Friday Journal Club

Sunita Parajuli ,MD PGY-3

Internal Medicine ,UAMS

Faculty: Dr Michael Saccente

Clinical scenario

65 year old CM , a Nursing Home resident with PMH of Dementia, with recent h/o admission 3 weeks back for PNA treated with 8 days of vanc and Zosyn was brought to the ED with C/C fever and diarrhea X 3 days --- thin watery stools mixed with blood , up to >3 times /day

His Vitals – HR – 103 , BP 100/70, Temp of 101 F, RR-16

PE remarkable for abd distension and tenderness, rest – WNL

Pertinent Labs – WBC -16,000 cells /micro L, Creat- 1.6 mg/dL ( B/L – 1.0), Lactate – 1

AAS – some dilated loops of bowel , no air fluid levels , ER did CT – E/o Colits

What do u think this patient has ?

Goals of todays presentation

C difficile Infection Introduction

Diagnosis and Interpretation of tests

Treatment of C diff infection per IDSA guidelines

Journal Fidaxomicin Vs PO Vancomycin – a RCT for the treatment of C. diff

Questions

C diff – Clinical Practice Guidelines

Clostridium Difficile – Introduction

Clostri – cluster ; spindle shaped , Difficile means difficult – name given because it was difficult to isolate and culture this organism

A gram positive anaerobic spore forming rod

found EVERYWHERE Most common cause of Nosocomial diarrhea History dates back to 1893 when first case of

pseudomembranous colitis was identified C diff bacteria described in 1935 1979- Therapy with Metron or Vanc started

Disease Burden

Increasing Incidence and Prevalance ; since 1990s almost 2 X incidence

Close to 3 million cases /year in USA Decreased response to Metron and Vancomycin and

increased recurrence rates

NEW HYPERVIRULENT STRAIN NAP 1/ BI/0127 identified , leading to Epidemics

Fidaxomicin approved by FDA for C diff in 2011

Epidemiology Global

Risk Factors

Endoscopic features of pseudomembranous colitis

Diagnosis and Treatment

Clinical scenario

65 year old CM , a Nursing Home resident with PMH of Dementia, with recent h/o admission for PNA treated with 8 days of Levaquin and completed course of Abx was brought to the ED with C/C fever and diarrhea X 3 days , Its thin watery stools mixed with blood , up to >3 times /day

His Vitals – HR – 103 , BP 100/70, Temp of 101 F, RR-16

PE remarkable abd distension and tenderness, BS +

Pertinent Labs – WBC -16,000 cells /micro L, Creat- 1.6 mg/dL ( B/L – 1.0), Lactate – 1

AAS – some dilated loops of bowel , no air fluid levels , ER did CT – E/o Colits

You suspect that the patient has C diff , send the tests

What treatment do you want to start ?

Clinical case

You started the treatment , Worsening of the symptoms

WBC ---22K ,

Creatinine 1.6-- 2.0

BP – 80/50 , HR -110

Lactate – 4

Next step –??

IDSA 2010 Practice Guidelines for the Treatment of C diff Infection

Clinical Scenario

Patient does well, and is discharged with 14 days of PO Vancomycin .

One week after his last dose of PO Vancomycin, he again develops recurrent watery stools without fever or other symptoms. There is no visible blood or mucus in the stools.

Physical examination findings are noncontributory.

Results of laboratory studies show a leukocyte count of 10,400/µL (10.4 × 109/L) and a normal serum creatinine level. A stool sample tests positive for occult blood, and results of a repeat stool assay are again positive for C. difficile toxin.

Question – Most appropriate Treatment ?

Options

PO Metron X 14 days

PO Metron taper over 42 days

PO vanc X 14 days

PO Vanc + Parenteral Metron X 14 days

PO vanc taper over 42 days

JOURNAL PRESENTATION

FIDAXOMICIN VS VANCOMYCIN

FOR CLOSTRIDIUM DIFFICILE

INFECTION

NEW ENGLAND JOURNAL OF MEDICINE, FEB 3 2011 -AUTHORS –LOUIE TJ, MILLER MA, MULLANE KM etal

Why was this trial needed

There is a significant recurrence rate in people treated with C. diff Infection with both PO Vanc and PO metronidazole after standard treatment

20-30 % relapse rate after the first Infection within 2 weeks

Patient with at least one recurrence , the subsequent rate of recurrence was 65 % after a standard treatment

PO Metron and PO Vanc also affect normal flora so there is a disruption of the colonic flora and puts patients at risk of further recurrences

Also Metronidazole and PO Vancomycin have lot of adverse effects , esp concerns for Vanc Resistant Enterococcus

Is there any other medication that would work like VANCOMYCIN ???

Could there be any other medication that could decrease the rate of recurrences ????

Fidaxomicin –Background

Macrocyclic antibiotic 8 times more active

than vancomycin in vitro Selective for C diff and few others Bactericidal Does not affect other flora Lower rate of recurrence in Phase

II Trial done in 2009

Purpose of the study

To compare the efficacy of Fidaxomicin with those of Vancomycin in treating C diff infection- Non inferior study

Parts of the paper

Abstract – Background , Methods , Results and Conclusions

Background

Methods – Study Design , Study Population , Randomization and Treatment , Definitions , Outcomes- Primary End point and secondary end point , Safety

Statistical Analysis

Results –Patients , Clinical Outcomes , Safety ,

Discussion

References

Methods – Study Design

Randomized Non Inferiority study Double blinded Parallel Group Multicenters in US and Canada Prospective study Phase III Trial Was done from May 2006-Aug 2008 Approved by local as well as central IRBs All patients gave the informed consent

Methods- Study Population

Inclusion Criteria 16 years or older

Clostridium difficile diagnosis –diarrhea with 3 or more unformed stools within 24 hours

Toxin A , B or both in stool obtained 48 hours before randomization

Exclusion criteria Life threatening or fulminant infection

Toxic megacolon

Previous exposure to fidaxomicin

H/o Ulcerative colitis or crohns disease

More than one occurrence of the C diff Infection 3 months before the start of the study

Methods -Intervention

Outcomes

Definitions

RANDOMIZATION AND FOLLOW UPFigure 1 , 5th page

Randomization – Contd…

Statistical Analysis

Was done with different methods

Post Hoc hypothesis /Kaplan – Mier Method etc

Results –Baseline Clinical Characteristics

Results –Clinical Outcomes

Results – Rates of Clinical cure in subgroups-Primary End Point

Results- Rates of Recurrence in Sub Groups Secondary End Points

Adverse events

There were no statistically different rates of adverse events or serious adverse events between Fidaxomicin and vancomycin

Common ones were nausea, vomiting

No subjects discontinued the study due to an adverse events

Conclusions

Rates of Clinical cure after treatment with Fidaxomicin were Non Inferior to those after treatment with Vancomycin

Fidaxomicin has a lower recurrence rate of CDI associated with Non –North American Pulsed Field Type 1 strains as compared to PO Vancomycin

45 % relative Reduction in the recurrences , improved rate of global cure - sustained or durable resolution of the disease

There was 69% relative reduction rate in the Non –virulent strain group

Critique/ Strong points about the trial

Study Design Appropriate

Double Blinded and Randomized by the computer - Less Bias

IRB approved

Study Population – was Multicentered and provided informed Consent and had similar baseline characteristics like age group and thus could be comparable

Established Results that Fidaxomicin is Non inferior to PO Vanc for clinical cure and associated with less recurrence

No one had any adverse event stop the trial

Overall Impression – WELL CONDUCTED STUDY /ETHICAL AND PROVIDED GOOD RESULTS

Weak points about the trial

This study was Funded by Optimer Pharmaceuticals who is the drug manufacturing company

One of the authors is an employee of the Optimer Pharmaceuticals

Severely ill patients were excluded so we don’t know if fidaxomicin acts well for the complicated severe CD infection

Sample size could have been bigger

Applications of the study /trial This study aided in the FDA decision for the approval of

Fidaxomicin in May 2011 And since then is available to general population for treatment of CDI

Proved that Fidaxomicin is a reasonable alternative for the treatment of Cdiff infection The MAJOR LIMITING FACTOR was the COST!!

Several studies have been done after this trial for the cost effectiveness

Not found to be cost effective than Vanc or Metron for Initial infection or first recurrence

( $3,360 for 10 day course of Fidaxomicin Vs 210 for Vanc and for Metron-4 $ )

But could be a good option for 2nd Recurrence

Consider to use in patients with severe CDI /recurrent CDI in Patients with severe Vancomycin allergy

Yet to be in the IDSA Guidelines

By now you should be an expert at these

Be able to identify, diagnose and classify c diff Infection based on severity– Treat based on the severity of the Infection

Know that Fidaxomicin is a new treatment for C diff and is a reasonable alternative to PO Vanc – Though cost factor is limiting

Solve Board Questions related to C. diff !

References

IDSA guidelines for C diff Infection 2010

Uptodate.comNEJM Pub Med