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Antibiotics and Hemolytic Uremic Syndrome
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University, School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Synopsis: Gnotobiotic piglets were challenged orally with a Shiga toxin-producing strain of E. coli O157:H7, then on day three left untreated, treated with ciprofloxacin, or treated it with azithromycin. After treatment with ciprofloxacin, infected piglets had diarrhea and severe neurologic symptoms associated with Stx2 and the presence of petechial cerebellar hemorrhage. Azithromycin-treated animals survived and had little or no brain hemorrhage.
Source: Zhang Q, et al. Gnotobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157:H7 infection. J Infect Dis. 2009;199:486-493.
In vitro treatment of clinical isolates and isogenic strains of E. coli O157:H7 with ciprofloxacin increased the production of Stx2 (as measured by ELISA) via phage induction but did not increase the production of Stx1. Azithromycin caused no significant increase in toxin production in vitro. Gnotobiotic piglets were orally challenged with a Stx-producing strain of E. coli O157:H7 which had originally been isolated from an outbreak of disease associated with HUS. After treatment with ciprofloxacin, infected piglets had diarrhea and severe fatal neurologic symptoms. At necropsy, characteristic petechial hemorrhages were seen in the cerebellum and were more severe than that seen in control animals. Azithromycintreated piglets survived infection and had little or no brain hemorrhage seen.
Shiga toxin (Stx)-producing E. coli (especially O157:H7) causes bloody diarrhea, and some infections are complicated by hemolytic uremic syndrome (HUS). Case-control studies suggest that administration of antimicrobials to patients with Stx-producing strains of E. coli is a major risk factor for development of HUS.1,2 In the commonly referenced CDC study,1 antimicrobial administration within three days of onset of diarrhea, especially in children < 13 years old, was the strongest risk factor (relative risk 11.5) for development of HUS. In these pediatric patients, 5 of 6 patients who developed HUS who were treated with antimicrobials received trimethoprim/sulfamethoxazole (TMP/SMZ). In the Seattle study,2 antibiotic administration was associated with a relative risk of 14.3 for development of HUS. The specific relative risk associated with TMP/SMZ was 17.7 and was 13.4 for β-lactam antibiotics. In addition to the case-control data implicating antibiotic administration with the development of HUS, some elegant basic science has been done to explain the mechanism for induction of Shiga toxin production by antibiotics in E. coli.3,4 In Shiga toxin-producing strains, it appears that toxin synthesis is regulated through induction of an integrated bacteriophage, which encodes the toxin gene. Phage production is linked to the bacterial SOS response to DNA damage. SOS-inducing antimicrobials, particularly fluoroquinolones, trimethoprim, and furazolidone were shown to induce toxin gene expression, particularly of Stx2.4
These in vitro and in vivo studies nicely explain the observed clinical association of antibiotic administration with induction of HUS. From a practical perspective, it is still probably prudent to withhold antibiotics in patients of all ages who present with the syndrome of afebrile bloody diarrhea (commonly seen with enterocolitis due to Stx-producing E. coli); but, realistically, many physicians will still treat such patients with antibiotics. Hopefully, the word will get out that if they decide to use antibiotics in such cases, they should choose a macrolide rather than ciprofloxacin, trimethoprim/sulfamethoxazole, or a β-lactam agent since the former appears much less likely to trigger HUS. Another reason to prefer azithromycin to ciprofloxacin for the empiric treatment of presumed bacterial enterocolitis is that the most common cause of febrile bloody diarrhea, Campylobacter, is now commonly resistant to ciprofloxacin.