Inter-hospital Geriatrics Meeting August 2014 The Watery Curse

Transcription

1 Inter-hospital Geriatrics Meeting August 2014 The Watery Curse Speaker: Dr. KK Yam (QMH) Supervisor: Dr. Patrick Chiu

2 Patient s history F/95 Lives with daughter & maid ADL partially dependent. Walks with stick (indoor); Wheelchair (outdoor)

3 Medical history & medications HT Aspirin AF Pantoprazole CHF Frusemide CVA (Lt cerebellar infarct) Duodenal ulcers Perindopril Diltiazem Uterine prolapse

4 Admission in Dec 2012 Presented with fever and dysuria MSU culture grew E. Coli sensitive to cefuroxime Given cefuroxime for 1 week and symptoms resolved Dec Jan Feb Mar Apr May UTI

5 Admission in Jan 2013 Presented with fever & cough CXR: RMZ consolidation ST: no dysphagia Treated as pneumonia with Augmentin for 1 week Dec Repeated CXR showed resolution of consolidation Jan Feb Mar Apr May UTI Pneumonia

6 Re-admission after 2 days Developed profuse watery diarrhea 2 days later With small amount of fresh blood in stool Colicky central abdominal pain No vomiting No recent contact / travel history / raw food Dec Jan Feb Mar Apr May UTI Pneumonia

7 Physical examination Mildly dehydrated Vital signs stable and afebrile Abdomen: mild tenderness over peri-umbilical region, soft with hyperactive bowel sounds PR: brownish stool Other systems unremarkable

8 Differential diagnoses Drug related: Augmentin Infective: viral GE, bacterial dysentery, C.difficile associated diarrhea Malignancy: Colorectal tumour Other causes of colitis

9 Investigations WCC and differential counts normal Hb 11.5 Electrolytes, renal, liver & serum amylase - unremarkable Albumin 29 g/l. CEA normal AXR unremarkable

10 Stool investigations Clostridium difficile culture & its cytotoxin - positive Other bacterial culture negative Norovirus study negative Clinical Impression Clostridium difficile associated diarrhea (CDAD)

11 A review on C. Difficile associated infection Microbiology /pathophysiology Epidemiology Risk factors Presentation and Diagnosis

12 C. difficile associated diarrhea (CDAD) % of all Antibiotic-associated diarrhea - A spectrum of diseases of different severity 1. C. difficile associated diarrhea (CDAD) with colitis 2. Pseudomembranous colitis 3. Fulminant colitis Different manifestations and endoscopic findings Mild disease Severe disease

13 C. Difficile Difficult clostridium" Microbiology Anaerobic, gram-positive, spore-forming, toxin-producing bacillus Spores are resistant to drying, temperature & many antiseptic solutions. Toxin A (enterotoxin) causes inflammation leading to intestinal fluid secretion, mucosal injury, directly activates neutrophils Toxin B (cytotoxin) essential for the virulence of C. difficile, approximately 10 times more potent than toxin A for mediating colonic mucosal damage

14 Pathophysiology Colonization of C. Difficile (pre-existing / spores via fecal oral route) Plus Disruption of normal intestinal flora by antimicrobial therapy Evasion of immunity & C. difficile multiplies 2 toxins that bind to receptors on intestinal epithelial cells Inflammation and diarrhea

15 A review on C. Difficile associated infection Microbiology /pathophysiology Epidemiology Risk factors Presentation and Diagnosis

16 Carrier state 3% of healthy adults carry this organism 16-35% in hospitalized adults 50% in institutionalized elderly Saima Aslam, Richard J Hamill, Daniel M Musher; Treatment of Clostridium difficileassociated disease: old therapies and new strategies; Lancet Infect Dis 2005; 5:

17 Epidemiology Increase in incidence since 2000 US National Hospital Discharge Survey CDI-associated hospitalizations 31 / in / in / in 2005 An approximate 25% annual increase each year since 2000 Associated with the rise of BI/NAP1/027 strain Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No 9

18 Hypervirulent strains Characterized by higher than usual toxin A and B production Presence of a third toxin, binary toxin (unknown effects) Designated as BI/NAP1/027 Associated with lower clinical cure rates, increased recurrence rates, increase mortality rate Jennifer R. O Connor et al. Clostridium difficile Infection Caused by the Epidemic BI/NAP1/027 Strain. GASTROENTEROLOGY 2009;136:

19 Prognosis in age >=80 70 patients with C. difficile infection (1/1 31/12/06) Mean age = 84.0 (range 80-94). 41.1% were male. Treatment failure 27.7% 90-day mortality 17.1%. 90-day mortality in hospitalized patients: 21.8%. 4.3% developed toxic megacolon. Reference: Eric D. Cober, Preeti N. Malani; Clostridium Difficile Infection in the Oldest Old Clinical Outcomes in Patients Aged 80 and Older; JAGS; 57: , 2009

20 Mortality due to Clostridium difficile infection 27 studies with cases of CDI great heterogeneity in the methods for reporting mortality The overall associated mortality to be at least 5.99% within 3 months of diagnosis (mostly due to severe diseases) Higher mortality is associated with advanced age, being 13.5% in patients over 80 years J.A. Karas a,*, D.A. Enoch b, S.H. Aliyu; A review of mortality due to Clostridium difficile infection; Journal of Infection (2010) 61, 1e8.

21 Predictors of fatal outcome Poor comorbidity status High WCC counts (>20 asso. with 18% mortality) Low diastolic BP Clinical signs of sepsis Renal and pulmonary dysfunction Haig Dudukgian et al; C. difficile colitis-predictors of fatal outcome; J Gastrointest Surg (2010) 14:

22 Situation in HK Situation in Queen Mary Hospital Between Sept 2008 to Dec 2008, 723 stool samples (496 patients) were collected for detection of C difficile cytotoxin. 37 samples (5.1%) demonstrate a positive result for the cytotoxin assay. Hypervirulent NAP-1/027 Strain Detected in 1 out of 37 stool samples +ve for C. difficile cytotoxin in Queen Mary Hospital in 2008 (Sept to Dec). Reference: Clostridium difficile ribotype 027 arrives in Hong Kong; Letters to the Editor/ International Journal of Antimicrobial Agents 34 (2009)

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24 A review on C. Difficile associated infection Microbiology /pathophysiology Epidemiology Risk factors of Clostridium Difficile associated disease (CDAD) Presentation and Diagnosis

25 4 Main Risk factors of (CDAD) 1: Antimicrobial use Clindamycin (RR=9), penicillins (Augmentin RR=22), cephalosporins (Rocephin RR=36), and fluoroquinolones (associated with the hypervirulent strain BI/NAP1/027 ) 2: Hospital admission Risk is proportional to duration of hospital stay Risk increases with increased exposure to antibiotics 3: Age > 65 years confers a relative risk > 10 4: Impaired immunity Reference: (1) Haihui Huang et al. Antimicrobial resistance in Clostridium difficile. International Journal of Antimicrobial Agents 34 (2009) (2) A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No 9 Saima Aslam, Richard J Hamill, Daniel M Musher; Treatment of Clostridium difficile-associated disease: old therapies and new strategies; Lancet Infect Dis 2005; 5: (3),(4) Kelly C, LaMont J. N Engl J Med 2008;359:

26 Hospital admission If we use the same antibiotics CDI complicated 0.5%-1% of hospital admissions CDI complicated <0.02% antimicrobial usage in the community Why? Exposure to toxigenic C difficile or its spores, everywhere inside the hospital environment Reference: Saima Aslam, Richard J Hamill, Daniel M Musher; Treatment of Clostridium difficile-associated disease: old therapies and new strategies; Lancet Infect Dis 2005; 5:

27 Impaired immunity Kelly C, LaMont J. N Engl J Med 2008;359:

28 A review on C. Difficile associated infection Microbiology /pathophysiology Epidemiology Risk factors Presentation and Diagnosis of Clostridium difficile associated disease (CDAD)

29 Clinical presentations Onset of diarrhea during or after antimicrobial usage (Disease onset can be delayed by 2 months or rarely 3 months) Mild disease Fever (28%), abdominal discomfort (22%) and neutrophilia (50%) indicating colitis Hypoalbuminemia Unexplained leukocytosis in hospitalized patients (even in the absence of diarrhea) may reflect underlying C. difficile infection; diarrhea often develops in the next one to two days Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No 9

30 Clinical presentations Severe disease / Fulminant colitis (10%) Abdominal pain - severe lower quadrant / diffuse; Peritonism may indicate bowel perforation Diarrhea - may be less prominent (atonic colon) Systemic manifestation - shock & high fever Metabolic acidosis On AXR: Toxic megacolon (4.3): colonic dilatation >7 cm in its greatest diameter accompanied by severe systemic toxicity Reference: Eric D. Cober, Preeti N. Malani; Clostridium Difficile Infection in the Oldest Old Clinical Outcomes in Patients Aged 80 and Older; JAGS; 57: , 2009

31 Diagnosis of CDAD Diarrhoea Diarrhoea (> 3 unformed stools per 24 hr for > 2 days) PLUS Toxin A/B in the stool OR Toxigenic C. difficile detected by stool culture OR Pseudomembranes seen in the colon Reference: Harrison s principles of Internal Medicine 16th edition

32 Diagnosis of CDAD Possibilities CDAD? Remarks Both Toxin and Culture -ve Both Toxin and Culture +ve No Yes Toxin +ve only Yes Contamination usually unlikely Culture +ve only Depends on clinical situation -Labile toxins may be lost -Carrier stage because culture in most lab does not distinguish between toxigenic and nontoxigenic strains References: -Uptodate.com -QMH microbiologists

33 Indications Endoscopy? High clinical suspicion for C. difficile with negative laboratory assays. Prompt C. difficile diagnosis needed before laboratory results can be obtained Failed to respond to antibiotic therapy Atypical presentation with ileus or minimal diarrhea Findings: Shallow ulcerations on the intestine mucosal surface Pseudomembranes: raised yellow or white plaques up to 2 cm in diameter, scattered over the colorectal mucosa Pathognomonic for C. difficile infection

34 Role of CT abdomen? CT abdomen shows marked thickening of colonic wall Usually done for suspected colonic perforation Or to rule out other diagnosis including ischemic bowel

35 Back to our patient

36 Progress Dx to have CDAD due to positive cytotoxin in stool Started on a 5 days course of Flagyl 500 mg tds po by parent team Symptoms improved and discharged. Dec Jan Feb Mar Apr May UTI Pneumonia C.Difficile infection

37 Admission in Feb 2014 LUT symptoms and fever Urine culture grew E.Coli (sensitive to cefuroxime) Prescribed with cefuroxime USG kidneys for recurrent UTI - only a few renal cysts Dec Jan Feb Mar Apr May UTI Pneumonia C.Difficile infection UTI

38 Admission in Mar 2014 Presented with watery diarrhoea for 2 days No fever, soft abdomen with hyperactive bowel sounds WCC normal, Liver and renal biochemistries unremarkable, Albumin 22 g/l AXR showed no dilated bowel shadow Dec Jan Feb Mar Apr May UTI Pneumonia C.Difficile infection UTI

39 Progress Stool C/ST grew Aeromonas, Clostridium difficile and its cytotoxin +ve Tx: Ciprofloxacin 500 mg BD po for 5 days. oral vancomycin 125 mg Q6H for 2 weeks (1 st recurrence of CDAD) Diarrhea subsided Dec Jan Feb Mar Apr May UTI Pneumonia C.Difficile infection UTI C.Difficile infection

40 Admission in May 2014 Dec Presented with watery diarrhea again. No intake of antibiotics in between PE: no signs of acute abdomen: soft with hyperactive bowel sounds WCC normal, Liver and renal biochemistries unremarkable, Albumin 22 g/l Jan Feb Mar Apr May Jun UTI Pneumonia C.Difficile infection UTI C.Difficile infection

41 Progress C. Difficile and its cytotoxin were +ve (2nd recurrence). Dec Jan Feb Mar Apr May Jun UTI Pneumonia C.Difficile infection UTI C.Difficile infection (First recurrence) C.Difficile infection (Second recurrence)

42 A review on C. Difficile associated infection Microbiology /pathophysiology Epidemiology Risk factors Presentation and Diagnosis Management (initial and recurrent disease)

43 Treatment of Initial Infection mild disease Stopped the inciting antibiotics 25% of patients have resolution of diarrhea within 48 hrs However, stopping the inciting antibiotic may not be practical clinically! Contact precautions and hand hygiene (soap better than alcohol based agent) Avoid anti-motility agents e.g. imodium linked to toxic megacolon / delay toxins excretion Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

44 Treatment of Initial Infection mild disease Regime: Oral metronidazole, 500 mg every 6 hours for 10 to 14 days - in frail patients - in patients whose inciting antimicrobials cannot be discontinued safely because of intercurrent infection The Society for Healthcare Epidemiology of America recommends initiating empirical therapy for C. difficile immediately after specimen procurement for patients with more severe symptoms consistent with CDI A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359: The Society for Healthcare Epidemiology of America

45 Treatment of Initial Infection - severe disease Regime: Oral vancomycin, 125 mg every 6 hours for 10 to 14 days Oral vancomycin also indicated for - metronidazole contraindications or intolerance - inadequate response to metronidazole treatment - proven metronidazole resistance strains - pregnancy - age <10 yo

46 Treatment of Initial Infection - severe disease Consulted surgeons: Peritoneal signs / suspicion of acute abdomen Severe ileus Toxic megacolon Implications: monitor IO, AXR closely

47 How to define severe infection? No consensus Predictors of fatal outcome Poor comorbidity status High WCC counts (>20 asso. with 18% mortality) Low diastolic BP Clinical signs of sepsis Renal impairment Presence of pseudomembranous colitis on endoscopy

48 Rationale of use of flagyl? Response Rates to Vancomycin and Metronidazole Therapy, According to the Severity of C. difficile Infection Oral vancomycin is generally reserved as 2 nd line to minimize the emergency of vancomycin resistant strains Kelly C, LaMont J. N Engl J Med 2008;359:

49 Comparison of minimal inhibitory conc (MICs) and resistance rates of C. difficile isolates from different countries Most isolates are still susceptible to vancomycin and metronidazole (MTZ) Haihui Huang et al; Antimicrobial resistance in Clostridium difficile; International Journal of Antimicrobial Agents 34 (2009)

50 Recurrent C. Difficile Infection

51 Risk factors for recurrence History of recurrence Age Use of additional / multiple antimicrobials Inadequate protective immune response Inadequate treatment Infection by hypervirulent strains Proton pump inhibitor use during incident CDI ICU stay / Long hospital stay Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359: Saima Aslam, Richard J Hamill, Daniel M Musher; Treatment of Clostridium difficile-associated disease: old therapies and new strategies; Lancet Infect Dis 2005; 5:

52 Mechanism of recurrence Poorly understood Rarely related to antimicrobial resistance Impaired immunity Could be re-infection by the same strain or infection by a new strain Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

53 Recurrence of C. Difficile Infection Typically occurs 1-2 weeks after stopping metronidazole or vancomycin. Recurrence rates following treatment with metronidazole or vancomycin are 20%. 2nd recurrence: > 40% risk of recurrence. 3rd recurrence: > 60% risk of recurrence. Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

54 Management of 1 st recurrence Same as for initial episode. Metronidazole [Flagyl] 500 mg tds po for 10 to 14 days. Vancomycin 125 mg QID po for 10 to 14 days. Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

55 Management of 2 nd recurrence Vancomycin in TAPERED and PULSED doses (response rate 86% ): 125 mg QID po for 14 days 125 mg BD for 7 days 125 mg daily for 7 days 125 mg every 2 days for 8 days [4 doses] 125 mg every 3 days for 15 days [5 doses] Prolonged metronidazole therapy is not advocated because of risk of peripheral neuropathy Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

56 Management of 3rd recurrence Vancomycin 125 mg QID po for 14 days and then Rifaximin 400 mg BD for 14 days (not available in HA formulary). Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

57 Back to our patient again

58 2 nd recurrence in our patient Tx: Started on Pulsed and Tapered dose of vancomycin. Still persistent watery diarrhea after around 1.5 weeks of treatment Impression: refractory disease Dec Jan Feb Mar Apr May Jun UTI Pneumonia C.Difficile infection UTI C.Difficile infection (First recurrence) C.Difficile infection (Second recurrence)

59 Most respond after 1 week of Tx

60 Management of refractory disease / not responding to initial agent(s) Change oral metronidazole to oral vancomycin Add IV Metronidazole 500 mg Q8H i.v. (IV vancomycin is not useful) Vancomycin enema usage of rectal tube with instillation of vancomycin (500 mg vancomycin into 1L of normal saline at 1-3 ml/min to maximum of 2 gram in 24 hrs). Reference: QMH microbiologists

61 Summary of Tx for CDAD Initial Management First recurrence Second recurrence Third recurrence Refractory and multiple recurrences For all Strict Contact precaution consider stopping the inciting antibiotics Mild Po Flagyl for days Same as initial Pulsed vancomycin -Vancomycin enema -intrgastric vancomycin -rifaximin -add iv flagyl Consider novel agents Severe Po Vancomycin for days Same as initial Pulsed vancomycin -Vancomycin enema - intrgastric vancomycin -rifaximin -add iv flagyl +/- intensive care +/- intensive care +/- intensive care

62 Novel therapy for refractory disease / multiple recurrences

63 Novel therapy 1. New antibiotics 2. Probiotics 3. IVIG 4. Monoclonal antibodies 5. Fecal Microbiota Transplantation

64 New antibiotics Fidaxomicin was approved in 2011 for treatment of CDI by USA FDA New class of narrow spectrum antibiotics Selective eradication of C. difficile with minimal disruption to the bacteria that make up the normal healthy intestinal flora A 20 tab pack costs upwards of Not a/v in HA formulatory

65 Probiotics Probiotics (S. Boulardii, lactobacillus species) Insufficient evidence for prophylactic measures Insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for colitis or alone in the treatment of colitis. May consider in refractory or recurrent diseases Risks do present (reports of fungemia) Reference: - Pillai, Anjana. Nelson, Richard L; Probiotics for treatment of Clostridium difficile-associated colitis in adults; Cochrane Database of Systematic Reviews. 1, Gareth C Parkes, Jeremy D Sanderson, Kevin Whelan; The mechanisms and effi cacy of probiotics in the prevention of Clostridium diffi cile-associated diarrhoea; Lancet Infect Dis 2009;9:

66 IVIG as an option for recurrent infection IVIG 400 mg/kg once every 3 weeks for 2 or 3 doses case series for patients with relapsing or severe C. difficile colitis No RCT yet Reference: A 76-Year-Old Man With Recurrent Clostridium difficile-associated Diarrhoea; JAMA, March 4, 2009 Vol 301 No Kelly C, LaMont J. N Engl J Med 2008;359:

67 Monoclonal antibodies Against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion in symptomatic CDAD patients in addition to antibiotics (VAN or MTZ) rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). Lowy I et al. N Engl J Med 2010;362:

68 Time to Recurrence of Clostridium difficile Infection Lowy I et al. N Engl J Med 2010;362:

69 Fecal Microbiota Transplantation An RCT published in the NEJM Jan 2013 Excellent efficacy in treatment of recurrent / refractory C.difficile infection 94% vs 31% cure rate by vancomycin Study is terminated prematurely because unethical NOT to offer this treatment to all patients in the study Accepted by patients? Van Nood E et al; "Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile". N Engl J Med368 (5):

70 Back to our patient

71 Our patient Started on IV Metronidazole for 2 weeks (Microbiologist s suggestion) Diarrhoea improved Dec Jan Feb Mar Apr May Jun Jul Aug UTI Pneumonia C.Difficile infection UTI C.Difficile infection (First recurrence) C.Difficile infection (Second recurrence)

72 Our patient Well until now after the 2 nd recurrence (which was treated with oral vancomycin and IV flagyl) Dec Jan Feb Mar Apr May Jun Jul Aug UTI Pneumonia C.Difficile infection UTI C.Difficile infection (First recurrence) C.Difficile infection (Second recurrence) Discharged

73 Conclusions Geriatrics patients possess many risk factors for C. Difficile infection Judicious use of antibiotics AND hand hygiene are important to prevent the disease Adequate treatment of C. Difficile infection is important to reduce recurrence Consult surgeons in case of severe disease Outcome is poorer in older adults Existence of hypervirulent strain

74 Thank you