Hemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: Clinical and epidemiologic observations

doi:10.1016/S0022-3476(05)81600-2

The Journal of Pediatrics

Volume 116, Issue 4, April 1990, Pages 544-551

https://doi.org/10.1016/S0022-3476(05)81600-2 Get rights and content

Purpose: To describe an outbreak ofEscherichia coli O175:H7 infection resulting in a high rate of progression to hemolytic-uremic syndrome, and to attempt to identify predictors of and risk factors for progression.

Design: Case-control study among employees and comparison of daily clinical features in two groups: infected residents with subsequent development of HUS and those who had no complications.

Setting: Two institutions for retarded persons in Utah.

Patients: Twenty residents with E. coll O157:H7 infection (13 culture confirmed, 2 probable, and 5 possible); HUS developed in 8, and 4 died. Thirty-one infected employees (3 with culture-confirmed, 6 with probable, and 22 with possible infection).

Measurements and main results: In a case-control study among employees, infection was independently assoclated with eating ground beef from a single lot prepared at several barbecues and with close contact with a resident who had diarrhea. Five of eight residents in whom HUS developed had received trimethoprim-sulfamethoxazole, compared with none of seven who had no subsequent complications (p=0.026); this finding may reflect antimicrobial treatment of patients with more severe illness. Compared with infected residents without complications, persons with HUS were younger (median age 13 vs 27 years, p=0.043) and, by the third day of illness, had higher leukocyte counts (median 23.7×10⁹/L vs 9.1×10⁹/L, p=0.018) and temperature (median 38.5°C vs 37.0° C, p=0.016). Leukocytosis peaked on day 4, more than 24 hours before signs of HUS appeared.

Conclusions: Food-borne outbreaks of E. coli O157:H7 in insitutions may have devastating effects. Leukocytosis and fever may precede and predict HUS in patients with E. coli O157:H7 infection.

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It did however prolong pathogen excretion in stool and may have increased the number of carriers. Ten studies, including five of those already mentioned, concluded that antibiotics increase the risk of HUS.8,38,39,49,51,52,54–57 Carter et al.54 reported an outbreak of E. coli O157:H7 colitis in a nursing home.
The administration of antibiotics in infections caused by Shiga toxin producing E. coli (STEC) strains, such as O157:H7, was and remains controversial, as it has been associated with the development of haemolytic uraemic syndrome (HUS). We conducted a literature review to better examine this association.
We searched the PubMed and Google Scholar databases for relevant articles, using the key words: ``haemolytic uraemic syndrome'', ``Shiga toxin'', ``E. coli O157:H7'', ``E. coli O104:H4'', ``STEC colitis'', ``STEC antibiotics'', ``STEC fosfomycin'', ``STEC trimethoprim sulfamethoxazole'', ``STEC fluoroquinolones'', ``STEC ciprofloxacin'', ``STEC rifaximin'', ``STEC gentamycin'', ``STEC colistin'', “Shiga toxin binding agent”, “Shiga toxin monoclonal antibody” and ``STEC Japan epidemic''.
Numerous studies report that antibiotics increase the risk of HUS development, while others report that antibiotics do not have any effect or can even reduce the rate of HUS development in STEC infections. The infecting STEC strain, the type of antibiotic as well as the timing of its administration appear to significantly affect the development of HUS in a STEC infected patient.
It appears that, while some antibiotics such as b-lactams and TMP/SMX may be detrimental, others appear to be safe and can prevent the development of HUS. Of note, fosfomycin appears to be the antibiotic with the most positive results from clinical studies, and may be able to avert HUS development, especially if administered within the first two or three days from diarrhoea onset. Fluoroquinolones have also shown positive outcomes in clinical studies, despite demonstrating unfavourable results in in vitro studies. Other agents, such as colistin, gentamycin and rifamycins, have shown promising results in in vitro studies and require further evaluation.
Effect of lactoferrin on release and bioactivity of Shiga toxins from different Escherichia coli O157:H7 strains
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Prevention of enterohemorrhagic Escherichia coli (EHEC) O157:H7 infections and of their severe clinical sequelae in humans remain to be a current challenge. Administration of bovine lactoferrin (bLF) proved to be effective in clearing EHEC from the bovine intestine, an important EHEC reservoir, suggesting that bLF may also be beneficial in human application against EHEC infections. To estimate the biological safety of this approach, we analyzed the effects of bLF on the main EHEC virulence factor, Shiga toxin (Stx). We quantified the release of Stx 1 and 2 from two O157:H7 EHEC strains (Stx1⁺Stx2⁺ and Stx2⁺ producing, respectively) cultured in the presence of bLF using ELISA assays and assessed cytotoxic effects of bLF and co-cultured EHEC on Vero cells. Effects of bLF on the stability of Stx2 were investigated using western blotting. ELISA results indicate a bLF concentration-dependent decrease of active, cell-free Stx2, but not Stx1 in EHEC cultures. High concentrations (100 and 50 mg/ml) of bLF resulted in significantly reduced (p < 0.05) metabolic activity rates of Vero cells, whereas a concentration of 10 mg/ml bLF was considered non-toxic for Vero cells. At concentrations of 1 or 0.1 mg/ml, bLF mitigated the verocytotoxicity of EHEC strains in a co-culture model up to 48 h after inoculation. When only colonizing bacteria were taken into account, cytotoxicity could be significantly reduced by 10 and 1 mg/ml bLF during 48 h. This effect of bLF at least partly results from degradation of the Stx2 receptor-binding B-subunit.
Inhibition of verotoxin (VT) 2 absorption into systemic blood from intestine by repeated administration of bovine immune colostral antibody against VT2 in mice
2015, Journal of Microbiology, Immunology and Infection
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Serum levels in control mice at 12 hours and 16 hours were significantly higher than those in mice repeatedly administered bovine immune colostral antibody. VT2 derived from E. coli O157:H7 in the intestine is known to induce serious complications, including HUS and brain damage, in patients infected with E. coli O157:H7.12–15 In infection models, mice showing intestinal bleeding died, but those not showing intestinal bleeding did not die.9,11
Whether absorption of verotoxin (VT) 2 from the intestine in mice is inhibited by administration bovine immune colostral antibody against VT2 was investigated.
Three-week-old mice were administered VT2 solution at 477.8 ng/mL or 955.6 ng/mL, and bovine immune colostral antibody against VT2 was then administered three times. Whey without antibody against VT2 was administered to control mice. Serum levels of VT2 were measured by fluorescence enzyme immunoassay.
Serum levels of VT2 in mice administered VT2 solution at 477.8 ng/mL and bovine immune colostral antibody against VT2 scarcely changed. By contrast, serum levels of VT2 in control mice increased and peaked 12 hours after administration. Peak values were 15.4 ± 5.04 ng/mL. Furthermore, serum levels of VT2 at 12 hours and 16 hours in control mice were significantly higher than in mice administered bovine colostral antibody against VT2. Serum levels of VT2 in mice administered antibody at 955.6 ng/mL showed no significant differences between repeated administration of bovine immune colostral antibody and controls.
These results suggest that absorption of VT2 from the intestine was inhibited by repeated administration of bovine immune colostral antibody against VT2 at early stages of Escherichia coli O157:H7 infection, whereas VT2 in the intestine remained at low levels.
A role for fosfomycin treatment in children for prevention of haemolytic-uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection
2015, International Journal of Antimicrobial Agents
The role of antimicrobial therapy for Shiga toxin-producing Escherichia coli (STEC) infection has not been clearly defined. A prospective study identified antibiotic use as a significant risk factor for subsequent development of haemolytic–uraemic syndrome (HUS). However, early treatment with fosfomycin, a bacteriostatic antibiotic, resulted in a significantly decreased risk of HUS. The aim of this study was to evaluate a role of fosfomycin therapy in the development of HUS in children who contracted STEC infection. The study included 118 children who contracted a STEC infection between 1997 and 2013. A pre-defined questionnaire was utilised to collect patient information regarding age, sex, presenting symptoms (fever, abdominal pain, diarrhoea and bloody stool), results of stool culture examination, initial results of white blood cell counts and C-reactive protein (CRP), use of antibiotics, the timing of introduction of antibiotics, and complications including HUS. Of the 118 patients, 64 were diagnosed with HUS and the remaining 54 did not develop HUS. Multivariate analysis showed that three independent factors (age, initial values of CRP and use of fosfomycin) were significantly associated with the occurrence of HUS; of particular note, the adjusted odds ratio for use of fosfomycin was 0.15 (95% confidence interval 0.05–0.45). Use of fosfomycin within the first 5 days of illness may decrease the development of STEC-related HUS in children.
Screening of the novel colicinogenic gram-negative rods against pathogenic Escherichia coli O157:H7
2015, Indian Journal of Medical Microbiology
Purpose: Escherichia coli (E. coli) O157:H7 is gram-negative enteric pathogen producing different types of Shiga toxin. This bacterium is the most corporate cause of haemorrhagic colitis in human. Administration of antibiotics (particularly sulfa drugs) against this pathogen is a debatable topic as this may increase the risk of uremic syndrome; especially in children and aged people. Around the world, microbiologists are in search of alternative therapeutic methods specially probiotics against this pathogen. In the present study, we have focused on the investigation of alternate bio-therapeutics (probiotics) for the treatment of patients infected with E. coli O157:H7. This study is based on the identification of colicin-producing gram-negative bacteria (particularly enterobacteriaceae) which can competently exclude E. coli O157:H7 from the gut of the infected individual. Materials and Methods: Hundred samples from human, animal faeces and septic tank water were analysed for nonpathogenic gram-negative rods (GNRs). Results: Out of these samples, 175 isolates of GNRs were checked for their activity against E. coli O157:H7. Only 47 isolates inhibited the growth of E. coli O157:H7, among which majority were identified as E. coli. These E. coli strains were found to be the efficient producers of colicin. Some of the closely related species i. e., Citrobacter sp, Pantoea sp. and Kluyvera sp. also showed considerable colicinogenic activity. Moreover, colicinogenic species were found to be nonhaemolytic, tolerant to acidic environment (pH 3) and sensitive to commonly used antibiotics. Conclusion: Nonhaemolytic, acid tolerant and sensitive to antibiotics suggests the possible use of these circulating endothelial cells (CEC) as inexpensive and inoffensive therapeutic agent (probiotics) in E. coli O157:H7 infections.
Oral immunization with Lactococcus lactis-expressing EspB induces protective immune responses against Escherichia coli O157: H7 in a murine model of colonization
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HC and HUS are caused by shiga-like toxins (Stxs), which are released by colonizing EHEC into the systemic circulation and induce endothelial damage in intestinal and renal vasculatures [4]. Several studies have linked antibiotic therapy to higher rates of HUS development and prolonged duration of the symptomatic disease, probably due to the excessive release of Stxs upon bacterial lysis [3,5–7]. Therefore, current disease intervention strategies are rather focusing on vaccination.
Enterohemorrhagic Escherichia coli (EHEC) have been responsible for several outbreaks of hemolytic–uremic syndrome (HUS) worldwide. HUS is the most common cause of acute renal failure in children and results in fatalities as high as 50% in the elderly. Currently, neither a specific treatment nor a vaccine is available for EHEC. Lactococcus lactis is a generally regarded as safe “GRAS” bacterium that offers a valuable platform for oral vaccine delivery. Toward the development of an oral vaccine against EHEC, we have previously constructed a recombinant L. lactis strain expressing the EHEC antigen, EspB in the cytoplasmic compartment. However, oral immunization of mice with this strain induced weak priming of the immune system. This outcome was attributed to the rather low levels of EspB expressed by this recombinant strain. Therefore, in the present study we optimized the expression of EspB in L. lactis by secreting the antigen either under constitutive or nisin-inducible control. Indeed, oral immunization of mice with the EspB-secreting strains successfully induced specific mucosal and systemic antibody responses. These responses were associated with mixed Th1/Th2 cell responses in Peyer's Patches and mesenteric lymph nodes. Moreover, immunized mice exhibited significant protection against E. coli O157:H7 colonization, as indicated by the reduced amount and/or duration of the bacterial fecal shedding. Our results demonstrate the protective potential of EspB as an oral vaccine against EHEC infection. Additionally, the study demonstrates the efficient delivery of recombinant EspB by the “GRAS” bacterium, L. lactis. The safety profile of L. lactis as a vaccine vehicle can particularly be beneficial to children and elderly as high-risk groups for HUS incidence.

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Original articleHemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: Clinical and epidemiologic observations

Pediatr Clin North Am

Lancet

Comput Biomed Res

J Pediatr

Lancet

J Pediatr

Lancet

Lancet

FEMS Microbiol Lett

Hamolytisch-uramische Syndrome: Bilaterale Nierenrindennekrosen bei akuten erworbenen hamolytischen Anamien

Schweiz Med Wochenschr

Hemolytic uremic syndrome—then and now

N Engl J Med

The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing strains of Escherichia coli

J Infect Dis

Further evidence associating hemolytic uremic syndrome with infection by verotoxin-producing Escherichia coli O157:H7

J Infect Dis

Escherichia coli O157:H7 as the predominant pathogen associated with the hemolytic uremic syndrome: a prospective study in the Pacific Northwest

Pediatrics

Haemorrhagic colitis and haemolytic uraemic syndrome associated with verocytotoxin-producing Escherichia coli (VTEC) in England and Wales

Sporadic occurrence of hemorrhagic colitis associated with Escherichia coli O157:H7 in Newfoundland

Can Med Assoc J

Sporadic cases of hemorrhagic colitis associated with Escherichia coli O157:H7

Ann Intern Med

Original article
Hemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: Clinical and epidemiologic observations