Key points from the evidence

The content of this evidence summary was up-to-date in March 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.


Use of broad‑spectrum antibiotics is associated with an increased incidence of Clostridium difficile infection. This briefing reviews the evidence assessing the risk of C. difficile infection associated with individual broad‑spectrum antibiotics based on the highest quality published evidence.

Both antibiotic prescribing practice and the epidemiology of C. difficile infections are changing. C. difficile has been reported with clindamycin since 1978 (Bartlett et al. 1978). Subsequently, since the early 1990s, the antibiotics most commonly reported as being associated with C. difficile infection were cephalosporins and quinolones. Antibiotic guidelines steadily adopted that evidence and prescribing of cephalosporins and quinolones decreased over the decade to 2013/14 in primary and secondary care in England. However, over the same period, the prescribing of combination penicillins increased: co‑amoxiclav prescribing increased in primary and secondary care and piperacillin‑tazobactam prescribing increased in secondary care. With further clarification of the epidemiology following the establishment of the C. difficile ribotyping network service, these combination penicillins have become the antibiotics most frequently reported as being associated with C. difficile infections. These data should be interpreted with caution and should not be considered to indicate conclusively which antibiotics have the highest risks of C. difficile infection.

Three meta‑analyses in people with hospital‑associated and community‑associated C. difficile infection confirmed that the antibiotics most strongly associated with the infection were clindamycin, cephalosporins and quinolones. However, the interpretation of data on the risk of C. difficile with different antibiotics is extremely difficult. Such data should be interpreted with caution and should not be considered to definitively show which antibiotics or subgroups of antibiotic classes carry higher risks of C. difficile infection.

Although the data have limitations that prevent firm conclusions, the evidence shows the importance of following antibiotic guidelines that recommend that all broad‑spectrum antibiotics are prescribed appropriately and with careful stewardship.

Introduction and current guidance

C. difficile are bacteria that exist widely in the environment, notably in soil, and may become established in the colon of healthy people. C. difficile produces spores, which are passed out in the faeces and may survive for months or years in the environment (for example, on clothes or bedding). Spores that get into the gut then develop into mature bacteria. C. difficile infection occurs when the other harmless bacteria in the gut are disrupted (for example, by taking antibiotics) or when the immune system is compromised, allowing the numbers of C. difficile bacteria to increase to high levels. Certain C. difficile strains produce toxins that damage the lining of the colon, causing symptoms ranging from mild, self‑limiting diarrhoea to pseudomembranous colitis, toxic megacolon, perforation of the colon, sepsis and death (NICE clinical knowledge summary: diarrhoea - antibiotic associated; Brown et al. 2013).

As well as broad‑spectrum antibiotics, other factors increase the risk of C. difficile infection. These include advanced age, underlying morbidity, hospitalisation, exposure to other people with the infection, long duration of antibiotic treatment, taking multiple antibiotics concurrently or taking multiple antibiotic courses, and inflammatory bowel disease (NICE clinical knowledge summary: diarrhoea - antibiotic associated; Public Health England and Department of Health guidance: Clostridium difficile infection: how to deal with the problem).

The number of C. difficile infections in the NHS in England has decreased substantially, from 55,498 cases in 2007/08 to 13,361 cases in 2013/14 (Public Health England annual epidemiological commentary: MRSA, MSSA and E. coli bacteraemia and C. difficile infection data, 2013/14). This decrease has occurred in conjunction with mandatory surveillance and target‑setting, additional measures to control of antibiotic prescribing, and increased compliance with isolation, hand‑washing and hygiene protocols (Department of Health: annual report of the Chief Medical Officer 2011, volume 2).

In 2008, the Department of Health and Public Health England's report on Clostridium difficile infection: how to deal with the problem recommended that trusts should develop restrictive antibiotic guidelines that use narrow‑spectrum agents alone or in combination as appropriate. These guidelines should avoid recommending clindamycin and second‑ and third‑generation cephalosporins (especially in older people) and should recommend minimising the use of quinolones, carbapenems (for example, imipenem and meropenem) and prolonged courses of aminopenicillins (for example, ampicillin and amoxicillin). Broad‑spectrum antibiotics should be used only when indicated by the person's clinical condition, and their use should be reviewed after the results of microbiological testing or based on the sensitivities of causative bacteria. The Department of Health Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection (ARHAI) recommends the Start smart − then focus approach. This recommends that, if immediate antibiotic treatment is necessary, the clinical diagnosis and continuing need for antibiotics should be reviewed within 48−72 hours.

When antibiotics are considered necessary to treat common infections in primary care, Public Health England's guidance on managing common infections recommends suitable options and advises that broad‑spectrum antibiotics should be used only when narrow‑spectrum antibiotics are ineffective.

Appropriate use of antimicrobials is also important to reduce the serious threat of antimicrobial resistance. A cross‑governmental UK 5 year antimicrobial resistance strategy was launched in 2013.

Full text of introduction and current guidance.

Evidence review

  • This evidence review outlines 1 meta‑analysis of hospital‑associated C. difficile infection (Slimings and Riley 2014) and 2 of community‑associated C. difficile infection (Brown et al. 2013 and Deshpande et al. 2013).

  • The results of the 3 meta‑analyses are similar. Slimings and Riley (2014) concluded that cephalosporins and clindamycin are the antibiotics most strongly associated with hospital‑associated C. difficile infection. Brown et al. (2013) and Deshpande et al. (2013) found that, for community‑associated infection, the strongest association was seen with clindamycin, cephalosporins and quinolones. Trimethoprim and sulfonamides were also associated with an increased risk of infection in all 3 meta‑analyses but data were not reported for trimethoprim alone. See table 1 for details.

  • Slimings and Riley (2014) also considered subgroups of antibiotic classes. They found that penicillin combination antibiotics, such as co‑amoxiclav and piperacillin‑tazobactam, were associated with a statistically significant (1.5 times) increase in the risk of hospital‑associated C. difficile infection. Second‑, third‑ and fourth‑generation cephalosporins were associated with 2 to 3 times the risk of infection, but the increased risk seen with first‑generation cephalosporins was not statistically significant. However, the 95% confidence intervals, which give a measure of the results' precision, overlapped.

  • The associations seen in the meta‑analyses of community‑associated infection are generally stronger than in the meta‑analysis of hospital‑associated infection. This may be because antimicrobial‑associated risk factors for community‑associated C. difficile infection are less likely to be confounded by other (hospital‑associated) risks.

  • The studies included in the 3 meta‑analyses are observational studies and are, therefore, prone to confounding and bias. Possible confounding factors include comorbidities, polypharmacy, duration and dose of antibiotic, and use of multiple antibiotics. Possible sources of bias include sampling bias (commonly prescribed antibiotics will be more often reported as being associated with cases), clinical susceptibility bias (patients with illnesses requiring antibiotics may have inherent increased risks of developing C. difficile, and cases may be falsely attributed solely to the clinically‑indicated use of antibiotics in such people), selection of inappropriate controls, and misclassification of C. difficile and exposures to antibiotics. Heterogeneity was commonly seen in the meta‑analyses because of, for example, differences in study populations and methodologies, definitions of cases, and strains of C. difficile. Also, there is the potential for publication bias and a lack of consensus regarding the appropriate time window to measure antibiotic exposure.

Table 1 Summary of risk of C. difficile infection associated with antibiotics

Slimings and Riley (2014)


Brown et al. (2013)


Deshpande et al. (2013)


13 case‑control studies and 1 cohort study

3202 cases 15,938 people in total

6 case‑control studies and 1 cohort study

2578 cases

Total number of people not reported

8 case‑control studies Number of cases not reported

30,184 people in total

All antibiotics

13 studies

OR 1.57

95% CI 1.31 to 1.87

5 studies

OR 3.55

95% CI 2.56 to 4.94

8 studies

OR 6.91

95% CI 4.17 to 11.44


6 studies

OR   2.86

95% CI   2.04 to 4.02

3 studies

OR 16.80

95% CI 7.48 to 37.76

2 studies

OR 20.43

95% CI 8.50 to 49.09


8 studies

OR   1.97

95% CI  1.21 to 3.23

5 studies

OR 5.68

95% CI 2.12 to 15.23

Also includes monobactams and carbapenems

3 studies

OR 4.47

95% CI 1.60 to 12.50

Subgroup analyses

1st generation:

no significant association seen OR 1.36

95% CI 0.92 to 2.00

2nd generation:

6 studies

OR 2.23

95% CI 1.47 to 3.37

3rd generation: 6 studies

OR 3.20

95% CI 1.80 to 5.71

4th generation:

2 studies

OR 2.14

95% CI 1.30 to 3.52


10 studies

OR  1.66

95% CI   1.17 to 2.35

5 studies

OR 5.50

95% CI 4.26 to 7.11

3 studies

OR 5.65

95% CI 4.38 to 7.28


No significant association seen overall

5 studies

OR 2.71

95% CI 1.75 to 4.21

4 studies

OR 3.25

95% CI 1.89 to 5.57

Subgroup analysis penicillin combination antibiotics (e.g. co‑amoxiclav and piperacillin‑tazobactam)

6 studies

OR 1.54

95% CI 1.05 to 2.24


No significant association seen

4 studies

OR 2.65

95% CI 1.92 to 3.64

3 studies

OR 2.55

95% CI 1.91 to 3.39

Trimethoprim and sulfonamides

5 studies

OR   1.78

95% CI  1.04 to 3.05

4 studies

OR 1.81

95% CI 1.34 to 2.43

3 studies

OR 1.84

95% CI 1.48 to 2.29


6 studies

OR 1.84

95% CI   1.26 to 2.68

Assessed with cephalosporins and monobactams

Not assessed


No significant association seen

No significant association seen

No significant association seen


No significant association seen

Not assessed

Not assessed

Abbreviations: CI, confidence interval; OR, odds ratio.

Full text of evidence review.


Reducing inappropriate use of cephalosporins and quinolones to reduce C. difficile infection (and MRSA infection) has been prioritised in both primary and secondary care since the late 1900s and early 2000s. Although there has been a marked decline in their use in the past decade, the use of other broad‑spectrum antibiotics has increased.

According to Public Health England's English surveillance programme antimicrobial utilisation and resistance (ESPAUR) report, in general practice, use of cephalosporins and quinolones decreased, but use of co‑amoxiclav significantly increased between 2010 and 2013. In hospitals, the use of narrow‑spectrum antibiotics (phenoxymethylpenicillin, flucloxacillin and erythromycin) decreased and the use of broad‑spectrum antibiotics such as co‑amoxiclav, piperacillin‑tazobactam and meropenem significantly increased during the same period.

According to Public Health England's C. difficile ribotyping network (CDRN) report, since 2007 the strains of C. difficile identified and the antibiotics most frequently reported as being associated with C. difficile infections referred to the CDRN have changed markedly. In 2007/08, cephalosporins and quinolones were the most commonly cited antibiotics, but they were superseded by co‑amoxiclav and piperacillin‑tazobactam in 2011/12 and 2012/13. These data should be interpreted with caution and should not be considered to indicate conclusively that these antibiotics have a higher risk of C. difficile infection. The CDRN states that the data probably reflect changes in antibiotic prescribing as one of the control measures for C. difficile infection.

Full text of context.

Estimated impact for the NHS

Because of the limitations of the data there is too much uncertainty to definitively assign levels of risk of C. difficile infection to different antibiotics or subgroups of antibiotic classes. Identifying the cephalosporin and quinolone classes as 'high‑risk' may have driven the increased prescribing of co‑amoxiclav and other broad‑spectrum antibiotics such as piperacillin‑tazobactam.

Without clear evidence showing that 1 particular antibiotic or class of antibiotic is 'low‑risk', only general recommendations are possible. Broad‑spectrum antibiotics should be used only in limited circumstances and when clinical need is greatest. Organisations should follow national guidance, support local antimicrobial stewardship programmes and follow local antimicrobial guidelines. These should be evidence based, relevant to the local healthcare setting and take into account local antibiotic resistance patterns.

Healthcare professionals should review and, if appropriate, revise current prescribing practice and ensure prescribing is in line with Public Health England's guidance for primary care on managing common infections, the Department of Health's guidance Start smart − then focus, and local trust antimicrobial guidelines. The total volume of all antibiotic prescribing and broad‑spectrum antibiotic prescribing should be reviewed against local and national data.

See the estimated impact for the NHS section of this medicines and prescribing briefing for information on resources to help reduce inappropriate antibiotic prescribing.

NICE has produced several guidelines relating to healthcare‑associated infections and antibiotic prescribing, which are listed in the relevance to NICE guidance programmes section of this medicines and prescribing briefing. NICE is also developing guidelines on antimicrobial stewardship (publication expected July 2015) and antimicrobial stewardship – changing risk-related behaviours (publication expected March 2016).

Full text of estimated impact for the NHS.

About this evidence summary: medicines and prescribing briefing

'Evidence summaries: medicines and prescribing briefings' aim to review the evidence for the clinical effectiveness of medicines within a therapeutic class or indication to provide advice on the relative position of different medicines as therapeutic options. This will assist localities in their planning on medicines optimisation priorities as well as providing individual prescribers with information to help informed decision making. The strengths and weaknesses of the relevant evidence are critically reviewed to provide useful information, but this medicines and prescribing briefing is not NICE guidance.