Table 1 Approach to management: summarizing trialed and experimental treatments.

Fluid and electrolyte imbalance

Intravenous fluids

Fluid balance and attention to the volume and sodium content of intravenous fluids administered early in the disease have been shown to reduce the risk of developing oligoanuric HUS after Escherichia coli O157:H7 infections

[25]

Intravenous fluids within first 4 days of onset of diarrhea (isotonic preferable).

The overall oligoanuric rate of the 50 participants was 68%, but was 84% among those not given intravenous fluids in the first 4 days of illness. The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% CI, 1.1 to 2.4; P = 0.02). Children with oligoanuric HUS were given less total intravenous fluid (r = -0.32; P = 0.02) and sodium (r = -0.27; P = 0.05) in the first 4 days of illness than those without oligoanuria.

[24]

Acute renal failure

Acute renal replacement therapy

Peritoneal dialysis (safe with thrombocytopenia) Hemodialysis

Plasma infusion and plasma exchange

[26]

[27]

[28]

Apheresis

Uncertain benefit

[29]

Antihypertensives

Where indicated

[13, 30]

Hematological: hemolytic anemia

Transfusion (packed red cells)

[13]

Hematological: thrombocytopenia

Platelet transfusion (usually avoided)

[13, 30]

Preventing further effects of toxin

Antibiotics

Generally to be avoided because of VT/Stx/endotoxin release from dying/dead bacteria. β-lactams to be avoided.

Subinhibitory levels may increase toxin production/release

[13]

[39]

[32]

The quinolone ciprofloxacin but not fosfomycin causes Shiga toxin-encoding bacteriophage induction and enhanced Stx production from E. coli O157:H7 in vitro and in vivo in a mouse model.

[33, 34]

Fosfomycin showed evidence of better outcomes in a

mouse-model of STEC infection and was recommended for human studies. Similar results were observed in a gnotobiotic piglet model. Pooled prospective data showed no benefit of antibiotics There is only a single study purportedly connecting fosfomycin with a reduced risk of HUS

[35]

Fosfomycin benefit in humans remains in doubt. The validity of the study has been questioned on the basis that the meta-analysis mischaracterized fosfomycin as being superior to no antibiotics.

[36]

Lumenal toxin neutralisers: Synthetic ligand mimics

Synsorb K; trial showed no benefit

[37]

Modified bacteria decorated with Gb3 or Gb4 Super Twig (Gb3 polymer)

Not yet trialed

Clinical trials awaited

[40]

Antibodies: Monoclonal against A subunit

Protective in lethally-challenged animals

[41]

Oral bovine colostrum

No effect on complications; decreases stool frequency but not STEC carriage

[42]

LPS antibodies

Reduces in vitro adherence. No human data. Experimental only.

[43]

Receptor blockers and toxin intracellular transport inhibitors

Ac-PPP-tet blocks intracellular transport of Stx2 from Golgi to endoplasmic reticulum (essential for Stx2 toxicity)

Watanabe-Takahashi et al. reviewed other neutralizers that do not act on receptor binding but disrupt intracellular transport of the toxin, effectively neutralizing the toxin.

[45]

Systemic (intravenous) toxin binders

[46]

[47]

Cell-permeable peptide binds to Stx2 and prevents acute kidney injury. Increases survival in juvenile baboon model. TVP (5 mg/kg) delivered intravenously and simultaneously with toxin or at 6 or 24 h after toxin with daily 1 mg/kg supplements up to day 4 prevented acute kidney injury and

[47]

delayed and reduced blood urea and creatinine levels and increased survival. Delayed administration of the peptide significantly reduced thrombocytopenia, but had no effect on anemia. This cell-permeable agent shows promise in counteracting Stx2 lethality in a baboon model; outcomes of human trials are awaited.

[48]

Blockers of endosome-to-Golgi trafficking of Stx

Recently it was shown that the metal manganese (Mn²⁺) blocks endosome-to-Golgi trafficking of STx and causes its degradation in lysosomes. Mn2+ targets the cycling Golgi protein GPP130. Direct trafficking of STx from early endosomes to the Golgi, (bypassing late endosomes and lysosomes), is a crucial step that allows STx to avoid degradation. Mn²⁺, as a small-molecule

inhibitor targeting this step therefore offers a cheap therapeutic modality given that mice injected with nontoxic doses of Mn2+ were completely resistant to a lethal STx challenge.

[49]

[49]

Blockers of bacterial and host cell interaction

Probiotics

Harmless recombinant bacteria expressing surface molecules that mimic host cell receptors, deceiving pathogen into attaching to probiotic cell rather than the host cell receptor. Unlikely to benefit symptomatic patients but could be beneficial as prophylactic for family and close contact/exposed persons. Supernatant of cultures of Bifidobacterium longum HY8001 is designed to inhibit the effect of VT/Stx through interference of B subunit of VTs in binding to Gb3.

[50]

Terminal complement complex formation

Eculizumab (intravenous)

This monoclonal antibody blocks activation of complement and Factor H binding via alternative pathway.

[51, 52]

Promising results in small clinical pilot study. The antibody was given intravenously at 7 day intervals, twice in two patients and four times in a third patient.

[53]

Immunoprophylaxis

Vaccines

Promising results in animal studies using:

(1) virulence proteins (Stx1/2, intimin, EspA;

peptides;

[54]

[55]

fusion proteins of A and B Stx subunits);

[56]

(2) avirulent ghost cells of EHEC O157:H7;

[57]

(3) live attenuated bacteria expressing

recombinant proteins. Gu et al. used a live attenuated EIS-producing Salmonella vaccine in mice model. Vaccination induced significant increases of EspA, intimin and Stx2 specific IgG in serum and secretory IgA in feces as well as antigen-specific T cell proliferation;

[58]

(4) recombinant fimbrial proteins have been developed in a quest to protect against the STEC-related entity piglet edema disease. Early results are mixed.

[59]

Tir, EspB, EspD, NleA, and EspA were highly immunogenic in vaccinated and naturally infected subjects and represent future candidates for a STEC vaccine;

[60]

(5) DNA vaccines: EHEC Stx2 A2 and B subunits confer immunity in a mouse model;

[61]

(6) plant-based oral recombinant Stx2 vaccine protects mice.

[62]