Current Thoughts on Infectious Diarrhea. Michael Gluck, MD Virginia Mason Medical Center November 11, 2017

Transcription

1 Current Thoughts on Infectious Diarrhea Michael Gluck, MD Virginia Mason Medical Center November 11, 2017

2 Disclosures I have no financial or other disclosures New guidelines from IDSA: 2017 Infectious Diseases Society of America Clinical Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clinical Infectious Diseases 669

3 Acute Diarrhea in Resource-rich Countries Most acute diarrheas are self-limited and underreported Definition: 200gms of stool, better definition is 3 or more stools conforming to the container Acute=14 days, persisting= 14 to 30, chronic>30 days. Incidence: highest in children, lowest in those more than 65 Non-foodborne gastroenteritis: 135M cases/year Foodborne: 76M cases/year, 5000 deaths, 325,000 hospitalizations. Highest likelihood of obtaining a positive etiology: bloody stools, IC and AIDS, hospitalization, fever, and need for rehydration. Site of infection: Small bowel: large volume, abdominal gas and cramps, rare fever, weight loss Colon: frequent small volume, tenesmus, Fevers+, blood and mucus.

4 Clinical Manifestations and Categorization Time from exposure to diarrhea: toxin=rapid, viral intermediate, duration, pain, fever, blood, vomiting, other organ system involvement, living in NH or discharge from hospital, recent travel. Alarm symptoms and signs: dehydration, abnormal electrolytes, rectal bleeding, weight loss, severe abdominal pain, symptoms in excess of one week, recent antibiotic use, age>65, pregnant, and co-morbidities. Labs: fecal lactoferrin, culture especially if blood, CBC. Treatment: fluids, antibiotics with organism identified or highly suspicious of C. diff, antidiarrheal generally avoided but can be used symptomatically in viral, diet as tolerated.

5 Causes of Acute Infectious Diarrhea Viral: Norovirus and Rotavirus most common Bacteria and protozoal causes taken from 30,000 specimens in 10 hospitals Campylobacter: 2.3% (can lead to reactive arthritis) Salmonella: 1.8% (besides food, can acquire from pets, reptiles, papayas from Mexico) Shigella: 1.1% (dysentery and only needs about 10 organisms) E. coli 0157:H7: 0.4% (HUS and TTP, undercooked hamburger) Bloody Diarrhea (20% of specimens were positive) E. coli: 7.8%, then Campylobacter, Shigella, Salmonella Highest likelihood of positive culture was having blood

6 Parasitic Causes Cryptosporidium: In immunocompetent it causes a self-limited, dehydrating diarrhea. In IC it can have a prolonged and severe course with dehydration. Transmission: contaminated water, person to person, daycare, sexual partners, healthcare workers. Giardia: sporadic and epidemic, stream water, day-cares, water supply Cyclospora: raspberries from Guatemala, three week duration E. histolytica: Amebiasis, travelers and migrant laborers, can lead to severe dysentery over three weeks, and can evolve into liver abscess.

7 Enteric Pathogens Pathogen Small Bowel Colon Bacteria Salmonella Clostridium Perfringens Staphylococcus Aureus Aeromonas hydrophyila Bacillus cereus Vibrio cholera E. Coli (food poisoning) Campylobacter Shigella Clostridium difficile Yersinia Vibrio parahemolyticus Enteroinvasice E. coli Plesiomonas shigelloides Virus Protozoa Norovrus Rotavirus Astrovirus Cryptosporidium Cyclospora Giardia Microsporidium Adenovirus Herpes Simples CMV (Immune compromised) Enatameba histolytica

8 Alarm Symptoms and Signs Volume depletion/dehydration dry mouth/increased thirst decreased skin turgor altered mental status/lethargy, confusion/ha tachycardia/hypotension/orthostasis/presyncope concentrated urine and decreased output Bloody stool/rectal bleeding Weight loss Severe abdominal pain Prolonged symptoms>1 week Recent hospitalization or antibiotics Age>65 Pregnancy Comorbidities to include HIV or any immunocompromised state

9 Foodborne Disease Clinical Presentation: N&V, abdominal pain, diarrhea,?fevers but some present with tingling, paralysis, HA, and renal failure Epidemiology: 48 M cases yearly in US, 3000 deaths, 125K hospitalizations, cost ~150B Lab confirmed cases/100,000 in Source of most=poultry and Beef Salmonella: Vibrio: 0.45 Campylobacter: Yersinia: 0.28 Shigella: 5.81 Listeria: 0.24 Shiga-toxin E. coli 0157: 0.92 Cryptosporidium: 2.44 Shiga-toxin E. coli non-0157: 1.43 Cyclospora: 0.05 Most common Cause of Outbreaks: Norovirus (leafy vegetables)

10 Toxin Foodborne Causes: Vomiting Staph aureus: enterotoxin, rapid onset by food handler. Bacillus cereus: enterotoxin, starchy foods, usually self-limited, profuse V. Noroviruses: Low Infectious dose, common in outbreaks, V and D, hours, minimal immunity, food handlers. Anisakiasis: raw fish with N, V, epigastric pain 1 to 12 hours after ingestion, resolves when the worm is regurgitated.

11 Foodborne Presenting with Diarrhea Clostridium perfringens: spores germinate in meats, poultry, produces toxin in GI tract, thrives in low motility environment (antipsychotic meds psych inpatient facilities.) Viral causes: norovirus, rotavirus, adenovirus, astrovirus Enterotoxigenic E. coli (ETEC): Traveler s D, also potato salad outbreak in Wisconsin and cruise ship outbreaks, fecal or water infected from another person. Cryptosporidium: chronic watery diarrhea in immunocompromised, endemic in cattle, from contaminated water or produce, and person to person.?nitazoxanide treatment in children Cyclospora: imported berries, treatable with TMP-SMX

12 Inflammatory Diarrhea: +Fecal lactoferrin, Blood, Mucoid, Abdominal Pain, Fevers. Salmonella: S. typhi colonizes humans, contaminated food or water, systemic illness with little or no diarrhea. Campylobacter: recognized in 1970 s, 2 to 5 days incubation, poultry and cross contamination. Shiga toxin producing E. coli (STEC): enterohemorrhagic E. coli, can cause acute renal failure in children, multiple serotypes but most recognized+0157:h7, ground beef, unpasteurized juice, 1 to 7 day incubation, bloody diarrhea, Hemolytic urea syndrome. Shigella: only colonize humans and a few primates, food and water transmission, food handler associated, chicken, milk, poultry.

13 Foodborne Pathogens with non-gi Presentations C. botulinum: visual disturbance, descending paralysis, canned food, fermented fish, home canning. Ciguatera toxin: N,V,D in first 2 to 6 hours, then paresthesias, weakness, can have cardiovascular abnormalities, large reef fish eating algae blooms producing dinoflagellates making toxin. Listeria: 20% mortality in IC, elderly or pregnant, unpasteurized cheese, raw hot dogs, deli meats. Vibrio vulnificus: affects the IC, chronic liver disease, raw shellfish, 1 to 7 days, presents with skin rash and D.

14 Prevention of Foodborne Disease Alert local health authorities: PFGE for identification, public awareness. Patient education to avoid spread: handwashing. Public health Agencies observance and monitoring of outbreak, followed by education of risks to specific populations: IC, pregnant, elderly. Most treatment is supportive with avoidance of dehydration, most antibiotics are not necessary and can make STEC dangerous. Determining etiology helps to direct antibiotics in some situations such as Shigella, Campylobacter, and certain subspecies of Salmonella.

15 Notifiable Diseases at the National Level (2017) Bacterial Campylobacteriosis Cholera Salmonellosis Shiga toxin producing E. coli Shigellosis Typhoid fever Vibriosis Non-bacterial or parasitic Cryptosporidiosis Cyclosporiasis Hemolytic-uremic syndrome, postdiarrheal Trichinellosis Giardiasis Foodborne disease outbreaks Indirectly, hospital acquired

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17 Travelers Diarrhea The most common illness in persons travelling from resource rich to resource limited regions. 40 to 60% develop diarrhea Generally self-limited but aggravating Largest health hazard is dehydration, especially in children and elderly Can present with multiple patterns: Classic: 3 or more liquid stools with N, V, cramps, some with fever and blood Moderate: 1 or 2 unformed stools/day with possible other symptoms Mild: 1 or 2 unformed stools

18 Clinical Manifestations of Travelers Diarrhea ETEC: classic turista with malaise, cramps, anorexia, then watery diarrhea and possible low grade fever. Some patients require bed rest with onset about 12 hours after diarrhea started. In some series 24% attack rate in Dutch to Jamaica. Onset: 4 to 14 days post arrival Duration: 1 to 5 days with 8-15% lasting more than 7 days. Sequelae: Sizeable minority develop post infectious IBS, generally resulting in a prolonged but fruitless w/u. Diagnosis: generally unnecessary based on history. However, stool cultures in those with fever, blood, predominately upper symptoms (Giardia in Nepal and St. Petersburg, Russia), and those who took antibiotics for prophylaxis, and most important those with systemic illness (Salmonella)

19 Management of Travelers Diarrhea Fluid Replacement: goal is regular urination, lightening in color Antibacterials shorten symptoms about one day, watch for adverse events or resistant bacteria Antimotility agents may help with symptoms, avoid if blood. Alarm signs: Fevers, abdominal pain, bloody, vomiting, and those who received empiric antibiotics ORS: ½ tsp salt, ½ tsp baking soda, 4 Tbs sugar in 1 liter of water. Not equivalent to Gatorade but can buy packets or fluid in most pharmacies. Start eating when able and most anything they want, most will be anorexic and only want blands.

20 Rationale and Use of Meds in Travelers Diarrhea Antibiotics will generally reduce symptom duration by 1 to 2 days Most give Rx to start if symptoms develop or can t miss events Fluoroquinolone first choice except to Asia where Azithromycin due to resistance, same for pregnant women and in children anywhere. Resistance makes Amp and TMP-SMX less useful, also not effective for Vibrio and Campylobacter Rifaxamin: non-absorbed and of unclear value in organisms that may invade. Reserved for patients were other meds unavailable Antimotility agents generally used only in conjunction with antibiotics and not in those with inflammatory infections. Bismuth: large and frequent doses

21 Oral Agents for Self-treatment of Travelers Diarrhea Agent Adult Pediatric Norfloxacin 400mg BID for 3 days Not recommended Ciprofloxacin 500mg BID for 3 days 20 to 30mg/day in 2 divided doses for 3 days. Max=500mg Ofloxacin 200mg BID for 3 days 7.5 mg/kg f q.12 hours for 3 days. Max=200mg Levofloxacin 500mg daily for 3 days 10mg/kg for 3 days. Max=500mg Azithromycin 1000mg single dose 10mg/kg single dose. Max=1000mg Rifaxamin 200mg tid for 3 days >12 years: 200mg tid for three days.

22 Norovirus and Rotavirus Norovirus is the most common cause of viral epidemic gastroenteritis worldwide 20 M cases with ~700 deaths, immunity is short lived and reinfection with different strain possible. Person to person transmission with incubation of 24 to 48 hours Only 100 viral particles to transmit Nosocomial transmission is common and outbreaks in many large accumulations of people Common implicated foods: shellfish, salads, sandwiches, veggies, fruits Duration of illness=12 to 60 hours. Location of injury is jejunum. Myalgias, HA, mild fevers, N/V, mild diarrhea for 24 hours Viral shedding for months after symptoms Clean surfaces with bleach, good hand washing and in hospital PPE Return to work 48 to 72 hours post after symptom resolution, virus not killed by alcohol based solutions Reportable to CDC and public health Rotavirus vaccination has reduced incidence in US

23 Enterohemorrhagic E. coli: EHEC EHEC can produce Shiga toxin 6 to 9% develop HUS with children at 15% Two major strains: 0157:H7 and 0104:H4 in Germany 3 to 4 day incubation with bloody diarrhea, elevated WBC, abdominal tenderness, 23 to 47% hospitalization of 6 to 14 days, high mortality in elderly and IC, resolution in about one week if uncomplicated. If HUS (ARF, MAHA, Thrombocytopenia): 50% dialyzed. Long term with hypertension, proteinuria, and neurological. Diagnosis on bloody stools, fever, abdominal tenderness: positive for sorbitol MacConkey agar, then serotesting. Treatment: supportive, avoid anti-peristaltic meds and probably antibiotics

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25 CDI: The Result of Overuse of Antibiotics 453,000 new cases and 29,000 deaths (2011) Virulent strain and high recurrence rates #1 healthcare acquired infection 40% Hospital acquired 40% SNF acquired 20% community onset/healthcare associated $4.8 billion dollars in healthcare expenses Multiple new therapies Guidance in healthcare institutions environmental management

26 A Toxic Mix Exposure to spores 50% infants carry 3-5% healthy adult carriage 20-40% in hospital Patient risk factors Age Acid suppression Comorbidities Dysbiosis Antibiotics Quinolone Clindamycin Clostridium difficile infection

27 Severity Classifications Severity classifications IDSA ACG 2013 Mild to Moderate WBC<15,000 Serum Creatinine<1.5 times baseline Diarrhea Mild No other criteria meeting severity Severe WBC>15,000 Serum Creatinine>1.5 times pre-morbid Serum Albumin<3 Plus 1 or more of WBC>15K and abdominal tenderness Severe and complicated Hypotension Ileus Megacolon >1 or more ICU, hypotension, fever>38.5, Ieus, Mental Status changes, WBC>35K, serum Lactate.2.2, end organ failure

28 C difficile 027/BI/NAP1 Epidemic hyper-virulent strain Characterized by Quinolone resistance Increased virulence Increased mortality and recurrence. Worldwide McDonald et al, N Engl J Med He et al, Nature Genetics 2013.

29 Characteristics of D. diff Infections in Minnesota: Community acquired n=157 Hospital acquired n=72 Age, median % Antibiotic exposure % Acid suppression Charleson comorbidity index % Severe CDI % Recurrent CDI % Female 76 60

30 Treatment Approaches Probiotics Antibiotics Toxin binder Antibiotics C. Difficile colonization Toxin production Diarrhea Immune system Active immunization: Toxoid vaccine Passive immunization: Monoclonal antibodies Immune globulin (IVIG) Anti-Toxin Response Recurrent Diarrhea Protection

31 Treatment (First Episode) Mild-moderate disease Metronidazole 500mg PO every 8 hours x14 d Preferred: effective as vancomycin, reduced VRE, cheap Vancomycin 125mg PO every 6 hours x 14 d Preferred: unable to tolerate/allergy to metro, preg/lactate, <10yrs age, failed metro tx 5 days, on warfarin tx, expensive Severe disease Vancomycin 125mg PO every 6 hours x14 d Metronidazole inferior to vancomycin Infect Control Hosp Epidemiol 2010; 31(5):

32 Treatment of Fulminant Disease PO high dose vancomycin +/- IV metronidazole Intracolonic vancomycin 500 mg in 500mL (100ml) retention enema q6 hrs IV Tigecycline (case reports) Intravenous gamma globulin (IVIG) Dose: mg/kg IV daily x1-3 days Limited data, expensive, side effects, dose? Bezlotuxamab: Toxin B antibody: FMT: both experimental Surgery (Total versus loop ileostomy) Indications toxic megacolon, perforation, peritonitis, systemic toxicity comorbidities

33 Treatment (Recurrences) First Recurrence: vancomycin x 14 days (metronidazole if vancomycin is contraindicated) 2 nd Recurrence and beyond Taper/pulse dosing of vancomycin May use if first recurrence is severe No metronidazole due to risk for peripheral neuropathy Fecal bacteriotherapy (fecal transplant) Fidaxomicin Rifaximin chaser after vancomycin (resistance) Probiotics + vancomycin (limited data) Older treatments (ineffective): colestipol, cholestyramine, bacitracin, fusidic acid, rifampin

34 Rationale for Fecal Transplant Normal colonic flora consists of 10,000 or more different bacterial species. Gut flora synthesize vitamins, ferment carbohydrates, and compete with pathogens, as well as assist in maturation of the immune system. Antibiotics selectively remove bacterial species exposing host to enteric infections such as C. difficile successful colonization by spores or the bacterium. Bacteroides and Firmicutes appear most beneficial and protective. FMT from healthy individuals restores these strains and provides competitive pressure against CDI.

35 Vanco vs. Duodenal Infusion of Donor Feces for Recurrent CDI van Nood et al; NEJM 2013; 368: Group N % resolution Vanco BL FMT Vanco x 14 days Vanco BL 13 23

36 FMT for Colonoscopy Delivery

37 Frozen FMT Tablet

38 Bezlotoxumab (Toxin B antibody) Two double blind, randomized, placebo controlled trials involving 2655 adults. Infusion of Bezlotoxumab. End point was recurrent infection within 12 weeks. Significant reduction in recurrent CDI but only about 10% less than standard of care. Adverse events equivalent in placebo and drug. Exact role unknown. Very expensive. Wilcox, et al, NEJM January 2017.

39 Guidelines for Controlling C. diff Infection in Healthcare Facilities 1. Frequent hand washing with soap 2. Glove when performing patient care 3. Clean environmental surfaces with sporicidals 4. Isolate symptomatic patients and probably C. diff toxin + patients. 5. Avoid reusable rectal thermometers 6. Judicious use of antibiotics: anti-microbial stewardship

40 Quiz Papayas Avoidance of antimotility drugs MAHA Cheap Sushi Tingling lips Montreal, Canada Gulf Coast Two Girls Bakery Cheese Salmonella (Mexico) Bloody Diarrhea, Shigella Shigella toxin producing E. coli Anisikaisis Ciguatera toxin Hypervirulent CDI Vibrio vulnificus Campylobacter Listeria