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From the inside out: Gastrointestinal decontamination in children with intestinal failure
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Intestinal failure in children is often caused by congenital disorders like gastroschisis or Hirshsprung’s disease, or may be a sequela of necrotizing enterocolitis incurred as a newborn. Short-bowel syndrome, or SBS, is the result of surgical intervention to correct these problems wherein much of the malfunctioning intestine is removed, ultimately leading to long-term IV parenteral nutrition. Additionally, small intestine bacterial overgrowth is common, promoting gastrointestinal inflammation and an impaired intestinal barrier. This barrier dysfunction predisposes patients to bacterial translocation, where bacteria normally restricted to the gastrointestinal tract are able to move elsewhere in the body, potentially causing bloodstream infections, or BSIs, and sepsis. Accordingly, SBS has been identified as an important risk factor for BSI, and bacterial overgrowth increases this risk. Pharmacologic intervention targeted at controlling gut flora and managing bacterial overgrowth has thus developed as an area of interest. While studies reviewed herein focus on preventing sepsis in children with intestinal failure, general principles, drug selection and dosing strategies may be considered for application across various patient populations and disease states.
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Parenteral nutrition (PN) is commonly associated with BSI, given the constant central venous access and the infusion of nutrients. Prophylactic measures such as maintenance of a sterile environment for line manipulations, adherence to aseptic technique and potentially the use of antibiotic or ethanol catheter locks are paramount to preventing BSI. These measures target contamination of the line from the access point outside of the body, where gram-positive pathogens, like Staphylococcus spp., can be found on skin. However, BSI among children with SBS are commonly caused by enteric bacteria like Escherichia coli, Klebsiella pneumoniae or enterococci, in addition to skin flora. This suggests the involvement of gastrointestinal bacterial translocation, and interventions targeted at IV catheter access sites alone may not be sufficient to prevent infections caused by some of the most common BSI pathogens in this population.
Data describing the impact of enteral antibiotics on BSI are limited to small studies. In one group of 15 children representing 9,512 PN days, the eight patients who received cycled oral antibiotics experienced a reduction in infection rate from 2.14 to 1.06 per 100 PN days (P = .014), compared with no difference among the seven control patients (from 1.91 to 2.36 infections per 100 PN days). Additionally, the rate of central venous catheter removal in the treatment group was almost half that among patients in the control group, although this difference in catheter longevity was not statistically significant (0.27 removals per 100 PN days vs. 0.44 removals per 100 PN days). Another small study administered oral antibiotics to pediatric small bowel transplant recipients during the first 30 days after surgery, and compared the incidence of BSI between postoperative days 0-30 and postoperative days 31-60. No significant difference in the overall rate of infection was seen (6.9 vs. 4.6 per 1,000 catheter days), but there was a change in the type of pathogen isolated. The majority (87%) of bloodstream pathogens recovered during postoperative days 0-30 were gram-positive, compared with 71% gram-negatives during postoperative days 31-60, when oral antibiotics were no longer administered. While these differences did not reach statistical significance, the relatively lower incidence of enteric bacteria in the bloodstream during receipt of oral agents targeted at these pathogens (tobramycin, colistin and amphotericin B) suggests some involvement of gastrointestinal flora on systemic infection.
While standardized guidelines do not exist, a number of institutional or study protocols have been described, and selected agents and doses are summarized in Table 1. Although specific agents, doses and schedules vary, they have common characteristics. First, antibiotics should be active against typical gastrointestinal flora and ideally undergo minimal absorption to limit systemic side effects or development of antimicrobial resistance while exerting effects on the gastrointestinal tract. Reported doses range from what may be used for prophylaxis up to those used for treatment of invasive infections, but typical doses for bacterial overgrowth are half of what is used therapeutically. In addition, many antibiotics used orally for selective gut decontamination are typically administered intravenously, requiring the development of novel oral/enteral dosing recommendations. Antibiotic schedules are cycled by giving 1 to 2 weeks of an antibiotic alternating with 1 to 2 weeks with no antibiotics. Some regimens include an additional 1 to 2 weeks of a different antibiotic. For example, Dobson and colleagues cycled 14 days of metronidazole followed by 14 days of colistin with tobramycin followed by 14 days of no antibiotics. The University of Alberta has described different schedules, including the repeating of 7 days of metronidazole followed by 7 days of gentamicin and then 7 days without antibiotics. In high-risk patients, those authors described eliminating the 7-day antibiotic-free period, or replacing it with a third week of antibiotic treatment using amoxicillin-clavulanate. No schedules have been compared in a prospective, randomized manner.
Other antibiotics aside from those in Table 1 described for gastrointestinal decontamination include ciprofloxacin, trimethoprim/sulfamethoxazole, erythromycin, tobramycin, colistin and nystatin. Ciprofloxacin is generally avoided in children unless there are issues like drug intolerance or antimicrobial resistance negating other treatment options. The reservation of fluoroquinolones for serious infections in the absence of alternative drugs for patients of all ages has recently been advocated by the FDA with a report in May citing the potential for severe side effects involving the musculoskeletal and nervous systems. Oral neomycin is not commercially available as an oral suspension, but a 25 mg/mL suspension may be compounded using neomycin powder, with sterile water and glycerin or simple syrup.
Gastrointestinal decontamination is used to limit systemic infections in selected situations, but literature remains limited with many variations in practice reported. Larger, randomized studies may be warranted to identify which patients are most likely to benefit, and to standardize recommended agents, doses and schedules.
- References:
- Cole CR, et al. J Pediatr. 2010;doi:10.1016/j.jpeds.2009.12.008.
- Dobson R, et al. Aliment Pharmacol Ther. 2011;doi:10.1111/j.1365-2036.2011.04826.x.
- FDA Drug Safety Communication. May 12, 2016. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM500591.pdf. Accessed August 22, 2016.
- Galloway D, et al. Pediatr Transplant. 2015;doi:10.1111/petr.12583.
- Gura KM. Pharmacological Issues with Bacterial Overgrowth: Causes and Treatment Strategies. Presented at: Oley Foundation Consumer/Clinical Conference; June 29-July 3, 2015; Saratoga Springs, New York.
- Malik BA, et al. Can J Gastroenterol. 2011;25:41-45.
- Miko BA, et al. J Ped Infect Dis. 2015;doi:10.1093/jpids/piu079.
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- For more information:
- Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.