Tag Archives: antibiotics

Antibiotics, Oral Contraceptives, and IBD

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Briefly noted:

“Physician Knowledge Regarding Concomitant Antibiotic and Oral Contraceptive Use in Patients with IBD.” Gastroenterology & Hepatology 2014; 10: 302-06.

Key finding:

  • IBD specialists and gynecologists were more likely to be aware that no evidence exists to support a link between a decrease in oral contraceptive pill (OCP) efficacy and concomitant use of ciprofloxacin or metronidazole.

Previous studies suggested that antibiotics reduced OCP efficacy.  The authors note that “more recent, prospective, pharmacokinetic studies in women demonstrate no evidence of an interaction between OCPs and most antibiotics, with the exception of rifampin.” (J Am Acad Dermatol 2002; 46: 917-23)

 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

 

Why is Celiac Disease Becoming More Prevalent?

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A recent editorial helps provide some answers and even explains the term “protopathic bias.”  Ostensibly, the editorial’s task is to explain the potential interaction of maternal serum iron ingestion and the risk of celiac disease (see previous blog post: Is There a Link Between Maternal Iron Supplementation and …).  However, the editorial provides an explanation for the Swedish epidemic and the ongoing slower, wider epidemic.

Here’s the link, http://ow.ly/vQGQ7, and here’s an excerpt:

The Swedish epidemic of CD of 1985–1994 has been extensively documented, and resulted in the development of hypotheses regarding environmental risk factors for this disorder.7 This epidemic was restricted to children younger than 2 years; in that age group, the incidence of diagnosed CD rose from 65 cases per 100,000 person-years to 198 cases per 100,000 person-years. In contrast, incidence data for older children were relatively flat during this period. The epidemic abruptly ended in 1995, although children born during the period of the epidemic have an ongoing increased risk of developing CD. Subsequent investigation led to the hypothesis that infant feeding practices affect the risk of CD in young children. The epidemic occurred during a period of relatively low rates of breastfeeding at the age of 6 months and during the same period of time, the quantity of gluten in infant formula greatly increased. Although it is difficult to separate the relative importance of each feeding practice, it seemed that high quantity of initial gluten intake without overlapping with breastfeeding was responsible for this epidemic. Although a systematic review of the issue has concluded that breastfeeding has not been definitively proved to be associated with risk of CD,8 subsequent research has indicated that the timing of gluten introduction is important in determining risk.9PreventCD, a prospective randomized trial of infants with a family history of CD, is testing specifically whether the introduction of small quantities of gluten beginning at age 4 months of age will induce tolerance to gluten in this high-risk group.

The second epidemic is more diffusely spread over time and space. Studies from the United States and elsewhere have shown that the seroprevalence of CD (as defined by positive tissue transglutaminase and endomysial antibodies) has increased markedly in recent decades. An analysis of stored serum from military recruits at the Warren Air Force Base in the years spanning 1948–1954 found a CD seroprevalence of 0.2%, whereas 2 recent cohorts from Olmsted County (spanning the years 2006–2008) matched by year of birth and age at sampling found a seroprevalence of 0.9% and 0.8%, respectively.11 An analysis of another cohort in this country found a doubling in seroprevalence during adulthood from 1974 (0.21%) to 1989 (0.45%).12 The mode of presentation of CD has changed in the past generation, with rising numbers of patients presenting without diarrhea.13 Patients presenting with anemia may have more severe disease expression (as measured by the degree of villous atrophy and the presence of metabolic bone disease) than patients presenting with diarrhea.14 Because most individuals in the United States with CD are undiagnosed,15 this is largely a hidden epidemic, but there is no reason to believe that the prevalence has peaked. In Finland, which had a higher prevalence of CD than the United States to begin with, the seroprevalence of CD doubled between the years 1978 (1.05%) and 2000 (1.99%).16 It is not known whether this epidemic will subside or if the prevalence of CD will continue to rise to a new set-point. But given the morbidity associated with CD17 and the cost and difficulty of the gluten-free diet18, 19 these data have sparked interest in identifying the cause of this less visible epidemic.

Certain infections (eg, rotavirus among infants20 and Campylobacter among adults21) have recently been shown to be associated with a increased risk of CD, but rates of these infections have not increased markedly, and so are not likely to be driving this epidemic. In contrast, a lack of exposure to certain microbes is a hallmark of modern times, and the increase in CD disease is congruent with the hygiene hypothesis, which states that decreased exposure to microbes may be driving the rise in autoimmune and atopic conditions. This hypothesis is particularly compelling in light of a recent study that found a dramatically different seroprevalence of CD in Finland (1.4%) and the Russian Karelia (0.6%), geographically proximate areas with a similar prevalence of HLA DQ2 and DQ8 but with major differences in economic development.22

Further evidence implicating the modern relationship with microbes is now accumulating. Children who were born by elective cesarean section are at increased risk of developing CD, whereas those born by emergent cesarean section (and may have had contact with the birth canal) are not.23 In addition, there seems to be an inverse relationship between Helicobacter pylori colonization and CD.24 Drugs are another modern innovation that may be affecting the CD epidemic. Population-based studies from Sweden have shown that prescription of antibiotics25 and proton pump inhibitors26 are each associated with an increased risk of the subsequent development of CD.

The associations identified in these studies are not necessarily causal. Studies of drug exposure in particular may be prone to protopathic bias, wherein early symptoms of the outcome of interest (CD) may lead to the prescription of the exposure (eg, antibiotics or proton pump inhibitors).

From the NY Times: Gluten-free, veggie snacks, vegan desserts, spring salads. They’re all in our new recipe finder.

Early antibiotic use and the development of inflammatory bowel disease

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Another study adds weight to the idea that early antibiotic use may increase the risk of developing inflammatory bowel disease (IBD) (J Pediatr 2013; 162: 510-4).

Using a nested case-control design, the authors matched 2377 controls to 294 children with IBD in a population-based database from Manitoba, Canada.  Specifically, the authors looked at the frequency of otitis media diagnosis and the likelihood of subsequent IBD.  By age 5 years, 89% of IBD cases had at least one diagnosis of otitis media, compared with 82% of the controls.  Despite the high frequency in both groups, the authors determined that individuals with a diagnosis of otitis media before age 5 years were 2.8-fold more likely to be an IBD case.

Some of the strengths of this study included the fact that it was a population-based analysis dating back to 1984 and likely captured almost all pediatric IBD cases (<19 years).  Nearly all physicians in Manitoba submit billing claims to a single publicly funded source.  Due to the nature of administrative data, this eliminates recall bias.

However, administrative data have several limitations as well.  Other confounding conditions may have been present and not identified; this could include family history and autoimmune diseases.

The authors “suspect” that the linkage between otitis media and IBD relates to the usage of antibiotics and subsequent alterations of the intestinal microflora.  Otitis media may serve as a “sensitive proxy measure” of antibiotic use.  Also, as boys are more frequently treated for otitis media, this may relate to the generally higher incidence of pediatric IBD in males.

For anyone interested in the association between antibiotic exposure and IBD, this study is useful and provides a number of references as well.

Related blog entries:

Preventing lethal antibiotic resistant outbreaks

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Establishing “rigorous infection-control procedures” remain the main tool to reign in these lethal outbreaks (NEJM 2012; 367:   2168-70).

While that message has been said before, the referenced article concisely discusses issues regarding multidrug-resistant gram-negative rods (MDR-GNRs) which are now much “more menacing” than methicillin-resistant Staphylococcus aureus (MRSA).  The reason: there are no effective drugs available to treat some life-threatening MDR-GNR infections.

With resistance to cephalosporins increasing, clinicians have turned to carbapenems; as a consequence, resistance is emerging to these agents as well.  Multidrug-resistant organisms (MDROs) are increasing; in addition, resistance that develops in one place of the world can quickly spread as shown by the MDR-GNRs with the New Delhi metallo-beta-lactamase 1.

Key points:

  • MDROs are transmitted mainly on the hands of caregivers.  The most effective aspect of “rigorous infection-control procedures” remains hand washing.
  • Some infections survive for prolonged periods on surfaces.  For example, during an NIH outbreak of a MDR-GNR Klebsiella pneumoniae, klebsiella survived on a ventilator that had been cleaned three times with two different disinfectants.
  • Antimicrobial stewardship is an important aspect of decreasing resistance. This includes sending cultures prior to antibiotics to tailor regimens, specifying the indication, documenting the expected duration of treatment, and assessing at 72 hours whether an ongoing antibiotic course is needed.
  • If we adhere to established practices, infections due to invasive devices which are the source of most ICU infections can be minimized.  For example, incorporating evidence-based “bundles” of care have been effective in reducing central line infections.

Related blog entry:

Electrons and Organic Food

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I still remember the Heisenberg uncertainty principle (Heisenberg states the uncertainty principle – PBS) from high school physics –thanks Mr. Pryor!  What quantum physicists don’t realize is that it is a leap of faith for anyone to believe in electrons much less to be concerned about measuring factors like speed or position.  I’ve never seen an electron but I’ve been convinced that they exist.

With organic foods, many people believe a health benefit exists, but does it and can it be proven?  A recent review weighs in (Ann Intern Med 2012; 157: 348-66) –thanks to Seth Marcus for pointing out this article.

This review from Stanford has been reported in multiple outlets and the soundbite is that organic foods are not better than conventional foods.  For example, the New York Times reports that the researchers “concluded that fruits and vegetables labeled organic were, on average, no more nutritious than their conventional counterparts, which tend to be far less expensive. Nor were they any less likely to be contaminated by dangerous bacteria like E. Coli.” Ultimately, “the researchers also found no obvious health advantages to organic meats.”

This is a vast oversimplification of this review.  So what did the researchers find and what were the limitations?

First –some background:

  • In 2010, U.S. sales of organic foods had increased to $26.7 billion; in contrast, only $3.6 billion was spent in 1997.
  • There are a number of different standards for organic foods, including U.S. Department of Agriculture (USDA), European Economic Community (EEC), and international federation of organic agriculture movement (IFOAM).
  • Typically organic foods are grown without synthetic pesticides or fertilizers or routine use of antibiotics/growth hormone.
  • Consumers often purchase organic foods due to concerns about effects of farming practices on environment, human health, animal welfare or perceptions of better taste.
  • Inclusion criteria for the cited reference allowed for 17 human studies and 223 nutrient/contamination studies of the initial 5908 potential relevant articles.

Key findings:

  • Conventional foods had 30% higher risk for pesticide contamination.
  • Conventional chicken and pork were more likely to have bacteria resistant to 3 or more antibiotics (33% risk difference).
  • Both organic and conventional products had frequent contamination with bacteria like Salmonella and Campylobacter.  Organic produce had higher risk for contamination with E. coli; this may have been due to some organic farms which used manure for fertilization.
  • There was not evidence that the organic foods were more nutritious.
  • Organic foods had higher levels of total phenols and ω-3 fatty acids.

Limitations:

  • No long-term studies of health outcomes have been performed.  The study with the longest duration included in this analysis was 2 years; the shortest was two days.
  • Variation in organic practices. Produce studies may not have reflected real-world organic practices.
  • Overall sample sizes were small (in total 13,806 human participants in 14 unique populations).
  • Reporting/publication bias.
  • Adherence with organic diets was varied; only 5 of the human studies evaluated participants who consumed a predominantly organic diet.

So, when one looks at this review, there are measurable differences in exposure to pesticides and antibiotic-resistant bacteria, despite variation in organic practices.  Specific nutrients are largely the same.  Whether any of these changes have a long-term health benefit is not known and would require an expensive long-term study to sort out.

 

One approach towards organic foods has been recommended by the Environmental Working Group.  They recommend “buying only organic when purchasing foods that contain the highest concentrations of pesticides, otherwise known as ‘the dirty dozen‘: peaches, strawberries, nectarines, apples, spinach, celery, pears, sweet bell peppers, cherries, potatoes, lettuce, and imported grapes” (Am J Clin Nutr 2010; 9 (suppl): 1499S-1505S).  This reference which discusses foods and potential hormonal effects on puberty goes on to state, “the biggest environmental exposure…is the ready availability of energy-dense foods” which contribute to obesity.

Related link:

Why are we seeing so many more cases

What do you know about the “exposome”?

How helpful are probiotics?

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Nobody really knows.  Claims about their efficacy are often based on poorly designed studies.  Efficacy of each strain for specific conditions and with specific dosing is often lacking.  One recent negative study demonstrates that probiotics are often not beneficial (J Pediatr 2012; 161: 40-3).

In this randomized, double-blind placebo controlled study of 106 Polish children (1-48 months of age), Lactobacillus reuteri had no effect in preventing nosocomial diarrhea in patients admitted for non-diarrheal illnesses.  While the authors contemplate that this could be due to the strain of probiotic chosen or the dose, it is clear that evidence that probiotics prevent infectious diarrhea “is still scant.”

This conclusion is backed by a large meta-analysis (JAMA 2012; 307: 1959-69).  While the study concludes that the use of probiotics is associated with a lower risk of antibiotic-associate diarrhea (RR 0.58), it predicted that the number to treat for one person to benefit would be 13.  The study was based on a systematic review of 82 randomized clinical studies.  Yet, overall the quality of the research was considered low; the studies were often had shortcomings:

  • 59 studies “lacked adequate information to assess the overall risk of bias”
  • 64 did not indicate if treatment randomization was blinded
  • 31 did not report an intent-to-treat analysis
  • 41 did not include a calculation of the study’s statistical power to detect differences
  • 17 trials were industry-sponsored and 52 did not clarify their funding/potential conflicts of interest
  • 59 did not report on adverse events specifically related to probiotic use; few trials addressed the risk of fungemia or sepsis
  • Trials rarely specified antibiotic agents; thus, it is difficult to know if a particular probiotic would be better with certain types of antibiotic therapy or duration.

Additional references/links:

  • Potential and pitfalls of probiotics with necrotizing enterocolitis
  • -JPGN 2010; 51:24. VSL#3 helpful for IBS, n=509 (4-18yr olds). 1 per day for <11yr, 2/day in 12-18yr olds
  • -Pediatrics 2008; 121:e850. Culturelle, during pregnancy and early infancy, not effective in preventing atopic dermatitis. Did increase wheezing.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, Lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Neurogastroenterol Motili 2007 (Quigley EM, et al), 19: 166-72. Review of probiotics and IBS.
  • -NASPGHAN 2007, author: Brian Dunlap, H. Yu, Y Elitsur. abstract -most commercial yogurts have LOW concentrations of probiotics.
  • -JPGN 2006; 43: 550. Review of probiotics for specific conditions.
  • -J Pediatr 2006; 149: 367. Probiotics reduce risk of antibiotic assoc diarrhea. If 7 pts (on abx) are treated with probiotics, one fewer will develop AAD.
  • -JPGN 2006; 42: 454. Evidenced-based review of probiotics.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -Gastroenterol 2004; 126: 1620-33.  Review of probiotics, prebiotics and antibiotics in IBD.

Outcomes of Biliary Atresia

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A retrospective study from the Netherlands showed that timely surgery and postoperative antibiotics were associated with better outcomes in Biliary Atresia (BA) (J Pediatr 2012; 160: 638-44).  While these results are not surprising, due to the length of the study period (1987-2008) and the number of patients (n=214), the study offers insight into a number of unresolved issues with regard to BA.

The type of BA in this series:

  • type I      14  (6.5%)
  • type II      27 (12.6%)
  • type III   172 (80.4%)
  • undetermined  1 (0.9%)

Other notable findings:

  • 10% of their patients had splenic malformations; no significant change in outcome was noted in this subgroup.
  • 18% received high-dose corticosteroids –no benefit was identified in this subgroup.  The authors state that previous studies are inconclusive; a large US trial of prednisolone (4 mg/kg/day initially) is pending.
  • 31% received ursodeoxycholic acid –no benefit was identified in this subgroup.
  • Overall survival improved a little during the study period, mostly due to increased availability of liver transplantation. 4-year transplant-free survival was 46% and 4-year overall survival was 73%.   Table II (pg 641) in their study lists six other international studies.  Recent studies in some countries have reported 4-year survivals of 82-91%.
  • Antibiotic usage (most commonly co-trimoxazole) was associated with improved outcomes, presumably due to less frequent bouts of cholangitis.  Yet, in this study the reported incidence of cholangitis was not lower.  The authors do not have an explanation for this finding.

Age at time of Kasai:

  • ≤45 days 19%
  • 46-60 days 37%
  • 61-89 days 36%
  • ≥90 days 8%
  • Median was 59 days.  Authors note that Netherland guidelines call for all infants with jaundice at 3 weeks to have a fractionated bilirubin.

Related blog entries:

Minimizing malnutrition in Biliary Atresia

The heart connection

MicroRNAs and biliary atresia

Additional references:

  • -JPGN 2010; 51: 631.  n=91.  Operation w/in 100 days.  Data suggesting that 60 day cutoff is not valid. (Hong Kong)
  • -J Pediatr Surg 2003; 38: 997-1000. n=735.  90 day cutoff was key with 5-yr & 10-yr survival. (Japan)
  • -JPGN 2010; 51:61.  Canadian experience. n=230.  Center size did not affect outcome.  Overall 39% at 4yrs had survival with native liver.
  • -Liver transplantation 2009; 15: 829, 876.  With combo of Kasai & Tx, >95% exteneded survival (previously 100% fatal).  >80% will need a liver Tx at some point –~50% before age 2.  Increased fibrosis & genes for fibrosis may increase risk for poor outcome.
  • -JPGN 2009; 48: 72.  Review of 13 year experience. n=91.
  • -Pediatrics 2008; 121: e1438.  Single center (Australia?) noted longer delay in dx of BA over 15-year period from 48.5 days (1990-94) to 59.5 (95-99) to 69 days (2000-2004).
  • -JPGN 2008; 46: 238, 299.  More data on age of dx of BA and outcomes from Sweden.
  • -J Pediatr 2006; 149: 393.  Long term outcome of BA -28yrs in England.  7/56 survived long term with native liver; 5-yr native liver survival was 46%, 10-yr was 32%.
  • -J Pediatr 2006; 148: 467, 432..  Outcome of BA in US.  Avg age of referral was 53 days and HPE avg at 61 days.  one-third will survive to age 10 with native liver; overall 90% survival with kasai/hpe & Tx; 50-60% clear jaundice p Kasai.  yellow alert campaign: www.childliverdisease.org/jaundice
  • -Clin Gastro & Hep 2006; 1411.  BA with choledochal cyst. Nice pics of types of BA. Japanese pathologic classification:  Type 1 with atresia after gallbladder (CBD), type II atresia of common hepatic duct/CBD/GB  c normal intrahepatic ducts, Type III atresia of entire ductal system.
  • -Pediartics 2006; 117: 1147.  Usefulness of stool color cards for screening program.
  • -J Pediatr 2005; 147: 142 & 180-5.  23% c BA survive c native liver for more than 20 yrs; 88% survival for 3 yrs p-OLT; risk factors for poor outcome discussed including poor nutrition & age <5 months.
  • -J Pediatr 2004; 144: 123-5.  severity of fibrosis at time of Kasai inversely correlated with survival
  • -JPGN 2003; 37: 430-33.  Residual fibrosis/cirrhosis noted in 54%/40% respectively of pts with normal labs, median age 13 yrs.
  • -JPGN 2003; 37: 4-21. Review of BA

Rifaximin for Crohn’s disease?

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Rifaximin (Xifaxan®) shows promise as a new treatment for Crohn’s disease (Gastroenterology 2012; 142: 473-81).  Rifaximin is an oral medication with minimal systemic absorption; it has a good track record in a number of GI indications, including bacterial gastroenteritis (traveler’s diarrhea), bacterial overgrowth in irritable bowel disease, and hepatic encephalopathy.  There are a few reasons why rifaximin would be considered a good candidate treatment for Crohn’s disease:

  • The pathophysiology of Crohn’s disease involves interaction of adherent bacteria to the intestinal mucosa and with the immune system
  • Other antimicrobials have shown benefit for Crohn’s disease
  • Animal models do not manifest Crohn’s disease when in a bacteria-free environment

In this study of 402 patients with moderate-to-severe Crohn’s disease, a multicenter randomized double-blind trial examined efficacy and safety of rifaximin at doses of 400mg, 800mg, and 1200mg twice daily.  The primary end point was remission based on Crohn’s Disease Activity Index (CDAI).

At the end of the 12-week treatment period, 62% of the 800mg group were in remission compared to 43% of the placebo group.  This difference was maintained 12 weeks afterwards with 45% maintaining remission compared with 43% of patients receiving placebo.  When looking at the other dosing regimens, at 12 weeks, 54% of the 400mg group and 47% of the 1200mg group were in remission based on CDAI.

Clinical response, but not remission, occurred in 56% of placebo patients compared with 63% for 400mg patients, 72% for 800mg patients, and 57% of 1200mg patients.  This trial may have been hampered by patient selection in that the placebo response was high.  This may be due to the fact that ~50% of patients had a low CRP value at baseline.

Safety was good in all patient groups.  However, one rifaximin-treated patient developed C difficile infection.

The fact that a clear dose response was not evident suggests the need for more studies.

Additional Rifaximin References:

  • -NEJM 2011; 364: 22 (pg 81-editorial).  About 10% improvement over placebo in pts with IBS-D.  (see abstract below).  Effects lasted up to 3 months.
  • -JPGN 2009; 49: 400-04. helped symptoms in 61% of IBD pts. n=23 (12 w Crohn). dose 10-30mg/kg/day.
  • -Aliment Pharm Ther 2005; 22: 31-35. Use in SBBO. n=90; 1200mg/day x 7 days. NL glucose breath test in 60% (vs 17% in low dose group); no side effects.
  • -Ann Intern Med 2006; 145: 557-563. double-blind, randomized controlled trial, n=87 for IBS. 400mg tid x 10days. Rx resulted in greater IBS improvement, ~40% improvement vs 20% w placebo during 10 week study
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -J Infect 2011; 62: 34-38. Rx may lead to resistant staphylococci.
  • -Hepatology 2010; 52: 1484. Review.

Additional Crohn’s Antibiotic/Probiotic References:

  • -IBD 2009; 15; 17. 40% response to Cipro in treatment of peranal fistulas. n=25. No response to metronidazole.
  • -IBD 2008; 14: 1597, 1585. No proven role for probiotics and IBD except pouchitis (after Abx)
  • -Clin Gastro & Hep 2008; 6: 145. Pouch problems reviewed -excellent review.
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -Curr Med Res Opinion 2005; 8: 1165-70. Rx for traveler’s diarrhea.  May be useful for Crohn’s as well.
  • -Gastroenterology 2005; 128: 856. Use of ornidazole prophylaxis reduced recurrence p-op from 37.5% to 8%.
  • -IBD 2004; 10: 318-325. antibiotics & IBD review.
  • -Gastroenterology 2004; 127: 412-21. adherent-invasive E. coli associated with ileal mucosa in 22% of Crohn’s (n=63) ileal mucosa vs. 6% of controls (n=16); higher colonization noted in neo-terminal ileums (36%).