Rachel Lutz

) infection remained elevated for up to a year after the conclusion of treatment with proton-pump inhibitors (PPIs), according to a 

Investigators from Copenhagen, Denmark used a nationwide cohort of adults with 

 infection in order to compare periods with and without exposure to PPIs. The adults were all treated between February 2010 and December 2013. The nationwide database included health information such as 

 testing, filled prescriptions, and patient characteristics. The investigators also accounted for previous hospitalization in the previous 12 weeks in the patients, in addition to chronic disease, genetics, socioeconomic status, length of hospital stay, and antibiotic and corticosteroid use.

Ultimately, the study authors identified 3583 episodes of community-acquired 

 infection, of which 964 occurred during current use of PPIs. This is an observation in the current literature, but what wasn’t understood was the full extent of the relationship due to missing data from randomized controlled trials, variability between studies, and insufficient adjustment for confounding.

“While a history of prior hospital admission, advanced age, and antibiotic use are well-known risk factors for 

 infection, the role of PPIs has remained controversial,” the study authors wrote.

The investigators defined new PPI use as a new prescription for individuals who had not used PPI in the prior 365 days. They split up the periods of 0-6 months and 6-12 months because in the first period, cessation was considered indeterminate use because of the possibility for intermittent use or drug exposure continuing beyond the use period. Exposure during the 6-12 month period was “unlikely.”

Of the infections that occurred with use of PPIs, 324 occurred within 0-6 months after treatment conclusion. Additionally, 123 cases occurred between 6 and 12 months after treatment cessation.

 infection cases occurred during time periods without use of PPIs, the investigators said.

Comparing use of PPIs with nonuse, the study authors found that the adjusted estimate incidence rate ratio (IRR) was 2.03, they said. But the risk remained elevated in later time periods too: 1.54 for 0-6 months, and 1.24 for 6-12 months.

“In conclusion, in this nationwide study in Denmark, we showed that exposure to PPIs was associated with a moderate increase in the risk of community-acquired 

 infection,” the study authors said, , while noting that the mechanism by which PPIs may increase the 

 infection risk remains unclear. “The increased risk was most prominent during current PPI use but also persisted after treatment discontinuation.”

One limitation the study authors provided for was that initial symptoms of 

 infection could have been misinterpreted and patients prescribed PPIs could not be excluded. But, they also admitted, “it is unlikely that this would lead to biased results because the symptoms of 

 infection (diarrhea) are distinct from the upper gastrointestinal symptoms that represent the most common indication for PPIs.”

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Exposure to PPIs was associated with a moderate increase in the risk of community-acquired C diff infection, even after treatment discontinuation. 

Elevated Risk for C diff with Proton-Pump Inhibitor Use

Using elevated white blood cell count alone as a predictor for 

) infection nucleic acid testing (NAAT) positivity is not sensitive enough and has low specificity, according to a 

Investigators from the University of Washington School of Medicine in Seattle retrospectively reviewed the laboratory testing, outcomes, and treatment of patients in order to determine a link between elevated white blood cell count and the results of 

 NAAT. The study authors noted that an elevated white blood cell count, measured at >15 thousand/μL, is an established prognostic marker for 

 patients, backed up by small observational studies. However, only limited evidence links white blood cell count elevation with the results of NAAT for 

The investigators identified 16,568 consecutive patients at 4 hospitals over a span of 4 years who underwent NAAT and white blood cell count testing on the same day.

The study authors observed no significant relationship between 

 NAAT results and concurrent white blood cell count in the inpatient setting, they wrote.

They did find that an elevated white blood cell count predicted NAAT results in the outpatient and emergency department populations, though. But the accuracy was poor, they said. Additionally, the receiver-operator areas were under the curve of 0.59 and 0.56.

“Although white blood cell count is an important prognostic indicator in patients with 

 infection, an isolated white blood cell count elevation has low sensitivity and specificity as a predictor of fecal 

 NAAT positivity in the inpatient setting,” the study authors concluded. “A high or rising white blood cell count in isolation is not a sufficient indication for 

Patients with an elevated white blood cell count with 

 were linked to a longer median hospital length of stay (15.5 days vs. 11 days). The investigators also said that this finding was consistent with leukocytosis as a prognostic marker in 

The research team also explored how these patients were treated with antibiotics. They observed that inpatients with positive NAAT results who had elevated white blood cell counts were more likely to be treated with metronidazole and/or vancomycin. They were also more likely to die in the hospital.

In October, NAAT use adjusted the estimate of total 

 infection burden from 24 percent between 2011 and 2017, as 

. High Point University Fred Wilson School of Pharmacy investigators made this observation while studying kidney injuries as a 

 that while the burden decreased, estimates of the burden of first recurrence and in-hospital deaths did not significantly change during that observation period.

“A high or rising white blood cell count in isolation is not a sufficient indication for C diff infection testing,” the study authors said. 

White Blood Cell Count Elevation Not Enough for C diff Testing 

Proton pump inhibitor (PPI) use does not lead to bacterial overgrowth in the small intestine, according to a 

Investigators from Cedars-Sinai Medical Center conducted microbiome sequencing and culture from 177 patients as part of the REIMAGINE study in order to compare duodenal and stool microbiomes in those who use and do not use PPI.

The patients were aged 18-58 years and underwent upper gastrointestinal endoscopy or double balloon enteroscopy without colonoscopy as part of their standard of care. The participants completed a questionnaire – which covered topics such as demographics, medical history, gastrointestinal symptoms, and medication use – provided a blood sample, and provided an optional stool sample.

While there is some off-label and over-the-counter use of PPI, the study authors wrote, they are among the most widely prescribed medications in some adult populations. Because PPI use decreases gastric acid secretion, it has been suggested that PPI use could lead to increased risks of 

) infection, as well as small intestinal bacterial overgrowth (SIBO).

SIBO is usually associated with gastrointestinal symptoms such as bloating, excessive gas, abdominal discomfort, diarrhea, and weight loss. SIBO can also be common among diseases such as irritable bowel syndrome, fatty liver, inflammatory bowel disease, diabetic gastroparesis, and Celiac.

Of the total number of patients enrolled in the study, 59 subjects were on PPI at the time of endoscopy and 118 controls were not. The types of PPI being taken by subjects in the cohort using them included omeprazole (27 patients), pantoprazole (23 patients), esomeprazole (6 patients), and others (2 patients).

There were no phylum-level differences between patients that used PPI and those that did not, the study authors said, after evaluating the duodenal microbiome. However, the PPI users showed significantly higher relative abundances of the families Campylobacteraceae (3.13-fold) and Bifidobacteriaceae (2.9-fold), the study authors learned. There was lower relative abundance of Clostridiaceae (88.24-fold) in PPI subjects compared to the non-users, the investigators found.

“We know that PPI increase the risk of 

,” corresponding author Mark Pimentel, MD, told 

. “Perhaps the reduction of normal commensal Clostridiacaea leaves the door open for bad actors/squatters such as 

SIBO rates were not significantly different between the groups, the study authors said, which was true when using cultures or 16S sequencing. It also remained true among PPI subjects taking different PPIs.

The stool microbiome analysis exhibited significantly higher abundance of family Streptococcaceae (2.14-fold) and lower Clostridiaceae (2.60-fold) in PPI patients when compared to non-PPI subjects, the study authors added.

“This is the first trial showing that PPI does not lead to bacterial overgrowth using the best technology available (microbiome sequencing and culture),” Pimentel added. “This paper in some ways settles the matter, but as in all science, needs duplication by other groups.”

He noted that their findings should assuage concerns about SIBO when prescribing treatment with PPI.

“Modest changes were seen in the small intestinal microbiome in PPI users, including a notable reduction in relative abundance of the family Clostridiaceae,” the study authors concluded. “Reduction in the relative abundance of Clostridiaceae was also seen in the stool microbiome, as well as an increase in relative abundance of Streptococcaceae. Based on these results, the overall effects of PPI use on the microbiome appear to be modest, although the clinical importance of these findings is as yet unknown.”

The findings should assuage concerns about small intestinal bacterial overgrowth when prescribing treatment with proton pump inhibitors. 

PPI Use Does Not Lead to Bacterial Overgrowth

Vitamin D supplementation did not significantly increase levels from insufficient or deficient to sufficient in chronic 

 patients after treatment with direct-acting antivirals, according to a 

Investigators from Thailand conducted a randomized trial of 75 patients with chronic hepatitis C and vitamin D deficiency in order to determine whether a treatment with vitamin D for 6 weeks would be effective in fibrosis amelioration. Half of the patients were treated with vitamin D (ergicalciferol) and the other half received placebo for 6 weeks between February and August 2018. The investigators used various biochemical analysis indicators detected from blood samples at baseline and after 6 weeks in order to make their observations.

Additionally, the patients were asked to refrain from using vitamin D supplements or multivitamin supplements that came from outside the trial for the duration of the study period, and were told to maintain their normal activity. The patients had a mean age of 60 years, were mostly female, and 60% of them had cirrhosis. There were no significant differences in any biochemical factor between the two groups, the investigators noted.

The mean serum 25-hydroxyvitamin D (25(OH)D) level increased from 17.2 ng/mL at baseline in the vitamin D group to a normal level, 41 ng/mL, by the end of the 6-week study, the authors said. Notably, though, 3 patients in the vitamin D group still had a 25(OH)D level less than 30 ng/mL after 6 weeks of therapy, they said, including 2 patients who changed from an initial deficient state to an insufficient state after supplementation.

However, the placebo group only saw a slight increase, which was still deficient, by the end of the 6 weeks (from 16.6 ng/mL to 23 ng/mL), the authors observed. All of the placebo patients had a vitamin D insufficiency or deficiency by the end of the 6 week study period.

There was no significant difference in the mean change from baseline to 6 weeks between the vitamin D and placebo groups in terms of serum transforming growth factor beta 1 (TGF-β1) levels or the tissue inhibitors of matrix metalloproteinases 1 (TIMP-1) levels, the study authors said. There was also no significant difference between the 2 groups after 6 weeks in terms of mean fibrolytic markers likematrix metalloproteinase 9 (MMP-9) levels, which were slightly increased in the vitamin D group, or mean amino terminal type III procollagen peptide (P3NP) levels, which were slightly decreased among both groups.

“Short-term vitamin D replacement after hepatitis C eradication by direct-acting antivirals did not improve serum hepatic fibrogenesis marker levels and, thus, might not clinically facilitate the amelioration of residual liver fibrosis,” the study authors concluded, while adding that overall, vitamin D supplementation did not vary according to baseline serum 25(OH)D levels or liver fibrosis severity.

The study authors said their findings seem to indicate that vitamin D may regulate and influence hepatic fibrogenesis through its immunomodulatory rather than its anti-fibrotic property, where it is not strong enough to affect the associated serum markers.

“Nevertheless, further investigation to determine whether a higher dose (vitamin D derivative) for a longer period could potentially help ameliorate liver fibrosis is warranted,” they wrote.

Vitamin D supplements did not change the biochemical markers significantly for hepatitis C patients with vitamin D insufficiencies. 