The HUS-Antibiotic Connection, and Vaccine News

Robert W. Steele, MD

Disclosures

August 02, 2000

E coliO157:H7 and Antibiotics Don't Mix

Investigators at Children's Hospital at the University of Washington in Seattle have begun to answer a question many clinicians have struggled with for many years: When a child has been identified as having gastroenteritis with Escherichia coli O157:H7, should antibiotics be started in an attempt to minimize the risk of sequelae? Previous studies have shown that the use of antibiotics in those infected with E coli O157:H7 does not improve outcomes,[1,2] but the answers have been far from clear.

Since the first publication linking hemolytic-uremic syndrome (HUS) to enterohemorrhagic E coli,[3] a significant amount of information has come forward concerning its epidemiology and pathophysiology. However, there has been a relative paucity of data guiding clinicians to prevention and treatment. Prevention has focused more on identifying colonized cattle, ensuring proper meat handling, and promoting appropriate cooking techniques. Therapy has been largely limited to supportive measures once HUS has been identified. Specifically, early antibiotic use to ameliorate disease has been difficult to study and has had conflicting results. One Japanese study during an outbreak of HUS showed a possible improved outcome in those treated with fosfomycin as compared with other antibiotics. However, almost all children in this retrospective study received antibiotics, making a comparison of those who did not receive them impossible.[4] Others have found a likely detrimental effect of antibiotic use in those with E coli O157:H7 gastroenteritis, but these investigations were also plagued by the limitations of a retrospective study.

In the most recent evaluation of this issue, recently published in The New England Journal of Medicine [https://www.nejm.org/content/2000/0342/0026/1930.asp], investigators conducted a prospective cohort study of 71 children younger than 10 years who had diarrhea from E coli O157:H7.[5] With impressive cooperation from laboratories in 3 states, patients were identified and immediately contacted by the research team. Those whose cultures had been obtained within 7 days of the onset of diarrhea were included in the study. Although only 9 had received antibiotics, half of those who developed HUS had received them (5 of 10). Using logistic-regression analysis, these researchers found that children treated with antimicrobials had a relative risk of 14.3 of developing HUS. They concluded that antibiotic treatment of children with E coli O157:H7 gastroenteritis significantly increases the risk of developing HUS.

This prospective study derived much of its data through a questionnaire. Nevertheless, Wong and colleagues did an excellent job of minimizing selection bias and recall error by using thorough and expedient identification and investigative techniques. And while the number of those who developed HUS was small, their appropriate use of multivariate analysis to adjust for confounding risk factors clearly shows a probable association between antibiotic use and the development of HUS in those infected with E coli O157:H7.

The detrimental effects of antibiotics are not without precedent. At least 1 study has shown how bacteria release more shiga-like toxin when exposed to antimicrobials.[6] The results of this study confirm that antibiotics can certainly do harm, and as such, their use should be withheld in those with bacterial diarrhea until the culture results confirm E. coli O157:H7 is not the offending agent.

This past year has seen a flurry of activity in the world of immunizations. But June and July have seen a plethora of analysis and subsequent recommendations concerning both previously available vaccines and those relatively new to the market.

[7]

Current guidelines from the Advisory Committee on Immunization Practices (ACIP) suggest that routine vaccination of civilians with the quadrivalent meningococcal polysaccharide vaccine is not recommended because of its relative ineffectiveness in children younger than 2 years (the age group with the highest risk for sporadic disease) and because of its relatively short duration of protection. However, this vaccine remains recommended for control of outbreaks of meningococcal disease with serogroup C. These outbreaks continue to occur sporadically. (An outbreak is defined by the occurrence of 3 or more confirmed or probable cases of serogroup C meningococcal disease during a period of 3 months or less, with a resulting primary attack rate of at least 10 cases per 100,000 population.) Threshold calculations for college students are age-specific, whereas outbreaks in non-college students are based on population-based rates.

While the CDC has made recommendations based on outbreaks with serogroup C, these same guidelines are applicable to outbreaks caused by the other vaccine-preventable meningococcal serogroups, including Y, W-135, and A.

[7]

Due to factors primarily related to close-quartered living arrangements in dormitories, college freshmen are at modestly increased risk for meningococcal disease relative to other persons their age. The currently available quadrivalent meningococcal polysaccharide vaccine is safe and effective and has been proven to decrease the risk for meningococcal disease among such persons. However, vaccination does not eliminate the risk because the vaccine confers no protection against serogroup B disease. In addition, while this vaccine is highly effective against serogroups C, Y, W-135, and A, it does not approach 100%.

The overall risk for meningococcal disease among college students is low. And financial analysis of vaccination for all college students, all freshmen, or only freshmen who live in dormitories shows it is not likely to be cost-effective for society as a whole. Therefore, the ACIP has now recently issued recommendations concerning the use of this vaccine in college students. These essentially mimic the recommendations the American Academy of Pediatrics (AAP) issued this past year. First, the risk of dormitory living only slightly increases the risk of meningococcal disease as compared with the rest of the population. Thus, no specific changes to residence halls or dormitories are necessary. However, because the risk is elevated, providers of medical care to incoming or current freshmen should inform both the parents and students about meningococcal disease and the benefits of vaccination. Universal vaccination is not necessary, but the vaccine should be made available to college freshmen or other undergraduates who want to reduce their risk for meningococcal disease.

The use of vaccines against polio became widespread in the 1950s, and since that time, the incidence of wild-type polio has significantly declined in most parts of the world. The success of the oral polio vaccine was so significant that the World Health Assembly resolved in 1988 to eradicate polio by the year 2000. During these past 12 years, enormous progress has been made in reaching this goal, with more than 180 countries and territories now considered polio-free. The effort to systematically and completely immunize the populations of even the most remote regions of the world has been nothing short of phenomenal.

Currently, there are only 30 countries in South Asia and Sub-Saharan Africa where polio still exists (CDC Director Jeffrey P. Koplan, MD, MPH, personal correspondence). The World Health Organization has been concentrating strategies, including national immunization days and "mop-up" efforts in these areas of the world. And while polio eradication by the end of the year 2000 remains the goal, it is anticipated that the last case of wild-polio will realistically be identified in 2002. This would allow for official certification of a polio-free world to be issued in 2005.

Officially
Recommended by the AAP

Ever since the FDA approved the heptavalent pneumococcal vaccine (PCV7; Prevnar, Lederle Laboratories/Wyeth-Ayerst Pharmaceuticals), there has been significant discussion among both the ACIP and the AAP concerning the recommendations of its universal use for those children younger than 2 years. The controversy stemmed from the financial aspect of this particular vaccine. In some cases, the cost almost doubled the total current expenditure of all other routine childhood vaccines.

The AAP Committee on Infectious Disease has now issued its policy statement concerning the use of PCV7.[8.9] The current recommended schedule for administration of this vaccine is similar to recommendations cited in previous published reports and is available elsewhere.[8] And while many of the recommendations are similar to previous releases from the ACIP, there are a couple notable exceptions as well as specific guidelines concerning special cases:

For children at high risk for invasive pneumococcal disease:

  • Those older than 2 years who have received the 4-dose schedule of PCV7 should also receive 1 dose of the 23-valent polysaccharide vaccine (23PS) 6-8 weeks after the last PCV7 dose.

  • Those older than 2 years who have received fewer than 4 doses should receive 2 doses of the 23PS, 6-8 weeks apart.

  • Those older than 2 years who received 1 dose of 23PS should receive a total of 2 PCV7 doses, followed by an additional 23PS dose 3-5 years after the last vaccine.

  • Infants of very low birth weight (≤ 1500 g) should be immunized at the time they reach chronologic age of 6-8 weeks, regardless of their calculated gestational age.

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