Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 4467 2023-03-11 10:28:36 |
2 format Meta information modification 4467 2023-03-13 03:03:04 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Liu, Y.; Thaker, H.; Wang, C.; Xu, Z.; Dong, M. STEC-HUS Therapeutic Strategies. Encyclopedia. Available online: (accessed on 21 June 2024).
Liu Y, Thaker H, Wang C, Xu Z, Dong M. STEC-HUS Therapeutic Strategies. Encyclopedia. Available at: Accessed June 21, 2024.
Liu, Yang, Hatim Thaker, Chunyan Wang, Zhonggao Xu, Min Dong. "STEC-HUS Therapeutic Strategies" Encyclopedia, (accessed June 21, 2024).
Liu, Y., Thaker, H., Wang, C., Xu, Z., & Dong, M. (2023, March 11). STEC-HUS Therapeutic Strategies. In Encyclopedia.
Liu, Yang, et al. "STEC-HUS Therapeutic Strategies." Encyclopedia. Web. 11 March, 2023.
STEC-HUS Therapeutic Strategies

Shiga toxin-producing Escherichia coli (STEC)-associated hemolytic uremic syndrome (STEC-HUS) is a clinical syndrome involving hemolytic anemia (with fragmented red blood cells), low levels of platelets in the blood (thrombocytopenia), and acute kidney injury (AKI). It is the major infectious cause of AKI in children. In severe cases, neurological complications and even death may occur. Treating STEC-HUS is challenging, as patients often already have organ injuries when they seek medical treatment.

Shiga toxin hemolytic uremic syndrome STEC-HUS

1. Introduction

Hemolytic uremic syndrome (HUS) is a group of clinical disorders characterized by low levels of red blood cells and platelets, as well as AKI [1]. The pathological manifestations of HUS are thrombotic microangiopathies. The key reason for the occurrence of HUS is the injury of endothelial cells in microvessels (arterioles, capillaries, and venules), although the etiology and pathogenesis vary. Shiga toxin-producing Escherichia coli (STEC) is the main pathogen causing typical and diarrhea-associated HUS (D+HUS). Atypical HUS (aHUS) is often caused by non-STEC factors, such as other infections, malignant hypertension, drugs (e.g., chemotherapy drugs, interferon-α/β, and calcineurin inhibitors), or inherent genetic mutations [2]. A STEC infection initially presents with symptoms of hemorrhagic colitis, such as abdominal pain and hemorrhagic diarrhea, and vascular damage can cause hemolytic anemia, thrombosis, and kidney injury [3]. Extrarenal manifestations occur in around 20% of STEC-HUS patients, including hypertension and cardiac, neurological, gastrointestinal, and endocrinal complications, which are associated with an increased risk of death [4]. In some cases, HUS presents with extensive extrarenal manifestations, of which gastrointestinal and central nervous system (CNS) complications can be the most severe. These complications can lead to encephalopathy, cerebrovascular accident, epilepsy, and death [5][6][7][8]. The combination of HUS with CNS dysfunction usually indicates a poor prognosis [9][10][11].
When STEC-contaminated food or water is consumed, STEC colonizes the colonic epithelium. Shiga toxins (Stxs), which are the main virulence factors of STEC, are released from STEC and further damage the vascular network of the intestinal mucosa, causing hemorrhagic colitis. Once Stx enters the systemic circulation, it can bind with the granulocytes and platelets in the blood circulation and be transferred to the kidney and other target organs [12]. Stxs can bind to glycolipid globotriaosylceramide (Gb3Cer) on the surface of the cell membrane and induce endocytosis. Then, the Stxs are transported to the trans-Golgi network through the retrograde transport pathway, reaching the endoplasmic reticulum (ER), where the enzymatic domains of Stxs are released into the cytoplasm, inhibiting protein synthesis and leading to apoptosis, ER stress, inflammation, and damage [13].

2. Volume Expansion

The occurrence of dehydration, anuria, or oliguria is related to higher rates of renal replacement therapy (RRT), longer hospitalization, and a worse prognosis for HUS [14][15][16][17][18]. In the early stage of a STEC infection (the first four days after the onset of diarrhea) and during the occurrence of HUS, intravenous fluid infusion and volume expansion can reduce the occurrence of oliguria and improve the prognosis of STEC-HUS. Therefore, the early identification of infected patients and the early application of isotonic liquid can reduce the severity and duration of STEC-HUS [14][18][19][20]. However, it should be noted that with intravenous infusion, it is necessary to closely monitor the development of renal failure, urine volume, blood pressure, and fluid overload.
There is no standardized clinical protocol for volume expansion in STEC-HUS. A phase III multinational embedded cluster crossover randomized trial (NCT05219110) in the United States and Canada is recruiting STEC-infected children to evaluate whether early aggressive volume expansion is associated with better renal outcomes and fewer adverse events than conservative management, as well as its efficacy and safety. The results of this clinical trial may provide additional evidence and a detailed approach to volume expansion for STEC infection.

3. Renal Replacement Therapy

Around 40~71% of STEC-HUS patients require RRT [21][22][23]. When patients develop oliguria AKI, fluid overload, refractory hyperkalemia, or uremia, RRT is required [24]. It includes peritoneal dialysis (PD), hemodialysis (HD), and continuous renal replacement therapy (CRRT). The selection of dialysis methods should be based on a comprehensive analysis of the characteristics of patients, the performance of dialysis methods (indications/contraindications and advantages/disadvantages), institutional resources, and local practices [25][26]. Current evidence indicates that there is no significant difference in mortality for PD, HD, and CRRT in AKI [26][27]. Although the application of PD has decreased significantly in the past few decades, overall, the application of PD in AKI has gradually increased recently in certain regions [28][29]. In Argentina, the country with the highest incidence of STEC-HUS in the world, PD is the most commonly used method, and has always been the main RRT method for the pediatric treatment of AKI [28]. The benefits of acute PD include the relatively low cost, simple technology, lack of requirement for anticoagulation or a central venous catheter, and better tolerance for patients with hemodynamic instability. It is especially applicable for patients with hypoglycemia or fluid restriction, such as neonates [26]. However, PD also has some potential disadvantages. The most common complications include catheter dysfunction, liquid leakage, hyperglycemia, and peritonitis. In addition, the following factors should also be considered in practice: the unpredictability of solute clearance and water ultrafiltration; the fact that PD is ineffective for patients in a highly catabolic state; the potential risk of hyperglycemia; the fact that PD is contraindicated in patients with recent abdominal surgery or active abdominal disease; the increased risk of pulmonary disease progression; and the higher nursing workload [26].
A multicenter retrospective study in Argentina involving 389 children with STEC-HUS requiring PD treatment showed that acute PD is a safe and effective treatment for AKI in STEC-HUS children. Although PD showed more complications compared to HD or CRRT, none of the patients needed to change to another form of RRT due to the ineffectiveness of the technique. Complications related to catheter implantation should be taken into consideration during PD, and the prophylactic use of antibiotics should be considered before placing a PD catheter, to reduce the incidence of peritonitis [25].
The main advantage of HD is rapid fluid and solute removal, making it suitable for children with congenital metabolic disorders and severe hyperammonemia who show no response to drug therapy [30][31]. Similar to PD, HD can be performed outside the ICU. The drawback is the need for well-functioning vascular access and hemodynamic stability. Anticoagulation with heparin, which is often necessary for patients undergoing HD, increases the risk of hemorrhage [26].
CRRT is the most appropriate treatment for critically ill patients with multiorgan dysfunction and hemodynamic instability [26][31][32][33]. Its significant advantages are better hemodynamic stability and reduced cross cell solute migration, avoiding the increased intracranial pressure that may be caused by HD. CRRT provides more efficient solute removal, liquid ultrafiltration, and easier fluid balance control than PD [26][33]. The disadvantages include the higher cost, the need for continuous anticoagulation, and the risk of circuit clotting, as well as the greater nursing workload and experience needed due to its technically challenging system [26]. As such, the use of CRRT required for AKI varies widely around the world and it is less widely used in low-income countries than in high-income countries [34].

4. Antibiotics

Antibiotics use in STEC-HUS is controversial and not currently recommended [35][36][37]. Opponents argue that the use of antibiotics may lead to an increase in Stx release from dead bacteria or to alterations in the intestinal flora that are conducive to the further attachment of STEC to the intestinal wall, the induction of phage production, and the expression of stx genes, which may lead to disease progression and deterioration [24][38][39]. Proponents argue that antibiotic use in the early stages of HUS reduces STEC, thereby improving HUS outcomes [24]. A prospective cohort study of 71 children under 10 years of age with diarrhea caused by E. coli O157:H7 was conducted to assess the impact of antibiotic treatment on the risk of developing HUS. The results showed that, among the 71 children, 10 (14%) developed HUS, of which 5 were treated with antibiotics. A higher initial white blood cell count, stool culture evaluation soon after onset, and antibiotic treatment were significantly associated with HUS. Their data confirm that the administration of sulfa-containing antibiotics to children infected with E. coli O157:H7 increases their risk of developing HUS and suggest that β-lactam antibiotics are associated with a similar risk.
However, most of the studies illustrating a relationship between antibiotics and HUS are prospective cohort studies, case-control studies, or retrospective studies, with a small sample size and different antibiotic treatment regimentations in different periods, and many results are contradictory [40][41][42]. A meta-analysis showed that antibiotic administration was not associated with a higher risk of HUS. A similar conclusion was drawn in another meta-analysis; however, antibiotic use was significantly associated with the occurrence of HUS after excluding studies with a high risk of bias and those without an acceptable definition of HUS. Therefore, antibiotics are not recommended for STEC infected individuals [36][37]. The relationship between HUS and antibiotic use is confounded by the fact that patients who become more unwell are more likely to develop HUS and receive antibiotic treatment. A single-center prospective randomized controlled trial examined the effect of trimethoprim-sulfamethoxazole on symptom duration, the fecal excretion of the pathogen, and the risk of developing HUS in children with E. coli O157:H7 enteritis. The results showed that antibiotic treatment had no statistically significant effect on symptom progression, the excretion of fecal pathogens, or the incidence of HUS [43]. Therefore, multicenter-randomized clinical trials with sufficient power to study this topic are needed to further determine whether it increases the risk of HUS [43]. Rapid diagnostic methods to permit early randomization and group statistical analysis according to the severity of the disease are required in the study [37].
Some of the determinants of the progression to HUS are the infectious STEC strain, the type of toxin that it produces, and the types of antibiotics used to treat the infection. One plausible mechanism by which antibiotics increase the risk of HUS is increasing the production and/or release of Stx by inducing a precursor phage containing the Stx-encoding gene, thereby enhancing Stx transcription, phage-mediated lysis, and bacterial cytotoxic release [44][45]. An in vitro study investigated the role of different antibiotic combinations in inducing Stx2-containing phages and correspondingly affecting Stx2 transcription and production during the EHEC O104: H4 outbreak in Germany [46]. The effects of antibiotics on Stx2-harboring phage induction and Stx2 under 1/4 MIC conditions were investigated. The results demonstrated that several antibiotics, including chloramphenicol, meropenem, azithromycin, rifaximin, and tigecycline, significantly reduced the baseline levels of phage induction, Stx2 transcription, and Stx2 production in an EHEC O104: H4 outbreak strain producing Stx2.
As one of the fluoroquinolone antibiotics, ciprofloxacin is often used to treat diarrhea and suspected gastrointestinal infections due to its inhibitory effect on bacterial DNA synthesis, however, its use for STEC-infected patients with diarrhea remains controversial. It has previously been shown to induce Stx-harboring phages containing Stx2 outbreak isolates in EHEC O157:H7 by inhibiting DNA replication and triggering a bacterial SOS response, significantly increased phage induction, and Stx2 production [45][46]. So far, in vitro studies on the use of fluoroquinolones have generally shown mostly unfavorable outcomes after administration. A number of studies found that ciprofloxacin can induce Stx production [35][47][48][49][50][51][52], however, only a few studies found that it can inhibit Stx production [50][51]. Most of these studies used the O157:H7 STEC strain. The results of the two studies that focused on the effect of antibiotics on STEC O104:H4 toxin production contradicted each other with regard to ciprofloxacin. In one study, ciprofloxacin induced toxin production [46], and in the other, it inhibited toxin production [51]. Similarly, results from in vivo studies of fluoroquinolones have varied widely, as some studies have found improved survival of STEC-infected animals after the administration of fluoroquinolones [53][54][55], while others found they caused HUS in animals, with no difference in survival compared to controls. On the contrary, results from clinical studies have shown surprisingly positive effects of fluoroquinolone use. A retrospective cohort study of 3323 symptomatic O157 STEC infections in the UK found no association between fluoroquinolone use and the development of HUS [56]. During the 2011 O104:H4 STEC outbreak, a small clinical study in Germany showed that ciprofloxacin reduced the risk of developing HUS [57]. In studies conducted in Japan, fluoroquinolones were found not to affect and may have even reduced, the incidence of HUS [40][58]. A clinical study has found that combination therapy with meropenem and ciprofloxacin (or rifaximin) can eradicate E. coli O157 in patients eight days earlier than in patients with no antibiotics administered with a lower epileptic seizure rate and mortality rate [59]. This indicates that the combination of suppressive antibiotics with antibiotics that rapidly eradicate infection may be beneficial [39]. However, given the current mixed and contradictory results and conclusions, there is still insufficient evidence that the administration of ciprofloxacin is better than no antibiotic use [39][60].
Studies have also reported that subinhibitory concentrations of meropenem, azithromycin, and gentamicin do not increase Stx production in 12 different serotypes of highly virulent STEC [61]. Gentamicin, which blocks ribosomal protein synthesis and is not absorbed by the intestinal wall to achieve high intestinal concentrations, may be a potential treatment for STEC infection, however, its potential renal injury side effects may limit its use in STEC-HUS. Azithromycin inhibits RNA-dependent protein synthesis, thereby inhibiting Stx production. Azithromycin treatment resulted in the lowest toxin production from 12 highly virulent STEC strains [61]. Furthermore, studies have reported that sub-inhibitory doses of azithromycin have no effect on toxin production in vitro, and azithromycin does not induce Stx2a transcription in STEC O104:H4 [48][61]. Some researchers have suggested that STEC infections can be treated with an oral protein synthesis inhibitor for three days, followed by a wall synthesis inhibitor for seven days [35]. RCT studies of azithromycin in the treatment of diarrhea-associated HUS are currently being conducted in France, and the results will further reveal whether azithromycin can be used to treat STEC-HUS.
In a recent review of antibiotics and HUS, Tarr and Freeman recommended against the use of antibiotics in patients with a confirmed or suspected STEC infection based on evidence from multiple retrospective cohort studies. The reason is that there is still no data that convincingly show that antibiotics are superior to no antibiotic treatment at all, and many studies have shown that antibiotics increase the risk of developing HUS [60]. As such, antibiotic administration is performed on a case-by-case basis in consideration of the necessity of antibiotic use, the STEC strain, the timing of treatment, and the type of antibiotics to be used. The necessity of antibiotic use includes whether infections of other systems exist or the need to prevent potential infection risks, such as the need for peritoneal dialysis catheter implantation and the combined use of eculizumab, among others [25][39].

5. Plasma Exchange

Plasma exchange (PE), which theoretically removes Stxs, proinflammatory cytokines, and prothrombotic factors, has been used clinically in some severe cases of STEC-HUS, especially in patients with neurological symptoms, as a final effort to treat the disease [62]. Studies have reported neurological complications in up to 19–26% of cases [63][64][65][66]. However, there is currently no high-quality evidence for the therapeutic role of PE in STEC-HUS. Based on limited evidence, most children with STEC-HUS improve after basic supportive therapy [63]. The utilization of PE in the early stage (24–48 h) of STEC-HUS has the potential to reduce mortality in elderly patients and possibly improve outcomes in severely affected children, especially in those with severe neurological complications [62][63][67][68][69][70].

6. Eculizumab

Eculizumab is a humanized anti-C5 monoclonal antibody with a high affinity for the human C5 complement protein. It inhibits the activation of the complement factor C5 and prevents the formation of the C5b9 membrane attack complex. This biological agent was approved by the FDA in September 2011 for the treatment of aHUS [71][72]. Although the role of the complement protein in STEC-HUS has not been fully understood, eculizumab has been used as an off-label treatment for STEC-HUS patients with severe complications of the nervous system, such as those with neurological or multiple-organ dysfunction. A positive clinical improvement after treatment has been reported, however, the overall quality of evidence is low [73][74]. For example, three children with STEC-HUS and progressive central nervous system involvement reported significant neurologic improvements within 24 h after the first eculizumab infusion. Screening for mutations in the genes encoding complement regulatory proteins and testing for anti-CFH antibodies were negative in these patients. This suggests that a complement activation blockade may provide potential benefits in patients with STEC-HUS [75].
In a retrospective single-center matched cohort study in France, the renal outcomes were compared in 18 and 36 matched children treated with or without eculizumab for STEC-HUS, respectively. There was no statistically significant difference in the evolution of hematological and renal parameters, the incidence of a decreased glomerular filtration rate, proteinuria, or hypertension between these two groups. Children treated with eculizumab frequently displayed neurological sequelae during follow-up, which may reflect the involvement of more severe neurological complications at the onset of HUS in the eculizumab group [76]. Notably, eculizumab increases the risk of Neisseria meningitis infections, so specific vaccinations and brief antibiotic coverage are required at the start of treatment [72].
In a review of STEC-HUS, 16 reports describing the use of eculizumab in STEC-HUS were reviewed (eight case reports/series, seven retrospective studies, and one prospective cohort study). All the studies described its use in severe STEC-HUS with neurological or multiorgan dysfunction; none of them were randomized or blind. Control groups were used in four studies. Despite the overall low quality of evidence, the study showed positive clinical improvements after the treatment of patients with severe progressive STEC-HUS with neurological involvement with eculizumab [74].
Since the majority of patients recover with supportive treatment, the risks and benefits of eculizumab need to be fully evaluated before its use, especially for those with complement activation, neurological involvement, and a high risk of death. In the meantime, randomized controlled trials of eculizumab after the stratification of disease severity will provide more convincing evidence, and positive results are expected in some ongoing clinical trials [76][77].

7. Antibodies

Antibodies can neutralize Stxs in the serum and potentially even in the gut, making these molecules powerful weapons against toxins. In order to produce antibodies for therapeutic use, there are three main approaches: polyclonal antibody (pAb) generation by animal immunization; monoclonal antibody (mAb) production for the secretion of mAbs specific to lymphocyte immortalization; and the creation of different recombinant antibody (rAb) forms for different targets through DNA recombination techniques and heterologous expression systems [78]. Compared with monoclonal antibodies, polyclonal antibodies (pAbs) have many advantages in antitoxin therapy, including the ability to recognize a large number of epitopes, stronger affinity than monoclonal antibodies, and the ability to recognize variants of toxins to reduce the risk of escape [79][80]. However, although polyclonal antibodies have shown promising neutralization in vitro and in vivo, animal sources of polyclonal antibodies may induce anti-antibody action that inactivates therapeutic antibodies before they can exert their toxin-neutralizing activity. In addition, the amount of animal serum is limited by the size of the immunized animal [78]. Equine polyclonal antibodies (EpAbs) are easy to manufacture and have been successfully used in a variety of diseases. In the past, serum diseases and anaphylactic shock (mainly due to the presence of Fc fragments) have discouraged the use of EpAb, however, the new-generation (third-generation serum) processed and purified EpAb contains a highly purified F(AB ‘)2 fragment and is well tolerated. Inmunova (San Martin, BA, Argentina) has developed an equine anti-Shiga toxin (NEAST, INM004). INM004 has the advantage of being broad-spectrum: it can recognize and neutralize different variants of Stx. Additionally, NEAST is designed to prevent HUS in patients with STEC infections [79]. The efficacy and potency of this antiserum against Stx1 and Stx2 have been demonstrated in different preclinical models, and it has been shown to be safe in animals [81]. A phase I clinical trial at a hospital in Buenos Aires demonstrated the product’s safety in healthy adult volunteers and evaluated its pharmacokinetics. Phase Ⅱ and phase III clinical trials were conducted in Argentina with enrolled children diagnosed with STEC infections, and the results are pending [79][82].
Several monoclonal antibodies have been developed to neutralize the toxicity of Stxs, such as monoclonal antibodies against Stx1 and 2 (cαStx1 and cαStx2, Shigamabs®), and urtoxazumab (TMA-15, Teijin Pharma Limited, Tokyo, Japan), which is a humanized monoclonal antibody against Stx2. These monoclonal antibodies have shown promising results in preclinical studies, and their efficacy will be further verified in clinical trials [83][84][85][86][87]. As a chimeric mouse–human monoclonal antibody, Shigamabs® demonstrated the ability to neutralize Stxs in mice and was well tolerated in healthy human volunteers and children infected with STEC in phase Ⅱ clinical trials [84][88]. TMA-15 (urtoxazumab) was produced by combining mouse antibody complementary regions with human frame and stationary regions; it could protect mice from death 24 h after STEC infections and reduce brain damage and death in probiotic piglet models [87][89][90]. TMA-15 was found to be well tolerated in healthy adults and pediatric patients with confirmed STEC infections when tested intravenously in phase Ⅰ and Ⅱ clinical trials [85]

8. Gb3Cer Inhibitors

Another promising therapeutic strategy is the use of Gb3Cer inhibitors. Glucosylceramide (GlcCer) is a biosynthetic precursor of glycolipids including Gb3Cer and other sphingolipids [91]. GlcCer synthesis is catalyzed by glucosylceramide synthase (GCS, also known as UGCG). Subsequently, galactose is added to produce lactosylceramide (LacCer). Additional glucose is then added to produce Gb3Cer and other sphingolipids [13]. Different inhibitors of GCS have been identified and used to treat several glycosphingolipidoses, such as Fabry disease [92]. These compounds inhibit sphingolipid synthesis in cultured cells without inhibiting cell growth or increasing intracellular ceramide levels [91].
Eliglustat (EG) and miglustat (MG) have been shown to inhibit Gb3Cer expression by blocking GCS; they can prevent the toxic effects of Stx2 on human colon epithelial cells, human renal tubular epithelial cells (HRTECs), human glomerular endothelial cells (HGECs), and proximal renal tubular epithelial cells (HK-2) [93][94][95]. HRTECs with 50 nmol/L EG at 24 h or 500 nmol/L EG for 6 h reduced Gb3Cer expression and completely inhibited the effects of Stx2 on cell viability, proliferation, and apoptosis. Pretreatment with MG for 24 h and especially for 48 h produced a significant protective effect with reduced Gb3Cer expression, cell death, intracellular edema, and cell detachment [93]. EG may be a potential therapeutic agent for preventing Stx2-induced AKI. EG is approved in the United States for patients diagnosed with Gaucher disease type 1 for whom enzyme replacement therapy is unsuitable, and it may be more suitable for clinical use in patients with STEC-HUS [94].
C-9 (GENZ-123346), an analog of EG, is a specific inhibitor of GCS, which reduces Gb3Cer, protecting target organs from toxins [96]. Primary human renal tubular epithelial cells (HRTECs) and human glomerular endothelial cells (HGECs), preincubated with C-9, showed reduced Gb3Cer expression and were protected from Stx2 challenge [97]. Oral C-9 treatment significantly reduced mortality to 50% in Stx2-treated rats with reduced Gb3Cer expression in the kidney. It also prevented kidney and colon lesions from Stx2. However, in animal studies, it is necessary to start the inhibitor’s administration two days in advance. In addition, a significant increase in 24-h urinary albumin was reported in mice administered C-9 for 3 weeks [98], although it is unknown whether this phenotype recovers after the withdrawal of the inhibitor. However, this may limit the clinical use of C-9 in the treatment of STEC-HUS patients.
Venglustat, a novel central nervous system (CNS)-active GCS inhibitor, has been shown to reduce cerebral glycolipids and prolong life in a murine model of both type 3 Gaucher disease and Sanhoff [99][100]. Venglustat is being developed as a substrate reduction therapy for a variety of diseases, including type 3 Gaucher disease and Fabry disease [101][102]. It showed good safety and tolerability in phase I clinical trials [102], and it is undergoing phase Ⅱ clinical trials for patients with Fabry disease, while patients with Gaucher type 3 are also being recruited [103].


SYNSORB Pk is an oral Stx-binding agent consisting of dioxide particles that covalently bind to the trisaccharide moiety of the globotriaosylceramide molecule and compete with endothelial and epithelial Gb3Cer receptor sites for Stx binding. It showed a good preclinical effect and was safely tolerated by healthy adult volunteers without any toxicity. SYNSORB Pk recovered from stool retained its Stx-binding activity and neutralized Stx in vitro when mixed with Stx-positive stool from children with hemorrhagic colitis or HUS [104]. In theory, this enteric binding agent of Stx may improve the prognosis of patients with HUS and hemorrhagic colitis. However, in the phase Ⅲ multicenter, randomized, double-blind, placebo-controlled clinical trial of SYNSORB Pk at 26 tertiary care pediatric renal centers in the United States and Canada, 145 children with diarrhea-associated HUS (96 experimental and 49 placebo) were assigned to receive the binder at 500 mg/kg daily, or an oral corn meal placebo, with no statistically significant differences in the incidence of death or severe extrarenal events/proportion of patients requiring dialysis between the experimental and placebo groups. The results showed that oral therapy with SYNSORB Pk failed to reduce the disease severity in pediatric patients with STEC-HUS. The result suggested that the optimal treatment timing may have already been missed when therapy was initiated [83][105].

10. Retro-2

Stxs bound to Gb3Cer on the cell membrane induce endocytosis of the toxins; they then bypass the late endocytic pathway to reach the Golgi apparatus and ER through a retrograde transport pathway. Blocking the retrograde transport of Stxs is another therapeutic strategy that can be considered. Stechmann et al. utilized high-throughput screening to identify Retro-1 and Retro-2, which are small-molecule inhibitors that can protect cells from ricin and Stxs by selectively blocking retrograde transport at the early endosomal-trans-Golgi interface without affecting organelle integrity. In mice, Retro-2 significantly protects against nasal exposure to the lethal dose of ricin [106]. Retro-2 was subsequently shown to have protective effects against Stxs in cells and mice [107]. Studies have shown that Retro-2 targets the ER outlet site component Sec16A and affects the downstream transport of the Golgi SNARE proteins syntaxin-5 from the ER to the Golgi apparatus [108].
However, the extremely poor solubility of Retro-2 at all gastrointestinal pH values limits its application. Gandhi et al. developed Retro-2-loaded self-nanoemulsifying drug delivery systems. Lauroyl arginine ethyl (LAE) is a cationic surfactant with L-arginine as a hydrophilic component and lauric acid as the hydrophilic part [109]. Due to their chemical properties, they can break down cell membranes at very low concentrations, altering their potential, affecting cell permeability, and causing bacterial cell death, and they can be used as antimicrobial agents. They can also be quickly metabolized by the body into natural dietary ingredients—lauric acid and arginine—making them safe for users [109]. In this technique, Retro-2-loaded arginine-anchored nanospheres (R-AR-NGs) were prepared by mixing solutions of LAE and Retro-2 in DMA with a solution of oil and surfactant in selected proportions. When R-AR-NG is added to the aqueous phase, positively charged nanospheres spontaneously form. AR-NG breaks down spontaneously into L-arginine and kills EHEC in the gut. AR-NG then binds to the LPS released by dead E. coli through electrostatic interaction. AR-NG is released in the gut environment and maintains Retro-2 lysis, thereby inhibiting the retrograde transport of Stx. The nanoglobule significantly increased the water solubility of Retro-2 and blocked Stx’s intestinal-to-blood transport. This technique opens up the possibility for Retro-2 to control EHEC O157:H7 infection in clinical applications [109].


  1. Noris, M.; Remuzzi, G. Hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2005, 16, 1035–1050.
  2. Noris, M.; Remuzzi, G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2009, 361, 1676–1687.
  3. Joseph, A.; Cointe, A.; Mariani Kurkdjian, P.; Rafat, C.; Hertig, A. Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review. Toxins 2020, 12, 67.
  4. Ashida, A.; Matsumura, H.; Sawai, T.; Fujimaru, R.; Fujii, Y.; Shirasu, A.; Nakakura, H.; Iijima, K. Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy. Clin. Exp. Nephrol. 2018, 22, 924–930.
  5. Hamano, S.; Nakanishi, Y.; Nara, T.; Seki, T.; Ohtani, T.; Oishi, T.; Joh, K.; Oikawa, T.; Muramatsu, Y.; Ogawa, Y.; et al. Neurological manifestations of hemorrhagic colitis in the outbreak of Escherichia coli O157:H7 infection in Japan. Acta Paediatr. 1993, 82, 454–458.
  6. Krogvold, L.; Henrichsen, T.; Bjerre, A.; Brackman, D.; Dollner, H.; Gudmundsdottir, H.; Syversen, G.; Naess, P.A.; Bangstad, H.J. Clinical aspects of a nationwide epidemic of severe haemolytic uremic syndrome (HUS) in children. Scand. J. Trauma Resusc. Emerg. Med. 2011, 19, 44.
  7. Verweyen, H.M.; Karch, H.; Allerberger, F.; Zimmerhackl, L.B. Enterohemorrhagic Escherichia coli (EHEC) in pediatric hemolytic-uremic syndrome: A prospective study in Germany and Austria. Infection 1999, 27, 341–347.
  8. Tarr, P.I.; Gordon, C.A.; Chandler, W.L. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005, 365, 1073–1086.
  9. Bale, J.F., Jr.; Brasher, C.; Siegler, R.L. CNS manifestations of the hemolytic-uremic syndrome. Relationship to metabolic alterations and prognosis. Am. J. Dis. Child. 1980, 134, 869–872.
  10. Cimolai, N.; Morrison, B.J.; Carter, J.E. Risk factors for the central nervous system manifestations of gastroenteritis-associated hemolytic-uremic syndrome. Pediatrics 1992, 90, 616–621.
  11. Sheth, K.J.; Swick, H.M.; Haworth, N. Neurological involvement in hemolytic-uremic syndrome. Ann. Neurol. 1986, 19, 90–93.
  12. Lee, M.S.; Tesh, V.L. Roles of Shiga Toxins in Immunopathology. Toxins 2019, 11, 212.
  13. Liu, Y.; Tian, S.; Thaker, H.; Dong, M. Shiga Toxins: An Update on Host Factors and Biomedical Applications. Toxins 2021, 13, 222.
  14. Ake, J.A.; Jelacic, S.; Ciol, M.A.; Watkins, S.L.; Murray, K.F.; Christie, D.L.; Klein, E.J.; Tarr, P.I. Relative nephroprotection during Escherichia coli O157:H7 infections: Association with intravenous volume expansion. Pediatrics 2005, 115, e673–e680.
  15. Balestracci, A.; Martin, S.M.; Toledo, I.; Alvarado, C.; Wainsztein, R.E. Dehydration at admission increased the need for dialysis in hemolytic uremic syndrome children. Pediatr. Nephrol. 2012, 27, 1407–1410.
  16. Ardissino, G.; Dacco, V.; Testa, S.; Civitillo, C.F.; Tel, F.; Possenti, I.; Belingheri, M.; Castorina, P.; Bolsa-Ghiringhelli, N.; Tedeschi, S.; et al. Hemoconcentration: A major risk factor for neurological involvement in hemolytic uremic syndrome. Pediatr. Nephrol. 2015, 30, 345–352.
  17. Grisaru, S.; Xie, J.; Samuel, S.; Hartling, L.; Tarr, P.I.; Schnadower, D.; Freedman, S.B.; Alberta Alberta Provincial Pediatric Enteric Infection Team. Associations Between Hydration Status, Intravenous Fluid Administration, and Outcomes of Patients Infected With Shiga Toxin-Producing Escherichia coli: A Systematic Review and Meta-analysis. JAMA Pediatr. 2017, 171, 68–76.
  18. Davis, T.K.; Van De Kar, N.; Tarr, P.I. Shiga Toxin/Verocytotoxin-Producing Escherichia coli Infections: Practical Clinical Perspectives. Microbiol. Spectr. 2014, 2, EHEC-0025-2014.
  19. Hickey, C.A.; Beattie, T.J.; Cowieson, J.; Miyashita, Y.; Strife, C.F.; Frem, J.C.; Peterson, J.M.; Butani, L.; Jones, D.P.; Havens, P.L.; et al. Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Arch. Pediatr. Adolesc. Med. 2011, 165, 884–889.
  20. Ardissino, G.; Tel, F.; Possenti, I.; Testa, S.; Consonni, D.; Paglialonga, F.; Salardi, S.; Borsa-Ghiringhelli, N.; Salice, P.; Tedeschi, S.; et al. Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. Pediatrics 2016, 137, e20152153.
  21. Mody, R.K.; Gu, W.; Griffin, P.M.; Jones, T.F.; Rounds, J.; Shiferaw, B.; Tobin-D’Angelo, M.; Smith, G.; Spina, N.; Hurd, S.; et al. Postdiarrheal hemolytic uremic syndrome in United States children: Clinical spectrum and predictors of in-hospital death. J. Pediatr. 2015, 166, 1022–1029.
  22. Wong, C.S.; Mooney, J.C.; Brandt, J.R.; Staples, A.O.; Jelacic, S.; Boster, D.R.; Watkins, S.L.; Tarr, P.I. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: A multivariable analysis. Clin. Infect. Dis. 2012, 55, 33–41.
  23. Trachtman, H.; Austin, C.; Lewinski, M.; Stahl, R.A. Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat. Rev. Nephrol. 2012, 8, 658–669.
  24. Harkins, V.J.; McAllister, D.A.; Reynolds, B.C. Shiga-Toxin E. coli Hemolytic Uremic Syndrome: Review of Management and Long-term Outcome. Curr. Pediatr. Rep. 2020, 8, 16–25.
  25. Coccia, P.A.; Ramirez, F.B.; Suarez, A.D.C.; Alconcher, L.F.; Balestracci, A.; Garcia Chervo, L.A.; Principi, I.; Vazquez, A.; Ratto, V.M.; Planells, M.C.; et al. Acute peritoneal dialysis, complications and outcomes in 389 children with STEC-HUS: A multicenter experience. Pediatr Nephrol 2021, 36, 1597–1606.
  26. de Galasso, L.; Picca, S.; Guzzo, I. Dialysis modalities for the management of pediatric acute kidney injury. Pediatr. Nephrol. 2020, 35, 753–765.
  27. Chionh, C.Y.; Soni, S.S.; Finkelstein, F.O.; Ronco, C.; Cruz, D.N. Use of peritoneal dialysis in AKI: A systematic review. Clin. J. Am. Soc. Nephrol. 2013, 8, 1649–1660.
  28. Ponce, D.; Gobo-Oliveira, M.; Balbi, A.L. Peritoneal Dialysis Treatment Modality Option in Acute Kidney Injury. Blood Purif. 2017, 43, 173–178.
  29. Cullis, B.; Abdelraheem, M.; Abrahams, G.; Balbi, A.; Cruz, D.N.; Frishberg, Y.; Koch, V.; McCulloch, M.; Numanoglu, A.; Nourse, P.; et al. Peritoneal dialysis for acute kidney injury. Perit. Dial. Int. 2014, 34, 494–517.
  30. Walters, S.; Porter, C.; Brophy, P.D. Dialysis and pediatric acute kidney injury: Choice of renal support modality. Pediatr. Nephrol. 2009, 24, 37–48.
  31. Strazdins, V.; Watson, A.R.; Harvey, B.; European Pediatric Peritoneal Sialysis Working, G. Renal replacement therapy for acute renal failure in children: European guidelines. Pediatr. Nephrol. 2004, 19, 199–207.
  32. Symons, J.M.; Chua, A.N.; Somers, M.J.; Baum, M.A.; Bunchman, T.E.; Benfield, M.R.; Brophy, P.D.; Blowey, D.; Fortenberry, J.D.; Chand, D.; et al. Demographic characteristics of pediatric continuous renal replacement therapy: A report of the prospective pediatric continuous renal replacement therapy registry. Clin. J. Am. Soc. Nephrol. 2007, 2, 732–738.
  33. Ostermann, M.; Bellomo, R.; Burdmann, E.A.; Doi, K.; Endre, Z.H.; Goldstein, S.L.; Kane-Gill, S.L.; Liu, K.D.; Prowle, J.R.; Shaw, A.D.; et al. Controversies in acute kidney injury: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2020, 98, 294–309.
  34. Hoste, E.A.J.; Kellum, J.A.; Selby, N.M.; Zarbock, A.; Palevsky, P.M.; Bagshaw, S.M.; Goldstein, S.L.; Cerda, J.; Chawla, L.S. Global epidemiology and outcomes of acute kidney injury. Nat. Rev. Nephrol. 2018, 14, 607–625.
  35. Agger, M.; Scheutz, F.; Villumsen, S.; Molbak, K.; Petersen, A.M. Antibiotic treatment of verocytotoxin-producing Escherichia coli (VTEC) infection: A systematic review and a proposal. J. Antimicrob. Chemother. 2015, 70, 2440–2446.
  36. Freedman, S.B.; Xie, J.; Neufeld, M.S.; Hamilton, W.L.; Hartling, L.; Tarr, P.I.; Alberta Provincial Pediatric Enteric Infection, T.; Nettel-Aguirre, A.; Chuck, A.; Lee, B.; et al. Shiga Toxin-Producing Escherichia coli Infection, Antibiotics, and Risk of Developing Hemolytic Uremic Syndrome: A Meta-analysis. Clin. Infect. Dis. 2016, 62, 1251–1258.
  37. Safdar, N.; Said, A.; Gangnon, R.E.; Maki, D.G. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: A meta-analysis. JAMA 2002, 288, 996–1001.
  38. Wong, C.S.; Jelacic, S.; Habeeb, R.L.; Watkins, S.L.; Tarr, P.I. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N. Engl. J. Med. 2000, 342, 1930–1936.
  39. Kakoullis, L.; Papachristodoulou, E.; Chra, P.; Panos, G. Shiga toxin-induced haemolytic uraemic syndrome and the role of antibiotics: A global overview. J. Infect. 2019, 79, 75–94.
  40. Ikeda, K.; Ida, O.; Kimoto, K.; Takatorige, T.; Nakanishi, N.; Tatara, K. Effect of early fosfomycin treatment on prevention of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection. Clin. Nephrol. 1999, 52, 357–362.
  41. Slutsker, L.; Ries, A.A.; Maloney, K.; Wells, J.G.; Greene, K.D.; Griffin, P.M. A nationwide case-control study of Escherichia coli O157:H7 infection in the United States. J. Infect. Dis. 1998, 177, 962–966.
  42. Dundas, S.; Todd, W.T.; Stewart, A.I.; Murdoch, P.S.; Chaudhuri, A.K.; Hutchinson, S.J. The central Scotland Escherichia coli O157:H7 outbreak: Risk factors for the hemolytic uremic syndrome and death among hospitalized patients. Clin. Infect. Dis. 2001, 33, 923–931.
  43. Proulx, F.; Turgeon, J.P.; Delage, G.; Lafleur, L.; Chicoine, L. Randomized, controlled trial of antibiotic therapy for Escherichia coli O157:H7 enteritis. J. Pediatr. 1992, 121, 299–303.
  44. Zhang, X.; McDaniel, A.D.; Wolf, L.E.; Keusch, G.T.; Waldor, M.K.; Acheson, D.W. Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J. Infect. Dis. 2000, 181, 664–670.
  45. Kimmitt, P.T.; Harwood, C.R.; Barer, M.R. Toxin gene expression by shiga toxin-producing Escherichia coli: The role of antibiotics and the bacterial SOS response. Emerg. Infect. Dis. 2000, 6, 458–465.
  46. Bielaszewska, M.; Idelevich, E.A.; Zhang, W.; Bauwens, A.; Schaumburg, F.; Mellmann, A.; Peters, G.; Karch, H. Effects of antibiotics on Shiga toxin 2 production and bacteriophage induction by epidemic Escherichia coli O104:H4 strain. Antimicrob. Agents Chemother. 2012, 56, 3277–3282.
  47. McGannon, C.M.; Fuller, C.A.; Weiss, A.A. Different classes of antibiotics differentially influence shiga toxin production. Antimicrob. Agents Chemother. 2010, 54, 3790–3798.
  48. Zhang, Q.; Donohue-Rolfe, A.; Krautz-Peterson, G.; Sevo, M.; Parry, N.; Abeijon, C.; Tzipori, S. Gnotobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157:H7 infection. J. Infect. Dis. 2009, 199, 486–493.
  49. Walterspiel, J.N.; Ashkenazi, S.; Morrow, A.L.; Cleary, T.G. Effect of subinhibitory concentrations of antibiotics on extracellular Shiga-like toxin I. Infection 1992, 20, 25–29.
  50. Grif, K.; Dierich, M.P.; Karch, H.; Allerberger, F. Strain-specific differences in the amount of Shiga toxin released from enterohemorrhagic Escherichia coli O157 following exposure to subinhibitory concentrations of antimicrobial agents. Eur. J. Clin. Microbiol. Infect. Dis. 1998, 17, 761–766.
  51. Corogeanu, D.; Willmes, R.; Wolke, M.; Plum, G.; Utermohlen, O.; Kronke, M. Therapeutic concentrations of antibiotics inhibit Shiga toxin release from enterohemorrhagic E. coli O104:H4 from the 2011 German outbreak. BMC Microbiol. 2012, 12, 160.
  52. Amran, M.Y.; Fujii, J.; Suzuki, S.O.; Kolling, G.L.; Villanueva, S.Y.; Kainuma, M.; Kobayashi, H.; Kameyama, H.; Yoshida, S. Investigation of encephalopathy caused by Shiga toxin 2c-producing Escherichia coli infection in mice. PLoS ONE 2013, 8, e58959.
  53. Yoshimura, K.; Fujii, J.; Taniguchi, H.; Yoshida, S. Chemotherapy for enterohemorrhagic Escherichia coli O157:H infection in a mouse model. FEMS Immunol. Med. Microbiol. 1999, 26, 101–108.
  54. Sawamura, S.; Tanaka, K.; Koga, Y. Therapeutic effects of antibiotics against enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) infection: In vivo analysis using germfree mice. Kansenshogaku Zasshi 1999, 73, 1054–1063.
  55. Kurioka, T.; Yunou, Y.; Harada, H.; Kita, E. Efficacy of antibiotic therapy for infection with Shiga-like toxin-producing Escherichia coli O157:H7 in mice with protein-calorie malnutrition. Eur. J. Clin. Microbiol. Infect. Dis. 1999, 18, 561–571.
  56. Launders, N.; Byrne, L.; Jenkins, C.; Harker, K.; Charlett, A.; Adak, G.K. Disease severity of Shiga toxin-producing E. coli O157 and factors influencing the development of typical haemolytic uraemic syndrome: A retrospective cohort study, 2009–2012. BMJ Open 2016, 6, e009933.
  57. Geerdes-Fenge, H.F.; Lobermann, M.; Nurnberg, M.; Fritzsche, C.; Koball, S.; Henschel, J.; Hohn, R.; Schober, H.C.; Mitzner, S.; Podbielski, A.; et al. Ciprofloxacin reduces the risk of hemolytic uremic syndrome in patients with Escherichia coli O104:H4-associated diarrhea. Infection 2013, 41, 669–673.
  58. Ohnishi, K.; Nakamura-Uchiyama, F. Does levofloxacin induce hemolytic uremic syndrome in patients infected with verotoxin-producing Escherichia coli O157 infections? Jpn. J. Infect. Dis. 2012, 65, 442–443.
  59. Menne, J.; Nitschke, M.; Stingele, R.; Abu-Tair, M.; Beneke, J.; Bramstedt, J.; Bremer, J.P.; Brunkhorst, R.; Busch, V.; Dengler, R.; et al. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: Case-control study. BMJ 2012, 345, e4565.
  60. Tarr, P.I.; Freedman, S.B. Why antibiotics should not be used to treat Shiga toxin-producing Escherichia coli infections. Curr. Opin. Gastroenterol. 2022, 38, 30–38.
  61. Ramstad, S.N.; Taxt, A.M.; Naseer, U.; Wasteson, Y.; Bjornholt, J.V.; Brandal, L.T. Effects of antimicrobials on Shiga toxin production in high-virulent Shiga toxin-producing Escherichia coli. Microb. Pathog. 2021, 152, 104636.
  62. Keenswijk, W.; Raes, A.; De Clerck, M.; Vande Walle, J. Is Plasma Exchange Efficacious in Shiga Toxin-Associated Hemolytic Uremic Syndrome? A Narrative Review of Current Evidence. Ther. Apher. Dial. 2019, 23, 118–125.
  63. Loos, S.; Ahlenstiel, T.; Kranz, B.; Staude, H.; Pape, L.; Hartel, C.; Vester, U.; Buchtala, L.; Benz, K.; Hoppe, B.; et al. An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: Presentation and short-term outcome in children. Clin. Infect. Dis. 2012, 55, 753–759.
  64. Gerber, A.; Karch, H.; Allerberger, F.; Verweyen, H.M.; Zimmerhackl, L.B. Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: A prospective study. J. Infect. Dis. 2002, 186, 493–500.
  65. Martin, D.L.; MacDonald, K.L.; White, K.E.; Soler, J.T.; Osterholm, M.T. The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota. N. Engl. J. Med. 1990, 323, 1161–1167.
  66. Banatvala, N.; Griffin, P.M.; Greene, K.D.; Barrett, T.J.; Bibb, W.F.; Green, J.H.; Wells, J.G.; Hemolytic Uremic Syndrome Study, C. The United States National Prospective Hemolytic Uremic Syndrome Study: Microbiologic, serologic, clinical, and epidemiologic findings. J. Infect. Dis. 2001, 183, 1063–1070.
  67. Colic, E.; Dieperink, H.; Titlestad, K.; Tepel, M. Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: An observational study. Lancet 2011, 378, 1089–1093.
  68. Dundas, S.; Murphy, J.; Soutar, R.L.; Jones, G.A.; Hutchinson, S.J.; Todd, W.T. Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O157:H7 outbreak. Lancet 1999, 354, 1327–1330.
  69. Nakatani, T.; Tsuchida, K.; Yoshimura, R.; Sugimura, K.; Takemoto, Y. Plasma exchange therapy for the treatment of Escherichia coli O-157 associated hemolytic uremic syndrome. Int. J. Mol. Med. 2002, 10, 585–588.
  70. Igarashi, T.; Ito, S.; Sako, M.; Saitoh, A.; Hataya, H.; Mizuguchi, M.; Morishima, T.; Ohnishi, K.; Kawamura, N.; Kitayama, H.; et al. Guidelines for the management and investigation of hemolytic uremic syndrome. Clin. Exp. Nephrol. 2014, 18, 525–557.
  71. Legendre, C.M.; Licht, C.; Muus, P.; Greenbaum, L.A.; Babu, S.; Bedrosian, C.; Bingham, C.; Cohen, D.J.; Delmas, Y.; Douglas, K.; et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2013, 368, 2169–2181.
  72. Fakhouri, F.; Hourmant, M.; Campistol, J.M.; Cataland, S.R.; Espinosa, M.; Gaber, A.O.; Menne, J.; Minetti, E.E.; Provot, F.; Rondeau, E.; et al. Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial. Am. J. Kidney Dis. 2016, 68, 84–93.
  73. Umscheid, J.H.; Nevil, C.; Vasudeva, R.; Ali, M.F.; Agasthya, N. Treatment of Shiga-Toxin Hus with Severe Neurologic Features with Eculizumab. Case Rep. Pediatr. 2021, 2021, 8053246.
  74. Mahat, U.; Matar, R.B.; Rotz, S.J. Use of complement monoclonal antibody eculizumab in Shiga toxin producing Escherichia coli associated hemolytic uremic syndrome: A review of current evidence. Pediatr. Blood Cancer 2019, 66, e27913.
  75. Lapeyraque, A.L.; Malina, M.; Fremeaux-Bacchi, V.; Boppel, T.; Kirschfink, M.; Oualha, M.; Proulx, F.; Clermont, M.J.; Le Deist, F.; Niaudet, P.; et al. Eculizumab in severe Shiga-toxin-associated HUS. N. Engl. J. Med. 2011, 364, 2561–2563.
  76. Monet-Didailler, C.; Chevallier, A.; Godron-Dubrasquet, A.; Allard, L.; Delmas, Y.; Contin-Bordes, C.; Brissaud, O.; Llanas, B.; Harambat, J. Outcome of children with Shiga toxin-associated haemolytic uraemic syndrome treated with eculizumab: A matched cohort study. Nephrol. Dial. Transplant. 2020, 35, 2147–2153.
  77. Bergan, J.; Dyve Lingelem, A.B.; Simm, R.; Skotland, T.; Sandvig, K. Shiga toxins. Toxicon 2012, 60, 1085–1107.
  78. Henrique, I.M.; Sacerdoti, F.; Ferreira, R.L.; Henrique, C.; Amaral, M.M.; Piazza, R.M.F.; Luz, D. Therapeutic Antibodies Against Shiga Toxins: Trends and Perspectives. Front. Cell Infect. Microbiol. 2022, 12, 825856.
  79. Yanina, H.; Romina, P.; Lucas, B.; Constanza, L.; Luciana, M.; L, B.; Mariana, C.; Ortega, H.; A, G.; Santiago, S.; et al. Preclinical Studies of NEAST (Neutralizing Equine Anti-Shiga To xin): A Potential Treatment for Prevention of Stec-Hus. Int. J. Drug Dev. Res. 2019, 11.
  80. Dixit, R.; Herz, J.; Dalton, R.; Booy, R. Benefits of using heterologous polyclonal antibodies and potential applications to new and undertreated infectious pathogens. Vaccine 2016, 34, 1152–1161.
  81. Mejias, M.P.; Ghersi, G.; Craig, P.O.; Panek, C.A.; Bentancor, L.V.; Baschkier, A.; Goldbaum, F.A.; Zylberman, V.; Palermo, M.S. Immunization with a chimera consisting of the B subunit of Shiga toxin type 2 and brucella lumazine synthase confers total protection against Shiga toxins in mice. J. Immunol. 2013, 191, 2403–2411.
  82. Hiriart, Y.; Pardo, R.; Bukata, L.; Lauche, C.; Munoz, L.; Colonna, M.; Goldbaum, F.; Sanguineti, S.; Zylberman, V. . Medicina 2018, 78, 107–112.
  83. Imdad, A.; Mackoff, S.P.; Urciuoli, D.M.; Syed, T.; Tanner-Smith, E.E.; Huang, D.; Gomez-Duarte, O.G. Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome. Cochrane Database Syst. Rev. 2021, 7, CD012997.
  84. Bitzan, M.; Poole, R.; Mehran, M.; Sicard, E.; Brockus, C.; Thuning-Roberson, C.; Riviere, M. Safety and pharmacokinetics of chimeric anti-Shiga toxin 1 and anti-Shiga toxin 2 monoclonal antibodies in healthy volunteers. Antimicrob. Agents Chemother. 2009, 53, 3081–3087.
  85. Lopez, E.L.; Contrini, M.M.; Glatstein, E.; Gonzalez Ayala, S.; Santoro, R.; Allende, D.; Ezcurra, G.; Teplitz, E.; Koyama, T.; Matsumoto, Y.; et al. Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli. Antimicrob. Agents Chemother. 2010, 54, 239–243.
  86. Melton-Celsa, A.R.; Carvalho, H.M.; Thuning-Roberson, C.; O’Brien, A.D. Protective efficacy and pharmacokinetics of human/mouse chimeric anti-Stx1 and anti-Stx2 antibodies in mice. Clin. Vaccine Immunol. 2015, 22, 448–455.
  87. Moxley, R.A.; Francis, D.H.; Tamura, M.; Marx, D.B.; Santiago-Mateo, K.; Zhao, M. Efficacy of Urtoxazumab (TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2) Against Post-Diarrheal Neurological Sequelae Caused by Escherichia coli O157:H7 Infection in the Neonatal Gnotobiotic Piglet Model. Toxins 2017, 9, 49.
  88. Dowling, T.C.; Chavaillaz, P.A.; Young, D.G.; Melton-Celsa, A.; O’Brien, A.; Thuning-Roberson, C.; Edelman, R.; Tacket, C.O. Phase 1 safety and pharmacokinetic study of chimeric murine-human monoclonal antibody c alpha Stx2 administered intravenously to healthy adult volunteers. Antimicrob. Agents Chemother. 2005, 49, 1808–1812.
  89. Yamagami, S.; Motoki, M.; Kimura, T.; Izumi, H.; Takeda, T.; Katsuura, Y.; Matsumoto, Y. Efficacy of postinfection treatment with anti-Shiga toxin (Stx) 2 humanized monoclonal antibody TMA-15 in mice lethally challenged with Stx-producing Escherichia coli. J. Infect. Dis. 2001, 184, 738–742.
  90. Kimura, T.; Co, M.S.; Vasquez, M.; Wei, S.; Xu, H.; Tani, S.; Sakai, Y.; Kawamura, T.; Matsumoto, Y.; Nakao, H.; et al. Development of humanized monoclonal antibody TMA-15 which neutralizes Shiga toxin 2. Hybrid. Hybridomics 2002, 21, 161–168.
  91. Lee, L.; Abe, A.; Shayman, J.A. Improved inhibitors of glucosylceramide synthase. J. Biol. Chem. 1999, 274, 14662–14669.
  92. Abe, A.; Gregory, S.; Lee, L.; Killen, P.D.; Brady, R.O.; Kulkarni, A.; Shayman, J.A. Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J. Clin. Investig. 2000, 105, 1563–1571.
  93. Feitz, W.J.C.; Bouwmeester, R.; van der Velden, T.; Goorden, S.; Licht, C.; van den Heuvel, L.; van de Kar, N. The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin E. coli Mediated HUS. Microorganisms 2021, 9, 2157.
  94. Sanchez, D.S.; Fischer Sigel, L.K.; Balestracci, A.; Ibarra, C.; Amaral, M.M.; Silberstein, C. Eliglustat prevents Shiga toxin 2 cytotoxic effects in human renal tubular epithelial cells. Pediatr. Res. 2022, 91, 1121–1129.
  95. Girard, M.C.; Sacerdoti, F.; Rivera, F.P.; Repetto, H.A.; Ibarra, C.; Amaral, M.M. Prevention of renal damage caused by Shiga toxin type 2: Action of Miglustat on human endothelial and epithelial cells. Toxicon 2015, 105, 27–33.
  96. Silberstein, C.; Lucero, M.S.; Zotta, E.; Copeland, D.P.; Lingyun, L.; Repetto, H.A.; Ibarra, C. A glucosylceramide synthase inhibitor protects rats against the cytotoxic effects of shiga toxin 2. Pediatr. Res. 2011, 69, 390–394.
  97. Amaral, M.M.; Sacerdoti, F.; Jancic, C.; Repetto, H.A.; Paton, A.W.; Paton, J.C.; Ibarra, C. Action of shiga toxin type-2 and subtilase cytotoxin on human microvascular endothelial cells. PLoS ONE 2013, 8, e70431.
  98. Morace, I.; Pilz, R.; Federico, G.; Jennemann, R.; Krunic, D.; Nordstrom, V.; von Gerichten, J.; Marsching, C.; Schiessl, I.M.; Muthing, J.; et al. Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury. Kidney Int. 2019, 96, 327–341.
  99. Marshall, J.; Nietupski, J.B.; Park, H.; Cao, J.; Bangari, D.S.; Silvescu, C.; Wilper, T.; Randall, K.; Tietz, D.; Wang, B.; et al. Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity. Mol. Ther. 2019, 27, 1495–1506.
  100. Marshall, J.; Sun, Y.; Bangari, D.S.; Budman, E.; Park, H.; Nietupski, J.B.; Allaire, A.; Cromwell, M.A.; Wang, B.; Grabowski, G.A.; et al. CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease. Mol. Ther. 2016, 24, 1019–1029.
  101. Viel, C.; Clarke, J.; Kayatekin, C.; Richards, A.M.; Chiang, M.S.R.; Park, H.; Wang, B.; Shihabuddin, L.S.; Sardi, S.P. Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model. Sci. Rep. 2021, 11, 20945.
  102. Peterschmitt, M.J.; Crawford, N.P.S.; Gaemers, S.J.M.; Ji, A.J.; Sharma, J.; Pham, T.T. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers. Clin. Pharmacol. Drug Dev. 2021, 10, 86–98.
  103. Wilson, M.W.; Shu, L.; Hinkovska-Galcheva, V.; Jin, Y.; Rajeswaran, W.; Abe, A.; Zhao, T.; Luo, R.; Wang, L.; Wen, B.; et al. Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3. ACS Chem. Neurosci. 2020, 11, 3464–3473.
  104. Armstrong, G.D.; Rowe, P.C.; Goodyer, P.; Orrbine, E.; Klassen, T.P.; Wells, G.; MacKenzie, A.; Lior, H.; Blanchard, C.; Auclair, F.; et al. A phase I study of chemically synthesized verotoxin (Shiga-like toxin) Pk-trisaccharide receptors attached to chromosorb for preventing hemolytic-uremic syndrome. J. Infect. Dis. 1995, 171, 1042–1045.
  105. Trachtman, H.; Cnaan, A.; Christen, E.; Gibbs, K.; Zhao, S.; Acheson, D.W.; Weiss, R.; Kaskel, F.J.; Spitzer, A.; Hirschman, G.H.; et al. Effect of an oral Shiga toxin-binding agent on diarrhea-associated hemolytic uremic syndrome in children: A randomized controlled trial. JAMA 2003, 290, 1337–1344.
  106. Stechmann, B.; Bai, S.K.; Gobbo, E.; Lopez, R.; Merer, G.; Pinchard, S.; Panigai, L.; Tenza, D.; Raposo, G.; Beaumelle, B.; et al. Inhibition of retrograde transport protects mice from lethal ricin challenge. Cell 2010, 141, 231–242.
  107. Secher, T.; Shima, A.; Hinsinger, K.; Cintrat, J.C.; Johannes, L.; Barbier, J.; Gillet, D.; Oswald, E. Retrograde Trafficking Inhibitor of Shiga Toxins Reduces Morbidity and Mortality of Mice Infected with Enterohemorrhagic Escherichia coli. Antimicrob. Agents Chemother. 2015, 59, 5010–5013.
  108. Forrester, A.; Rathjen, S.J.; Daniela Garcia-Castillo, M.; Bachert, C.; Couhert, A.; Tepshi, L.; Pichard, S.; Martinez, J.; Munier, M.; Sierocki, R.; et al. Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2. Nat. Chem. Biol. 2020, 16, 327–336.
  109. Gandhi, T.; Patki, M.; Kong, J.; Koya, J.; Yoganathan, S.; Reznik, S.; Patel, K. Development of an Arginine Anchored Nanoglobule with Retrograde Trafficking Inhibitor (Retro-2) for the Treatment of an Enterohemorrhagic Escherichia coli Outbreak. Mol. Pharm. 2019, 16, 4405–4415.
Subjects: Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , ,
View Times: 243
Revisions: 2 times (View History)
Update Date: 13 Mar 2023
Video Production Service