An Audit of the Usage of C.

Difcile Associated Antibiotics in General Practice

June 2011 Edward Gill Supervisor: Dr C. Chen
Chorlton Health Centre

Word count : 3493 words

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Abstract
Over use of antibiotic therapy is known to be a signicant cause of Clostridium Difcile infection - something which is largely responsible for ward closures and mortality in the elderly and immunocompromised. This link has resulted in a greater push for cleanliness in secondary care facilities to reduce the spread of infection; and the introduction of restricted antibiotic formularies by many NHS trusts. In a small Manchester GP practice 45% of off-formulary antibiotic prescriptions were deemed as inappropriate (judged against trust guidance); suggesting greater care needs to be made in documenting reasons for using these irregular drugs.

Introduction
Diarrhoea is a well documented side effect of antibiotic therapy, seen in around 2-25% of patients. This may simply be caused by an upset of the intestinal ora, or as a known side effect of the drug independent of antimicrobial effect.1 However, one particular mechanisms implicated since the late 1970s as a major cause of both simple diarrhoea and colitis following antibiotic use is the proliferation of the bacterium Clostridium difcile (C.difcile). Therapy causes the normal intestinal ora to become depleted; allowing C. difcile colonisation and toxin production which damages the colonic wall, leading to diarrhoea. This can progress to a condition called Pseudomembranous Colitis, which carries a signicant mortality risk (especially given that many cases occur in secondary care facilities, involving the elderly or those with chronic illnesses).2 Given that the bacteria can also be easily spread, a single case in a hospital or care home facility can result in a larger scale outbreak; with the subsequent closing and cleansing of wards having a negative effect on patient care.

Due to the reported link between certain antibiotics and infections such as C. difcile a restricted formulary has been developed by most trusts, which consists of ten so-called low-risk antibiotics. The purpose of this report is to rst examine the mechanisms through which antibiotic therapy can lead to C. difcile infection; with subsequent auditing of the prescription of three high-risk antibiotics (cefalexin, ciprooxacin, co-amoxiclav) within a small (3300 patients) Manchester GP surgery over a 12 month period.

Clostridium difcile
Antibiotic-associated diarrhoea is dened as otherwise unexplained diarrhoea that occurs in association with the administration of antibiotics 3 . The role of Clostridium difcile in these infections was recognised in the late 1970s by studies such as George et al.4, with the bacteria now being seen as almost exclusively causative of antibiotic-associated diarrhoea.

The microbe itself is an anaerobic, gram positive, spore-forming rod bacterium. A exible genome, and numerous physiological factors (including the production of rugged spores) allow a comfortable survival in the human gastrointestinal tract; with the spores even allowing recurrence following the completion of antimicrobial therapy.5 These spores are also key to the transmission of the bacterium, which is via an indirect faeco-oral route (either through personal carriers of environmentally).6

Inside the colon the organism colonises in the mucus, before producing two toxins: Toxin A, a cytotoxin & enterotoxin; and Toxin B a cytotoxin. These toxins inltrate the colonic wall, resulting in the development of characteristic pseudomembranes - discrete, widely disseminated yellow-white plaques which can be easily removed (hence pseudomembranous) (as seen in Fig 1.).7 These lesions are usually 2-7mm in diameter, and may cover large portions of the colonic mucosa in severe disease.
Figure 1. Endoscopic view of pseudomembranous plaques associated with C. difcile infection 7

The symptoms of infection range from mild diarrhoea and bloating to a severe manifestation with evidence of peritoneal involvement. The most common presentation is watery diarrhoea which may include mucus, along with abdominal pain and a mild fever 5-10 days post-antibiotic therapy. Severe pseudomembranous colitis may present as an acute medical emergency, with potential progression to toxic megacolon and sepsis. Diagnosis tends to be via laboratory testing in conjunction with a tting clinical history. The most common test looks to discover the presence C. difcile cytotoxins in the stool, with a sensitivity of 67-100% and a specicity of 85-100%. Culture of the organism itself from the stool may also be performed, however this neglects to differentiate between different forms of the bacteria. Endoscopy may also be used as a second line investigation when a negative cytotoxic assay is seen in conjunction with a strong clinical probability. Computed tomography of the abdomen may show a thickened colonic wall, with pericolonic inammation and colonic dilatation.8

Key to treatment is the termination of any ongoing antibiotic therapy, leading to resolution in under 3 days in 22% of patients. If ceasing of causative therapy does not lead to improvement then a 10 day course of metronidazole (rst line) or vancomycin (second line) is usually favoured. Recurrence of the infection is seen in 15-35% of patients, treatment being a repeat course of metronidazole.9 10

Epidemiology & Risk Factors for Infection

Since 1990 there has been voluntary surveillance of the incidence of infection in the United Kingdom, with trusts choosing whether they wished to report their infection levels. In 2004 this was extended to mandatory reporting for infections involving those over 65 years old in England. This was extended once again to include all cases aged over 2 years old in April 2007.11 A total of 25,604 cases of C. difcile infection were reported between April 2009 and March 2010 in the whole of the UK, with the Manchester Primary Care Trust reporting 294 of these infections.

Asymptomatic colonisation of C. difcile is seen in around 3-5% of the population in the community; rising to up to 20% in those being treated in hospital (especially the elderly).12 Bignardi identied several signicant risk factors through a literature review: increasing age (excluding infancy), severity of underlying diseases, non- surgical gastrointestinal procedures, presence of a nasogastric tube, anti-ulcer medications, stay on ITU, duration of hospital stay, duration of antibiotic course and administration of multiple antibiotics. It was also determined that there was a strong link between antibiotic exposure and both C. difcile carriage and infection.13 Chemotherapy, immunosuppressant agents and gastric acid suppression therapy (particularly proton pump inhibitors) have also all been implicated as increasing risk of infection.14

The use of (particularly) broad-spectrum antibiotics is seen to disrupt the colonic ora, predisposing an individual to infection. The relative risk of a selection of antibiotics is shown in Table 1.15

Low risk Aminoglycosides Vancomycin Trimethoprim Tetracyclines Piptazobactam Benzylpenicillin

Medium risk Co-amoxiclav Macrolides Amoxicillin/Ampicillin

High Risk Second/third generation cephlasporins Clindamycin Fluroquinolones

Table 1: Relative risk of C. difcile for different antibiotics

A natural defence against infective microbes is formed by the normal intestinal ora. When antibiotic therapy is used the ora are inadvertently reduced, allowing the C. difcile microbe to colonise. Cephlasporins are a group of drugs which are continually implicated in increasing risk of infection. When observing 5885 patients with antibiotic-associated diarrhoea in Sweden, Aronsson et al. found risk of C. difcile infection to be 40 times greater with the use of cephlasporins than when using narrow spectrum penicillins.16 Similar results have been seen in numerous different studies. The use of quinolones (such as Ciprooxacin) has also been observed to increase C. difcile risk. A study by Yip et al. found that infection risk was at least 5 times higher in patients treated with Ciprooxacin compared to a control group; attributing this to a proven link between quinolone use and depletion of the intestinal ora.17 The nal high risk antibiotic is Clindamycin, which has been shown to result in a prolonged susceptibility to infection through allowing a wider window of opportunity for bacterial colonisation. Due to these proven links the prescription of Clindamycin has now almost vanished, with many trusts devising their own formularies.18 For example, the formulary for Manchester PCT is: a. Amoxicillin b. Clarithromycin c. Doxycycline d. Erythromycin e. Flucloxacillin
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f. Metronidazole g. Nitrofurantoin h. Oxytetracycline i. Phenoxymethylpenicillin j. Trimethoprin

Introduction to Audit
The purpose of this audit was to examine the prescription of cefalexin, ciprooxacin and co-amoxiclav at Dr Chen, Dr Davis & Dr Chavdarovs practice at Chorlton Health Centre over a 12 month period for appropriate usage. The practice is considered small, with a list size of approximately 3300 patients. Whilst commonly used in the past, these antibiotics are now recognised as providing a higher risk of C. difcile infection, and therefore should be avoided in many instances. Given that the Manchester Primary Care Trust has a very clear set of antibiotic guidelines for differing infections the audit is looking to identify instances whereby off-guidance antibiotics have been prescribed; to identify why they were prescribed in this instance; and to ascertain if a more appropriate drug could have been used in there place.

Methodology
A search of patient records was made over a period of 12 months, between 16th June 2010 and 16th June 2011, to identify prescriptions of Cefalexin, Ciprooxacin and Coamoxiclav. This yielded 54 prescriptions. Data collected included sex, indication, dosage and prescriber. The sample was then ltered to remove prescriptions from secondary care (including Accident & Emergency); leaving 33 prescriptions from the practice GPs and Out of Hours consultations (OOH). Indication for prescription was then compared against the NHS Manchester Antibiotic Guidelines (Version 3.0, January 2011) to ascertain whether the prescription of the high-risk antibiotic was appropriate.

A specimen data collection sheet is included below as Table 2.

DOB Sex

Abx

Indication

Dose

Duration

Any other Abx

Comments

Date

Prescriber

Table 2: Sample data collection sheet.

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Discussion of Findings
Within the 12 month period there were 33 prescriptions of the 3 drugs within a primary care setting - 9 for Cefalexin, 10 for Ciprooxacin and 14 for Co-amoxiclav. The most common indications were for respiratory and urinary tract infections, which matches with the expected case load in primary care. Other indications seen included the prescription of Co-amoxiclav for dog bites and a dental infection; and the use of Cefalexin prophylactically in a catheterised Multiple Sclerosis sufferer with repeat urinary tract infections. A full list of indications is detailed below in Table 3, and illustrated graphically.

Cefalexin
UTI Upper RTI Lower RTI Prophylactic 6 1 1 1 2 4 4 1 1 2

Co-amoxiclav
UTI Upper RTI Lower RTI Dog Bite Dental Infection Skin/Tissue Infection

Ciprooxacin
UTI Upper RTI Lower RTI GI Infection Table 3: Indication for antibiotic prescription 4 3 1 2

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Indication for Cefalexin

UTI Upper RTI Lower RTI Prophylactic

11% 11% 11% 67%

Indication for Co-Amoxiclav

14% 7% 7%

14%

UTI Upper RTI Lower RTI Dog Bite Dental Infection Skin/Tissue Infection

29% 29%

Indication for Ciprofloxacin

UTI Upper RTI Lower RTI GI Infection

20% 40% 10%

30%

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The indications were compared against the Manchester antibiotic guidelines, and were classied to be either appropriate, inappropriate; or inappropriate, but subsequently changed to a more appropriate drug. Of the 33 prescriptions, 18 (55% were found to be appropriate and in line with guidance. A further 5 prescriptions (15%) had been made against guidelines, although subsequently recognised and changed to a more appropriate drug. The further 10 prescriptions (30%) were seen to be outside of guidelines.

Changed 15%

Changed Inappropriate Appropriate

Appropriate 55%

Inappropriate 30%

Chart 4: Suitability of total antibiotic prescriptions

Prescriptions for Cefalexin were seen to be mostly outside of guidance, with 6 out of 9 (66%) marked as inappropriate. Of these 6 prescriptions, 4 were for urinary tract infections, 1 was for an upper respiratory tract infection, and 1 for an infective exacerbation of asthma. Three of the prescriptions were recognised to be inappropriate, and thus changed to other antibiotics (2 urinary tract infections changed to Trimethoprim and Nitrofurantoin; infective exacerbation of asthma changed to Erythromycin). The single prescription for an upper respiratory tract infection was stopped as it was deemed that the illness with viral. The other two inappropriate prescriptions were for suspected urinary tract

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infections in the absence of cultures, where guidance advises the use of trimethoprim as a rst line treatment.

The prescriptions that were deemed appropriate were all related to urinary tract infections. Two of the scripts issued were indicated as third line therapy (in line with guidance); and one instance was indicated as prophylaxis for recurrent urinary tract infections in a multiple sclerosis sufferer (dosed at 250mg once a day).

Of the 10 Ciprooxacin prescriptions, 6 were seen to be appropriate (60%), with 4 deemed inappropriate. Half (2) of the inappropriate prescriptions were for the treatment of Otitis media; whereby the use of Amoxicillin as a rst line drug would be more appropriate. Neither of these patients were noted to be allergic to Penicillin. Of the other 2 inappropriate prescriptions, one of the prescriptions was for an exacerbation of COPD whereby it is recommended in the guidelines that quinolones should not be prescribed rst line (Amoxicillin/Doxycycline/Clarithromycin/Erythromycin are instead endorsed). A prescription for travellers diarrhoea following a trip to Pakistan was also seen to be inappropriate; especially considering the link between uoroquinolones and antibioticassociated diarrhoea.19

Quinolones are often used as a rst line treatment for urinary tract infections; and so 3 prescriptions of Ciprooxacin for these infections were seen as appropriate. A prescription for Pyelonephritis was considered appropriate due to a Phenoxymethylpenicillin allergy; as was a prescription for an upper respiratory tract infection due to an allergy to both Penicillin and Erythromycin. The use of Ciprooxacin to treat a case of infectious diarrhoea was also deemed to be suitable in the setting of an immunocompromised HIV+ patient.

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Of the 3 drugs, Co-amoxiclav had the largest number of prescriptions at 14. Of these 9 were judged to be appropriate (64%), with 5 inappropriate (36%). Those deemed inappropriate were for a variety of ailments. A prescription for a wound infection was deemed inappropriate in the absence of sensitivity or allergy to other antibiotics. The use of Co-amoxiclav for a case of Mastitis was also seen to be inappropriate, with Fluxcloxacillin being the drug of choice (it is, however, recognised that early antibiotic treatment is indicated to prevent abscess formation). The other inappropriate cases were for nasal folliculitis, an upper respiratory tract (throat) infection (with the patient later admitted to hospital with tonsillitis) and a dental infection (although subsequent treatment may have been changed by dental specialists - not documented).

The appropriate prescriptions of Co-amoxiclav were second line in 5 of the 9 cases, for Cellulitis and respiratory tract infections. A Klebsiella Pneumoniae urinary tract infection sensitive to Co-amoxiclav was also seen to be an apt prescription, however it was also deemed to be sensitive to Trimethoprim which may have been more appropriate in the absence of allergy or adverse reaction. The drug was indicated as rst line treatment for a dog bite and a case of Pyelonoephritis; and was also suggested as a backup antibiotic for a long term sufferer of Silicosis.

Of the 33 primary care prescriptions, the majority were made by the practice itself (26 61%), with 7 being made by the Out of Hours GP service.

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Locum 3% Out of Hours 21%

CC DAD Out of Hours Locum

CC 36%

DAD 39%

Chart 5: Prescribers of Cefalexin/Co-Amoxiclav/Ciprooxacin

When looking at those prescribing inappropriate prescriptions, it is somewhat striking that of 7 prescriptions by the Out of Hours GP service, all 7 were deemed to be improper (with 3 of the 7 being subsequently stopped or changed to a more appropriate antibiotic). Prescriber numbers are noted in Table 4 below.

Prescriber

Number of inappropriate prescriptions

Total number of prescriptions

Inappropriate prescriptions as percentage of prescriber total 12 13 7 1 25% 38% 100% 0%

CC DAD Out of Hours Locum

3 5 7 0 Table 4: Prescribers of inappropriate antibiotics

Whilst it is recognised that the Out of Hours GPs do not have access to (amongst other things) test results to aid sensitive antibiotic prescription it is still alarming to see straying from the trust guidance to such a degree - especially given that improper prescription
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levels equal those of the GP surgery itself (8 prescriptions to the Out of Hours 7), which has a much higher case load. In those given by the surgery prescribers (CC/DAD) it is recognised that drugs on the approved formulary may not always be appropriate in each individual situation. It is therefore suggested that more notation is given when prescribing these inappropriate drugs in order to justify there usage. Given that the practice prescribed 207 antibiotics in total over the 3 month period of January to March 2011 the signicance of 10 inappropriate antibiotics over a 12 month period is somewhat lost (less than ~5% of total antibiotic prescriptions). It should be noted that within the same JanuaryMarch 2011 period the percentage of cephlasporins & quinolones prescribed by the practice was 3.4%; 1.3% below the primary care trust average of 4.7% and over half that of the England average (7.5%). The practice may also be noted to be generally good at withholding antibiotic treatment in inappropriate cases, with 93 less prescriptions than the primary care trust average of 300.

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Recommendations
The two main recommendations based on the audit results are as follows:

i. Documentation of indication for off-guidance antibiotics when used ii. Scrutiny of Out of Hours prescriptions, with a change to a more suitable antibiotic of appropriate

More thorough recording of data in these cases will aid in the identication of any mitigating factors which may have been missed when reviewing data for this audit. This might be particularly useful when accounting for prescription of Co-amoxiclav, given that it is generally seen to have an increased spectrum of action than other antibiotics.

The examination of Out of Hours prescriptions appears to be crucial, given that all 7 prescriptions were found to be improper. It might be the case that a review of these consultations with proper culture results or a more complete clinical picture (in a further encounter) will aid in the initiation of therapy from the approved list (or prevent therapy in the case of viral illness).

A further audit cycle in 12 months should hopefully show a more settled picture with the introduction of these matters - I would expect to see a greater proportion of inappropriate prescriptions changed to alternative on-formulary drugs, and more appropriate prescriptions (given justication in the patient notes). However, as previously noted, I feel that overall antibiotic prescription is generally good, with a low proportion of inappropriate therapy and prescription numbers way below both primary care trust and national averages.

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Conclusion
The key points in relation to this audit very much echo the recommendations for practice put forward by the Greater Manchester Medicines Management Group.20 Prescription of antibiotics should be narrow-spectrum and targeted whenever possible, except when sensitivity information is unavailable. This includes withholding prescriptions when the causative organism is thought to be viral; disregarding the so-called placebo effect. Wherever possibly local guidance and formulary should be followed; however it is accepted that there will always be individual cases which require the use of a novel antibiotic. As was previously stated in my recommendations, documentation of rationale in these instances could be seen as sensible, not least to aid future prescribers in initiating the correct therapy.

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Starr J. Clostridium difcile associated diarrhoea: Diagnosis and treatment. BMJ 2005, Sep 3;331(7515): 498-501..
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Bignardi GE. Risk factors for clostridium difcile infection. J Hosp Infect 1998, Sep;40(1):1-15.

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Northern & Yorkshire Regional Drug and Therapeutics Centre. Safer medication use: Drug-induced Clostridium difcile infection; January 2009. Available from: http://www.nyrdtc.nhs.uk/GMMMG/Publications/ smu/GMMMG_SMU_04.pdf.
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Aronsson B, Mllby R, Nord CE. Antimicrobial agents and clostridium difcile in acute enteric disease: Epidemiological data from sweden, 1980-1982. J Infect Dis 1985, Mar;151(3):476-81.
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Yip C, Loeb M, Salama S, Moss L, Olde J. Quinolone use as a risk factor for nosocomial clostridium difcile-associated diarrhea. Infect Control Hosp Epidemiol 2001, Sep;22(9):572-5.
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