Download C diff treatment guidelin~minor update Sep2011

Cross-county
Guideline:
Medical Management
Title:
Medical Management of Clostridium difficile Infection (CDI)
Authors: Mike Smith (Consultant Microbiologist),
Tim Jobson (Consultant Gastroenterologist - MPH)
Steve Gore (Consultant Gastroenterologist - YDH)
Policy Lead: Dr Mike Smith
Ratified by: Policy Review Group
Active date: 14th May 2010
Ratification date: 13th May 2010
Review date: 14th May 2012
Applies to: Medical staff
Exclusions: Paediatrics
Purpose: To provide guidelines for doctors, and other health care workers, on the
medical management of patients with C. difficile infection in Taunton & Somerset NHS
Trust and Yeovil District Hospital NHS Trust - to be read in conjunction with the relevant
Trust infection prevention and control policy.
To be read in conjunction with the relevant Trust’s Infection Control
Policy for Clostridium difficile
(click here for MPH and here for YDH)
(Click here to go straight to the two management algorithms)
1.
Introduction
Clostridium difficile is a major healthcare acquired infection associated with
antibiotic use and environmental contamination; it mainly affects the over
65’s. The patients’ dignity is often compromised, as they may be incontinent
of foul smelling diarrhoea up to 30 times a day. This infection can be life
threatening, especially if pseudo-membranous colitis develops. Occasionally,
severe CDI may present with abdominal distension, ileus and little or no
diarrhoea. CDI can cause outbreaks in hospital.
There is also a cost in
excess of £4,000 per case (Wilcox et al, 1996) and increased lengths of stay.
2.
What causes it?
Clostridium difficile is an anaerobic Gram-positive bacterium that produces
spores in adverse conditions i.e. when oxygen is present. The spores are
resistant to many disinfectants and harsh environmental conditions where
they can survive for several months. These bacteria may also produce toxins,
which cause the symptoms of diarrhoea. The test to confirm CDI determines
the presence of these toxin-producing strains.
It is possible to be an
asymptomatic carrier of C. difficile (about 3% of the general population and
higher in the elderly and hospital populations), however there is no evidence
to suggest that such carriers are sources of cross infection.
Recent outbreaks of CDI, associated with increased severity, high relapse
rates and significant mortality, have been reported from many UK hospitals,
as well as north America, Europe and Japan. A toxin hyper-producing strain –
ribotype 027 – has been implicated.
3.
Signs & Symptoms of Infection (see Appendix D for Bristol Stool Chart)
Signs and symptoms vary from mild self-limiting diarrhoea (ie Bristol Stool
Chart Type 6-7) to severe, life-threatening pseudo-membranous colitis.
Patients may present with as many as 20-30 episodes of watery, green, foul,
smelling diarrhoea a day.
The patients may also have fever, abdominal
cramps, and blood in the stools. Occasionally, severe CDI may present with
abdominal distension and tenderness, ileus or dilated colon, raised WCC and
little or no diarrhoea. Complications associated with the infection include
dehydration, electrolyte imbalance and toxic megacolon and perforation.
4.
Vulnerable Patients & Spread
4.1
CDI mainly affects the elderly (over 65), the debilitated and the
immunocompromised. The infection is particularly associated with the use of
certain antibiotics, particularly cephalosporins, and also if a ‘cocktail’ of
antibiotics are used. See Table 1. The fluoroquinolones (e.g. ciprofloxacin)
are also regarded as high risk antibiotics due to the emergence of ribotype
027 which is resistant to these agents. Antimicrobials alter the normal gut
flora, therefore allowing C. difficile to multiply and produce toxins in the
absence of competition from the other organisms that make up normal gut
flora.
The gut flora may also be altered by aperients, enemas, acid
suppressants and bowel surgery. See table 2.
Table 1. Potential for antibiotics to cause CDI
High Risk
Clindamycin
Cephalosporins
Quinolones (eg
ciprofloxacin, levofloxacin)
Medium Risk
Amoxicillin / Co-amoxiclav
Piperacillin-tazobactam
(Tazocin®)
Macrolides (eg clarithromycin,
erythromycin)
Carbapenems (eg
meropenem)
Low Risk
Gentamicin
Benzyl penicillin /
Flucloxacillin
Tetracyclines (eg
doxycycline)
Vancomycin /
teicoplanin
Trimethoprim
Metronidazole
Table 2. Non-antibiotic medications in patients with CDI
Drug group
Proton pump
inhibitors (PPIs)
Tube feeds
Opioids
Antimotility agents
Laxatives
4.2
Action
Review need for PPIs
Review
Consider stopping for
duration of diarrhoea
Discontinue and do not
prescribe
Discontinue treatment
while diarrhoea persists
Reason
Suppression of gastric acid can
increase host susceptibility
Disrupts normal gut flora
May mask symptoms and may
worsen course of disease
Can mask symptoms and may
worsen course of disease
Not required and may worsen
symptoms and increase spread of
spores
C. difficile is spread by the faecal-oral route.
Spores in the faeces can
contaminate the patients’ skin and hands, the hands of health care workers
and the immediate environment around a symptomatic patient. Spores may
remain viable in the environment for many months.
4.3
The risk associated with antibiotics remains for several weeks. It is important
to know about antibiotics that may have been given in the preceding 4-6
weeks.
5.
Preventing the spread of Infection (see relevant Infection Control Policy
for Clostridium difficile for full details - MPH policy and YDH policy .
The following are general principles that are to be utilized to help prevent the
spread of C. difficile. The Infection Prevention and Control Team (IP&CT)
can give specific infection control advice on an individual case basis.
5.1
Isolation - until 48 hr without diarrhoea and a return to normal bowel habit.
5.2
Hand Hygiene - strict and thorough hand washing with soap and water (NOT
alcohol hand gel)
5.3
Protective Clothing - Disposable non-sterile examination gloves and apron
5.4
Cleaning - Clean room twice daily with a chlorine-containing cleaning agent
(at least 1000ppm available chlorine).
6.
Diagnosis of CDI
Send stool for culture and C. difficile testing on ALL adult inpatients who
develop diarrhoea or who are admitted with unexplained diarrhoea. Testing
may also be indicated in children 2 years or older.
C. difficile tests are performed 7 days a week. If the first sample is negative
and CDI is strongly suspected, a second sample (48 hr later) should be
tested.
Following a positive test, please do not send any further samples for, at least,
28 days as toxin may persist in the faeces even after symptomatic
improvement.
The microbiology laboratory now uses a two-step testing method (which gives
more accurate results, compared to the previous single test for toxins A & B).
The initial screening test detects a clostridial enzyme “GDH”.
If this GDH test is negative, it is reported as

“C. difficile screening test (GDH) NEGATIVE”
If the GDH screening test is “positive”, the lab then uses a PCR test to look
for specific C. difficile toxin genes.
If this PCR is negative it will be reported as

“Toxigenic C. difficile NOT detected by PCR”
If this PCR is positive it will be reported as

“Toxigenic C. difficile DETECTED by PCR”
- in which case the patient should be managed as C. difficile infection.
In suspected cases of “silent” CDI (eg. Ileus, toxic megacolon or PMC) other
diagnostic procedures such as flexible sigmoidoscopy/colonoscopy or CT
scanning may be required.
7.
Management & Specific Treatment
(See flow chart in Appendix A for summary)

Stop implicated antibiotics if possible (see Table 1).

Contact Consultant Microbiologist for advice if patient still needs
antibiotics.

Investigate for other causes of diarrhoea e.g. tube feeds, antacids

Review antimotility drugs, laxatives and proton pump inhibitors (see
Table 2)

Supportive measures as indicated i.e. adequate fluid and electrolyte
replacement

Isolate patient immediately (Do NOT wait for results of stool
culture/toxin test)
7.1

Assess severity of CDI (this should be re-assessed daily)

Start specific empirical antibiotic therapy for C. difficile
Severity assessment
 Mild CDI – no rise in WCC; typically associated with < 3 stools/day of
type 5-7 on Bristol Stool Chart (Appendix C)
 Moderate CDI – raised WCC but < 15 x 109/L; typically associated
with 3-5 stools/day of types 5-7.
 Severe CDI – raised WCC > 15 x 109/L, or acute rising creatinine
(>50% increase above baseline), or temperature > 38.5oC, or
evidence of severe colitis eg.:
o
abdominal distension
o
dilated colon on AXR
o
pseudomembranous colitis
The number of stools may be a less reliable indicator of severe
disease.
 Life-threatening CDI – any of the following:
7.2
o
hypotension
o
partial or complete ileus
o
toxic megacolon
o
CT evidence of severe disease
Initial therapy
 Mild and moderate CDI
Oral metronidazole 400 mg tds, for 10-14 days.
o
However, if <3 stools in 24 hours and systemically well (ie mild
disease),
supportive
treatment
may
only
be
required,
particularly if implicated antibiotics have just been stopped.
If there is no improvement in symptoms after 7 days metronidazole, or if
worsens and signs of severe disease develop, switch to oral vancomycin
125 mg qds, for 10-14 days.
 Severe CDI
Oral vancomycin 125 mg qds, for 10-14 days.
If not improving after 5-7 days, or if worsens, increase dose of oral
vancomycin (up to 500 mg qds) and consider adding IV metronidazole
500 mg tds; discuss with Consultant Microbiologist.
A Gastroenterologist should review all ‘severe’ cases, particularly if
no/poor response to vancomycin, and will also advise on the need for a
flexible sigmoidoscopy.
 Life-threatening CDI
Oral vancomycin 500 mg qds (via NG tube if necessary) plus IV
metronidazole 500 mg tds, for 10-14 days.
Consider intracolonic vancomycin (refer to treatment Algorithm).
These patients should be monitored closely, with specialist surgical and
gastroenterology input, and should have blood lactate measured.
Colectomy should be considered, especially if caecal dilation is > 10 cm.
Colectomy is best performed before blood lactate rises > 5 mmol/L, when
survival is extremely poor.
If CDT-ve: review diagnosis and send a second stool to laboratory. Continue
treatment if CDI strongly suspected, but consider other diagnoses.
8.
Non-responders – further treatment options
The initial treatment changes for non-responders are detailed above (Section
7). There is no consensus on treatment after failure of both metronidazole
and vancomycin, and further treatment must be discussed with a
gastroenterologist or microbiologist. Options are set out in Appendix C and
include the addition of oral rifampicin or IV immunoglobulin.
9.
Recurrence / relapse
Disease recurs in approximately 20% of patients with a first episode of CDI
over the following 3 months. Recurrence occurs in 50-60% after a second
episode. This incidence may be higher with the 027 ribotype of C. difficile.
There is no need to send a stool for C. difficile testing if a positive result has
been obtained in the previous 28 days.
A further course of metronidazole or vancomycin (depending on which the
patient responded to previously) is recommended initially.
Refer to Appendix B for the management of third, and subsequent, episodes
of CDI. Some further treatment options are given in Appendix C.
10.
References and further reading
Clostridium difficile infection: how to deal with the problem. Department of
Health and Health Protection Agency. Jan 2009. DH website.
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAnd
Guidance/DH_093220
Aas J, Gessert CE, Bakken S. Recurrent Clostridium difficile colitis: case
series involving 18 patients treated with donor stool administered via a nasogastric
tube. Clin Infect Dis 2003; 36: 580−585.
Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic
vancomycin for severe Clostridium difficile colitis: case series and review of the
literature. Clin Infect Dis 2002; 35: 690−696.
Johnson S. Recurrent Clostridium difficile infection: A review of risk factors,
treatments, and outcomes. J Infection 2009; 58: 403-410.
McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for
163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97:
1769−1775.
Nelson RL. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults.
Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004610. DOI:
10.1002/14651858.CD004610.pub3.
Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile-associated colitis
in adults. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.:
CD004611. DOI: 10.1002/14651858.CD004611.pub2.
Wilcox MH. Descriptive study of intravenous immunoglobulin for the
treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 2004;
53: 882−884.
Wullt M, Odenholt I. A double blind randomised controlled trial of fusidic acid and
metronidazole for the treatment of an initial episode of Clostridium difficile associated
diarrhoea. JAC 2004;54:211-216
Appendix A - Flow chart for the management of suspected CDI – first or
second episodes of infection.
Diarrhoea AND one of the following
Positive C.difficile toxin PCR test OR results of C.difficile
tests pending AND clinical suspicion of CDI
NB. severe CDI may
present with abdominal
distension, ileus and
little or no diarrhoea
Ideally discontinue non-C.difficile-treatment antibiotics
To allow normal intestinal flora to be re-established
Suspected cases must be isolated
Symptoms/signs of
non-severe CDI
Oral metronidazole
400 mg tds 10–14 days
Symptoms/signs of severe CDI
(WCC > 15 x 109/L, or acute rising creatinine >50%
increase above baseline, or temperature > 38.5oC,
or evidence of severe colitis)
Oral vancomycin 125 mg qds 10–14 days
DAILY ASSESSMENT
Symptoms improving
Diarrhoea should resolve in 1–2 weeks
Recurrence occurs in
~20% after first episode,
50–60% after second episode
Symptoms not improving or
worsening
(should not normally be
Anti-motility
deemedshould
a treatment
agents
not failure until
received
at
least
one
be prescribed week of treatment)
DAILY ASSESSMENT
Symptoms not improving
(should not normally be deemed
a treatment failure until received
at least one week of treatment)
Or, if evidence of severe CDI continues
or worsens
Surgery / GI / Micro / ID consultation
in acute CDI
Or, if there is evidence of severe CDI
(WCC > 15 x 109/L, or acute rising
creatinine >50% increase above
baseline, or temperature > 38.5oC,
or evidence of severe colitis)
Switch to oral vancomycin 125 mg qds
10–14 days
AND, depending on degree of ileus,
vancomycin 125–500 mg PO/NG qds, +/metronidazole 500 mg iv tds 10 days
PLUS CONSIDER intracolonic vancomycin (500 mg in
100–500 ml saline 4–12-hourly) given as retention
enema: 18 gauge Foley catheter with 30 ml balloon
inserted per rectum; vancomycin instilled; catheter
clamped for 60 minutes; deflate and remove.
Further surgery/GI/micro/ID consultation
Anti-motility
agents should not
be prescribed
in acute CDI
Depending on choice of therapy (see above), consider:
1. high-dose oral/NG vancomycin (500 mg PO qds)
+/.
2. IV immunoglobulin 400 mg/kg, one dose, and
consider repeating.
There is no robust evidence for the effectiveness of
these approaches in severe CDI. See appendix C.
Policy for the Medical Management of Clostridium difficile Infection (CDI)
Page 9
05/05/2017
Appendix B - Flow chart for the management of recurrent CDI – third or subsequent
episodes of infection.
Diarrhoea AND one of the following:
Positive C. difficile toxin PCR test OR results of C. difficile
tests pending AND clinical suspicion of CDI
Must discontinue non-C. difficile-treatment antibiotics if at all
possible to allow normal intestinal flora to be re-established
Suspected cases must be isolated
Symptoms/signs of non-severe CDI
Oral vancomycin 125 mg tds for 14 days
DAILY ASSESSMENT
(include review of severity markers, fluid/electrolytes)
Symptoms improving
Diarrhoea should resolve in 1–2 weeks
Recurrence occurs in
40–60% of relapsing cases or third episode
If multiple recurrences, especially if evidence of
malnutrition, wasting etc.
1. Review ALL antibiotic and other drug therapy
(consider stopping PPIs and/or other GI active drugs)
2. Consider supervised trial of anti-motility agents alone
(if NO abdominal symptoms or signs of severe CDI)
Also consider (see Appendix C for details):
3. vancomycin tapering/pulse therapy (4–6-week regimen)
4. oral vancomycin 125 mg qds + oral rifampicin 300 mg bd
for two weeks (no robust evidence for effectiveness)
5. iv immunoglobulin, especially if albumin status worsens
6. donor stool transplant
Taunton & Somerset NHS Foundation Trust
Page 9 of 12
If severe CDI
see algorithm for
first or second
episode of CDI
Policy for the Medical Management of Clostridium difficile Infection (CDI)
Page 10
05/05/2017
APPENDIX C – Further treatment options in non-responders
There is little consensus in this area (underpinned by a lack of evidence). Options are outlined
below – the gastroenterologist will advise on which approach to use.
1. Tapering / pulsed vancomycin regimen
Vancomycin 125 mg po qds for 1 week
Vancomycin 125 mg po tds for 1 week
Vancomycin 125 mg po bd for 1 week
Vancomycin 125 mg po od for 1 week
Vancomycin 125 mg po every other day for 1 week
Vancomycin 125 mg po every third day for 1 week
- then stop
2. Other antibiotics
Rifampicin (300 mg bd orally) – some authorities recommend giving rifampicin in addition. No
randomised, controlled trials have been reported; there is no robust evidence to support the use
of rifampicin as an adjunctive agent.
Teicoplanin (100-400mg bd orally) – the Cochrane review 2007 comes down in favour of this. It
is very expensive and superiority to vancomycin/metronidazole is marginal at best.
Fusidic acid (500mg tds orally) - the response rates in one randomised, double-blind trial
comparing metronidazole with fusidic acid showed no significant difference. Recurrence rates
were similar, but development of fusidic acid resistance was seen in 55% of recipients who
remained culture-positive. Fusidic acid should not be used as a first-line treatment in CDI; its
role in treating recurrences is unclear but resistance is likely to limit this use.
3. Non-antibiotic treatments
Theoretically there are advantages to non-antibiotic treatments: firstly antibiotics are only able to
target vegetative C. difficile cells and not spores, and secondly, antibiotics will disrupt the
normal colonic flora, thereby compromising resistance to further C. difficile colonization.
Probiotics
These are mono- or mixed-cultures of live microorganisms which are postulated to work by a
number of methods eg to enhance re-establishment of the normal flora, or to inactivate the C
difficile toxin. There is a lot of published data in this area and a number of systematic reviews –
meta-analyses have failed to demonstrate statistically any significant efficacy in treating or
preventing CDI. So the evidence of benefit is nil to weak and further RCTs are warranted.
Perhaps the most promising candidate is Saccharomyces boulardii (1g/day for 28 days) which
may have some benefit in recurrent cases. There are risks (fungaemia, variable virulence, nonviability in many commercial preparations), and it is NOT recommended for widespread use.
IV immunoglobulin
Several case reports and small series have been published regarding the use of this method to
treat refractory disease. A dosage of 400mg/kg IV as a stat dose has been beneficial in about
two thirds of intractable cases. No randomized controlled clinical trials have been performed to
evaluate the efficacy of immunoglobulin in recurrent or severe CDI.
Taunton & Somerset NHS Foundation Trust
Page 10 of 12
Policy for the Medical Management of Clostridium difficile Infection (CDI)
Page 11
05/05/2017
Donor stool faecal enemas
There is evidence for efficiency of faecal transplant in animal models. Although the number
of human studies reported is small, the results are promising for refractory/relapsing CDI. A
fresh stool from a healthy donor is administered in normal saline by enema, slurries via
nasogastric tube, or flexible sigmoidoscopy / colonoscopy as advised by a Gastroenterologist
(Aas et al, 2003). This is used as a last resort as there are no comparative studies to verify its
effectiveness in CDI, and concerns remain about the safety
of the approach. There is a randomised trial of this approach under way in the Netherlands.
Adsorbents
Oral cholestyramine (4 g packet tds) has been used in the treatment of refractory CDI because
it is thought to bind C. difficile toxins. There is no robust evidence to support the use of
cholestyramine as an adjunctive agent, and there is a risk that it may bind antibiotics used to
treat CDI. It is not recommended.
4. Colectomy
Colectomy is required in some patients with megacolon (dilatation >10 cm), perforation or
septic shock, and should be done before the blood lactate rises above 5 mmol/L. Patients
should have a total or subtotal colectomy rather than a hemicolectomy or a caecostomy. It may
be preferable to preserve the rectal stump for subsequent ileo-rectal anastomosis. The rectocolonic stoma can then be perfused with vancomycin liquid if necessary (see Appendix A for
details).
Taunton & Somerset NHS Foundation Trust
Page 11 of 12
Policy for the Medical Management of Clostridium difficile Infection (CDI)
Page 12
05/05/2017
APPENDIX D – Bristol Stool Chart
To ensure consistent recording of stool type please use the scale below to
guide your classification of stools. Record the type on the appropriate
patient record.
Taunton & Somerset NHS Foundation Trust
Page 12 of 12