c diff increasing; and using bacteriophages??


this blog deals with 2 likely interrelated articles, one on the increase in community-acquired C difficile infections, the other with the potential use of bacteriophages in treating drug-resistant infections
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A large, long-term multicenter cohort study in the southeastern US found that an increasing percentage of Clostridioides difficile (formally Clostridium difficile) infections are community-based (see cdiff commun acq increasing jama2019 in dropbox, or doi:10.1001/jamanetworkopen.2019.14149)

Details:
-- a network of 43 regional hospitals in the Duke Infection Control Outreach Network (DICON) were assessed from 2013-18.
-- 2,025,678 admissions and 21,254 C. difficile infection cases (CDI) were included
-- 60% female, median 69-year-old
-- community acquired CDI was defined as a positive C. difficile test obtained on hospital day 1, 2, or 3 in patients who had not been admitted to the index facility in the previous 28 days
-- healthcare facility acquired CDI: those admitted to a hospital with CDI diagnosed more than 3 days after admission and before discharge, or someone with CDI diagnosed within the 1st 3 days but had been discharged from the index facility within the past 28 days

Results:
-- total CDI cases: increased slightly from 7.9 cases /1000 admissions in 2013 to 9.3 /1000 admissions in 2017
-- healthcare facility based cases: stable, ranging from 8.4 cases per 10,000 patient days in 2013 to 8.5 cases per 10,000 patient days in 2017; though after adjustment, overall incidence of healthcare facility associated CDI declined, incidence rate ratio of 0.995 (0.990-0.999), p=0.03
-- community acquired CDI: increased from 3.7 cases /1000 admissions in 2013 to 5.6 cases /1000 admissions in 2017
-- the percentage of CDI cases from the community increased from 49% in 2013 to 61% in 2017
-- rates of C. diff NAPI/027 strain (a fluoroquinolone-resistant strain that led to multiple nosocomial epidemics in the early 2000’s, and in some studies has been found to be more virulent): no significant change, remaining at about 23%

Commentary:
-- 500,000 cases of CDI occur in the US each year with more than 29,000 deaths
-- CDI is the most common cause of healthcare associated diarrhea and the most common healthcare associated infection

-- one important epidemiological question is how do CDIs arise? it seems that C diff colonizes the GI tract typically after antibiotics that disrupt the GI microbiome
    --we know that asymptomatic carriage of C. difficile runs in the 5 to 15% range in patients presenting to healthcare facilities, though seems to be about 3% in healthy adults in the community (which also means that some patients with diarrhea who happen to be C diff carriers may well have diarrhea from other causes that may be classified is CDI cases, and the C. difficile may be an innocent bystander)
        --stool toxin concentrations in the asymptomatic carriers are similar to those with CDI, so cannot differentiate true CDI infections from carrier state by presence of toxins
    --it seems that most hospital-based cases are in people with new exposure to C diff, which seems to be contracted from hospital roommates or contaminated hospital rooms from prior occupants, and transmission seems to be more frequent from those who had symptomatic CDI vs asymptomatic carriers.
    --but, is this transmission the same in community-dwellers? or are there more of these asymptomatic C. diff carriers who have disruption of their microbiome and then develop CDI?? 
        --a study in Olmsted County Minnesota found that patients with community-acquired CDI (41% of their total CDI cases) were somewhat different than those with hospital-acquired infections: younger, lower comorbidity scores, less likely to be on a gastric acid suppressant, less likely to have recent antibiotics (78% in the community but 94% in the hospital), and also less likely to have severe disease
        --so what is causing the CDI in those community-dwellers not on antibiotics and without recent hospitalization??  are there other microbiome stressors involved (and which ones)?? is it exposure to foods, or domestic animals (and is it related to antibiotic overuse in industrialized farming/livestock production??, as well as by us clinicians???) See below for other blogs on this
-- other major epidemiologic concerns: overall data on CDI prevalence. is not so accurate: CDI is not a reportable disease; testing is done in multiple settings and facilities so there may be inconsistencies in the data; and there has been a change in the laboratory tests from toxin A/B assay to NAAT (the latter being more sensitive but less specific) making it difficult to compare prior vs current prevalences of C diff. 
    --Also, (my guess): there is much lower rate of CDI reporting less from CDI infections that are diagnosed and treated in the community setting vs healthcare facility reporting (ie, the actual % of community cases may be much higher than in this study).
    -- and,  all of the community acquired cases in the current study were determined at the hospital. 

-- An advantage of the study is that it was huge, and covered a pretty large geographical area (though limited to the southeastern United States. There are complications in different diagnostic tests for CDI being used in different hospitals, which they attempted to control for mathematically. There may have been issues with the accuracy of the data in all of the different hospitals and possible misclassification of the site of infection. And, it did not include real community data, just from those patients likely community infected who then went to the hospital

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A recent article in Scientific American (see https://www.scientificamerican.com/article/phage-therapy-could-beat-drug-resistant-illnesses/ ) promoted the use of bacteriophages in the treatment of resistant bacterial infection, highlighting, for example, people with cystic fibrosis and multi-drug resistant Pseudomonas aeruginosa. Phages are ubiquitous viruses (estimates of >1031 bacteriophages on earth) that can be injected into bacteria, reproduce, and ultimately kill the bacteria.

--in this case, the phage targets the efflux pump that pumps the antibiotics out of the bacteria (creating the resistance), injecting their genetic material (preselected virus that killed the efflux pumps) into the bacteria, with remarkable clinical success. Phages target the pathologic bacteria specifically (leaving the other bacteria in the microbiome intact). 

--in general, there are options to phage therapy: 
    --sequential monophage therapy (giving sequential phage treatments, each targeting different bacterial variants
    --phage cocktails (several different phages given at once, targeting different bacterial receptors to decrease the likelihood of emerging phage resistance)
    --combo of phage and antibiotics (eg: killing the resistant P. aeruginosa as in the above case, then following with antibiotics to kill the non-resistant remainders); this can sometimes lead to decreased antibiotic doses
-- there was a case report of a 15 yo patient with cystic fibrosis who, after a lung transplant, developed a disseminated drug-resistant Mycobacterium abscessus infection, who was treated with a 3-phage cocktail that effectively killed the infection (see bacteriophage therapy NatMed2019 in dropbox, or Dedrick R. Nature Medicine. May 2019; 25: 730-3. ). There were NO adverse reactions.  This case involved the development of phages through genome engineering. It does raise the possibility of using both naturally occurring phages as well as engineered ones (and, perhaps, adding these engineered phages to the ongoing phage library for others to access as needed??)

-- see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387922/ for an article on the combo of bacteriophages and antibiotics, with the purported advantages to more efficient penetration into biofilms, and  lowered chances for development of phage resistance. Even sub-inhibitory antibiotic concentrations can augment phage productivity.

--phage therapy does sound like a reasonable, targeted approach to dealing with difficult drug-resistant infections. Phage resistance can occur, hence the different methods noted above to try to decrease this possibility. And there are concerns about the safety of the bacteriophages’ injecting virus into bacteria: these viruses’ genetic material does take over the bacteria, reproduces lots, and ultimately can lead to bacterial death. But lots of viral material are released into the body. It should be noted that phages are omnipresent, and have been used in the past to treat infections: in World War I to treat typhoid, dysentery, cholera and some other bacterial illnesses; in WWII were reported to decrease gangrene mortality by 1/3 in soldiers.  Their use stopped in the 1940s with the advent of antibiotics. But the phage library has already been used in the development of some therapeutic monoclonal antibodies (eg: adalimumab, raxibacumab and belimumab)

--this study does bring to light the potential for the development of widespread phage therapy in treating bacterial infections

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-- These 2 articles basically reinforce the importance of minimizing antibiotic use. In the case of the C. difficile infections, these are likely related to antibiotic-induced microbiome changes increasing the likelihood of infection; and the bacteriophage articles highlight the difficulty in treating patients who have developed drug-resistant infections (although it also raises the intriguing possibility of using fewer antibiotics in treating infections, if the much more targeted bacteriophage therapy really makes it into prime time)

here is a sampling of relevant prior blogs:

blogs on antibiotic resistance:
    --a really shocking report by the WHO in 2014 of worldwide dramatic antibiotic resistance, with some organisms (like gonorrhea) being resistant to all drugs we currently use: http://gmodestmedblogs.blogspot.com/2014/05/who-report-on-antimicrobial-resistance.html 
    --a CDC report highlighting the increasing gonorrhea resistance: http://gmodestmedblogs.blogspot.com/2016/07/gonorrhea-resistance-increasing.html  
    --the development of more largely untreatable superbugs, eg e. coli and klebsiella: http://gmodestmedblogs.blogspot.com/2016/06/more-superbugs.html
    --an argument that we should mostly NOT be asking patients to take the full 10-day course of antibiotics, which in many cases leads to more antibiotic resistance without clear benefithttp://gmodestmedblogs.blogspot.com/2017/07/take-full-course-of-antibiotics.html

blogs on microbiome changes:
    --a study finding similar outcomes and fewer adverse events in kids on narrower-spectrum antibiotics: http://gmodestmedblogs.blogspot.com/2018/01/antibiotic-use-in-kids-narrow-spectrum.html
    --a small study showing that there can be long-term effects (12 month) on the gut microbiome even after a single exposure to antibiotics: http://gmodestmedblogs.blogspot.com/2015/11/longterm-microbiome-changes-with.html 
    --increased colorectal adenomas, including advanced ones, in women exposed to antibiotics: http://gmodestmedblogs.blogspot.com/2017/04/antibiotics-microbiome-changes-and.html
   --increased risk of colon cancer in those exposed to antibiotics, perhaps moreso with penicillins: http://gmodestmedblogs.blogspot.com/2019/10/antibiotics-increased-colon-cancer-risk.html
    --increased obesity and allergy in kids exposed to antibiotics: http://gmodestmedblogs.blogspot.com/2018/12/antibiotics-ppish2ras-increase-obesity.html
    --and a blog with 2 articles, one showing an unfortunate shift from prescribing narrow to broad-spectrum antibiotics and another showing that clinicians tend to prescribe more antibiotics late in a clinical session ("clinician fatigue"): http://gmodestmedblogs.blogspot.com/2015/07/antibiotic-overprescribing.html

other blogs on antibiotic overprescribing 
    --4 articles noting high prescription rates of antibiotics for URIs, pharyngitis and acute rhinosinusitis: http://gmodestmedblogs.blogspot.com/2016/01/antibiotic-overprescribing-and-acute.html 
    --another with a CDC report from 2013 finding huge overprescription of antibiotics for respiratory infections:http://gmodestmedblogs.blogspot.com/2015/07/antibiotic-overprescribing.html
a couple of hopeful notes: 
    --we are moving (slowly) in the right direction, see http://gmodestmedblogs.blogspot.com/2017/08/antibiotic-use-decreasing.html
    --antibiotic resistance can be decreased by hospital antibiotic stewardship programs: http://gmodestmedblogs.blogspot.com/2017/06/decreasing-antibiotic-resistance-by.html 

but a somewhat less hopeful one: 
    --drug companies are largely abandoning antibiotic development (it is much more profitable to develop a long-term drug for a chronic condition than even a high-priced one used for a few weeks): http://gmodestmedblogs.blogspot.com/2018/07/novartis-dumps-antibiotic-research.html . 
    --And, the above blog http://gmodestmedblogs.blogspot.com/2014/05/who-report-on-antimicrobial-resistance.html  also summarizes a pretty great BMJ article debunking the really exaggerated statement that R&D costs come close to justifying the astronomical cost of new drugs

geoff​

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