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Background: Background: Pneumonia and bloodstream infections (BSI) due to extensively drug resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. Methods: The OVERCOME trial was an international, randomized, doubleblind, placebo-controlled trial performed at 21 sites in 7 countries. Participants were randomly assigned to receive colistin (5 mg/kg x 1 followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI due to XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality and secondary outcomes included clinical failure and microbiological cure. Results: Between 2012 and 2020, 464 participants were randomized, and 423 eligible patients comprised the modified intent to treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43% vs. 37%; p = 0.17), clinical failure (65% vs 58%; difference 6.8% percentage points (95% Confidence Interval (CI) - 3.1, 16.6)), microbiological cure (65% vs 60% 4.8% percentage points (95% CI -5.6%, 15.2%)), or adverse events (acute kidney injury 52% vs 49%; p = 0.55; hypersensitivity reaction 1% vs 3%; p = 0.22; neurotoxicity 5% vs 2%; p = 0.29) between patients receiving monotherapy and combination therapy, respectively. Conclusions: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI due to these pathogens. NCT0159797

Objectives In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. Methods This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. Results The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). Discussion In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.

We aimed to describe regional differences in therapy for bloodstream infection (BSI) caused by extended-spectrum ?-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). 1,482 patients in 12 countries were included from an observational study of BSI caused by ESBL-E or CPE. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) for the influence of country of recruitment on empirical use of ?-lactam/?-lactamase inhibitors (BLBLI) or carbapenems, targeted use of BLBLI for ESBL-E and use of targeted combination therapy for CPE. The use of BLBLI for empirical therapy was least likely in sites from Israel (aOR 0.34, 95% CI 0.14-0.81), Greece (aOR 0.49, 95% CI 0.26-0.94) and Canada (aOR 0.31, 95% CI 0.11-0.88) but more likely in Italy (aOR 1.58, 95% CI 1.11-2.2) and Turkey (aOR 2.09, 95% CI 1.14-3.81), compared to Spain as a reference. Empirical carbapenems were more likely to be used in sites from Taiwan (aOR 1.73, 95% CI 1.03-2.92) and USA (aOR 1.89; 95% CI 1.05-3.39), and less likely in Italy (aOR 0.44, 95% CI 0.28-0.69) and Canada (aOR 0.10, 95% CI 0.01-0.74). Targeted BLBLI for ESBL-E was more likely in sites from Italy. Treatment at sites within Israel, Taiwan, Turkey and Brazil was associated with less combination therapy for CPE. Although this study does not provide precise data on the relative prevalence of ESBL-E or CPE, significant variation in therapy exists across countries even after adjustment for patient factors. A better understanding of what influences therapeutic choices for these infections will aid antimicrobial stewardship efforts. PH is supported by an Australian Postgraduate Award from the University of Queensland. The study was funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III - co-financed by European Development Regional Fund "A way to achieve Europe" ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). BGG, JRB, APH and YC also received funds from the COMBACTE-CARE project (grant agreement 115620), Innovative Medicines Initiative (IMI), the European Union's Seventh Framework Programme (FP7/2007-2013) and in-kind contributions from EFPIA companies.

Rapid urease test (CLO-test) is an inexpensive and quick method for diagnosis of Helicobacter pylori infection with controversial results in children. We evaluated the performance of CLO-test in relation to endoscopic and histological findings in children with H. pylori infection.We studied the medical records of children with H. pylori infection who were diagnosed between 1989 and 2009. Noninfected children were used as controls. H. pylori infection was defined by positive culture or by two other positive tests (histology and CLO-test, or urea breath test when a single test was positive). All children had histology together with CLO-test. Tissue culture was performed whenever possible.Five hundred thirty infected children (10.4 +/- 3.0 years) and 1060 controls (7.3 +/- 4.4 years) were studied. Sensitivity of CLO-test was 83.4% (95% CI, 79.9-86.3%), of culture 84.6% (95% CI, 78.7-89.1%), of histology 93.2% (95% CI, 90.7-95.1%), and specificity 99% (95% CI, 98.2-99.4%), 100%, and 100% respectively. CLO-test positivity was correlated with higher bacterial density (p.001), activity (p.001) and severity of gastritis (p.01), older age (p.01), and the presence of antral nodularity (p.001). When CLO-test was positive, the concordance with histology and culture was high (95.5 and 89.2% respectively), whereas low concordance was observed when CLO-test was negative (17.05 and 45.83% respectively).CLO-test had lower sensitivity and comparable specificity with histology. Both tests should be performed concurrently to accurately diagnose H. pylori infection in children.

Summary Concentrated human serum gamma globulin has been shown to contain virus neutralizing antibody for herpes simplex virus by means of protection tests in which mice were employed. When the globulin was administered prior to the challenge dose of virus the protective effect was definite although slight. No more than a minimal protective effect was observed when the viral injection preceded the administration of globulin by as little as 12 or 24 hours. Porcine and bovine gamma globulin had no demonstrable protective effect. No antigenic relationship between the viruses of herpes simplex and epidemic keratoconjunctivitis was revealed by protection tests with human gamma globulin.

SummarySixty-three cases of thyrotoxicosis that have been treated with radioiodine were followed-up from 3 to 21 months and examined by the triiodothyronine suppression test. Twenty-five of them (39.6%) showed a normal and 38 of them (60.4%) abnormal response to T. Twenty cases of the first group that showed normal response were clinically euthyroid and five were clinically hyperthyroid. Of the second group that showed abnormal response 12 appeared clinically euthyroid and the remaining 26 were hyperthyroid.Of the first group, which did not have many signs and symptoms of thyrotoxicosis even before treatment, only 4 (16%) required a second radioiodine treatment. Of the second group, which was polysymptomatic and displayed a refractoriness to treatment, 24 out of 38 cases required a second radioiodine therapy.Six cases were also tested for response to T. after their second therapeutic administration. All of them retain their glandular autonomy even after the second treatment.Two cases are of particular interest as showing a change in the clinico-laboratory picture and in their response to T. One had a normal response temporarily but reverted to abnormal thereafter. The other shifted from myxedema to abnormal response and thyrotoxicosis and after the second administration to normal response again.In the first 6 months of follow-up after treatment 11 cases exhibited normal and 21 abnormal response. In the following periods the distribution of the cases is about equal, comparable numbers showing normal and abnormal response.The meaning of the above observations is discussed.

Conclusions(1) The administration of penicillin to patients with streptococcal pharyngitis depresses the formation of type-specific antibacterial antibody. (2) There is a relation between the dose and route of administration of penicillin and the degree to which antibacterial activity develops. (3) Suppression of antibody formation by penicillin is probably due to rapid removal of the antigenic focus. (4) Failure to develop type-specific antibacterial antibody for the Streptococcus following penicillin therapy increases the risk of subsequent infection by homologous serological types.