significant bacteriuria were followed up. All pivmecillinam therapies were superior to placebo (p < 0.001). From day six until first follow-up, the mean values of all symptoms were higher and the bacteriological cure was lower at first follow-up in the three days (84%) compared with the seven days regimens (93–94%, p < 0.001). At final follow-up clinical cure was similar in all pivmecillinam regimens (65–72%) as was bacteriological cure (83–89%). Pivmecillinam had few low to mild adverse reactions, comparable to placebo. Conclusions. Symptoms are not conclusive for diagnosis of LUTIW. Pivmecillinam therapies are superior to placebo and seven days regimens are more efficient than three days. Pivmecillinam 200 mg×2×7 days is recommended as a first-line therapy for LUTIW.

Alpha-Streptococci as Supplementary Treatment of Recurrent Streptococcal Tonsillitis: A randomized Placebo-controlled Study

Recurrences are a common finding after antibiotic treatment of acute group A streptococcal tonsillitis. This has been attributed to several factors, among others a disturbed normal throat flora and especially a lack of alpha-streptococci. It thus seems logical in patients with recurrent streptococcal tonsillitis, to restore the normal alpha-streptococcal flora by reimplantation of alpha-streptococci. This was performed in a double blinded, randomized, placebo-controlled study. 36 patients with recurrent streptococcal group A tonsillitis were treated with antibiotics followed by either placebo (19 patients) or a pool of 4 selected alpha-streptococcal strains (17 patients) with good interfering activity against clinical isolates of beta-streptococci. No patient recurred during the first 2 months of follow-up in the alpha-treated group, but 7 in those treated with antibiotics and placebo. After 3 months 1 in the patient group treated with antibiotics and alpha-streptococci and 11 in the placebo-treated group recurred. These results are statistically highly significant and show that recolonisation with alpha-streptococci seems to offer a new way to lower the rate of recurrence in streptococcal throat infections.

Correlation between Serum TNFα and IL6 levels and Severity of Group: A Streptococcal Infections

The multiorgan failure syndrome caused by group A streptococci (GAS) designated streptococcal toxic shock syndrome (STSS) is believed to be mediated by cytokines induced by superantigens. In order to study the relationship between superantigen production, cytokine levels in patient sera, and clinical GAS manifestation we examined acute-phase sera and strains from 25 patients with GAS bacteremia. The patients had various disease manifestations, including STSS (44%), erysipelas (28%), septicemia (24%), wound infections (16%), and pneumonia (12%). Serotype T1M1 dominated, representing 56% of the isolates, but also strains of other serotypes were identified. The strains were found to produce the streptococcal pyrogenic exotoxins (Spe) A, B, and F, as determined by immuno-blot analyses. There was no difference in amounts of toxin produced between strains isolated from patients with different manifestations of disease. Levels of TNF alpha, IL1 alpha, IL6, IL8, and IFN gamma in acute-phase sera were determined by use of ELISA and RIA assays. The analyses showed higher levels of IL6 in sera from patients with STSS than in sera from patients with bacteremia without shock. TNF alpha was elevated in sera from patients with STSS, as compared to sera from patients with uncomplicated pharyngotonsillitis. No increase in the levels of IL1 alpha, IL8, and IFN gamma could be found in the patient sera and there was no difference in the level of those cytokines between the various patient categories.

Pulsed-Field Gel Electrophoresis Typing of Escherichia coli Strains from Samples Collected before and after Pivmecillinam or Placebo Treatment of Uncomplicated Community-Acquired Urinary Tract Infection in Women

ABSTRACT The primary infecting Escherichia coli strains from 156 women with community-acquired uncomplicated urinary tract infection (UTI) randomized to pivmecillinam or placebo and the E. coli strains causing UTI at two follow-up visits were typed using pulsed-field gel electrophoresis (PFGE). In the pivmecillinam treatment group PFGE showed that among patients having a negative urine culture at the first follow-up 77% (46/60) had a relapse with the primary infecting E. coli strain and 23% (14/60) had reinfection with a new E. coli strain at the second follow-up. Among patients having E. coli at the first follow-up PFGE showed that 80% (32/40) had persistence with the primary infecting E. coli strain, 15% (6/40) had reinfection with a new E. coli strain, and 5% (2/40) had different E. coli strains at the two follow-up visits (one had reinfection followed by relapse, and the other had persistence followed by reinfection). In the placebo group the majority had E. coli at the first follow-up. PFGE showed that among these patients 96% (50/52) had persistence with the primary infecting E. coli strain and 4% (2/50) had different E. coli strains at the two follow-up visits (both had persistence followed by reinfection). The finding that the majority of UTIs at follow-up are caused by the primary infecting E. coli strain supports the theory of a vaginal and rectal reservoir but could also support the recent discovery that E. coli strains are able to persist in the bladder epithelium despite appropriate antibiotic treatment, constituting a reservoir for recurrent UTI.

Antibacterial Effect of Zinc Oxide in Vitro

Antibacterial activity, zinc concentrations and pH were measured in Müller-Hinton broth containing different amounts of zinc oxide and inoculated with Staphylococcus aureus (10(6) colony forming units/ml). The minimum inhibitory concentrations (MIC) of zinc oxide to different clinical isolates were determined using the Müller-Hinton agar dilution tests. Gram-positive bacteria were most susceptible. Gram-negative aerobic bacteria and streptococci were usually not inhibited even at the highest concentrations used (1024 micrograms/ml), but staphylococci--particularly some isolates of Staphylococcus epidermidis--were sensitive enough to allow determination of their MIC.