escmid online lecture library by author enemy”

Helen Giamarellou, MD, PhD Athens, Greece

“Clostiridium difficile:

Battling the New Enemy”

ESCMID Online Lecture Library

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CDI: Incidence in Europe (2008: 34 countries)

Finland

Austria

Italy

Spain Turkey

Georgia

Syria

Iraq

Iran

Kazakhstan

Azerbaijan

Armenia

Lebanon

Cyprus

Sweden

Norway

Germany

France

Portugal

Hungary

Romania

Bulgaria

Denmark

Poland

Belarus

Ukraine

Czech Rep. Slovakia

Greece

Malta

Netherlands

Liechtenstein

San Marino

Belgium

Ireland

Serbia

Montenegro

Albania

Moldova

Lithuania

Latvia

Estonia

Luxembourg

Andorra

Bosnia &

Herzegovina

Croatia Slovenia

Switzerland

Macedonia

Iceland

Russia

Russia United Kingdom

<1/10,000

1–2/10,000

2–5/10,000

5–10/10,000

>10/10,000

Bauer MP et al, Lancet 2011;377:63–73


© by author

CDI: Epidemiology in Europe

Healthcare 80%

Community

16%

Indeterminate



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CDI: Mortality

Data Cases % Death 101/455 22% Death related 40/455 40%

Clostiridium difficile infection in Europe: A Hospital Based Survey



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The Pool of Clostiridium difficile

The Hospital Pool: 20-40% colonization

Patients, health care workers, the contaminated nosocomial environment

Residents of Health Care Facilities

The Community Pool: 20-41% colonization

Usually without risk factors

Soil, waters, meat, vegetables, domestic animals

S.O.S.: Normal neonates until 1 year of age: 5-70% colonization

CID 2012; 55: 1209


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Factors Associated with the Increased Nosocomial Incidence of CDI

1. Inadequate number of nursing staff

2. Decreased compliance in Hand Hygiene

3. Inadequate environmental desinfection

4. Fast patients discharge and new-admissions

5. Common toilets

6. Lack of wards for isolation

7. Prevalence of virulent strains BI/NAP1/027 and 078 associated with individuals not “in risk” and the animal chain respectively


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Well Known and Emerging Risk Factors for Clostridium difficile Infection in Adults

Factors related to the patient

• Age greater than 65 years

• Prolonged duration of hospital stay

• Previous gastrointestinal surgery

Comorbidity or underlying conditions

• Inflammatory bowel diseases (IBDs)

• Immunodeficiency and HIV

• Malnutrition • Low serum albumin level

(<2.5 g/dl) • Neoplastic diseases • Cystic fibrosis (risk of

severe or fulminant disease, mainly post lung transplantation)

• Diabetes

Pharmacological therapies and special treatments

• Prolonged use of antibiotic

• Antineoplastic chemotherapies

• Use of proton pump inhibitors: • Conflicting Evidence:

rather a marker of multiple co-existing comorbidities!

• Solid organ transplantation

• Hematopoietic stem cell transplantation

• Narcotic and antidiarrheal medication

Lo Vecchio A, Zacur G. Curr Opin Gastroenterol 2012;28:1-9


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Antimicrobial Agents that May Induce Clostiridum difficile Diarrhoea and Colitis

Frequently associated

• Fluoroquinolones • Clindamycin • Penicillins (broad

spectrum)

Occasionally associated

• Macrolides • Trimethoprim • Sulfonamides

Rarely associated

• Aminoglycosides • Tetracyclines • Chloramphenicol • Metronidazole • Vancomycin

96% of patients with CDI have received antibiotics within the 14 days previous days and 100% within the previous 3 months


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The Risk of CDI: Adjusted hazard Ratio

Characteristic Adjusted hazard ratio (95% CI)

Quinolones 4.0 Third- and fourth- generation cephalosporins 3.1 Vancomycin 2.6 First- and second- generation cephalosporins 2.4 β-lactamase inhibitor combinations 2.3 Clindamycin 1.9 Sulfas 1.9 Macrolides 1.5 Miscellaneous 1.3 Aminoglycosides 0.9 Metronidazole 0.3

CID 2011;53:42


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Of 320 participants, 9.7% were positive for toxigenic CD. Using

multivariate logistic regression, independent predictors of CD

colonization were recent hospitalization, chronic dialysis and

corticosteroid use.

Screening patients with risk factors would identify 74% of CD carriers.


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Role of host antibody-mediated responses in CDI pathogenesis: Not all colonized patients become infected. Why?

Rupnik et al. Nat Rev Microbiol 2009;7:526–6.

Patients with risk factors for CDI,

including antibacterial use in hospital setting

Exposure to toxigenic C. difficile accompanied by

IgG response to toxin A

C. difficile negative

Asymptomatically colonised

Asymptomatically colonised

Symptomatic CDI

Exposure to toxigenic C. difficile without

an IgG response to toxin A

Exposure to non-toxigenic C. difficile

CDI, Clostridium difficile infection; IgG, Immunoglobulin G antibody

Figure reproduced with permission


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CDI: Clinical Presentations

Bartlett J & Gerding D, Clin Infect Dis 2008;46:S12–18

15 – 25% of antibiotic-associated diarrhoea result to CDI

Fulminant colitis

Pseudomembranous colitis

Non-specific colitis

Colonisation


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Das Bild kann zurzeit nicht angezeigt werden.

Clinical Manifestations of CDAD

Type of infection GI tract symptoms Systemic signs Laboratory findings

Mild (non specific colitis)

4-5 UBM/day - WBC: ≤12.000mm3

No blood

Moderate (with of without pseudomembranes)

6-10 UBM/day Anorexia, fever, malaise, dehydration

WBC: ~15.000mm3 Occult blood

Severe

>10 UBM/day or little diarrhoea with severe abdominal pain

High fever with chills WBC: 15.000mm3 → 50.000mm3

Occult blood

Severe complicated Ileus Hypotension, Lethargy shock, toxic megacolon

Leukemoid reaction → 100.000 mm3 Poutanen & Simor. CMAJ 2004;171:51–8;

Kelly & LaMont. Annu Rev Med 1998;49:375–90; Rupnik et al. Nat Rev Microbiol 2009;7:526–36;

Bauer et al. Clin Microbiol Infect 2009;15:1067–79.


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Treatment Guidelines for CDI

General Measures:

• Discontinuation of inciting antibiotics

• Discontinuation of acid suppression therapy (PPIs!)

• Review of risk factors for CDI

• Avoid antiperistaltic medications

• Adequate replacement of fluid and electrolytes

• Patients may have regular diet as tolerated

• Appropriate attention to infection prevention and control

Current Opinion in Gastroenterology 2011, 27:38–47


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Mild-to-Moderate CDI: First episode or First Relapse

• Oral metronidazole 500mg, three times daily for 10-14 days

• Limitations: Metronidazole Dose-dependent peripheral neuropathy-nausea-metallic taste

• Alternative: Vancomycin


Treatment Guidelines for CDI Stratified by Disease Severity

The Classical Therapy


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Severe CDI

• Oral vancomycin 125-250mg, four times

daily for 10-14 days



The Classical Therapy


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Severe, complicated CDI as suggested by:

• Rising serum Lactic Acid levels, Hypotension, Shock, Ileus, Megacolon

• Vancomycin 500mg, oral or nasogastric administration four times daily -never iv-

plus

• Metronidazole 500mg, intravenous administration three times daily

• Consider intracolonic vancomycin 500mg in 100ml saline, four to six times daily if ileus present or suspected

• Surgical Intervention Current Opinion in Gastroenterology 2011, 27:38–47


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Clinical Limitations Associated With Classical Therapy for CDI

• Therapy remains suboptimal: Why? • Among the most significant drawbacks of current therapy for

CDI are: – Rates of treatment failure with metronidazole of

approximately 18% plus longer time to resolution of diarrhea

– Recurrent infection following treatment with metronidazole and vancomycin of up to 29% within 30 days following treatment

– Risk of overgrowth of vancomycin-resistant enterococci (VRE) in patients who are already colonised with VRE

Aslam et al. Lancet Infect Dis 2005;5:549–57; Louie et al. N Engl J Med 2011;364:422–31; Lowy et al. N Engl J Med 2010;362:197–205;

Bouza et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4; Al-Nassir et al. Antimicrob Agents Chemother 2008;52:2403–6.


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ESCMID Recommendations for Surgical Intervention

• In the minority (<5%) of patients who develop fulminant colitis:

– Subtotal Colectomy plus

– Diverting loop ileostomy (with vanco lavage)

• Surgical intervention carries a high rate of mortality

• Optimal timing for colectomy has not been established

• Patients with Megacolon may benefit from colonoscopic decompression and placement of a tube in the right colon perfused with 1mg/ml solution of Vancomycin (1-2g/day)

• Current guidelines recommend surgical intervention before:

– The disease becomes too severe

– Serum lactate levels exceed 5 mmol/L

Bauer et al. Clin Microbiol Infect 2009;15:1067–79.


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Initial episode

First recurrence

Second recurrence

80%

60%

40%

20%

0%

Recurrence rate

McFarland et al. JAMA 1994;271:1913–8; Pépin et al. Clin Infect Dis 2005;40:1591–7; McFarland et al. Am J Gastroenterol 2002;97:1769–75.

~25%

~65%

~45%

Prior CDI recurrence and recurrence risk

*

* Up to 85%


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Risk Factors for Recurrence of CDI

• Patients at high risk of recurrence or for whom the impact of recurrence would be most dramatic include those who:

– Are immunocompromised

– Are on certain concomitant antibiotics

– Have had CDI previously

– Are renally impaired

– Are aged 65 years or over

– Are prolonged hospitalized and/or ICU stay


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Why Recurrence of CDI?

• Recurrence appears to be related to a combination of:

– A failure to re-establish the colonic microflora

– The presence in the intestines of spores of C. difficile

– A sub-optimal host immune response to the infecting organism and its toxins

Bauer et al. Clin Microbiol Infect 2009;15:1067–79; Louie et al. N Engl J Med 2011;364:422–31; Lowy et al. N Engl J Med 2010;362:197–205;

Bouza et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4; DuPont. N Engl J Med 2011;364:473–4.


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Treatment of CDI Recurrences: The Classical Approach

First relapse

-Metronidazole as in mild or moderate 1st episode

Second relapse

-Tapering and pulsed oral vancomycin, with of without probiotics (Saccharomyces boulardii 500mg orally twice daily) as follows:

• 125mg orally four times daily for 7 to 14 days

• 125mg orally twice daily for 7 days

• 125mg orally once daily for 7 days

• 125mg orally every other day for 7 days

• 125mg orally every 3 days for 14 days

UpToDate 2012


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Treatment of CDI Recurrences: The Classical Approach

Subsequent Relapses

• Vancomycin 125-250mg orally four times daily for 14 days, followed by rifaximin 400mg twice daily for 14 days

UpToDate 2012


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The Rationale for a New Treatment

• CDI remains a disease for which there are significant unmet needs e.g.:

– Therapy to provide sustained clinical cure

– Therapy to reduce recurrence (relapse and/or reinfection)

– Better identification of patients at risk of recurrence or those for whom the impact of recurrence would be most dramatic

• A new agent that effectively treats an acute episode of CDI simultaneusly reducing recurrence would represent a significant therapeutic advance: Is it available? ESCMID Online Lectu

re Library

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Alternative Therapies in the Treatment of CDI: Which Would be the Ideal Drug?

• Alternative antibiotics

– Fidaxomicin

– Fusidic acid

– Nitazoxanide

– Teicoplanin

– Ramoplanin

– Rifampin

– Rifaximin

– Bacitracin

• Anion-bunding resins

– Colestipol-Cholestyramine

– Tolevamer

• Probiotics

• Immunoglobulins

• Monoclonal antibodies

• Fecal bacteriotherapy

• Vaccines (!) ESCMID Online Lectu

re Library

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Tolevamer: Nonabsorbable Anionic Polymer

• Bind to C. difficile toxins in vitro

• Non inferior to Vancomycin in mild cases

• Not to be given simmultaneusly with Vancomycin because it binds Vancomycin preventing its activity

CID 2006;43:411


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Clinical Response Rates at the End of Therapy in the First Phase 3 Tolevamer Trial

Trial No. cured/total no. in group (%) Difference (%) (95% CI)

Study drug Tolevamer

Comparator Metro

Tolevamer vs metronidazole

124/266 (47%) 103/143 (72%) - 25.4 (-34.9 to -15.9)

Johnson S, et al. AAC 2012;56:4043

Conclusion: Tolevamer was inferior to metronidazole

Patients were randomized to receive 9g loading dose of Tolevamer followed by 3g every 8h x14 days

versus metronidazole 375mg every 6h x10 days


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Nitazoxanide

• Nitazoxanide, an intenstinal antiparasitic drug, exhibits in-vivo and in-vitro activity against C. difficile.

• It is at least as effective as metronidazole in treating hospitalized adults with C. difficile colitis and those who failed metronidazole therapy.

• Its efficacy against CDI seems to be comparable to vancomycin.

• Suggested as salvage therapy for refractory or recurrent CDI?



© by author

Rifaximin

• It has a negligible impact on the intestinal microbiome, and excellent in-vitro activity against Clostiridium difficile

• Used off-label for the treatment of multiple recurrence of CDI

• A resolution rate of 86% for patients with recurrent CDI postvancomycin treatment has been demonstrated (400mg x2 x2 weeks)

• The potential for C. difficile to develop resistance against rifaximin, however, could limit its routine use



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Intravenous Tigecycline as Adjunctive or Alternative Therapy for Severe Refractory

Clostridium difficile Infection

• Four patients with severe refractory CDI who were successfully treated with tigecycline are described

• Symptoms improved within 1 week

• No relapses were observed

• This favorable outcome suggests that tigecycline might be a useful alternative for treating severe refractory CDI

• However, a recent case refused its efficacy and demonstrated the acquisition of other antimicrobial resistant microorganisms CID 2009;48:1732

Curr Opin Gastroenterol 2012;28:1-9


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Probiotics: For Prophylaxis or as Therapeutic Supplements?

• Evidence supporting the benefit in CDI remains sparse

• Saccharomyces boulardii and a blend containing Lactobacilli as prophylactic treatment for CDI reported a significantly reduced risk of CDI in hospitalized patients on antibiotics

• However, there is insufficient evidence to make strong consensus recommendations

• S.O.S.:Break-through bacteremias-fungemias in immunocompromised patients



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Intravenous Immunoglobulin

• IVIG has been used to treat recurrent and severe CDI with varying results

• It has been suggested that IVIG may be a useful adjunctive treatment option in those who have failed initial therapies or in seriously ill patients in whom surgery is being considered and whenever CDI is confined to colon

Lo Vecchio A, Zacur G. Curr Opin Gastroenterol 2012;28:1-9 Abougerg I, et al. J Hosp Med 2010;5


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Monoclonal Antibodies

• A large multicenter, randomized, double-blind, placebo-controlled trial of two fully human neutralizing monoclonal antibodies against C. difficile toxins A and B.

• Treatment was associated with a 72% relative reduction in recurrence rates compared to placebo; however, it did not reduce the severity of infection, the duration of diarrhea or hospitalization.

• Further studies are required to establish the role of monoclonal antibodies in CDI therapy and their cost-effectiveness.



© by author

Fidaxomicin (DIFICLIR™) chemical structure

• First in a new class of antibacterials known as macrocycles

• Fermentation product from Dactylosporangium aurantiacum • Main metabolite of fidaxomicin is the hydrolysis product, OP-1118 • DIFICLIR inhibits bacterial DNA-dependent RNA polymerase1,2

– Results in inhibition of the initiation of bacterial RNA synthesis – Causes cell death

Fidaxomicin (C52H74Cl2O18)

Miller. Expert Opin Pharmacother 2010;11:1569–1578; Swanson et al. Antimicrobial Agents Chemother 1991;35:1108–11; Astellas Pharma Europe Ltd. Data on file, FDX/11/0003/EU. Sergio et al. J Antibiotics 1975;28:543–9;

Astellas Pharma Europe Ltd. DIFICLIR (fidaxomicin). Summary of Product Characteristics, 19 December 2011.



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Treatment Trials of Clostridium difficile-Associated Diarrhea

• Fidaxomicin was recently approved by the FDA

(May 2011) and Europe (March 2012) for the

treatment of CDAD on the basis of noninferiority

to vancomycin for an initial cure at the end of

therapy and superiority for a sustained response

25 days after therapy.



© by author

Indication, Posology and Administration of Fidaxomicin

Fidaxomicin (DIFICLIR™)

Posology and administration DIFICLIR is intended for oral administration

Supplied as capsule-shaped, film-coated tablets containing 200 mg fidaxomicin

Recommended dose is 200 mg bid for 10 consecutive days



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In vitro activity of fidaxomicin against C. difficile isolates: Susceptibility breakpoint (<1μg/ml)

No. isolates tested

MIC50 μg/mL MIC90 μg/mL MIC range μg/mL

21 ≤0.016 ≤0.125 ≤0.016–0.25

23 ≤0.12 ≤0.25 0.06–2

207 ≤0.002 ≤0.008 ≤0.001–0.06

110 0.125 0.125 0.015–0.25

208 0.25 0.5 0.06–1

Credito & Appelbaum. Antimicrob Agents Chemother 2004;48:4430–4; Finegold et al. Antimicrob Agents Chemother 2004;48:4898–902; Ackermann et al. Antimicrob Agents Chemother 2004;48:2280–2;

Hecht et al. Antimicrob Agents Chemother 2007;51:2716–19; Karlowsky et al. Antimicrob Agents Chemother 2008;52:4163–5.

MIC, minimum inhibitory concentration required to inhibit 50%/90% of organisms

• Fidaxomicin shows excellent in vitro activity against all strains of C. difficile that have been tested ESCMID Online Lectu

re Library

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Fidaxomicin PK/PDs

• Very low serum levels: 7.1-23.9 ng/ml

• T1/2: 8-10 hours

• >92% fecal excretion 906

1636 mg/day

• Mean fecal levels were >5000 times the MIC for C. difficile of 0.25μg/ml

Shue et al. Antimicrob Agents Chemother 2008;52:1391–5.


© by author

Bactericidal effects against C. difficile strains

Babakhani et al. J Med Microbiol 2011;60:1213–37.

1

104

1

102

1

108

CFU

/mL 1

106

2 48 6 24

Control (no drug)

Fidaxomicin (4 x MIC; 0.5 µg/mL)

Vancomycin (4 x MIC; 4 µg/mL)

In vitro activity of fidaxomicin and vancomycin against C. difficile strain ATCC 43255 over time

Time (hours)

• Bactericidal activity is defined as a 3 log10 reduction in CFU



© by author

Post-antibiotic effect

• Due to the rapid transit time in the bowel associated with severe diarrhoea there is a risk that a drug is eliminated from the bowel before the next dose is given

• Antibacterials with a prolonged PAE may have the potential to provide antibacterial activity against C. difficile even in the absence of therapeutic concentrations

– This may offer protection between doses

– A prolonged PAE may also permit less frequent dosing

• PAE for fidaxomicin was 5.5 h vs. 1.5–3 h for Vancomycin and 3h for Metronidazole

Babakhani et al. Antimicrob Agents Chemother 2011;55:4427–9.


© by author

Inhibition of C. difficile sporulation

Gomez et al. ICAAC 2011;C1-632.

Effect of exposure to fidaxomicin or vancomycin on sporulation by C. difficile strain ATCC 43255

1.0

109

3 23 48 72 96 Time (hours)

Spor

e CF

U/m

L

120 144 168

Control (no drug) Fidaxomicin (1/4 x MIC) Vancomycin (1/4 x MIC)

1.0

107

1.0

105

1.0

103

Detection limit

Drug added 192 216



© by author

Inhibition of C. difficile toxin production

Toxi

n co

ncen

trat

ion

ng/m

L

Sims et al. ICAAC 2011;C1-634.

Effect of exposure to fidaxomicin and vancomycin on C. difficile toxin production


© by author

Is Fidaxomicin Active Against Other Gram-positive bacteria?

• Fidaxomicin has MICs in the range of 2–16 μg/mL against Enterococcus spp.

– Fidaxomicin is 2–4-fold less active against Enterococci than vancomycin (MIC range 0.5–4 μg/mL)

– Synergy with Rifaximin

1. Finegold et al. Antimicrob Agents Chemother 2004;48:4898–902; 2. Nerandzic et al. ICAAC 2009; K-1915.


© by author

7%

33%

0%

10%

20%

30%

40%

DIFICLIR Vancomycin

Patie

nts w

ho

acqu

ired

VRE

(%)

Low risk of acquisition of VRE because of the modest activity of fidaxomicin against enterococci

p<0.001

Comparative effects of fidaxomicin and vancomycin on acquisition of VRE

Fidaxomicin Vancomycin

Nerandzic et al. ICAAC 2009; K-1915.


© by author

Phase 3 Registration Trials: Study Design

30-day follow up

Fidaxomicin 200 mg bid

Vancomycin 125 mg qid

10 days of treatment Baseline assessment

Assessment at end of

treatment

Assessment at end of

study

Louie et al. N Engl J Med 2011;364:422–31; Cornely et al. Lancet Infect Dis 2012;12:281–9.

Fulminant colitis and toxic megacolon cases (i.e. severe complicated) as underlying

Crohn disease and Ulcerative colitis were excluded

1st episode or 1st recurence

included


© by author

Distribution of Patients Treated with Fidaxomicin According to CDAD Severity

Degree of Severity

Study 003 Study 004

Fidaxomicin (N=287)

Vancomycin (N=309)

Fidaxomicin (N=252)

Vancomycin (N=257)

Mild 22.3% 25.9% 30.6% 37.0%

Moderate 38.7% 34.3% 32.5% 28.4%

Severe 39.0% 39.8% 35.7% 34.2%

Baseline disease severity categories defined as: Mild, 4–5 UBM/day or WBC ≤12,000/mm3; Moderate, 6–9 UBM/day or WBC 12,001–15,000 mm3; Severe, ≥10 UBM/day or WBC ≥15,001/mm3

Astellas Pharma Europe Ltd. Data on file, FDX/11/0011/EU; Astellas Pharma Europe Ltd. Data on file, FDX/11/0012/EU.

Data from mITT population


© by author

Rates of Clinical Cure

mITT PP

Louie et al. N Engl J Med 2011;364:422–31; Astellas Pharma Europe Ltd. Data on file, FDX/11/0012/EU;

Astellas Pharma Europe Ltd. Data on file, AI/11/0004/EU.

No difference among mild, moderate or severe cases


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Fidaxomicin vs Vancomycin in CDI: Rates of Recurrence

p=0.005 p=0.004 p<0.001 p=0.002

mITT PP

Louie et al. N Engl J Med 2011;364:422–31; Astellas Pharma Europe Ltd. Data on file, FDX/11/0012/EU;

Astellas Pharma Europe Ltd. Data on file, AI/11/0004/EU.


© by author

Sustained Clinical Response as an Endpoint in Treatment Trials of Clostridium difficile-

Associated Diarrhea

• Sustained response is a new clinical endpoint

proposed to account for differences among

treatment agents, i.e. resolution of diarrhoea

without recurrence.



© by author

Fidaxomicin vs Vancomycin: Rates of Sustained Clinical Cure

p=0.006 p=0.006 p=0.001 p<0.001

mITT PP Louie et al. N Engl J Med 2011;364:422–31; Astellas Pharma Europe Ltd. Data on file, FDX/11/0012/EU; Astellas Pharma Europe Ltd. Data on file, AI/11/0004/EU.


© by author

Rates of second CDI recurrence

Astellas Pharma Europe Ltd. Data on file, FDX/11/0014/EU.

Data from pooled analysis

p=0.045


© by author

Recurrence Rates in Severe CDI %

pat

ien

ts

Louie και Συν. N Engl J Med 2011, 364:422-31, Cornely et al. Lancet Infect Dis 2012;12:281–9.

P=0.005 P=NA


© by author

Sustained Clinical Response in Severe CDI %

pat

ien

ts

Louie και Συν. N Engl J Med 2011, 364:422-31, Cornely et al. Lancet Infect Dis 2012;12:281–9.

P=NS P < 0.012


© by author

• Whereas vancomycin and fidaxomicin are equally effective in resolving CDI symptoms, preservation of the microflora by fidaxomicin is associated with a lower likelihood of CDI recurrence, because it provides colonization resistance in the colon.

CID 2012;55:S132 AAC 2012;56:4043


© by author

• Analysis of the combined 003/004 data for 1164

patients showed that fidaxomicin reduced persistent

diarrhea, recurrence, or death by 47% (P <.0001)

compared with vancomycin through day 40.

CID 2012;55:S93


© by author

Efficacy of Fidaxomicin Versus Vancomycin as Therapy for Clostridium difficile Infection in Individuals Taking Concomitant Antibiotics

for Other Concurrent Infections

• Treatment guidelines recommend stopping all implicated antibiotics at the onset of Clostridium difficile infection, but many individuals have persistent or new infections necessitating the use of concomitant antibiotics

• Subjects with CDI were treated for 10 days with fidaxomicin 200 mg every 12 hours or vancomycin 125 mg every 6 hours, assessed for resolution of symptoms, and followed up for an additional 4 weeks for evidence of recurrence.

Mullane K, et al. CID 2011;53:440


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Clinical cure in patients on concomitant antibiotics

Mullane et al. Clin Infect Dis 2011;53:440–7.

p=0.80 p=0.04


807 pts 192 pts


© by author

Effect of concomitant antibiotics on CDI recurrence

12.2

17.2

11.5

21.3

11.9

16.9

23.4

30.0

23.9

27.9

23.1

29.2

0

10

20

30

40

−CA +CA −CA +CA −CA +CA

Treatment (Days 1–10)

Follow-up (Days 11–40)

At any time (Days 1–40)

Patie

nts (

%)

FidaxomicinVancomycin

p<0.001 p<0.001 p=NS p=NS p<0.001 p=0.048

Mullane et al. Clin Infect Dis 2011;53:440–7.



© by author

Effect of concomitant antibiotics on sustained clinical cure

p=0.02 p<0.001

Mullane et al. Clin Infect Dis 2011;53:440–7. Data from pooled analysis

Why and How? By reducing the

risk of regrowth or residend C. difficile ESCMID Online Lectu

re Library

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Emergence of Resistance to Fidaxomicin

• Low propensity for resistance development

• No shifts in MIC during fidaxomicin therapy

• No cross-resistance with existing classes of antibacterial agents

Swanson et al. Antimicrob Agents Chemother 1991;35:1108–11; Astellas Pharma Europe Ltd. Data on file, FDX/11/0024/EU;

Astellas Pharma Europe Ltd. Data on file, FDX/11/0009/EU; Louie et al. N Engl J Med 2011;364:422–31.


© by author

The Incidence of Adverse Effects

Preferred AE term, n (%) Fidaxomicin (N=564)

Vancomycin (N=583)

Any AE 373 (66.1) 372 (63.8) Nausea 56 (9.9) 58 (9.9) Hypokalaemia 40 (7.1) 35 (6.0) Headache 35 (6.2) 25 (4.3) Vomiting 34 (6.0) 34 (5.8) Abdominal pain 32 (5.7) 18 (3.1) Diarrhoea 17 (3.0) 26 (4.5) Any AE leading to discontinuation 45 (8.0) 49 (8.4)

All-cause mortality 36 (6.4) 38 (6.5)


Commons AE (1:10): vomits, nausea, constipation


© by author

Overview of Fidaxomicin Drug Interactions: Cytochrome P450 system

• No dose adjustment is necessary when fidaxomicin is co-administered with drugs that are CYP substrates

• Fidaxomicin should not be co-administered with drugs that are potent P-gp inhibitors, i.e. Cyclosporine, Digoxin, Amiodorile


Drug Metabolic pathway Potential for interaction

Warfarin CYP2C9 substrate None

Omeprazole CYP2C19 substrate None

Midazolam CYP3A4/5 substrate None


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Patient population Recommendation Older patients (≥65 years) No dosage adjustment necessary

Paediatric Avoid use; there are no data in this population

Kidney dysfunction No dosage adjustment necessary, use with caution in severe kidney dysfunction due to limited clinical data

Liver dysfunction No dosage adjustment necessary, use with caution in moderate-to-severe liver dysfunction due to limited clinical data

Inflammatory bowel disease No data, use with caution

Pseudomembranous colitis Limited data; use with caution

Pregnant No data; avoid use

Breastfeeding

Exposure of drug to newborns/infants via breast milk cannot be excluded. Consider whether to discontinue breastfeeding or to discontinue/abstain from DIFICLIR therapy

Use of Fidaxomicin in Specific Patient Populations



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Conclusions: Fidaxomicin vs Vancomycin in CDI

• Fidaxomicin compared to Vancomycin is non inferior in CDI clinical cure, but more effective reducing subsequent recurrences of CDI by 47% translating into clinically significant sustained clinical cure as a result of lack of disturbance of “colonization resistance” in the gut flora

• Patients on concomitant antibiotics treated with Fidaxomicin exhibited significantly batter cure rates, lower rates of recurrence and greater rates of sustained clinical cure versus Vancomycin treated patients

• No difference in patients infected with the hypercirulent 027 strain of C. difficile was observed

• Fidaxomicin is well-tolerated with a safety profile comparable to oral Vancomycin

CID 2012;55:593


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Fidaxomicin: Budget Impact Analysis

The cost of 10 days therapy in 100 patients

Administration of Fidaxomicin for the 1st episode of CDAD plus 11 recurences: 8.131 Euros

Administration of Fidaxomicin post Metronidazole + Vancomycin regimen for 37 recurences: 15.886 Euros

London New Drugs Group www.nelm.nhs.uk, July 2012


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http://www.nelm.nhs.uk/

Fecal Microbiota Transplantation (FMT)

• It was recently reported that Intenstinal Microbiota Transplantation was effective in 91% (>500 patients) and 98% with the 2nd FMT of CDI. The response appears rapid and enduring.

• The first (FECAL trial) assesses the efficacy of a 4-day vancomycin treatment followed by fecal infusion and subsequent conventional 14-day vancomycin therapy, is under way.

• Barriers to the use of bacteriotherapy include acceptability of treatment, a minimal risk of transmitting pathogens from the donor, and the theoretical risk of small intestinal bacterial overgrowth after duodenal installation of feces.

Brandt LJ. CID 2012;55:1659 Lo Vecchio A, Zacur G. Curr Opin Gastroenterol 2012;28:1-9


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Prevention of CDI

• The major step in prevention of CDI is appropriate use of antimicrobial therapy

• Early reliable detection and in-hospital isolation of infected or suspected patients to interrupt patient to patient transmission

• Thorough hand hygiene with chlorhexidine gluconate - containing soap

• Not ethanol solutions because these do not kill spores

• Wearing protective gowns by all healthcare providers after every contact with a patient with suspected or known CDI are essential.

• Appropriate cleaning of rooms vacated by patients with CDI, preferably employing sodium hypochlorite, is also essential.

MMWR 9 March 2012 Am J Med Sci, 1 Sept 2011


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• Cumulative antibiotic exposures appear to be associated with the risk of CDI.

• Antimicrobial stewardship programs that focus on the overall reduction of total dose as well as number and days of antibiotic exposure and the substitution of high-risk antibiotic classes for lower-risk alternatives, may reduce the incidence of hospital-acquired CDI.

CID 2011;53:42

In the Mean Time…


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• 2305 patients were studied

• 43 patients developed CDI within 30 days of ceftriaxone receipt, an incidence of 5.60 cases per 10 000 patient-days.

• The incidence of CDI was 1.67 cases per 10 000 patient-days in those receiving doxycycline, in addition to ceftriaxone

CID 2012;55:615


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Why Doxycycline is Associated with Lower CDI Risk?

1. In vitro activity against anaerobic bacteria, including C. difficile

2. As a protein synthesis inhibitor, doxycycline attenuates C. difficile toxin production

3. Maximal absorption in the upper gastrointestinal tract with minimal effects on gut flora

Doernberg S, et al. CID 2012;55:615


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However…

• To start therapy of CDAD the soonest,

as well as to apply prophylaxis measures,

prompt diagnosis is required


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First report from European, multi-centre, prospective bi-annual point prevalence study of C. difficile

Infection in hospitalised patients with Diarrhoea (EUCLID)

• Objectives: To measure the extent of under-testing and under-detection of C. difficile infection (CDI) in 20 European countries in 3923 fecal samples (Dec 2012 or Jan 2013)

• Conclusions: Under-testing (not testing all samples) and under-detection (inadequate laboratory diagnostics) likely account for a large disparity between reported and actual rates of CDI across Europe.

• Wrong diagnoses in up to 23% of patients may lead to inappropriate or inadequate treatment of patients and inadequate infection control measures.


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Collection Transplantation and Presentation of Fecal Specimen

• Correct amount: 2-10gr or 5ml

• Prompt transportation to the Lab and elaboration in ≤2 hours

• Preservation of specimens:

– 4-6

C → 2-48 hours

– 20

C → ≥2 days

National Standard Methods BSOP 10, 2008


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