Morten Helms

Excess Mortality Associated with Antimicrobial Drug-Resistant Salmonella Typhimurium

In a matched cohort study, we determined the death rates associated with drug resistance in Salmonella Typhimurium. We linked data from the Danish Surveillance Registry for Enteric Pathogens with the Civil Registration System and the Danish National Discharge Registry. By survival analysis, the 2-year death rates were compared with a matched sample of the general Danish population, after the data were adjusted for differences in comorbidity. In 2,047 patients with S. Typhimurium, 59 deaths were identified. Patients with pansusceptible strains of S. Typhimurium were 2.3 times more likely to die 2 years after infection than persons in the general Danish population. Patients infected with strains resistant to ampicillin, chloramphenicol, streptomycin, sulfonamide, and tetracycline were 4.8 times (95% CI 2.2 to 10.2) more likely to die, whereas quinolone resistance was associated with a mortality rate 10.3 times higher than the general population.

Short and long term mortality associated with foodborne bacterial gastrointestinal infections: registry based study

Abstract Objectives: To determine the excess mortality associated with infections with Salmonella, Campylobacter, Yersinia enterocolitica, and Shigella and to examine the effect of pre-existing illness. Design: Registry based, matched cohort study. Setting: Denmark. Participants: 48 857 people with gastrointestinal infections plus 487 138 controls from the general population. Main outcome measure: One year mortality among patients with gastrointestinal infections compared with controls after adjustment for comorbidity. Results: 1071 (2.2%) people with gastrointestinal infections died within one year after infection compared with 3636 (0.7%) controls. The relative mortality within one year was 3.1 times higher in patients than in controls. The relative mortality within 30 days of infection was high in all four bacterial groups. Furthermore, there was excess mortality one to six months after infection with Yersinia enterocolitica (relative risk 2.53, 95% confidence interval 1.38 to 4.62) and from six months to one year after infection with Campylobacter (1.35, 1.02 to 1.80) and Salmonella (1.53, 1.31 to 1.79). Conclusions: Infections with all these bacteria were associated with an increased short term risk of death, even after pre-existing illnesses were taken into account. Salmonella, Campylobacter, and Yersinia enterocolitica infections were also associated with increased long term mortality.

International Salmonella Typhimurium DT104 Infections, 1992-2001

The incidence of multidrug-resistant (MDR) Salmonella Typhimurium infections in humans, and in particular MDR definitive phage type 104 (DT104), has increased substantially in many countries in the last 2 decades, often associated with increased illness. To examine the magnitude of this problem, a survey was conducted among countries with available antimicrobial resistance or phage typing surveillance data. A total of 29, primarily industrialized, countries participated in the survey, which covered the years 1992–2001. Overall, the incidence of MDR S. Typhimurium and DT104 increased continuously during this period, although the problem affected primarily Europe and North America. The increase appeared to have peaked in the United Kingdom but not in other countries. Also, the incidence of quinolone-resistant S. Typhimurium was increasing. This survey implies that MDR S. Typhimurium constitutes an increasing public health problem in large parts of the world and emphasizes the importance of surveillance and control programs.

Etiology of Diarrhea in Young Children in Denmark: a Case-Control Study

ABSTRACT Infectious gastroenteritis is one of the most common diseases in young children. To clarify the infectious etiology of diarrhea in Danish children less than 5 years of age, we conducted a 2-year prospective case-control study. Stools from 424 children with diarrhea and 870 asymptomatic age-matched controls were examined, and their parents were interviewed concerning symptoms. Rotavirus, adenovirus, and astrovirus were detected by enzyme-linked immunosorbent assay, and norovirus and sapovirus were detected by PCR. Salmonella, thermotolerant Campylobacter, Yersinia, Shigella, and Vibrio spp. were detected by standard methods. Shiga toxin-producing (STEC), attaching-and-effacing (A/EEC), enteropathogenic (EPEC), enterotoxigenic, enteroinvasive, and enteroaggregative Escherichia coli were detected by using colony hybridization with virulence gene probes and serotyping. Parasites were detected by microscopy. Overall, a potential pathogen was found in 54% of cases. More cases than controls were infected with rotavirus, Salmonella, norovirus, adenovirus, Campylobacter, sapovirus, STEC, classical EPEC, Yersinia, and Cryptosporidium strains, whereas A/EEC, although common, was not associated with illness. The single most important cause of diarrhea was rotavirus, which points toward the need for a childhood vaccine for this pathogen, but norovirus, adenovirus, and sapovirus were also major etiologies. Salmonella sp. was the most common bacterial pathogen, followed by Campylobacter, STEC, Yersinia, and classical EPEC strains. A/EEC not belonging to the classical EPEC serotypes was not associated with diarrhea, underscoring the importance of serotyping for the definition of EPEC.

Adverse Health Events Associated with Antimicrobial Drug Resistance in Campylobacter Species: A Registry-Based Cohort Study

BACKGROUND Resistance to clinically important antimicrobial agents, particularly fluoroquinolones and macrolides, is increasing among Campylobacter isolates, but few studies have explored the human health consequences of such resistance. METHODS In a registry-based cohort study, we determined the risk of invasive illness and death associated with infection with quinolone- and erythromycin-resistant Campylobacter strains, while adjusting for comorbidity. We linked data from the Danish Surveillance Registry for Enteric Pathogens with data from the Civil Registration System and National Health Registries. RESULTS Of 3471 patients with Campylobacter infection, 22 (0.63%) had an adverse event, defined as invasive illness or death, within 90 days of the date of receipt of samples. Patients infected with quinolone-resistant Campylobacter strains had a 6-fold increased risk of an adverse event within 30 days of the date of receipt of samples, compared with patients infected with quinolone- and erythromycin-susceptible Campylobacter strains (adjusted odds ratio [AOR], 6.17 [95% confidence interval {CI}, 1.62-23.47]). However, infection with erythromycin-resistant strains was associated with a >5-fold risk of an adverse event within 90 days of the date of receipt of samples (AOR, 5.51 [95% CI, 1.19-25.50]). CONCLUSIONS The present study provides evidence of the human health consequences of resistance to clinically important agents among Campylobacter infections and the need for increased efforts to mitigate such resistance.

Quinolone Resistance Is Associated with Increased Risk of Invasive Illness or Death during Infection with Salmonella Serotype Typhimurium

In a registry-based cohort study, we determined the risk of invasive illness or death associated with infection with quinolone-resistant Salmonella serotype Typhimurium. We linked data from the Danish surveillance registry of enteric pathogens with data from the Danish civil registration system and 2 national health registries. Of 1323 patients infected with Salmonella Typhimurium, 46 (3.5%) were hospitalized due an invasive illness within 90 days of infection, and 16 (1.2%) died within 90 days of infection. After adjustment for age, sex, and comorbidity, infection with quinolone-resistant Salmonella Typhimurium was associated with a 3.15-fold (95% confidence interval, 1.39-7.10-fold) higher risk of invasive illness or death within 90 days of infection, compared with that observed for infection with pansusceptible strains.

Foodborne Bacterial Infection and Hospitalization: A Registry-Based Study

Background. Foodborne bacterial gastrointestinal infections are important causes of morbidity and mortality worldwide, and despite successful control programs in some developed countries, these infections continue to have a major impact on public health and economy. Methods. On the basis of data from 3 national registries, we determined short- and long-term risks of hospitalization due to gastroenteritis, short-term complications, and long-term sequelae after infections with nontyphoid Salmonella enterica, Campylobacter species, Yersinia enterocolitica, diarrheagenic Escherichia coli, and Shigella species. Results. Among 52,121 patients, 7524 (14.4%) were hospitalized with a diagnosis of gastroenteritis within 90 days after microbiological diagnosis. A total of 4941 patients (17.7%) with infections due to S. enterica and 1937 (10.8%) with infections due to Campylobacter species were admitted to the hospital. Complications, such as gastrointestinal perforation and invasive illness, occurred in 647 patients (1.2%). The risk of invasive illness was >6-fold higher in patients with infections due to S. enterica (odds ratio [OR] compared with the general population, 30.3; 95% confidence interval [CI], 26.2-35.1) than in those with infections due to Campylobacter species (OR, 4.9; 95% CI, 3.5-6.8) (P<.001). Long-term sequelae were seen in 865 patients (1.7%). Among 1000 patients with infections due to S. enterica, 1820 days of hospital stay were attributable to gastroenteritis, complications, and long-term sequelae. The corresponding figure for Campylobacter infections was 714 days. Conclusions. Infections with bacteria that are usually foodborne cause considerable morbidity, in terms of severe gastroenteritis that requires admission to hospital, as well as complications and long-term sequelae. The risk of complications and sequelae depends on bacterial species, and nontyphoid Salmonella is particularly associated with a burden of severe morbidity.

Risk factors for diarrhea among children in an industrialized country.

Background: Risk factors for childhood diarrhea in industrialized countries are not well characterized, although diarrhea remains an important cause of morbidity. Methods: We conducted a case–control study of 422 cases and 866 controls over 22 months in Denmark. We selected cases among children under 5 years of age with diarrhea. Age-matched healthy controls were selected from the background population using a population register. Parents were interviewed about possible exposures and underlying conditions. In addition, stool samples from both cases and controls were analyzed for viruses, parasites, and bacteria. We analyzed risk factors for diarrhea in general and for diarrhea of a viral, bacterial, or “unknown” etiology using logistic regression. Results: The following factors were independently associated with an increased risk of diarrhea: recent foreign travel, contact with symptomatic persons (particularly in daycare centers), hospitalization, contact with a dog with diarrhea, private daycare, consumption of products containing formula milk, unemployment and low educational status of parents, and prior diagnosis of several types of atopic diseases. In a pathogenic-specific analysis of diarrhea of bacterial (73 patients), viral (88), or “unknown” (222) etiology, the major risk factor for viral diarrhea was contact with symptomatic persons. For bacterial diarrhea, foreign travel and socioeconomic factors were the main risk factors. Conclusions: Viral diarrhea appears to be transmitted predominantly from person to person, whereas bacterial diarrhea appears to be primarily foodborne. A substantial portion of the diarrheal episodes may be of noninfectious etiology. Limiting child-to-child transmission of disease in daycare centers may substantially reduce the disease burden.

DNA microarray analysis of Salmonella serotype Typhimurium strains causing different symptoms of disease

BackgroundSalmonella enterica subsp. enterica is one of the leading food-borne pathogens in the USA and European countries. Outcome of human Salmonella serotype Typhimurium infections ranges from mild self-limiting diarrhoea to severe diarrhoea that requires hospitalization. Increased knowledge of the mechanisms that are responsible for causing infection and especially the severity of infection is of high interest.ResultsStrains were selected from patients with mild infections (n = 9) and patients with severe infections (n = 9) and clinical data allowed us to correct for known underlying diseases. Additionally, outbreak isolates (n = 3) were selected. Strains were analyzed on a DNA-DNA microarray for presence or absence of 281 genes covering marker groups of genes related to pathogenicity, phages, antimicrobial resistance, fimbriae, mobility, serotype and metabolism. Strains showed highly similar profiles when comparing virulence associated genes, but differences between strains were detected in the prophage marker group. The Salmonella virulence plasmid was present in 72% of the strains, but presence or absence of the virulence plasmid did not correspond to disease symptoms. A dendrogram clustered strains into four groups. Clustering confirmed DT104 as being a clonal phagetype. Clustering of the remaining strains was mainly correlated to presence or absence of the virulence plasmid and mobile elements such as transposons. Each of the four clusters in the tree represented an almost equal amount of strains causing severe or mild symptoms of infection.ConclusionsWe investigated clinical significance of known virulence factors of Salmonella serotype Typhimurium strains causing different disease symptoms, and conclude that the few detected differences in Salmonella serotype Typhimurium do not affect outcome of human disease.

Rectal bacteriotherapy for recurrent Clostridium difficile-associated diarrhoea: results from a case series of 55 patients in Denmark 2000–2012

Clostridium difficile infection is one of the most common nosocomial infections. Among other alternatives to standard treatment with vancomycin for recurrent infection are faecal microbiota transplantation and rectal bacteriotherapy with a fixed mixture of intestinal bacterial strains isolated from faeces of healthy persons to mimic a theoretical normal microflora. Developed by Dr. Tvede and Dr. Rask-Madsen, the latter method has been in use for selected patients during the last 25 years in Denmark. In this study we reviewed the medical records of patients treated with rectal bacteriotherapy for relapsing C. difficile in Denmark, 2000-2012. The primary end point was recurrent diarrhoea within 30 days after treatment. A total of 55 patients were included in this case series. Thirty-five patients (64%) had no recurrence within 30 days of bacteriotherapy. Patients with recurrence tended to be older (75.8 years vs. 61.3 years; p 0.26), and more often have preexisting gastrointestinal illness and longer duration of time from the first CDI to bacteriotherapy (221.6 days vs. 175.3 days; p 0.18). Treatment success was 80% in the subgroup of patients with no known gastrointestinal illness and first C. difficile episode less than 6 months before bacteriotherapy. The most common adverse events were abdominal pain (10.9%) and worsening diarrhoea (4.3%). One patient was hospitalized 10 days after treatment with appendicitis, fever, and Escherichia coli bacteremia. The results from this study indicate that rectal bacteriotherapy is a viable alternative to faecal microbiota transplantation in patients with relapsing C. difficile-associated diarrhoea.