Clostridium difficileassociated of deaths. This has been the case for both hospital- and communityacquired

Introduction

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The authors

Dr Katie ellarD gastronenterologist in private practice, St Leonards, NSW.

Epidemiology

Risk factors

Presentation

Diagnostic tests

Management

Recurrent episodes

Clostridium difficile

-associated diarrhoea

Dr nemes sanDanayaKe

consultant physician and

gastroenterologist, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, and the Mater Hospital, Crows Nest, NSW.

TWENTY-five years ago, Clostrid-ium difficile-associated diarrhoea was a footnote in medical textbooks as a very rare cause of infective diarr-hoea. It was known to occur after exposure to antibiotics, particularly clindamycin.

However, over the past decade there has been a very worrying increase in both the frequency and the severity of C. difficile diarrhoea, coupled with a significant number

of deaths. This has been the case for both hospital- and community-acquired infections.

There are several reasons for this, including the appearance of hyper-virulent strains that have been ident-ified in Australia in recent years, and the widespread and inappropriate use of antibiotics in hospitals and the community.

Proton-pump inhibitors may also be a risk factor and the US Food

and Drug Administration has issued a specific warning highlighting a possible connection between acid suppression from PPI drugs and C. difficile-associated diarrhoea, partic-ularly in the elderly.

C. difficile-associated diarrhoea could well be a “canary in the mine” — a warning of the possible implicat-ions of indiscriminate use of potent antibiotics and PPIs.

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CLOSTRIDIUM difficile is a gram-positive toxin-producing anaerobic bacterium. It was first isolated, with difficulty, from healthy neonates in 1935 and was originally named Bacillius diffici-lis.

In the 1970s it was recognised as a cause of antibiotic-associated colitis.

C. difficile can be carried in the colon without developing symp-toms and about 2% of healthy adults and 70% of healthy neonates have C. difficile in their stools. The percentage of people who carry C. difficile but do not have diarrhoea increases markedly once people have been admitted to hospital and, in many hospitals in the US and UK, 20% of inpatients carry C. difficile in their stools. Transmission occurs via the fae-cal–oral route.

In some nursing homes, the rier rate approaches 50%, and car-riers act as a reservoir of infection in these institutions. Treatment of carriers is not recommended in this setting because eradication is difficult.

There has been a dramatic increase in the incidence of C. difficile-associated diarrhoea in the past couple of decades and it is now the most common cause of diarrhoea in the healthcare context. It is estimated there are three million cases in the US each year, making C. difficile the most common cause of bacterial diarr-hoea in that country.

The reasons for the increase in

C. difficile-associated diarrhoea are multifactorial, but it has been suggested that important factors include increased pathogenicity of new strains, food and water con-tamination, more frequent carrier state in humans, the ageing of the population, and the widespread use of antibiotics and proton pump inhibitors.

Outside the colon, C. difficile

takes the form of an extremely robust spore that is routinely found on all types of surfaces in hospitals and is difficult to eradi-cate with commonly used surface cleaners, particularly alcohol-based agents.

In some NHS hospitals in the UK that have experienced signif-icant mortality owing to C. diff-icile diarrhoea, wards have had to be closed for long periods in order to eradicate the spores. If a patient suspected of carrying the infection requires a colonoscopy, infection control guidelines state that the procedure should be done at the end of the list, so that the room can be thoroughly cleaned after-wards.

As a result of the widespread presence of spores, infection can be spread easily from person to person in hospitals, regardless of the use of antibiotics. It is inter-esting to note that patients who enter a hospital colonised with C. difficile are less likely to develop

diarrhoea, indicating that previ-ous colonisation may offer some immunity.

Data from the US Centers for Disease Control and Prevention note that while more than 90% of people who presented with

C. difficile-associated diarrhoea had attended a healthcare facility before the onset of their illness, fewer than 25% were hospitalised at the time they became unwell. A significant proportion of those who acquired the infection in hos-pital had been discharged before symptoms began.

This emphasises the fact that GPs need to be aware of the pos-sibility of C. difficile as a cause of diarrhoea in the community and the importance of a history of the patient’s recent antibiotic use.

Community-acquired

C. difficile

infection

At present, community-acquired

C. difficile-associated diarrhoea accounts for about 20% of infec-tious diarrhoea. If a person devel-ops diarrhoea associated with

C. difficile within 48 hours of admission to a healthcare facility or 12 weeks after discharge, the infection is classified as having been acquired within the comm-unity. The incidence appears to be increasing and infection is not always associated with antibiotics, with fewer than 50% of affected patients having received any anti-biotics within the three months before onset of symptoms. Patients who have community-acquired C. difficile-associated diarrhoea tend to be younger than the patients of hospital-acquired cases.

The association between C. dif-ficile-associated diarrhoea and PPI use is also less clear in people with community-acquired infection.

Community-acquired C. diff-icile diarrhoea is usually less severe than that acquired in hos-pital. However, in a large study

from Olmsted County in the US, 40% of people with community-acquired C. difficile infection required admission to hospital for treatment.

Nursing home residents are particularly vulnerable to C. dif-ficile-associated diarrhoea. This is because the carrier rate of C. diff-icile is often high in these commu-nities, the elderly are frequently treated with antibiotics for other infections and C. difficile spores are easily spread as a result of the challenges associated with toilet-ing elderly, infirm residents.

During any outbreak of diarr-hoea in an aged-care facility, stool samples should be tested specifi-cally for C. difficile. Residents diagnosed with C. difficile -associ-ated diarrhoea should be nursed in a single room, and sharing of bathrooms and commodes with other residents should be avoided. The importance of regular hand washing with soap and water should be stressed to staff as spores are resistant to alcohol sanitisers.

Hypervirulent strains of

C. difficile

The most significant hyperviru-lent strain of C. difficile is NAP1/ BI/027, which produces more spores and appears to be more toxic due to a single gene deletion, resulting in the loss of an inhibi-tory protein signal. This leads to significantly larger production of toxins.

A further mechanism is via pro-duction of a binary toxin which is an extra toxin not found in the less virulent strains.

These factors are associated with an increased rate of septic shock and toxic megacolon. The increasing use of fluoroquinolones worldwide may be associated with the emergence of this particular strain, which has also been ident-ified in Australia.

Epidemiology

Antibiotics

CLINDAMYCIN was the first antibiotic associated with C. diff-icile-associated diarrhoea. How-ever, any antibiotic can be the precipitant.

The classes of antibiotics that most frequently induce C. diffi-cile-associated diarrhoea include spectrum penicillins, broad-spectrum cephalosporins and fluoroquinolones. Sulfonamides, trimethoprim and macrolides are also implicated. Even metronid-azole and vancomycin, which are the mainstay of treatment for C. difficile-associated diarrhoea, have been reported to cause the condi-tion.

It is reasonable to suspect that any patient taking an antibiotic who presents with diarrhoea, part-icularly if it does not resolve after stopping the antibiotic, could have

C. difficile-associated diarrhoea and should be investigated with a stool sample.

Patients who receive long-term antibiotics, for example, for an infected joint replacement or

sub-acute bacterial endocarditis, should be warned that they need to report a change in bowel habit due to their increased risk of C. difficile -assoc-iated diarrhoea.

Patients presenting with diarr-hoea should be asked about recent antibiotic use, including treatment for Helicobacter pylori infection and dental work. It is also import-ant to remember that the diarrhoea doesn’t necessarily start during the course of antibiotics — there are reports of the diarrhoea develop-ing up to 12 weeks after antibiotics

have stopped — so causality may not be obvious.

Even brief exposure to anti-biotics — for example, a couple of doses — may cause C. difficile -associated diarrhoea.

Proton-pump inhibitors

There is some controversy about whether or not PPIs increase the risk of acquiring C. difficile infec-tion. However, the evidence is suffi-cient to have prompted the US Food and Drug Administration to issue a Drug Safety Communication in February 2012 advising that, partic-ularly in elderly people, a “diagnosis of C. difficile-associated diarrhoea should be considered for patients taking PPIs who develop diarrhoea that does not improve”.

The possibility that H2 recep-tor antagonists are also a potential risk factor was mentioned.

Some experts have suggested that the association is spurious, because PPI prescriptions are more common in elderly people, who are also more likely to be or have been hospitalised and are more

likely to have comorbidities. However, studies have shown that patients who develop C. dif-ficile-associated diarrhoea in hos-pital are often on PPI therapy for no specific indication for example, no history of peptic ulcer, GORD or medications that increase the risk of peptic ulceration. The pos-sibility that PPIs are contributing to the increase in C. difficile -asso-ciated diarrhoea is a good reason to assess the appropriateness of therapy, both in the community and hospital.

Age

The risk of C. difficile-associated diarrhoea increases over the age of 65, however age is not a clear risk factor in community-acquired

C. difficile-associated diarrhoea.

Inflammatory bowel disease

Patients with ulcerative colitis and Crohn’s disease are at increased risk of acquiring C. difficile -associ-ated diarrhoea. These patients are also likely to be receiving immuno-suppressive drugs as part of their

treatment, including prednisone, azathioprine and anti-tumour necrosis factor antibodies.

Antibiotics such as metronid-azole and ciprofloxacin are used in the treatment of Crohn’s disease in particular. However, patients with inflammatory bowel disease may present with C. difficile-associated diarrhoea without having been exposed to antibiotics.

Sometimes the symptoms will be very similar to those caused by an exacerbation of inflammatory bowel disease. It is important to have a high index of suspicion for

C. difficile-associated diarrhoea in this group of patients and stool testing should be performed when there is a poor response to their usual therapy.

Immunosuppression

Immunosuppression is an import-ant risk factor and can be iatro-genic or associated with underlying disease. Hospital patients receiv-ing chemotherapy are particularly vulnerable to C. difficile-associated diarrhoea.

Risk factors

Risk factors

Antibiotics Age Immunosuppression Gastric acid suppression

Antibiotics most commonly

associated with

C. difficile

-associated diarrhoea

Cephalosporins Ampicillin/amoxycillin Clindamycin

C. difficile

spores

are easily spread

as a result of the

challenges associated

with tolieting elderly,

infirm residents.

Stool sample

IT is appropriate to arrange for a stool sample to be examined for C. difficile if a patient has significant diarrhoea while taking antibiotics or after completion of a course of antibiotics in the past 12 weeks.

The stool test is only useful in the proper clinical setting where a patient has watery diarrhoea. For instance, it would not be appro-priate to test a young person with typical IBS symptoms of alternat-ing constipation and diarrhoea for

C. difficile-associated diarrhoea. There are several different types of stool tests available and GPs don’t have to specify the type of C. difficile test.

Each pathology provider has its preferred testing methods, from those described below.

The pathogenic strains of C. dif-ficile produce a toxin that causes the inflammation and some tests focus on the presence or absence of toxin. However, as the tests require a certain threshold of toxin to be present to give a posi-tive result, there is a risk of a false-negative result.

The toxin can also be assessed in a test that measures cytotoxicity, but this test is difficult to perform and relatively slow.

An alternative is to test for the presence of C. difficile glutamate dehydrogenase, which is produced by all C. difficile strains and then, if it is present, test for the toxin.

Several Australian laboratories use a PCR test, which is directed at the gene that confers pathogenicity and allows toxin production by C. difficile. The PCR test, also called the gene test, is both sensitive and specific.

Culture is difficult, slow and not usually performed.

Colonoscopy

Colonoscopy is not mandatory in all cases of C. difficile-associated diarrhoea. If the diagnosis is con-firmed via a positive stool test, treatment should begin without

waiting to visualise the colon or take biopsies to confirm the pres-ence of a pseudomembrane (figure 1).

However, colonoscopy can be helpful, particularly in people with inflammatory bowel disease, where there might be some doubt about whether symptoms are from the underlying inflammation or a superimposed infection. A per-centage of patients with IBD may be carriers of C. difficile that is not causing their diarrhoea.

Some patients will also have a colonoscopy arranged to investi-gate diarrhoea where C. difficile

is clinically less risky, particularly those who haven’t had antibiotics. A normal sigmoidoscopy is not sufficient to rule out C. difficile

infection as occasionally the infec-tion is apparent only in the right colon.

The classic appearance of C. dif-ficile infection at colonoscopy is a yellowish pseudomembrane that can be washed off the inflamed mucosa (figure 2B). About 20% of patients will have a visible pseu-domembrane.

As with all pathological proc-esses, there is a progression in the severity of the findings. Occasion-ally the colon will appear mildly inflamed rather than showing a distinct pseudomembrane. Biop-sies should be taken and the result-ing pathology should show the typical changes. It is not always possible for the endoscopist or the pathologist to distinguish between inflammatory bowel disease and

C. difficile-associated diarrhoea, so stool testing is still essential.

Imaging

If there is any suspicion of toxic megacolon, colonoscopy is con-traindicated because of the risk of bowel perforation.

Toxic megacolon can be diag-nosed on a plain abdominal X-ray, while a CT scan of the abdomen and pelvis with IV con-trast — patient renal function permitting — can be useful to assess the extent and severity of disease and exclude microperfo-ration.

THE classic presentation of C. difficile-associated diarrhoea is watery diarrhoea, up to 10-15 times a day, during or after a course of antibiotics.

This can be associated with

fever, crampy abdominal pain and/or severe abdominal pain as a result of toxic megacolon. Spontaneous perforation of the colon can occur.

There are less severe forms of

illness, where the stool is more formed and less frequent.

Patients with inflammatory bowel disease may appear to have an exacerbation of their usual symptoms.

Very occasionally, C. difficile -associated diarrhoea can present with ileus, fever, abdominal pain and distension, and no diarrhoea, which can present a real diagnos-tic challenge.

A normal

sigmoidoscopy is not

sufficient to rule out

the possibility of

C.

difficile

infection,

as occasionally the

infection is apparent

only in the right

colon.

Presentation

Diagnostic tests

Tests for

C. difficile

-associated diarrhoea

C. difficile toxin assay

C. difficile glutamate dehydrogenase PCR (gene test) for pathogenic loci in the C. difficile

Cell culture with cytotoxic assay Colonoscopy with biopsy for pseudomembrane

Figure 1: Histology: pseuodomembrane consisting of a dense inflammatory infiltrate on the surface of the colonic mucosa (H&e ×10).

Management

SOME patients with C. difficile -associated diarrhoea recover without treatment, or indeed diag-nosis. However, there is substan-tial mortality in frail elderly and immunosuppressed patients. In some studies this has reached 25% in this group.

The high mortality is multifact-orial but probably relates in part to the greater pathogenicity of new strains of C. difficile, as well an increase in elderly population numbers.

Once the diagnosis of C. dif-ficile-associated diarrhoea has been confirmed, there are some

general treatment measures and some specific therapies. Antibiot-ics should be withdrawn if at all possible and, if not, there is some benefit in avoiding broad-spec-trum antibiotics. It is also advisa-ble to avoid drugs that will reduce colonic peristalsis; for example, narcotics and loperamide.

Medical treatment

Treatment should target the colon. It is important to consider how unwell the patient is as a result of the C. difficile -associ-ated diarrhoea. If they are mildly or moderately unwell, first-line

therapy is oral metronidazole. Australian guidelines recommend initial treatment of metronidazole 400mg orally tds for 10 days. If the patient can’t tolerate oral metronid-azole, it can be administered IV, 500mg hourly for 10 days. If treat-ment with metronidazole is ineffect-ive clinically, it is appropriate to switch to oral vancomycin.

Patients who are very unwell should be treated initially with oral vancomycin, 125mg qid for 10 days. IV vancomycin is not effective.

Vancomycin is usually well toler-ated; however, there are cases of a rare but severe side effect called the

‘Red Man Syndrome’ caused by a direct effect of vancomycin on mast cells. This hypersensitivity reac-tion causes an itchy, erythematous rash that invloves the face, neck and upper torso. In rare cases, the flushing can be generalised and the patient can drop their blood press-ure. The syndrome is more likely to be associated with the administ-ration of IV vancomycin.

Vancomycin is generally not absorbed from the gut, but theoret-ically a patient with significant gut inflammation (increasing absorp-tion) and renal impairment (limiting

cont’d page 28

Figure 2: a: normal colonic mucosa. B: mucosa showing yellow pseudomembrane.

A

excretion) could develop blood lev-els of vancomycin sufficient to cause Red Man Syndrome.

If the patient has difficulty swal-lowing or has an ileus, vancomy-cin can be administered through a nasogastric tube or as an enema. A pharmacist can make up a reten-tion enema as vancomycin 500mg in 100mL of normal saline per rec-tum, to be administered 2-3 times daily.

As vancomycin is not well absorbed from the GI tract, moni-toring serum levels is not required except in patients initially diag-nosed with acute severe colitis who may have increased absorption of the drug due to profound mucosal inflammation.

In Australia, vancomycin requires an authority script, stating that the patient has “antibiotic-associated pseudomembranous colitis due to

C. difficile that is either unrespon-sive or intolerant to metronidazole”. This is aimed at limiting inapprop-riate use of vancomycin because of its important role in treating entero-cocci. Generally, vancomycin is well tolerated.

It is not appropriate to do a stool sample for C. difficile on comple-tion of therapy in a patient who has clinically responded to treatment, or prescribe additional treatment on the basis of a positive test, as C. diff-icile may still be present in the stool sample. Further treatment is not required in these cases and has not been shown to be helpful in decreas-ing the relapse rate. The situation is different in a sick patient with ongo-ing diarrhoea.

Surgical treatment

C. difficile infection can cause toxic megacolon with a high risk of perforation and death. Therefore if there is evidence of increasing abdominal pain and distension of the colon on imag-ing, it is appropriate to obtain surgical opinion where colectomy may be indicated. This is more likely in the elderly and the imm-unosuppressed.

Alternative and emerging

treatment

The balance and alterations in colonic flora are suspected to be of great importance in a variety of gastrointestinal diseases from IBS to IBD, and there is no doubt it plays a significant role in C. difficile -associ-ated diarrhoea.

The difficulty has been to discover the most effective way to alter the colonic flora, as it appears to be an ecosystem that not only varies from person to person — as individual

as a fingerprint — but also tends to return to its original equilibrium when left alone.

Changing diet can bring about lasting modifications in the profile of colonic flora. The evidence that probiotics can do this is variable.

Probiotics

The idea of probiotics to treat

C. difficile-associated diarrhoea is attractive; however, the science of using probiotics is complicated by the fact that there are so many different strains of probiotic bac-teria available, which may have

a variable effect on the colonic flora of different individuals.

This is a problem encountered in trials using probiotics to treat IBS, IBD and recurrent C. difficile -asso-ciated diarrhoea. Studies using the probiotic Saccharomyces boulardii

have been encouraging.

Patients on long-term antibiotics will often spontaneously take pro-biotics or eat yoghurt, but there is no evidence this reduces the risk of

C. difficile-associated diarrhoea.

Immunotherapy

Studies have been conducted using IV immunoglobulin and monoclonal antibodies to neutralise the toxin produced by the C. difficile and vac-cines have been proposed as a poten-tial therapy in recurrent disease.

Faecal microbiota transplant

One area of great interest to the medical profession and the tabloid

press is faecal microbiota trans-plant.

Faecal microbiota transplant has been used in a number of studies of recurrent C. difficile-associated diarrhoea. It was initially proposed as a means of providing the patient with “healthy” flora that could suppress the pathogenic C. difficile.

A donor is identified who is well, has no gastrointestinal disease, and has been screened for infections, including HIV, and hepatitis B and C. They ‘donate’, after having taken a laxative the night before, and a liquid mixture is prepared and then infused into the recipi-ent’s caecum at colonoscopy. The recipient takes loperamide to slow colonic emptying after receiving the donation.

At this time there are about 275 cases in the medical literature and it will be of great interest to see the results of randomised trials.

Antibiotic treatment of

C. difficile

-associated diarrhoea

Metronidazole 400mg tds for 10 days

If unsuccessful or not tolerated: Vancomycin 125mg orally qid for 10 days

UP to 35% of patients will relapse with a further episode of signif-icant C. difficile diarrhoea and, unfortunately, recurrent episodes are associated with less effective responses to the antibiotic that was initially successful.

Recurrences will usually, but not always, occur about a week after antibiotic treatment is stopped. This, after the increased incidence and virulence of infec-tion, is the next big problem with

C. difficile-associated diarrhoea.

Management

The first recurrence should be treated as for the initial episode, with either metronidazole or vancomycin. Unfortunately, this treatment is less likely to be effec-tive with recurrence.

There are several possible approaches following a second relapse. It would be inappropri-ate to retrial metronidazole; how-ever, vancomycin can be used again. The dose of vancomycin is either tapered from the initial

dose and/or used as a “pulse ther-apy” every two days at the end of the course. The dosing pat-tern of vancomycin is changed to 125mg qid for 14 days, followed by 125mg bd for a week, then 125mg bd every second day for a week.

Novel antibiotics

Several new antibiotics have been studied for recurrent C. difficile -associated diarrhoea. They are not available on the PBS, although

nitazoxanide and rifaximin can be obtained in Australia after appli-cation to the Therapeutic Goods Administration. Consultation with a microbiologist regarding treatment is recommended before contemplating prescription of these drugs.

However, it is worthwhile men-tioning these drugs as a ‘watch this space’ message. Nitazoxa-nide has been shown to be equal to both vancomycin and metro-nidazole in efficacy. Rifaximin,

which is enjoying popularity in the US as a therapy for IBS, has been shown to be effective in C. difficile-associated diarrhoea without having a negative effect on the colonic flora.

Fidaxomicin is the most prom-ising new antibiotic as it appears to have quite specific activity against C. difficile without alter-ing the colonic flora significantly. There is also optimism that this drug might reduce the risk of relapse.

Recurrent episodes

Changing diet can

bring about lasting

modifications in

the profile of flora.

The evidence that

probiotics can do this

is variable.

THE incidence of C. difficile- assoc-iated diarrhoea is increasing and it is an important cause to consider when assessing community-acquired diarr-hoea.

Doctors need to remain mind-ful to prescribe antibiotics and PPIs

judiciously, as there is a definite association with antibiotics and research is indicating that PPIs may be implicated in the increase in

C. difficile-associated diarrhoea. Hand washing in hospitals and residential facilities needs to

be emphasised as an important strategy in reducing the spread of

C. difficile and there are encour-aging results from research into novel antibiotics and treatments in treating this frequently recurr-ent disease.

Case 1

A 65-YEAR-old man presents with explosive, painless diarrhoea 5-6 times a day over the past six weeks. He has lost a little weight as a result of not eating in order to reduce the frequency of the diarrhoea.

He hasn’t changed medication, travelled or started any supp-lements recently. He reports that he had three courses of ampicil-lin and metronidazole for a root-canal infection. He was well for six weeks after the final course.

In the past his bowel habit has been normal. He had a nor-mal colonoscopy three years ago because of a family history of colorectal cancer in a first-degree relative. He presents on this occa-sion to arrange a repeat colono-scopy as he is worried that these symptoms represent a change in bowel habit that could indicate malignancy.

Physical examination is normal and the patient looks perfectly well. His FBC is normal, TSH is within normal limits and coe-liac serology, consisting of tissue transglutaminase antibody and endomysial antibody, is normal.

A stool sample is examined for red and white blood cells, ova, cysts and parasites, bacterial cul-ture and C. difficile toxin. The toxin is present and the patient is initially treated with metronid-azole (even though one of the anti-biotics he received for treatment of his dental infection was metronid-azole).

There is no response to treat-ment after a 10-day course, so he is treated with oral vancomycin for 10 days. There is an immediate improvement in his bowel habit in terms of consistency and frequency of motion. After completion of the course of vancomycin, there is still a mild change in his bowel habit compared with his usual pattern of one formed motion every morning, consisting of a less-well-formed motion twice a day, with a marked gastrocolic reflex, resulting in an urge to defecate after meals.

C. difficile testing is not repeated at this stage because it may still be positive despite adequate treat-ment. He is reassured that his con-tinuing symptoms are most likely a form of post-infectious IBS that is very likely to resolve with time. There is gradual improvement over the next couple of months.

He is advised that he should mention this episode if he is pre-scribed antibiotics in the future to reduce the risk of further C. diff-icile infection. In particular, an effort should be made to avoid broad-spectrum antibiotics.

Case 2

A 25-year-old woman has had ulcerative colitis for eight years.

Colonoscopy has demonstrated a left-sided colitis that has been severe enough to require admis-sion to hospital for intravenous steroids in the past.

She has been well for the past three years on oral mesalazine 3g nocte and azathioprine 125mg daily. Her LFTs and FBC are tested every six weeks because of the association between azathio-prine and drug-induced hepatitis and bone marrow suppression, but her blood tests have been satisfac-tory.

She presents with an exacerba-tion of diarrhoea, consisting of 6-7 motions per day, which are unformed and mixed with blood and mucus. She has crampy, lower-abdominal pain and thinks she may have had a fever. She had a recent episode of sinusitis and was prescribed cephalexin for a week.

As she has been documented as having a left-sided colitis in the past, she is started on mesalazine enemas 4gm/60mL nocte in addi-tion to her usual medicaaddi-tions, but there is no improvement in her symptoms. After a two-week period she commences 40mg of prednisolone mane, but there is still no improvement after two weeks. She then attends for a flex-ible sigmoidoscopy under seda-tion, without receiving any bowel prep other than 24 hours of a diet

limited to clear fluids.

The mucosa in the rectum and left colon shows inflammation, with a typical pseudomembrane. Biopsies are consistent with C. difficile infection, as well as show-ing chronic changes consistent with ulcerative colitis.

A stool sample taken at the time of the flexible sigmoidoscopy dem-onstrated C. difficile toxin.

The young woman was started on oral vancomycin and her diarr-hoea resolved within three days. The dose of prednisolone was quickly tapered and ceased, and the mesalazine enemas were ceased immediately.

The patient had stated on a number of occasions that this par-ticular exacerbation felt different to the episodes of diarrhoea she had suffered with inflammatory bowel disease in the past.

It is prudent to have a very low threshold for testing the faeces of patients with ulcerative colitis or Crohn’s disease for C. difficile, as they are in a high-risk group.

Case 3

An independent 84-year-old woman presented to hospital after two weeks of profuse watery diarrhoea, nausea and vomiting. She had received amoxycillin for a week, followed by amoxycillin and clavulanic acid for five days for an

Further reading

• Hamilton M et al. Standardised frozen preparation for transplantation of Fecal Microbiota for Recurrent Clostridium Difficile

Infection. American Journal of Gastroenterology 2012; 107:761-67.

• Cheng A et al. Australasian Society for Infectious Diseases Guidelines for the diagnosis and treatment of Clostridium difficile

infection. Medical Journal of Australia 2011; 194:353-58.

Case studies

Conclusion

cont’d next page

It is prudent to have

a very low threshold

for testing the faeces

of patients with

ulcerative colitis or

Crohn’s disease for

upper respiratory chest infection three weeks before the onset of the diarrhoea.

She was admitted to hospital and given IV fluids. A stool sam-ple was positive for C. difficile

glutamate dehydrogenase antigen and she was treated with oral metronidazole 400mg tds for five days, without improvement. She was changed to oral vancomycin 125mg qid for a week.

There was sufficient improve-ment for her to leave hospital, but she was readmitted a couple of weeks later with the same symp-toms, a CRP of 150 (<5mg/L), serum albumin of 21 (36-45g/ L). She was treated with both oral vancomycin, IV metronid-azole and IV tigecycline and also required total parenteral nutrition. The frequency of her diarrhoea decreased and her CRP fell, but she had persistent loose stools and abdominal pain.

On the basis of recurrent, severe

C. difficile-associated diarrhoea and PCR detection of the hypervir-ulent strain, the decision was made to perform a faecal microbiota

transplant, which was performed two days after the antibiotics and the total parenteral nutrition were ceased. There was a good clinical response over several days and there has been no recurrence of diarrhoea nine months later.

NExT wEEk

More than three million Australians are obese. Finding a solution to this massive health problem is difficult, however, bariatric surgery is one solution. Next week’s How To Treat examines bariatric surgery options, their safety and effectiveness. The author is Emeritus Professor Paul O’Brien, head of the Centre for Bariatric Surgery and Emeritus Professor of Surgery at Monash University, Melbourne, Victoria.

1. Which THREE statements regarding epidemiology of C. difficile-associated diarrhoea are correct?

a) About 30% of healthy adults are carriers of

C. difficile

b) About 70% of healthy neonates have

C. difficile in their stools

c) In many UK and US hospitals, up to 20% of inpatients carry C. difficile

d) In some nursing homes the carrier rate of

C. difficile approaches 50%

2. Several reasons have been suggested for the increased incidence of C. difficile -associated diarrhoea. Which THREE of the following reasons are correct?

a) The decreased pathogenicity of new strains of C. difficile

b) Development of more frequent carrier status of C. difficile in humans

c) The ageing of the population d) The widespread use of antibiotics

3. Which THREE statements are correct?

a) C. difficile is spread via the faecal–oral route b) C. difficile is difficult to eradicate with

commonly used surface cleaners, particularly alcohol-based agents, since

C. difficile spores are resistant to killing by alcohol

c) Patients who enter hospital colonised with C. difficile are more likely to develop diarrhoea

d) A significant proportion of patients who acquire the infection in hospital are discharged before symptoms begin

4. Which THREE statements regarding

community-acquired C. difficile -associated diarrhoea are correct?

a) Community-acquired C. difficile-associated diarrhoea accounts for about 20% of cases of infectious diarrhoea

b) C. difficile-associated diarrhoea diagnosed within 48 hours of admission to a health care facility is classified as community acquired c) C. difficile-associated diarrhoea diagnosed

three weeks after discharge from a health facility is classified as community acquired d) Patients who have community-acquired

C. difficile-associated diarrhoea tend to be younger than the patients with hospital-acquired infection

5. Which THREE statements are correct regarding nursing home residents and

C. difficile-associated diarrhoea?

a) The carrier rate of C. difficile is often high in nursing home residents

b) All nursing home residents should have testing and treatment to eradicate C. difficile

c) C. difficile spores are easily spread due to challenges associated with toileting elderly, infirm residents

d) The importance of regular hand washing with soap and water should be stressed to staff in nursing homes, as C. difficile spores are resistant to alcohol sanitisers

6. Which TWO statements are correct?

a) The increasing use of fluoroquinolones worldwide may be associated with the emergence of the most significant hypervirulent strain of C. difficile that has been identified in Australia, NAP1/BI/027

b) The classes of antibiotics that most frequently induce C. difficile-associated diarrhoea include broad-spectrum penicillins, broad-spectrum cephalosporins and fluoroquinolones

c) Metronidazole and vancomycin never induce

C. difficile-associated diarrhoea

d) There is definite evidence that proton-pump inhibitors increase the risk of acquiring

C. difficile infection

7. Which TWO statements are correct?

a) Age over 65 is a clear risk factor for community-acquired C. difficile-associated diarrhoea

b) Patients with ulcerative colitis and Crohn’s disease have a decreased risk of acquiring

C. difficile-associated diarrhoea c) In patients with ulcerative colitis and

Crohn’s disease, stool testing for C. difficile

should be performed when there is a poor response to their usual therapy

d) Hospital patients receiving chemotherapy are particularly vulnerable to C. difficile -associated diarrhoea

8. Which TWO statements regarding

C. difficile investigations are correct?

a) Stool culture provides the fastest result for the presence of C. difficile

b) Testing for the presence of glutamate dehydrogenase, which is produced by all C. difficile strains, is often used in combination with a test for toxin c) The C. difficile PCR test, also called the

gene test, is both sensitive and specific d) Colonoscopy is mandatory in all cases of

C. difficile-associated diarrhoea

9. Which TWO statements regarding treatment of C. difficile-associated diarrhoea are correct?

a) First-line therapy for mild-to-moderate

C. difficile-associated diarrhoea is oral metronidazole

b) IV vancomycin is very successful in the treatment of C. difficile-associated diarrhoea c) Assessment of treatment with probiotics is

complicated by the fact that there are so many different strains of probiotic bacteria available, which may have a variable effect on the colonic flora of different individuals d) Faecal microbiota transplant is a

well-established treatment for recurrent

C. difficile-associated diarrhoea

10. Which THREE statements regarding recurrent C. difficile-associated diarrhoea are correct?

a) Fewer than 5% of patients will relapse with a further episode of significant C. difficile

diarrhoea

b) A first recurrence of C. difficile-associated diarrhoea should be treated with the same antibiotic regime as the initial episode; however, the response is less likely to be effective

c) Following a second recurrence of C. difficile -associated diarrhoea, vancomycin can be used as a tapering dose or as a “pulse” therapy

d) Fidaxomicin is the most promising new antibiotic for treatment of C. difficile -associated diarrhoea, as it appears to have quite specific activity against C. difficile

without significant alteration of the colonic flora

Clostridium difficile

-associated

diarrhoea — 28 September 2012

InstructIons

Complete this quiz online and fill in the Gp evaluation form to earn 2 CpD or pDp points. we no longer accept quizzes by post or fax.

The mark required to obtain points is 80%. Please note that some questions have more than one correct answer.

ONlINE ONlY

www.australiandoctor.com.au/cpd/ for immediate feedback

How to Treat Quiz

CPD QUIZ UPDATE

The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2011-13 triennium. You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

HOw TO TREATEditor: Dr Barbara Tink

Email: [email protected]

from previous page

A stool sample

was positive for

C.

difficile

glutamate

dehydrogenase

antigen and she

was treated with

oral metronidazole

400mg tds for

five days, without

improvement.