FLUOROQUINOLONE USE IS THE PREDOMINANT RISK FACTOR FOR THE DEVELOPMENT OF A NEW STRAIN OF CLOSTRIDIUM DIFFICILE-ASSOCIATED DISEASE

Authors


Nilay S. Patel, Harold Hopkins Department of Urology, Royal Berkshire Hospital, Reading, UK.
e-mail: n1lay@doctors.net.uk

Abbreviations
CDAD

Clostridium difficile-associated disease

INTRODUCTION

Clostridium difficile-associated disease (CDAD) has been a significant clinical problem for many years. The pattern of this disease appears to be changing, with increasing incidence and disease-related mortality. This increase in CDAD has been attributed to a new hypertoxin-producing bacterial strain, Ribotype 027. It recently emerged that the predominant risk factor for the prevalence of this strain of C. difficile is the use of fluoroquinolone antibiotics such as ciprofloxacin. C. difficile is a Gram-positive, anaerobic, spore-forming bacillus that is the most common cause of nosocomial diarrhoea and antibiotic-associated colitis. CDAD is a diverse symptom complex that ranges from asymptomatic colonization to pseudo-membranous colitis. The disease arises as a result of the feco-oral transmission of C. difficile spores. Affected patients have usually been treated with antibiotics that alter the composition of the colonic bacterial flora. Once colonization has occurred, progression to CDAD depends on the coexistence of underlying illnesses and the efficacy of the host immune response. Pathogenicity is the result of the release of C. difficile toxins A and B, which bind to specific receptors on the intestinal epithelium. These toxins initiate the recruitment of monocytes and the release of inflammatory cytokines, which cause fluid secretion, mucosal destruction and tissue necrosis.

In the UK the incidence of voluntarily reported C. difficile infections has risen from 1172 in 1990 to 46 501 in 2005 [1]; this increase coincided with an increase in deaths involving CDAD (975 in 1999, 2247 in 2004). CDAD caused twice as many deaths as methicillin-resistant Staphylococcus aureus in the UK in 2003 [2]. The financial consequences of CDAD are considerable; in 2005 CDAD is thought to have cost the NHS £200 million and resulted in the need for 1 million extra bed-days.

CDAD came to the forefront of the healthcare agenda in 2003, when hospitals throughout Quebec, Canada, reported a five-fold increase in infection rates and a two- to three-fold increase in mortality [3]. A similar outbreak of CDAD was reported at Stoke Mandeville Hospital, UK, in 2003 and 2005, when 334 cases were identified with 38 deaths (11%) [4]. In both these cases one strain of C. difficile, termed Ribotype 027, was identified as the causative organism [5]. Before these outbreaks Ribotype 027 accounted for <1% of C. difficile infections, but a report in 2005 showed that Ribotype 027 now accounts for >25% of such infections in the UK [6].

Analysis of the biological characteristics of Ribotype 027 showed that the increased severity and mortality associated with Ribotype 027 infection is the result of the hyper-production of C. difficile toxins. An 18-base-pair deletion in the pathogenicity locus (PaLoc) of Ribotype 027 results in 16 times more toxin A and 23 times more toxin B production than conventional strains of C. difficile[5]. The profuse diarrhoea that subsequently develops as a result of this hyper-toxin production is thought to aid the widespread dissemination of C. difficile spores.

The rapid increase in the incidence of Ribotype 027 CDAD might be the result of changing patterns of antibiotic use. A retrospective analysis of the risk factors involved in the CDAD outbreak in Quebec showed that the use of fluoroquinolones was the predominant risk factor in Ribotype 027 CDAD (adjusted hazard ratio 3.44) [7]. Antibiotic sensitivity testing showed that Ribotype 027 is resistant to fluoroquinolone antibiotics, suggesting that the use of these antibiotics might specifically select for this hyper-virulent strain of C. difficile[8].

Fluoroquinolone use has increased dramatically over the past decade; they are now the most prescribed group of antibiotics in the USA [9]. The use of fluoroquinolones is common practice in urology, where they have become the antibiotic of choice for a variety of infections. The latest European Urology Association guidelines recommend the use of fluoroquinolones in the treatment of simple cystitis (where resistance to trimethoprim is >20%), pyelonephritis, epididymo-orchitis, prostatitis and urosepsis [10]. The newly identified relationship between fluoroquinolone use and CDAD should encourage urologists to use fluoroquinolones with more caution. Alternative antibiotics such as trimethoprim, gentamicin, penicillin and co-amoxiclav are less likely to cause Ribotype 027 CDAD, with adjusted hazard ratios of 0.88–1.37 [7]. It might be prudent to consider the use of these antibiotics in preference to fluoroquinolones for treating some urological infections.

CDAD is a common problem on most urology wards; apart from antibiotic exposure, other risk factors for the development of CDAD include; age >65 years, the presence of comorbidities, the use of proton-pump inhibitors, laxatives, naso-gastric tubes and prolonged hospital stay.

The treatment of patients with CDAD is proving to be increasingly challenging. The key principles of management are early diagnosis, mandatory reporting, cessation of precipitating antibiotics, avoidance of anti-peristaltic agents and prompt treatment of symptomatic patients. Patients should be isolated and barrier-nursed to prevent the dissemination of C. difficile spores, which once spread are difficult to eliminate, as they are resistant to heat, alcohol and most commonly used detergents. Healthcare workers in contact with patients infected with C. difficile must wash their hands with soap and water, as alcohol-based hand rubs are ineffective against C. difficile spores. The scarcity of single hospital rooms often means that patients are not adequately isolated and barrier-nursed. First-line therapy is with oral metronidazole, with oral vancomycin being reserved for serious or recurrent infections. The efficacy of these treatments historically has been 75–98% for metronidazole and 86–100% for vancomycin. Of some concern is the recent observation of an increase in refractory and recurrent disease.

It is essential that urologists recognize the impact that CDAD can have on their patients. By minimizing exposure to risk factors for CDAD the devastating effects of outbreaks of Ribotype 027 CDAD can be avoided. A significant proportion of urological patients are aged >65 years, and as such are at high risk of developing CDAD. To minimize the risk, unnecessary exposure to high-risk antibiotics such as the fluoroquinolones must be ensured. Responsible prescribing in conjunction with good hygiene and nursing care will help to limit the consequences of CDAD.

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