During the 2011 outbreak in Northern Germany, clinicians were confronted with a large number of mainly adult patients with HUS associated with severe hemolysis and neurological complications [18
]. A large proportion of patients required renal replacement therapy. However, we also observed some STEC-infected patients with severe neurological disorders but lacking renal or hematologic signs of HUS (unpublished data).
Prior to the outbreak, no standardized causative treatment existed for STEC-HUS, and randomized clinical trials approving any therapeutic concept to be beneficial beyond best supportive therapy were missing [37
]. Therefore, different therapeutic concepts were rapidly proposed [38
] on the basis of theoretical considerations and preceding observations, but without evidence for the effectiveness of such “best guess” strategies. Moreover, these ad hoc strategies were adjusted to new observations [39
] made during the outbreak. Thus, individual medical centers used varying therapeutic regimens [17
••], including plasmapheresis, glucocorticoids, and the anti-C5 monoclonal antibody eculizumab.
The use of plasmapheresis was based on observations from the Scotland outbreak in 1996, with 24 adult patients suffering from HUS [40
]. In a multicenter case–control analysis of the 2011 German outbreak with STEC O104:H4, no short term benefit for plasmapheresis with or without additional application of glucocorticoids was found in 251 patients receiving plasmapheresis, as compared with 47 patients without plasma exchange [17
••]. In an additional single-center analysis of 130 HUS patients, again no benefit of plasmaphesesis was observed [36
], whereas the risk of severe AKI and neurological complication was increased [36
]. Likewise, analysis of 90 children with HUS caused by STEC O104:H4 did not justify recommending plasma exchange in pediatric HUS [41
]. This is in accordance with a recent prospective follow-up study of 274 children showing that plasma exchange therapy was associated with a poor long-term outcome for children with STEC-HUS [42
]. Unfortunately, most of these studies are limited by their retrospective character and biased by indication, since sicker patients were more often treated with plasmapheresis. Taken together, the relevance for plasma exchange therapy in STEC-HUS is highly questionable and might even be adverse.
A small group of 12 patients with severe neurological complications were enrolled in a non-controlled trial with immunoadsorption therapy [43
] after several other interventions were assumed to be ineffective. This included multiple plasmapheresis sessions and/or eculizumab application. Only 2 patients proceeded directly to immunoadsorption. Hence, the authors stated that antibodies could play a role in the pathogenesis of neurological disorders and that immunoadsorption might amend the neurological symptoms. This study is limited by very heterogeneous treatment procedures and a very small sample size.
At the end of May 2011, a case series of three children suffering from STEC-HUS was published reporting rapid clinical improvement under therapy with eculizumab [39
]. Therefore, starting from the end of May, over 300 patients of the German outbreak were treated with eculizumab off-label, initially as a compassionate use trial that was transformed to a nonrandomized trial including 198 patients. Final evaluation of this trial is pending. A short-term outcome analysis of 67 patients treated with eculizumab outside the above-mentioned trial showed no significant therapeutic benefit, as compared with a matched control group not having received eculizumab [17
••]. However, in many medical centers, eculizumab was administered only to patients who had no clinical improvement during plasmapheresis and/or were suffering from severe neurological complications, which might imply a selection bias. Therefore, no definite conclusions can be drawn concerning the effect of eculizumab on the course of HUS. However, the treatment with eculizumab can be considered as a save intervention, and therefore, its prognostic impact, as well as optimal time-point and dosage, should be evaluated in future prospective randomized trials.
A major issue discussed during the outbreak was the question of whether or not antibiotics should be used. In previous retrospective analyses of STEC outbreaks and sporadic infections, patients treated with antibiotics were found to have an increased risk of HUS development [32
]. This dogma was recently confirmed by a large multicenter trial investigating risk factors for the development of HUS in EHEC O157:H7 infected children [45
]. Therefore, the use of antibiotics was strongly discouraged unless secondary complications made antibiotic treatment urgent. In our center, we strictly abstained from using antibiotics unless it was unavoidable. However, since the C5a antibody eculizumab disrupts the complement cascade and, thereby, increases the risk for bacterial meningitis [46
], antibiotic meningitis prophylaxis was mandatory in patients receiving eculizumab. Because several in vitro studies did not show any induction but, rather, suppression of Stx expression by azithromycin, this antibiotic was selected for recommendation by the German Society of Nephrology in the ad hoc guidelines for meningitis prophylaxis to be given orally for 14 days [38
]. The close monitoring of STEC-shedding in stool samples revealed that all patients receiving azithromycin were rapidly decolonized from the outbreak strain, while untreated patients remained positive for STEC significantly longer [27
••]. In detail, among antibiotic-treated patients, long-term STEC carriage (>28 days) was observed in 1 of 22 patients (4.5 %; 95 % CI, 0 %–13.3 %), as compared with 35 of 43 patients (81.4 %; 95 % CI, 69.8 %–93.0 %) who were not treated with antibiotics (p
.001). All 22 patients receiving azithromycin had at least 3 STEC-negative stool specimens after the completion of treatment, and no recurrence of STEC was observed. Therefore, as a proof of principle, a 3-day course of oral azithromycin was offered as decolonization therapy to long-term carriers (>28 days) of STEC O104:H4 who were initially not treated with antibiotics, if they were restricted in their social or working life (e.g., ban from work). All 15 patients treated with azithromycin for STEC decolonization had negative stool specimens after the 3-day course, without any deterioration of renal function or development of other HUS-related symptoms [27
••]. Therefore, successful decolonization treatment was extended to more than 40 patients, without any adverse effects until now (unpublished data). Such decolonization regimen has always to be weighed cautiously against the risk of other potential, pathogen-independent adverse drug side effects [47
The in vitro finding that azithromycin does not induce Stx expression was confirmed recently for STEC O104:H4 by Bielaszewska et al. [48
•]. Comparing the effect of subinhibitory concentrations of several antibiotics on the induction of Stx production of STEC O104:H4, they found that ciprofloxacin increased Stx production, while meropenem, rifaximin, tigecycline, and azithromycin did not [48
•]. Interestingly, STEC O104:H4 appears to respond differently to antibiotics, as compared with the “classical” STEC strains O157:H7 [49
]. In the situation of acute STEC disease, the differential response of various STEC strains to antibiotics requires an early evaluation of these interactions in order to enable precise warnings or recommendations concerning antibiotic treatment.
Despite the in vitro induction of Shiga toxin expression by quinolones, preemptive therapy of STEC-HUS patients with a combination therapy of meropenem and ciprofloxacin in one other medical center resulted in statistically significant reduction of death, seizures, and STEC shedding [17
However, it has to be taken into account that all promising results concerning the use of antibiotics for the treatment of STEC during the German STEC O104:H4 outbreak were retrieved either in patients suffering already from HUS or in clinically recovered, now asymptomatic long-term carriers with a shedding time of at least 28 days. Therefore, at present, no definite conclusions can be drawn for the use of antibiotics in acute STEC diarrhea. Future trials might further elucidate the pros and cons of this issue. Any antibiotics should be handled cautiously in patients with acute bloody diarrhea caused by STEC until their benefit is approved in controlled trials.