Clostridium difficile Update

Transcription

1 Clostridium difficile Update Nicholas Havens MD FACP Chief of Medicine Primary Care Harry S Truman Memorial Veterans Hospital Clinical Assistant Professor of Medicine Infectious Diseases University of Missouri Columbia The Player Clostridium difficile is an obligate anaerobic, gram-positive, spore-forming bacillus Widely in nature Greatest in hospitals and chronic-care facilities Ribosomal DNA sequence analysis indicates that C. difficile is closely related to C. sordellii but not to other toxigenic clostridia, such as C. perfringens, Clostridium botulinum, and Clostridium tetani. The Player LARGE (2 to 17 µm in length) Fast-growing. Many strains have flagellae or fimbria-like structures. Surface-layer proteins are immunologically recognized 1

2 The History Previously not thought of as a pathogen First described by Hall and O'Toole in 1935 as a suspect of intestinal disease in children. Isolated it in the intestinal biota of newborn infants. They described an obligatory anaerobic, sporeproducing, gram-positive rod that was toxigenic. Pseudomembranous colitis occurred in patients receiving broad-spectrum antibiotics before the 1970s but was often attributed to Staphylococcus aureus. Because of the unusual difficulty which was encountered in its isolation and study, it was first named Bacillus difficilis Clinical description of pseudomembranous colitis dates to the 1890s first described in the pre-antibiotic era An animal model for antibiotic-associated GI disease was created in the 1940 s Staph was nearly universally found in surgical specimens Unfortunately the same held true for those without disease In one case series however, there was noted to be an absence of S. aureus in 11/18 patients with pseudomembranous colitis, Dearing and associates concluded that such findings Cast doubt on the concept that all cases of pseudomembranous enteritis are produced by S. aureus in the intestine. 2

3 In 1974, investigators in St. Louis found that 20% of patients receiving clindamycin developed diarrhea ½ had pseudomembranous colitis A hamster model was created of AAC showing that vancomycin prevented AAC induced with clindamycin This led to the theory that it was a gram-positive organism. In the late 1970s Larson found evidence of a toxin mediator. Attempted to isolate presumed viruses from the feces of a 12-year-old girl with a history of penicillin exposure with diarrhea She had negative stool cultures, and proven pseudomembranous colitis Fecal suspensions from the girl and 4 others with pseudomembranous colitis had cytopathic effects on several cell cultures HeLa cells Rhesus monkey kidney cells Human embryonic lung fibroblast cells 3

4 Bartlett (Hopkins) created a hamster model of clindamycin-associated enterocolitis The found that intracecal material transferred the disease from affected hamsters to healthy ones They also found that gas gangrene antiserum neutralized it Rifkin found that taking stool filtrates from humans with pseudomembranous colitis caused hamsters to explode caused edema, hemorrhage, and increased vascular permeability in rabbit skin possessed cytotoxic activity that was neutralized by Clostridium sordellii antitoxin. An additional study found that C. sordellii antitoxin apparently neutralized this toxin in 9/9 patients with pseudomembranous colitis and 2/2 others with antibiotic-associated nonspecific colitis. Identified as the cause of CDAD in

5 Since the late 1960s, and after the discovery of C. difficile as the major cause of antibiotic-associated colitis in 1977, antibiotic-associated staphylococcal diarrhea has virtually disappeared from the medical literature The Disease Wide ranging manifestations Self limiting disease that ends with Abx are stopped Fulminant with toxic megacolon and death While characteristic of C. diff, Pseudomembranes are not pathognomonic for CDAD and can with other pathogens Symptoms may occur while on Abx (usually after 5-10 days) or 2-10 weeks up to ending therapy The Disease Symptoms may occur while on Abx (usually after 5-10 days) or 2-10 weeks up to ending therapy All classes of antibiotics have been associated with CDAD EVEN VANC!!!! Most common symptom is mild fever with diarrhea. In severe cases it may be bloody Leukocytosis is common 5

6 C. difficile diarrhea may be associated with the passage of mucus or occult blood in the stool, but melena or hematochezia are rare. Fever, cramping, abdominal discomfort, and a peripheral leukocytosis are common but found in fewer than 1/2 of patients. Extraintestinal manifestations are rare C. diff ileitis or pouchitis in patients who have previously undergone a total colectomy is rare Clinicians should consider the possibility of CDI in hospitalized patients with unexplained leukocytosis Patients with severe disease may develop a colonic ileus or toxic dilatation and have abdominal pain with minimal or no diarrhea. Complications of severe C. diff colitis Electrolyte disturbances Dehydration Hypoalbuminemia Toxic megacolon Bowel perforation Hypotension Renal failure SIRS Sepsis,and death 6

7 The Background Significant increase through the early 2000 s 4 fold increase in Canada from 1991 to 2003 In 2011, CDC estimated 453,000 cases in the US (147.2 cases/100,000 people) 83,000 were 1 st recurrence 29,3000 deaths ( % normal, during epidemics) 33% increased risk for mortality at 180 days without recurrence 159,700 community cases 293,000 health care associated 107,600 hospital acquired The Background Projected cost in the USA in 2012 was billion The majority of the increased severity has been isolated to a single strain BI, or North American Pulsed Field type 1 (NAP1) and PCR ribotype 027 (BI/NAP1/027) 7

8 Pathogenesis The initiating event for CDAD involves the disruption of the intestinal microbiota (generally with antibiotics or antineoplastics that affect bacteria) Because C. difficile spores can survive even high concentrations of antibiotics, germination of spores and rapid growth of the organism may occur as antibiotic levels in the lumen of the bowel decrease below MIC for C. difficile before the recovery of the normal microbiota. This Key step allows the C. diff to selectively colonize or replace the prior tenants The normal microbiota of the gut is complex and not fully understood There are hundreds of distinct organisms compose this ecosystem. Animal models show that each play a part in resisting C. difficile colonization Unfortunately a simple course of Abx can disrupt this balance for up to 1 year afterwards 8

9 Colonization occurs by fecal-oral transmission. Vegetative cells are killed by stomach acid but the spores which are acid resistant carry on their merry way Once in the small intestine they convert to a vegetative state. The bio-load can be quite large More than 10 8 colony-forming units per gram of feces is typical in patients with C. difficile disease Once colonized they release toxins which mediates the diarrhea/colitis The virulence is due to 2 large toxins TcdA: Enterotoxin TcdB: Cytoxin Rank among the most lethal bacterial toxins studied and have proved active against more than 20 cell lines from different mammalian species and tissues. Intestinal epithelial cells endocytose the toxins where they irreversibly deactivate members of the Rho family of small GTP-binding proteins (regulate actin cytoskeleton and signal transduction). This causes alterations of the cells actin cytoskeletons (rounding and retraction) and leads to the cytotoxic effects (apoptosis) Compromises the cell's ability to internalize nutrients Disrupts vesicular transport The end result is cell death 9

10 In animals, toxin A causes intestinal fluid secretion mucosal injury inflammation Instilled into ligated loops of rabbit small intestine, toxin A stimulates fluid secretion as efficiently as cholera toxin Histopathologic changes in rabbit small intestine exposed to toxin A Primary diffuse lymphocytic infiltrate in the lamina propria, Secondary edema and bulging of the lamina propria of the villi End cytolysis and separation of the basal portions of the apical epithelial cells. An acute inflammatory response also occurs, with PMN infiltration. Toxin B has no demonstrable effect in the rabbit model permeability, fluid secretion, neutrophil migration, or changes in intestinal morphology In humans however it disrupts tight junctions in human epithelial cell monolayers 10 times more potent on a molar basis than toxin A in mediating damage to human colonic mucosa Strains lacking toxin A can still show the full range of virulence in humans. In addition to the Toxin A/B combo, there is a TcdC toxin found on the TcdC gene This appears to down regulate total toxin production Deletion of the TcdC gene can create hyper-virulent species Ribotype, O27/BI/NAP1 C. Diff Grande A final toxin, Binary ADP ribosylating toxin, It is a A-B toxin motif but its importance is unknown Not all strains of C. difficile produce all three toxins. 65% of strains producing both TcdA and TcdB 97% at least produce Toxin B 10

11 NAP1 has been noted to make increase toxins A, B (the cause of diarrhea) Increased fluroquinolone resistance Increased binary toxin This is secondary due to the lack the TcdC protien which inhibits these toxins production While this has largely been a disease of the frail and elderly, this new strain has began affecting healthy individuals and the young, even without hospital of antibiotic exposure The Scope (not rubber one) The incidence ranges greatly Depends on antibiotic prescribing patterns, Endemic strains Toxigenic C. difficile is the most common cause of nosocomial diarrhea Incidence of collitis in acute-care hospital 30 to 40 cases per 100,000 population in the 1990s 84 per 100,000 by

12 The Scope (not rubber one) Colonization with C. difficile occurs frequently among residents long term care/rehab centers. Still relatively uncommon in the outpatient world (even those with Abx) A retrospective cohort study of a 265,000- member HMO found: Risk of less than 1/10,000 antibiotic prescriptions. With NAP1/027 this is changing In 2006 ¼ of all cases of communityacquired C. difficile in Connecticut lacked established predisposing risk factor ALL CLASSES OF ABX HAVE BEEN ASSOCIATED WITH C. DIFF Most common causes however are: Clindamycin, penicillins, cephalosporins Recently fluoroquinolones While clindamycin was the initial smoking gun, we use more tonage of penicillins and cephalosporins 3rd gen cephalosporins > PCN Non-Abx: Doxorubicin, cisplatin, cyclophosphamide, 5-FU, chlorambucil, and methotrexate. Host and environmental factors should not be under-estimated Advanced age and severity of underlying illness are major factors Host immunoglobulin G responses have been shown to protect against symptomatic disease and relapse HIV does not appear to predispose to C. difficile colonization Non-toxigenic strains appear to protect against the disease 12

13 We are the reservoir! Healthy adults have a carrier rate of toxigenic strains of 3-8% Hospitalized patients have a carriage rate of 20-50% These rarely carry large quantities of toxin A or B in the stool Hospitals have a thick fecal veneer In a prospective cohort study of patients admitted to a Seattle teaching hospital Acquisition of the organism was documented in 21% of 399 patients who initially had negative culture results Of these patients, 37% developed diarrhea. Another study showed that 59% of hospital workers caring for patients shedding C. difficile, had positive results on culture for C. diff from their hands. Even without symptoms, carriers can shed spores in their stool. Symptoms only occur in 50% of those colonized In those without symptoms there is a rise in IgG levels against Toxin A Diagnostics 13

14 First, have a healthy suspicion Any patient with diarrhea and recent Abx in the last 2 mo or diarrhea starting 72h after hospitalization Toxin testing or C. difficile culture of a single stool specimen effectively establishes the diagnosis Rec to use stool toxin as part of a multistep algorithm Glutamate dehydrogenase plus toxin NAAT plus toxin Sensitivity and Specificity of Tests for the Diagnosis of Clostridium difficile Associated Disease Testing should only be done on loose stool The Stick Test Testing of stool from asymptomatic patients is not clinically useful Including use as a test of cure! Repeat testing during the same episode of diarrhea is of limited value and should be discouraged 14

15 Test Sensitivity Specificity Substance Detected Toxigenic Culture High Low C. Diff Vegetative Cells or Spores Nucleic acid Amplification High Low/Moderate C. Diff Nucleic Acid (Toxin Genes) Glutamate Dehydrogenase High Low C. Diff Common Antigen Cell culture cytotoxicity High High Free Toxins neutralization assay Tox A and B enzyme immunoassays Low Moderate Free Toxins Large explosion in NAATs in the mid 2000 s 12 commercial platforms with different gene targets More sensitive than toxin EIA s Retesting What is the role of retesting or test for cure? NONE! 15

16 An Ounce of Prevention In hospital settings, CDI patients should be in a private room with a dedicated toilet Cohorting C. diff patients if needed is acceptable but should not be cohorted with other infectious isolations Empiric isolation should occur if the lab test wont be back in the first 24h Isolation should remain until 48h after diarrhea has resolved (weak recommendation/low quality of evidence) If an institutions CDI rates are high, the rec. is to keep contact precautions through discharge. Soap vs Alcohol? Healthcare workers and visitors must use gloves (strong rec/high quality evidence) and gowns (Strong rec/moderate quality of evidence) on entry to a room of a patient with CDI. Before/After routine contact with a patient and after removing gloves, hand hygiene with alcohol based product or soap/water should be performed If fecal contamination occurred, use soap and water 16

17 Soap vs EtOH Alcohol is very effective in killing vegetative cells however the spores of C. diff are strongly resistant Limiting to sinks reduces overall hand hygiene compliance and may increase spread Numerous studies have not shown an association between alcohol based hand cleaners and increased incidence of C. diff infection. Maintain contact precautions for the duration of diarrhea (C-III) Once you stop the flow, the gowns can go. Routine identification of asymptomatic carriers (patients or healthcare workers) for infection control purposes is not recommended (A-III) Treatment of such identified patients is not effective (B-I) What about Clothes? While C. diff has been found on nursing uniforms, there is not evidence that uniforms are a source of transmission to patients. Gowns are rec. due to potential of soiling as well as data of vertical transmission with other enteric organisms such as VRE 17

18 Misc Patients should be encouraged to wash their hands frequently as well as shower to reduce the burden of spores on skin. Disposable patient equipment should be used when possible or cleaned with a sporicidal disinfectant Terminal room cleaning (with a sporicidal agent) should occur in conjunction with other control measures These are not the Droids you re looking for Automated terminal disinfection At this time, limited data to rec. automated/uv disinfection 18

19 Other Control Measures Minimize the frequency and duration of antimicrobial therapy and the number of antimicrobial agents prescribed, to reduce CDI risk Implement an antimicrobial stewardship program Antimicrobials to be targeted should be based on the local epidemiology and the C. difficile strains present, but restricting the use of cephalosporin and clindamycin may be particularly useful PPI Epidemiologically, there is an association between PPI use and CDI Unnecessary PPIs should be stopped (regardless of C. diff) No evidence for stopping PPI during C. diff treatment Probiotics Insufficient data to recommend probiotics for primary prevention At baseline, risk for CDI in pts >65y hospitalized for >2 days on antibiotics is still <3%, even during outbreaks Studies that show positive effect have 7-20x the incidence of CDI in their placebo arms at baseline (question the data) 19

20 Anything else? Stop Antibiotics as soon as possible Treatment Metro vs Vanc? For 30 years, Metronidazole and oral Vancomycin have been the mainstays Newer agents such as fidaxomycin Fecal transplants immunotherapy 20

21 Vanc vs Metro Early RCTs in the 80 s/90 s showed no difference in outcomes but were small Since 2000, several RC-Placebo trials have further demonstrated vancomycin superiority Since 2000, reports have shown increasing resistance to metronidazole with a failure rate increasing to 18.2% Case Treatment Strength/Quality Initial (non-severe) WBC <15k, Cr <1.5 Initial (severe) WBC>15k, or Cr >1.5 Initial (fulminant) Hypotention/Shock/ Ileus/megacolon Vanc 125mg QID x 10d Fidaxomycin 200mg q12 x 10d (alt metro 500mg TID) Vanc 125mg QID x 10d Fidaxomycin 200mg q12 x 10d Vanc 500mg q6h If ileus add rectal infusion & IV Metro 500mg q8h 1 st Recurrence Vanc 125mg QID x 10d Vanc taper Fidaxomycin 200mg q12 x 10d (if vanc used) 2 nd or Subsequent Failure Vanc taper Vanc 125mg QID x 10 days followed by rifaximin 400mg TID x 20d Fidaxomycin 200mg q12 x 10d Fecal transplant Strong/High Strong/High Weak/High Strong/High Strong/High Strong/Moderate Weak/Low Strong/Moderate Weak/Low Weak/Low Weak/Moderate Weak/Low Weak/Low Weak/Low Strong/Moderate 21

22 Vancomycin Taper 125mg po QID x days BID for 7 days Qday for 7 days Q2-3 days for 2-8 weeks Considerations 10d should be enough however if a patient is slow to improve their diarrhea, consider a 14d course If metronidazole is used, limit to 1 course to minimize neurotoxicity associated with prolonged or repeated use 22

23 Vanc vs Fidaxomycin Failure predicted by Fever, WBC >15, Cr >1.5mg/dL Head to Head both work equally as well No Recurrence at 25d: 71% Fidaxo vs 57% Vanc This is reduced if you separate out the NAP1/BI strains Other Agents FDA Approved: Rifaximin Tigecycline Bacitracin Not FDA Approved Nitazoxanide Fusidic Acid Cost $$$$ = >$1,000 $$$ = $501-1,000 $$ = $ $ = $

24 High Dose Vancomycin Why the high dose for fulminant disease? There remains a lack of high-quality evidence supporting it Appears safe however there have been some noted serum concentrations if prolonged, renal failure, or disrupted intestinal epithelial integrity Non-Responders If not responding to Vanc/Metro IV tigecycline (100mg loading dose followed by 50mg q12h) Passive immunotherapy (IVIG) No controlled trials for either 24

25 When Bad Goes to Worse Consider colectomy for severely ill patients. Serum lactate level >5 mmol/l and WBC>50k have been associated with greatly increased perioperative mortality. If surgical management is necessary Perform subtotal colectomy with preservation of the rectum. New research had focused on diversion illeostomies with preservation of the colon for future reattachment Less extreme surgery with lower mortality/morbidity an the poor guy gets to keep his colon. Return of the Drip Both Vancomycin and Metro have a recurrence rate close to 20% Both impair resistance to colonization Reoccurrence escalates with each infection 20% 40% 60% This is likely due to a selection towards those who don t form a natural immunity 25

26 Reoccurrence Therapy 4 key points Stop offending antibiotics Discontinue therapy with the inciting antimicrobial agent(s) as soon as possible, as this may influence the risk of CDI recurrence If diarrhea reoccurs, look for other sources Don t treat positive assays if pt asymptomatic If diarrhea persists despite treatment with vanc/metro, look elsewhere New Recs 1 st Recurrence treated with tapered/pulse Vanc or fidaxomycin (if metro used initially, do a 10d vanc course) >1 recurrence: Tapered/pulse vanc 10d vanc followed by Rifaximin Fidaxomycin Out There Therapies Immunotherapy Over 50% of adults have antibodies ergo IVIG Passive immunity Inactivated Toxoids A&B Fill the Void Giving non-toxogenic C. diff Familial fecal transplant via NG or enema Stool banking 26

27 New Antimicrobials Rifaximin, Fidaxomicin nitazoxanide, ramoplanin, difimicin Tolevamer (a high molecular weight polymer) binds toxin A&B rendering it inactive while not having an antimicrobial effect against the good guys Colonization with non-toxogenic C diff? Rifaximin A semi-synthetic rifamycin Very little GI absorption Currently used for travelers diarrhea and hepatic encephalopathy as a FDA orphan drug In an open-label study rifaximin (200 mg TID x 10 days) was compared to vanc (500mg po BID x 10 days) N=20 Time to toxin disappearance was significantly shorter with vancomycin (4.8 vs 8.1 days) Time to stool normalization was similar with vancomycin, at (3.8 vs 4.9 days) Rifaximin was found to be effective in 9/10 patients Vancomycin was successful in 10/10 Fecal Transplant Hope you finished your lunch 27

28 FFT Fecal transplant remains an effective but seldom used therapy Involves instilling the supernatant from stool via NG Theory is that the micro-biome of house members becomes similar with time This is a means to re-introduce what was previously there. 28

29 Enema Colonoscopy NJ tube Pills? Contraindications Risk of infectious agent Known HIV, hepatitis B or C infections Known exposure to HIV or viral hepatitis (within the previous 12 months) High-risk sexual behaviors Use of illicit drugs Tattoo or body piercing within six months Incarceration or history of incarceration Known current communicable disease (eg, upper respiratory tract infection) Risk factors for variant Creutzfeldt-Jakob disease Travel (within the last six months) to areas of the world where diarrheal illnesses are endemic or risk of traveler's diarrhea is high Contraindications History of inflammatory bowel disease History of IBS, idiopathic chronic constipation, or chronic diarrhea History of gastrointestinal malignancy or known polyposis Factors that can or do affect the composition of the intestinal microbiota Antibiotics within the preceding three months Major immunosuppressive medications (eg, calcineurin inhibitors, exogenous glucocorticoids, biological agents, etc) Systemic antineoplastic agents 29

30 The Good It s cheap It s readily available It s not likely to be addictive "Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) Michael Silverman, Ian Davis, Dylan Pillai. Success of Self-Admisistered Home Fecal Tranplantation for Chronic Clostridium difficile Infection Burden of Clostridium difficile Infection in the United States, Fernanda Et Al. NEJM Feb 26, 2015 Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009; 15:285. Kelly CR, Kahn S, Kashyap P, et al. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology 2015; 149:

31 Burden of Clostridium difficile Infection in the United States Fernanda Et Al. NEJM Feb 26,