Microbiome;

Do proton pump inhibitors (PPIs) reduce the risk of bleeding from lower gastrointestinal tract?

FA Manian MD, MPH, , , , , , , , , , , , , , Leave a comment

The short answer is “No”!  Although proton pump inhibitors (PPIs) are effective in reducing the risk of upper gastrointestinal bleed (GIB) in high-risk patients, they do not protect against lower GIB. 1 In fact, their use has been associated with an increased risk of small bowel injury related to non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin.2,3

A 2015 case-control study involving over 1,000 patients hospitalized for GIB found that although concomitant use of PPI in patients on NSAIDs, low-dose aspirin, other antiplatelet agents or anticoagulants was associated with a reduced risk of UGIB, it was not associated with reduced risk of lower GIB.  Interestingly, in this study, PPIs were associated with higher risk of lower GIB which might have been related to confounding factors and not necessarily a direct causal effect.4 Lack of an impact of PPIs on lower GIB among patients on aspirin or NSAIDS has also been supported by others. 5-7

The fact that PPIs don’t seem to reduce the risk of GIB distal to the duodenum should not be surprising given their primary mechanism of action through inhibition of acid production by gastric parietal cells. 8  What is perhaps more intriguing is how they may potentially increase the risk of small intestinal injury while still protecting the gastro-duodenum from NSAID-induced mucosal damage.

In a cool laboratory study involving rats, treatment with a PPI was associated with exacerbation of NSAID-induced intestinal ulceration and bleeding; by itself treatment with PPI was not associated with intestinal mucosa injury.9 Interestingly, in this study, a marked shifts in numbers and types of enteric bacteria with a significant reduction in jejunal Bifidobacteria spp was noted with PPI therapy. Restoration of small intestine Bifididobacteria during treatment with a PPI along with an NSAID prevented intestinal ulceration/bleeding. The investigators concluded that when used along with an NSAID, PPIs may cause small intestinal injury through alteration in the microbiome of the gut.  Fascinating!

Bonus Pearl: Did you know that the 2022 American Gastroenterological Association (AGA) clinical practice update on de-prescribing of PPIs lists several conditions for which acute/short term use of PPIs are NOT indicated, such as isolated lower GI symptomatology, acute nausea and vomiting not believed to be related to GERD/esophagitis, acute undifferentiated abdominal pain, and empiric treatment of laryngopharyngeal symptomatology? 10 

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References

  1. Lue A, Lanas A. Proton pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits. World J Gastroenterol 2016;22:10477-10481. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192259/#:~:text=PPIs%20do%20not%20prevent%20NSAID,and%20the%20risk%20of%20LGB.
  2. Endo H, Sakai E, Taniguchi L, et al. Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry. Gastrointes Endosc 2014;80:826-34. https://pubmed.ncbi.nlm.nih.gov/24830581/
  3. Washio E, Esaki M, Maehata Y, et al. Proton pump inhibitors increase incidence of nonsteroidal anti-inflammatory drug-induced small bowel injury: A randomized, placebo-controlled trial. Clin Gastroenterol Hepatol 2016;14:809-815. https://pubmed.ncbi.nlm.nih.gov/26538205/
  4. Lanas A, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-12. https://pubmed.ncbi.nlm.nih.gov/25460554/
  5. Nagata N, Niikura R, Aoki T, et al. Effect of proton-pump inhibitors on the risk of lower gastrointestinal bleeding associated with NSAIDs, aspirin, clopidogrel, and warfarin. J Gastroenterol 2015;50:1079-1086. https://pubmed.ncbi.nlm.nih.gov/25700638/
  6. Garcia Rodriguez LA, Lanas A, Soriano-Gabarro M, et al. Effect of proton pump inhibitors on risks of upper and lower gastrointestinal bleeding among users of low-dose aspirin: A population-based observational study. J Clin Med 2020;9:928. https://www.mdpi.com/2077-0383/9/4/928
  7. Casado Arroyo R, Polo-Tomas M, Roncales MP, et al. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of a patients commonly using PPI co-therapy. Heart 2012;98:718-723. https://pubmed.ncbi.nlm.nih.gov/22523056/
  8. Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol Rev 2020;100:573-602. The Physiology of the Gastric Parietal Cell – PMC (nih.gov)
  9. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 2011;141:1314-22. https://www.gastrojournal.org/action/showPdf?pii=S0016-5085%2811%2900926-7
  10. Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review. Gastroenterology 2022;162:1334-1342. https://www.gastrojournal.org/article/S0016-5085(21)04083-X/fulltext

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Do proton pump inhibitors (PPIs) reduce the risk of bleeding from lower gastrointestinal tract?

The urine culture of my female patient with urgency is growing Lactobacillus spp.  Should I treat it?

FA Manian MD, MPH, , , , , , , , Leave a comment

Lactobacillus spp. isolated from urine generally does not require treatment because these organisms are often part of the normal bacterial flora of the genitourinary (GU) and gastrointestinal tracts, are generally of low virulence, are rarely associated with urinary tract infections (UTIs) and may in fact have potential benefits in preventing UTIs. 1-4

In a study involving female urinary microbiome, subjects with urgency urinary incontinence were less likely to have Lactobacillus spp. based on 16S rRNA gene sequencing of transurethral catheter urine than those without symptoms, suggestive of possible protective role of this organism in female GU tract.1

Although Lactobacillus UTI is rare, one particular species, Lactobacillus delbrueckii, has been implicated in several case reports involving primarily elderly women.3,4

Vaginal colonization with lactobacilli provides a natural, nonspecific defense mechanism against infection in part by production of lactic acid and lowering of the regional pH which, when combined with hydrogen peroxide production by commensal anaerobes, interferes with colonization of the vaginal mucosal surfaces by potential pathogens. Lactobacilli also interfere with the adherence of pathogens by production of biosurfactants.3 It’s no surprise that lactobacilli are often considered “friendly bugs” and used in many probiotic preparations.

Bonus Pearl: Did you know that contrary to the current dogma, urine is not necessarily sterile.  Even in asymptomatic people, it may contain several organisms, including Lactobacillus, Gardnerella, Streptococcus, Staphylococcus (not aureus) and Corynebacterium? 5

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References

  1. Pearce MM, Hilt EE, Rosenfeld AM, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio 2014;5:e01283-14. https://pubmed.ncbi.nlm.nih.gov/25006228/
  2. Thomas-White K, Forster SC, Kumar N, et al. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nature Communications 2018;9:1557. https://www.nature.com/articles/s41467-018-03968-5.pdf (urine not sterile, bladder with lactobacillus prevention, normal asymptomatic
  3. Darbro BW, Petroelje BK, Doern GV. Lactobacillus delbureckii as the cause of urinary tract infection. J Clin Microbiol 2009;47:275-277. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2620876/#:~:text=Urinary%20tract%20infections%20caused%20by,a%20setting%20of%20ureteral%20obstruction.
  4. Maillet F, Passeron A, Podglajen I, et al. Lactobacillus delbrueckii urinary tract infection in a male patient. Med Mal Infect 2019;49:225-230. https://www.sciencedirect.com/science/article/pii/S0399077X1830787X?via%3Dihub
  5. Reid G. The scientific basis for probiotic strains of Lactobacillus. App Env Microbiol 1999;65:3763-3766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC99697/

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

The urine culture of my female patient with urgency is growing Lactobacillus spp.  Should I treat it?

Are women at higher risk of Covid-19 vaccine-related adverse events?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Data to date shows a preponderance of Covid-19 vaccine-related adverse events (AEs) among women compared to men. This finding may be due to the generally more robust immunological response to infections and vaccines among women, increased reporting of AEs by women, genetic factors, microbiome differences as well as other factors.1-3

A CDC study involving mRNA vaccines (Pfizer and Moderna) during the 1st month of vaccination roll out in the US, found that nearly 80% of adverse events were reported by women.  The great majority (>90%) of these AEs were not serious and included symptoms such as headache, dizziness and fatigue.1

A JAMA study involving individuals receiving one of the mRNA vaccines found that 94% (Pfizer) and 100% (Moderna) of anaphylaxis events occurred among women. Of note, the median age was ~40 years  with the majority of anaphylaxis events were reported after the first dose. 2

Higher incidence of AEs following Covid-19 vaccination is not surprising and may be explained biologically. Women typically have a more robust immune response to infections and vaccination, both at the level of innate and adaptive immunity with higher antibody responses.  

These findings may be in part due to hormones such as estrogen which is known to enhance differentiation of dendritic cells and proinflammatory cytokine production. Other proposed mechanisms include differences in microbiome between sexes and sex-based genetic influences on humoral immune profile with the X chromosome expressing 10 times more genes than the Y chromosome, including genes that influence immunity.3

Bonus Pearl: Did you know that anaphylactic reaction to the mRNA Covid-19 vaccines is extremely rare, occurring in only 2-5 cases/ million!2

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References

  1. Gee J, Marquez P, Su J, et al. First month of Covid-19 vaccine safety monitoring—United States, December 14, 2020—January 13, 2021. MMWR 2021;70:283-88. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm
  2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA Covid-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA 20201;325:1101-1102. https://jamanetwork.com/journals/jama/fullarticle/2776557
  3. Fischinger S, Boudreau CM, Butler AL, et al. Sex differences in vaccine-induced humoral immunity. Semin Immunopath 2019;41:239-49. https://pubmed.ncbi.nlm.nih.gov/30547182/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Are women at higher risk of Covid-19 vaccine-related adverse events?

Is my hospitalized patient with possible pneumonia at risk of Clostridium difficile-associated disease after only 1-3 days of empiric antibiotic therapy?

FA Manian MD, MPH, , , , , , , , Leave a comment

Yes! Even relatively brief duration of antibiotic therapy may increase the risk of Clostridium difficile-associated disease (CDAD) in a susceptible host.
In a study of hospitalized patients with new-onset diarrhea, prior exposure to levofloxacin and cefazolin was significantly associated with CDAD with the median duration of therapy for levofloxacin of 3 days (range 1-18 days), and for cefazolin 2 days (range 1-3 days) (1). Similarly, a study in hospitalized patients during a CDAD epidemic found a significantly increased risk of CDAD among patients who received fluoroquinolones for only 1-3 days (hazard ratio 2.4) with a 95% confidence interval (1.6-3.6) that overlapped 4-6 days and ≥ 7 days treatment groups (2). Yet another study found no significant difference in the risk of CDAD between those on antibiotic for < 4 days vs 4-7 days of antibiotics (3). CDAD following a single dose of cefazolin has also been reported (4).
Of interest, laboratory studies in mice have shown a profound alteration of intestinal microbiota following a single dose of clindamycin, resulting in increased susceptibility to C. difficile colitis (5).
So although duration of antibiotic therapy is an important factor in CDAD (3, 6) and we should minimize the duration of antibiotic therapy whenever possible, not starting antibiotics in the absence of clear indication is even better!

References
1. Manian FA, Aradhyula S, Greisnauer S, et al. Is it Clostridium difficile infection or something else? A case-control study of 352 hospitalized patients with new-onset diarrhea. S Med J 2007;100:782-786. https://www.ncbi.nlm.nih.gov/pubmed/17713303
2. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254-60. https://www.ncbi.nlm.nih.gov/pubmed/16206099
3. Stevens V, Dumyati G, Fine LS, et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011;53:42-48. https://www.ncbi.nlm.nih.gov/pubmed/21653301
4. Mcneeley SG, Anderson GD, Sibai BM. Clostridium difficile colitis associated with single dose cefazolin prophylaxis. Ob Gynecol 1985;66:737-8. https://www.ncbi.nlm.nih.gov/pubmed/4058831
5. Buffie CG, Jarchum I, Equinda M, et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect Immun 2011;80: 62-73. https://www.ncbi.nlm.nih.gov/pubmed/22006564
6. Chalmers JD, Akram AR, Sinanayagam A, et al. Risk factors for Clostridium difficile infection in hospitalized patients with community-acquired pneumonia. J Infect 2016;73:45-53. https://www.ncbi.nlm.nih.gov/pubmed/27105657

Disclosure: The contributor of this post was a coinvestigator of a cited study (ref. 1).

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Is my hospitalized patient with possible pneumonia at risk of Clostridium difficile-associated disease after only 1-3 days of empiric antibiotic therapy?