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What’s New for Clostridium difficile and other Infectious Diarrheas 2014. John Lynch MD MPH Harborview Medical Center University of Washington. http:// bit.ly /1wb7KOz. Airline food linked to illnesses May 20, 2005. - PowerPoint PPT Presentation
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What’s New for Clostridium difficile and
other Infectious Diarrheas 2014
John Lynch MD MPHHarborview Medical Center
University of Washington
http://bit.ly/1wb7KOz
HONOLULU, Hawaii (AP) -- Contaminated carrots served on several flights out of Honolulu likely caused 45 people to suffer food poisoning across 22 states, Japan, Australia and American Samoa, a state epidemiologist said Thursday.
Airline food linked to illnessesMay 20, 2005
The outbreak has sparked one lawsuit, filed Thursday, against airline caterer Gate Gourmet Inc., which included the carrots in meals served last August 22-24.The company, based in Virginia and Switzerland, was sent a warning letter by the federal FDA on April 21 citing violations found in a February inspection of its Honolulu facility -- such as a "pink slimy substance" dripping onto the conveyor of the pot washing machine, live cockroaches and flies, and mold growing on the windows of a refrigerator.Gate Gourmet provides meals for Northwest, Delta, United, Hawaiian and Aloha airlines.
Airline food linked to illnessesMay 20, 2005
Pathogenic Mechanisms of Diarrhea
• Toxins:– Preformed: S aureus, C perfringens, B cereus– Formed in the intestine by ingested bacteria:
• Stimulate intestinal secretion: V cholerae, enterotoxigenic E coli
• Cytotoxins: C difficile, Shigella, enterohemorrhagic E coli
• Invasion: Shigella, Salmonella, Campylobacter, Yersinia
• Disruption of enterocytes leading to decreased absoprtion: Giardia, Cryptosporidium
Fred Buckner MD
Diarrhea is # 2 highest ID mortality with 2.16 M deaths/year
A. HIV/AIDSB. MalariaC. TuberculosisD. Lower respiratory infectionsE. MRSA
What is # 1?
What are the four leading causes of infectious diarrhea in children <2 yrs in developing countries?
1. Rotavirus
2. Cryptosporidium
3. ETEC
4. Shigella
Global Enteric Multicenter Study (GEMS). Lancet 382:209, 2013
Intestinal Fluid Balance:
Site L In / L Out Efficiency
Jejunum 9-10/4-5 50%
Ileum 4-5/3-4 80%
Colon 1.5/1.4 95%
Stool 100-200 ml 98-99%
Diarrhea occurs when reabsorption decreases to around 95-96%; minor changes result in major fluid losses
Case 1
• 36 y/o man has crampy abdominal pain, bloody diarrhea x 1 day, and fever (102). He just returned from a 1 month trip to India and Thailand.– What is this syndrome?
• Dysentery
– What else do you want to know about the patient?• HIV status?• Other medications? Antibiotics? Immunosuppressives?• Sexual contacts? (Could this be proctitis?)• Foods? (e.g. shellfish are risk for vibrios)• Other travelers with similar illness?
Is the pathology in the small bowel or colon?
Small Bowel Colon
Symptoms Nausea, bloating, cramping, gas, weight loss
Fever, rectal pain, frequent painful stools
Physical signs Dehydration, orthostasis, decreased skin tugor
Fever, abdominal pain
Diarrhea Large volume, watery Small volume, pasty, and/or blood, mucous
Microscopic exam of stool
Without inflammatory cells or blood, with/without mucous
Inflammatory cells, blood, mucous
Agents of diarrhea based on localization within the intestine
Small Bowel Colon
Bacteria E. coli (ETEC, EPEC), Staphylococcus aureus, Clostridium perfringens, Bacillus cereus, Vibrio cholera, Salmonella sp.
Campylobacter sp., Shigella sp., Salmonella sp., Clostridium difficile, Yersinia sp., STEC (0157:H7),Vibrio parahemolyticus, Plesiomonas shigelloides,Aeromonas hydrophila
Viruses RotavirusNorwalk agentAstrovirusesCaliciviruses
CytomegalovirusAdenovirus
Parasites Giardia lamblia, Cyclospora cayatenensis, Cryptosporidium parvum, Microsporidium sp., Dientamoeba fragilis, Isospora belli
Entamoeba histolytica,Balantidium coli
Case 1: (Scenario A)
Pt is otherwise healthy and taking no medications. Stool studies are sent.
– Do you want to give empiric treatment?• What antibiotics?
– Azithromycin 500 mg PO QD x 3 days (Note: C. jejuni resistance to FQs is widespread)
• Antimotility drugs?– Usually not for dysentery, although they are
probably safe if antibiotics are being co-administered
Recommended treatments• Shigella spp.
– Cipro (or other FQ) 750 mg PO QD x 3 days
• Campylobacter jejuni– Azithromycin 500 mg PO QD x 3 days
• Salmonella (non-typhoidal)– Mild disease: none*– Possible bacteremia:
• Levo (or other FQ) 500 QD– 7 days if immune competent– 14 days if immune suppressed
• Aeromonas, non-cholera vibrios, Yersina: treat as for Shigella
* Onwuezobe et al. Cochrane Database Syst. Rev. 2012
Case 1: Scenario B
Instead of India, the patient just returned from Germany (June, 2011)
– He has dysentery symptoms but afebrile
• What are you concerned about?– STEC (shiga-toxic producing E. coli)
• Including non-O157 serotypes (e.g., O104)
• How do you treat?– Supportive. No antibiotics!
Germany outbreak, May 2011Shiga toxin-producing E. coli (STEC)• By July, 2011:
– 4000 illnesses– 823 pts with hemolytic uremic syndrome (HUS)– 50 deaths– 71% females
• Five confirmed travel-associated cases in USA.• Cause of outbreak:
– E. coli serotype O104:H4– Produces: Shiga toxin 2 AND aggregative adherence
factors
• Source:
Case 1: Scenario C
• Traveler to India with dysentery; stool O&P shows:
Entamoeba histolytica/Entamoeba dispar trophozoites have a single nucleus, which have a centrally placed karyosome and uniformly distributed peripheral chromatin. E. histolytica/E. dispar trophozoites usually measure 15 to 20 µm (range 10 to 60 µm), tending to be more elongated in diarrheal stool.Erythrophagocytosis (ingestion of red blood cells by the parasite) is the only morphologic characteristic that can be used to differentiate E. histolytica from the nonpathogenic E. dispar. However, erthrophagocytosis is not typically observed on stained smears of E. histolytica.
Treatment: MTZ 750 mg TID x 5-10 days, followed by a luminal amebicide
Paromomycin 500 mg TID x 10 dIodoquinol 650 mg TID x 20 d
Drug side effects
• Metronidazole:– Nausea/vomiting– Metallic taste– Peripheral neuropathy– Seizures– Black Box warning: Carcinogenic– Pregnancy: category B
• Paromomycin (oral): non-absorbed aminoglycoside– Nausea/diarrhea
• Iodoquinol:– Optic neuritis– Peripheral neuropathy
Case 2
65 y/o man with DM, COPD is hospitalized with CAP and dehydration. He is treated with ceftriaxone and azithromycin. On HD #5 he is ready for discharge except he has a new fever of 102 F, abdominal cramping, and watery diarrhea.
Labs: WBC 21,000 (from 11,000), Cr 1.7 (from 1.4)
Antibiotic-associated Diarrhea DDx
Osmotic Diarrhea
Antibiotics alter colonic microflora (dysbiosis)
Increased osmotic concentration in colonic lumen
Osmotic diarrhea (80%)
Impaired carbohydrate fermentation
C difficile infection
Organism grows and releases toxin
Toxin mediated diarrhea and colitis
(20%)
C difficile colonizes bowel
adapted from UpToDate 2007
Biology of C difficile
• Obligate anaerobic, Gram-positive, spore-forming rod
• Difficult to isolate due to slow growth compared to other clostridia(1), resistant to high temps and 70% ethanol
• Vegetative (replicating) and spore (dormant, transmissible) phases
1. Hall and O’Toole
Biology of C difficile
• Toxin A and Toxin B– TcdA is an enterotoxin, historically assoc with
virulence– TcdB is a cytotoxin assoc with outbreaks of severe
disease• Binary toxin in 6% - 12.5% of strains, disrupts cell
cytoskeleton• Surface proteins for adherence to epithelial cells
stimulate inflammation, upregulated by ampicillin and clindamycin
1. Hall and O’Toole
C. difficile hypervirulent straina) Known as: 027/NAP1/BI epidemic strain b) 16-fold increased expression of toxin A and 23-fold
expression of toxin Bc) Toxin is produced earlier in the course of CDId) The strain is associated with increased severity of disease,
death, and higher recurrence ratese) Uniformly quinolone resistantf) UW/Harborview perform reflex testing to identify
027/NAP1/BI strains*
*How is this information being clinically used? Maybego straight to Vanco instead of metronidazole?
McDonald et al. N Engl J Med. 2005;353:2433-41.Warny et al. Lancet. 2005;366:1079-84.Stabler et al. J Med Micro. 2008;57:771–5.Akerlund et al. J Clin Microbiol. 2008;46:1530–3.
Community-acquired CDAD
• ~20% of CDI is community associated (20-50/100,000)
• CDC, 8 EIP surveillance sites, 2009-2011• 984 patients with community-associated CDI
– 35.9% did not receive antibiotics*– 18% had no outpatient healthcare exposure– 40.7% had low-level outpatient healthcare exposure– No healthcare exposure: higher exposure to infants
under 1 year and household members with CDI– Trend towards more PPI use among those w/o abx
exposure
Chitnis JAMA Internal Med 2013
C. difficile infectionRisk factors for CDI: Which is false?
a) Increasing age
b) Systemic antibiotic therapy
c) Use of proton pump inhibitors
d) Female sex
e) Presence of comorbid conditions
f) Contact with active carriers
g) Inflammatory bowel disease
C. difficile infectionRisk factors for CDI: Which is false?
a) Increasing age
b) Systemic antibiotic therapy
c) Use of proton pump inhibitors
d) Female sex
e) Presence of comorbid conditions
f) Contact with active carriers
g) Inflammatory bowel disease
Risk Factors for CDAD
• Infection– Older age: increases 2% every year after 18yo– Antibiotic use– PPI use– More often NAP1 strains
• Colonization– Hospitalization– Chemotherapy– PPI/H2-blockers
• Antibiotic exposure• Acquisition of C difficile
Loo NEJM 2011
Main modifiable risk factors
C difficile Testing
• Enzyme immunoassay– rapid, low cost, simple– Sensitivity 60%-80%
• PCR for toxin B gene– Sensitivity 98.8%– Specificity 90.8%
• When hospitals switch to PCR, 2-fold increase in rates and case load
Belmares SHEA 2011 Meeting
CDAD Treatment Basics
STOP the offending abx (if possible)
START anti-C.diff therapy as soon as you start to rule out CDAD (unless pt looks clinically great, in which case you could consider waiting for testing to come back)
AVOID anti-motility drugs
No “test of cure”
Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010
Request imaging (Abd CT) and obtain surgery consult if evidence for toxic megacolon
C difficile Treatment- Drugs
• Metronidazole• Vancomycin• Fidaxomicin• Nitazoxanide• Since 2000, failure rates increased from 2.5%
to >18%, and >60% after multiple recurrences
Fidaxomicin Fidaxomicin: Narrow spectrum macrocyclic
antibiotic. Small study showed lower rate of early recurrence with fidaxomicin compared to vancomycin. 15% vs. 25% recurrence rates (Advantage only for “non-
epidemic” strains)
Drug Cost for 10 day course
Metronidazole $15-$30
Vancomycin pills $1100
Vancomycin (IV given orally) $40-$300 (compounding pharmacy)
Fidaxomicin $2700
NEJM 364:422, 2011
Crook CID 2012
54 year old man with DM in the hospital for tx of pneumonia x 5 days, now with diarrhea, WBC 26K, lactate of 4, hypotensive and has a tender belly.
Imaging:
C. difficile infection (CDI)Among risk factors for and predictors of SEVERE CDI, which is false?
a) Age >65
b) Neonates
c) Narcotic medication use
d) Immunosuppressive medication use
e) Altered mental status
f) Fever
g) Hypoalbuminemia
h) Acute kidney injury or chronic kidney disease
)i 10 bowel movements per day
j) Leukocytosis
C. difficile infection (CDI)Among risk factors for and predictors of SEVERE CDI, which is false?
a) Age >65
b) Neonates
c) Narcotic medication use
d) Immunosuppressive medication use
e) Altered mental status
f) Fever
g) Hypoalbuminemia
h) Acute kidney injury or chronic kidney disease
)i 10 bowel movements per day
j) Leukocytosis
54 year old man with DM in the hospital for tx of pneumonia x 5 days, now with diarrhea, WBC 26K, lactate of 4, hypotensive and has a tender belly.
Options?
Indications for Operative Management
Neal Ann Surgery 2011
Surgery
• Surgical intervention in up to 20% of cases (?)• Post-operative mortality 35% to 80%• Traditional: subtotal colectomy with resection
based on visual exam + end ileostomy• New approach?
Markelov Am Surg 2011
Colon sparing surgery
Clostridium difficileand Surgery
• When to operate??– Strong indications:
• Megacolon• Prolonged and (?) irreversible ileus• Perforation
• Mortality rates (in reported series) of cases requiring surgery range from 30 to > 50%. Are we waiting too long??
Case 4
Pt with C. diff recurence following 14 day course of MTZ 500 PO TID. What next?
About 1/3 of patients have recurrence within 60 days
CDI: 2nd recurrence
• Tapering doses of Vanco (varying regimens) – 125 mg PO QID x 2 wk– 125 mg PO BID x 1 wk– 125 mg PO QD x 1 wk– 125 mg PO every 2 days x 4 doses– 125 mg PO every 3 days x 5 doses
OR– 125 mg PO QID x 10 d followed by – 125 mg PO Q-3 days x 10 doses
NEJM 359:1932, 2008
CID 58:1507, 2014
C difficile and Recurrence
• Most patients respond to therapy• 15% to 30% recur• Of those who recur 40% have a 2nd
recurrence• Of those with 2 recurrences, 65%
have a 3rd
Risks for Relapse based on EMR
Hebert ICHE 2013
CDI: 3nd recurrence
CDI: 3nd recurrence
May soon become preferred treatment for second or even first relapses
Konejeti et al, Cost-effectiveness of competing strategies for managementof recurrent Clostridium difficile infection: a decision analysis. Clin. Infect. Dis. 58:1507, 2014
Suggested Indications
Recurrent or relapsing CDI defined as: at least 3 episodes of mild to moderate CDI and failure of 6 to 8 weeks of vancomycin with or without an alternative antibiotic (such as rifaximin or nitazoxanide)
Fecal Microbiota Transplantation Workgroup
Fecal Microbiota Transplantation
• Transfaunation, Fabricius Aquapendente in the 17th Century
• 1958, Eiseman treated 4 patients with pseudomembranous colitis
Fecal Microbiota Transplantation
• Fecal retention enemas common till 1989• NG tube in 1991• Colonoscopy in 2000• Self-administered enemas in 2010• ~325 reported cases worldwide, ¾ by
colonoscopy or retention enema
Van Nood NEJM 2013
Fecal Microbiota Transplantation
• One systemic review:– 317 patients, 8 countries, 27 case series/reports– Overall cure rate of 92%
• One long-term follow-up study– 5 US centers (including HMC)– F/U 3-68 months– 74% had resolution of diarrhea in <4 days– 82% had resolution with 5 days, 17% had improvement– 91% had primary cure, 98% secondary cure, 1 death of
unk etiology while in hospice care
Gough CID 2011
Brandt Am J Gastro 2012
Pre-FMT patient data
Brandt Am J Gastro 2012
FMT: Nuts and Bolts
• Donors: no abx x 3m, no chemo, no HIV,HBV,HCV, ID, high risk behaviors, illicit drugs, incarceration, endemic diarrhea exposure, IBS, IBD, Giardia, cryptosporidium
• Pt abx till day -2 or -3, donor stool collected collected and used within 8hrs
• Dose: 6 tablespoons to entire donation (300-700cc) depending on institution
• All via colonoscopy into various parts of colon from terminal ileum to rectum
Gough CID 2011
Post-FMT patient data
Brandt Am J Gastro 2012
After FMT
• 53% of patients stated they would prefer FMT as 1st treatment option with another recurrence
• 4 pts did not report improvement in abdominal pain after FMT
• Fatigue: 42% resolved, 51% improved, took avg of 4 weeks • 4 pts w/ recurrence responded to vancomycin or
nitazoxanide, 2 had successful 2nd FMT• 2 pts reported improvement in allergic sinusitis and
arthritis• 4 pts reported new conditions: peripheral neuropathy,
Sjogren disease, ITP and RA
Fecal microbiota diversity after FMT
Clin. Inf. Dis. 58:1515, 2014
Fecal transplantation
• Meta-analysis* of 317 pts (27 case series)– Disease resolution in 92%– Better outcomes with the following:
• Related donor (including spouse to partner)• Administration by enema or colonoscope as
opposed to gastroscope or NJ tube• Increased volume (e.g. 500 mL and >50g of stool)
• Donor selection** – Exclude pts with HIV, HCV, IBD, others
Gough E. et al. CID 53:994, 2011Fecal Microbiota Transplantation Workgroup. Clin. Gastro. Hep. 9:1044, 2011
Fecal transplantation
Clin. Inf. Dis. 58:1515, 2014
• Unrelated donors• Screened for HIV, etc., etc.• No antibiotics for >6 months• Avoid allergens (peanuts, shellfish, etc.) for 5 days
• Stool samples processed and frozen in glycerol (41 g per sample)
Fecal transplantation from unrelated donors(colonoscopy or NG tube?)
Clin. Inf. Dis. 58:1515, 2014
Colonoscopy NG tube
Cure with 1st Rx 8/10 (80%) 6/10 (60%)
With second Rx 10/10 (100%) 8/10 (80%)
An additional 11 patients were treated by NGT with 10/11 cures
Treatment details: no antibiotics for 2 days for all patients•Colonoscopy:
• standard 4 liter PEG solution• Administration of 90 cc of thawed inoculum to right colon• Given dose of loperamide
•Nasogastric tube:• Given omeprazole (up to 20 mg QD) x 2 days• NGT inserted to stomach and position checked by Xray• Administration of 90 cc of thawed inoculum to stomach• Remove NGT and drink glass of water
Stool Substitute Transplant Therapy
• Two patients infected with hyper-virulent C difficile (ribotype 078) with recurrent disease
• RePOOPulate = 62 anaerobic bacterial isolates from a 41 yo woman
• Purified isolates sequenced and underwent drug susceptibility testing
• 33 isolates representing commensals were used for the substitute
• 100ml via colonoscopyPetrof Microbiome 2013
C difficile Prevention
• Stop antibiotic therapy if possible• Probiotics
C difficile and Probiotics
• Johnston Ann Intern Med 2012: moderate quality evidence from 13 trials suggests there is a large reduction in CDAD and few adverse effects
• Goldenberg Cochrane Review 2013: 23 RCTs support moderate quality evidence that probiotics are “safe and effective for preventing” C difficile-associated diarrhea
“Administration of currently available probiotics is not recommended to prevent primary CDI, as there are limited data to support this approach and there is a potential risk of bloodstream infection (C-III)”
Clinical Practice Guidelines for Clostridium difficile Infections in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Inf. Control and Hosp. Epid. 31: 431, 2010.
C difficile and Probiotics
Control Measures
• Barrier protection:– Gloves– Gowns
• Alcohol hand-gel products are not sporicidal
• Hand washing with chlorhexidine gluconate containing soap
• Patient isolation until diarrhea resolved
• Cleaning and disinfection of environmental surfaces after pt discharge
A Systems Approach to Prevention
• Bundle at Rhode Island Hospital– Infection control plan based on risk assessment– Monitor hospital-wide morbidity and mortality
associated with CDAD– Switch to PCR-based testing– Enhanced environmental cleaning– Standardized CDAD treatment plan
• 2006- 12/1000 discharges, 52 deaths • 2012- 3.6/1000 discharges, 19 deaths
Mermel Jt Comm J Qual Patient Saf 2013
Recommended