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Antibiotics, HUS, and Gastroenteritis

The issue of whether antibiotics used to treat Shiga toxin-producing E. coli increase the risk of the hemolytic uremic syndrome (HUS) has been a vexing one.  But beyond E. coli, antibiotic use in general for treatment of infectious gastroenteritis poses conflicting risks and benefits.  Since it is hard for even the most diligent medical practitioner to keep abreast of current medical research, consumers of medical services may find it helpful to review some of these issues.

The first study that looked at whether antibiotic use increased the risk of HUS in children was published in 2000. [1] The study found that antibiotic use was a strong and independent risk for the development of HUS regardless of the severity of the inciting infection.  Two years later, a meta-analysis of nine pooled studies found no effect in the risk for HUS with antibiotic use. [2] But the analysis noted that limitations in the studies examined limited interpretation of the data.

More recent studies indicate that the risk of HUS is increased by the use of some antibiotics.  The differing mechanisms of action in different antibiotics impact the production of Shiga toxin (Stx) differentially. [3]

In a study that used piglets as a model for human infection, ciprofloxacin (Cipro) increased the production of Shiga toxin 2 (Stx2) but not the production of Stx1. Azithromycin [4] caused no significant increase in Shiga toxin production. After treatment with ciprofloxacin, infected piglets had diarrhea and the severe fatal neurological symptoms associated with Stx2 intoxication. “Characteristic petechial hemorrhages in the cerebellum were more severe in ciprofloxacin-treated animals than in control animals. In contrast, azithromycin-treated piglets survived the infection and had little or no brain hemorrhaging.” [5]

The study concludes that: “The increased in vitro toxin production caused by ciprofloxacin was strongly correlated with death and an increased rate of cerebellar hemorrhage, in contrast to the effect of azithromycin. The piglet is a suitable model for determining the effectiveness and safety of antibiotics available to treat patients.” [6]

A just published study [7] assessed Stx production in the presence of different types of antibiotics.  The authors report that: “Sub-inhibitory levels of antibiotics that target DNA synthesis [8], including ciprofloxacin (CIP) increased Stx production, while antibiotics that target the cell wall, transcription, or translation did not….Remarkably, very high levels of Stx were detected even when growth of O157:H7 was completely suppressed by CIP. In contrast, azithromycin (AZM) significantly reduced Stx levels even when O157:H7 viability remained high.” [9]

So the evidence mounts that the class of antibiotic that includes Cipro (a fluoroquinolone) may drive the risk of HUS through increased Stx production. However, it is important to note that antibiotics are clearly indicated for some gram negative bacterial infections of the gut including infections such as Campylobacter jejuni and Shigella, which clinically resemble E. coli O157:H7 enteritis.  Further, antibiotic use in the elderly, immune compromised, and those with co-morbidities may be indicated even if the face of a Shiga toxin-producing infection. Thus, wholesale avoidance of antimicrobials for infectious diarrhea is not prudent, but identification of the infectious agent before antibiotic administration is very helpful.

Antibiotics are often prescribed to patients who have presumed bacterial gastroenteritis without consideration of the effects beyond the acute illness.  Because antibiotics can dramatically affect the native bacteria in the intestines, they have the potential to increase a patient’s risk of infection.  Persons who are already receiving antimicrobial treatment are more susceptible to infection with drug-resistant pathogens. [10]

Few of us consider the effects of bacteria on the natural flora of our intestinal tracts–unless one develops post-infection GI problems.  But the use of antibiotics has effects well past the time of consumption and may leave the user vulnerable to opportunistic bacterial pathogens.

Experiments done with mice show that antibiotic treatment alters the gut flora but does not eliminate it. [11] The effects of antimicrobials on microflora vary with the type of antibiotic and the location–the small intestine versus the beginning and end of the large intestine.  The graph below shows the recovery of aerobic bacteria after withdrawal of antibiotics in the mice.  There was a rapid overgrowth of aerobic bacteria which steadily fell over the next three weeks.
table1-hus-antibiotics.pngThe same study shows the relative numbers of Salmonella in the GI tract after antibiotic treatment of the mice for one week.  Three days after Salmonella bacteria were inoculated in the gut of the mice they were sacrificed in order to assess the extent of introduction of Salmonella colonization. While results varied by antibiotic, all antibiotics used increased the presence of Salmonella versus controls. [12]

table2-hus-antibiotics.pngThe disruption of intestinal mucosa, among other things, appears to increase host susceptibility to Salmonella infection.  As the Discussion section of the study emphasizes, even careful use of antibiotics poses potential risks:

“Even routine and appropriate use of antibiotics may have a detrimental impact on the host microbial ecosystem, which is important for host mucosal protection….Oral Salmonella challenge of antibiotic-treated mice resulted in comparable increases in intestinal Salmonella colonization, enteritis, and invasion irrespective of the antibiotic combinations used…. Despite the rapid recovery of several measurable parameters of the biome, residual subtle alterations in bacterial composition can persist and result in profoundly enhanced susceptibility to bacterial enteritis.” [13]

Cirpo is a widely prescribed antibiotic for bacterial infections of the GI tract.  It is often prescribed as empirical treatment–treatment before a diagnosis is confirmed–which can be problematic if the diagnosis is infection with Shiga toxin-producing E. coli.  Presented with a patient suffering bloody diarrhea, the clinician is probably advised to avoid Cipro and choose an antimicrobial with a different mechanism of action if antibiotic treatment is deemed necessary.  A person suffering gastroenteritis who is offered antibiotic treatment is well-served to ask questions about potential deleterious effects.

And for those Cipro users who don’t worry about the microbiotic flora of their intestines, you may want to watch your joints.  In July 2008, the FDA directed the maker of Cipro to add a black bo
x warning to the drug’s label about increased risk of developing tendinitis and tendon rupture in patients taking fluoroquinolones.

References

1.  Wong CS et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000 Jun 29 342 1930 -1936.  This cohort study found a 14 fold increase in the risk of HUS when antibiotics were used.

2.  Safdar N, et al. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis. JAMA 2002;288(8):996-1001.

3.  McGannon CM et al, Different classes of antibiotics differentially influence Shiga toxin production Antimicrob. Agents Chemother. doi:10.1128/AAC.01783-09. Published online ahead of print: http://aac.asm.org/cgi/content/abstract/AAC.01783-09v1.

4.  Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It is a macrolide antibiotic chemically related to erythromycin and clarithromycin.  It is among the more widely prescribed antibiotics in the US.

5.  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 Feb 15;199(4):486-93.

6.  Id.

7.  Supra, note 3.

8.  Cipro kills bacteria by interfering with an enzyme (DNA gyrase) that causes DNA to unwind and duplicate and thus stops cell division.

9.  Supra, note 3.

10.  Mølbak K. Human health consequences of antimicrobial drug-resistant Salmonella and other foodborne pathogens. Clin Infect Dis. Dec 1 2005;41(11):1613-20.

11.  Croswell A, et al, Prolonged Impact of Antibiotics on Intestinal Microbial Ecology and Susceptibility to Enteric Salmonella Infection.  Infect Immun. 2009 July; 77(7): 2741-2753.

12.  DSI = distal small intestine and LI = large intestine.

13.  Id.

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