Rifaximin Does Not Induce Toxin Production or Phage-Mediated Lysis of Shiga Toxin-Producing Escherichia coli

Abstract

Diarrhea in children is often caused by enteropathogen infections that might benefit from early empirical antibiotic therapy. However, when the definition of the pathogen requires sophisticated laboratory studies, the etiology of enteritis is not known early in illness. Empirical therapy may be dangerous if the child is infected with a Shiga toxin-producing Escherichia coli (STEC) strain because antimicrobials may increase Shiga toxin (Stx) release, resulting in increased risk of microangiopathic hemolytic anemia with acute renal failure (hemolytic-uremic syndrome [HUS]) and death. There is a need for antimicrobials that would be effective against multiple bacterial enteropathogens yet not induce Stx release or increase the risk of HUS. Rifaximin has been evaluated in adults for treatment of bacterial enteritis and has a good record for safety and efficacy, but it has not been evaluated extensively in children with gastroenteritis. We therefore evaluated rifaximin's potential for phage induction, drug-induced bacteriolysis, and toxin release in 57 STEC strains (26 O157 and 31 non-O157 strains). Growth in ciprofloxacin, a known Stx phage inducer, caused bacteriolysis and release of toxin in 25/26 (96%) O157 strains and 15/31 (48%) non-O157 strains. In contrast, rifaximin did not induce phage replication or lysis in any strain. Toxin release in the presence of rifaximin was not different from release in the absence of antibiotic. Rifaximin, unlike many antibiotics used to treat pediatric gastroenteritis, does not induce phage-mediated bacteriolysis and Stx release.Bacterial enteropathogens represent important pediatric pathogens worldwide. Many of the agents causing gastroenteritis are known or predicted to respond to antibiotic therapy (e.g., Shigella,

Effects of Antibiotics on Shiga Toxin 2 Production and Bacteriophage Induction by Epidemic Escherichia coli O104:H4 Strain

“…Except for ciprofloxacin (32), no other antibiotics have previously been investigated thusly. We were particularly interested in those antibiotics that had been proposed for indicated use during the O104:H4 outbreak (15) based on their inability to induce stx 2 -harboring phages and Stx2 production in EHEC O157:H7 (23,24,28,39), i.e., azithromycin, rifaximin, and meropenem (though another carbapenem, imipenem, not meropenem itself, was investigated with EHEC O157:H7 in this respect) (23). We also included tigecycline because of its broad activity against Gram-positive and Gram-negative bacteria (14) and because, to our knowledge, its effects on induction of stx-harboring phages and Stx production have not yet been studied.…”

“…We also included tigecycline because of its broad activity against Gram-positive and Gram-negative bacteria (14) and because, to our knowledge, its effects on induction of stx-harboring phages and Stx production have not yet been studied. We used various subinhibitory antibiotic concentrations, the methodology commonly applied to investigate effects of antibiotics on Stx production and/or stx-harboring phage induction in other EHEC strains (16,23,24,28,39), which allows determination of the concentration dependence of the effects studied. In contrast, therapeutic concentrations rapidly inhibit or kill bacteria in vitro, thus hampering unbiased measurement of antibiotic effects.…”

“…However, the effects of different antibiotic classes on Stx production in vitro differ and are also dependent on the antibiotic concentration and the nature of the EHEC strain (e.g., O group or Stx type) (16,22,24,28,29,39). In studies performed with EHEC O157:H7, fluoroquinolones, trimethoprim-sulfamethoxazole, and ampicillin significantly increased Stx2 production (16,20,22,23,24,29,39,40), whereas macrolides (24,29,39), carbapenems (22,23), aminoglycosides (22,24), rifampin (31), rifaximin (28), and fosfomycin (22,24,40) either had no effect on Stx2 production or suppressed it. These in vitro data are in accordance with experiments with animal models (31,39,40).…”

Different Classes of Antibiotics Differentially Influence Shiga Toxin Production

“…Some studies report antibiotic treatment of patients with STEC infection to be beneficial and others do not (reviewed in reference 23). Similarly, studies examining the ability of antibiotics to promote Stx production in vitro have given mixed results (9,13,18,21,25,37). In several studies Stx expression was assessed by enzyme-linked immunosorbent assay (ELISA), Western blotting, or mRNA levels, and these indirect assays may not accurately reflect levels of biologically active Stx, since not all subunits may be part of assembled functional AB 5 complexes.…”

Children Acute Enteric Infections in Paediatrician Practice: Possibilities of Diagnostics and Therapy

“…Согласно данным антибиотикограмм, для этого возбуди-теля была характерна множественная антибиотикоре-зистентность (13 из 21 препарата) [29]. В то же время в предыдущие годы данный возбудитель не регистри-ровался при вспышках ОКИ, кроме того, их течение не сопровождалось развитием гемолитико-уремического синдрома [30]. Полученные данные позволили Немецкой ассоциации инфекционистов рекомендовать в качестве препарата стартовой терапии энтерогеморрагической E. coli О104:Н4 рифаксимин, а также аминогликозиды (амикацин), хлорамфеникол, фторхинолоны в возрастных дозировках.…”