Clostridium difficile (new taxonomy Clostridioides difficile  is a gram-positive spore forming rod shaped bacterium being the main cause for nosocomial diarrhea. C. difficile infection (CDI) may include mild to severe symptoms up to fulminant colitis resulting in toxic megacolon, sepsis, multiorgan dysfunction, permanent impairment contributing to a high mortality rate. Antibiotics are thought to be the main driver for CDI, as C. difficile can strive when the gut microbiome is disrupted . Classically the “4 C” antibiotics clindamycin, fluoroquinolones, cephalosporins and aminopenicillins with beta-lactamase inhibitors (e.g. amoxicillin/clavulanic acid) are associated with high risk of CDI development . Antibiotics with a lower risk of CDI are tetracyclins (e.g. doxycycline) and tigecyclin as well as vancomycin and daptomycin  CDI is treated with metronidazole, vancomycin and fidaxomicin and resistance testing is usually not necessary  For epidemiological purposes isolates can be differentiated by their Ribotype (RT) . In recent years virulent RTs such as RT027 showed global spreading  leading to a higher CDI incidence and more severe courses of disease.
Virulence factors of this pathogen are the toxins A (tcdA) and B (tcdB) . Some isolates inhabit additionally the binary toxin which is encoded by cdtA and cdtB . Binary toxin is found preferably in epidemic isolates associated with more severe infections . One of these strains is RT027 which has showed global spreading in recent years . An important factor for selection and spreading of virulent strains like RT027 is their resistance towards a variety of antibiotics, mainly macrolides and flourochinolones . In orthopedic surgery often antibiotics are administrated over long periods due to complicated soft tissue or osteoarticular infections resulting in an increased risk for CDI. In recent years an increase in CDI incidence has been noted in orthopedic patients  with a CDI rate of 0.19% in one major study including more than 100.000 patients . Especially in patients with non-elective procedures (e.g. following trauma) CDI incidence is much more prevalent [11,12].
Rifampicin is a drug frequently used in orthopedics. The mode of action is inhibition of bacterial RNA polymerases  while resistance might be triggered by mutations in the rpoB gene in C. difficile isolates . One major field of use are infections with biofilm formations due to staphylococci .In the past it has been proposed that rifampicin might hold a protective effect towards CDI development [14,16, 17]. This effect might be favored by the usually low resistance rate of C. difficile strains against rifampicin .On the other hand other data indicate that rifampicin might favor CDI , especially with C. difficile strains harboring rifampicin resistance. In German patients suffering from osteoarticular infections rifampicin resistant RT027 isolates seemed to be a major driving factor for CDI . In this study application of antibiotic stewardship which resulted in a reduction of overall antimicrobial use was able to significantly lower the CDI incidence. Similarly, in Poland, another study concluded that in an epidemiological setting with a dominance of a rifampicin resistant C. difficile strain (RT046) patients on tuberculosis treatment with rifampicin are at a higher risk do develop CDI .
Thus, rifampicin might work as a double-edged sword: In rifampicin sensitive RTs it might protect from CDI, however, it might select rifampicin resistant C. difficile strains, and these are often strains with a higher virulence such as RT001, RT017, RT027 and RT176 . The main goal of preventing CDI is to reduce the antibiotic use in general with a switch to drugs associated with a low risk of inducing CDI (e.g. tetracyclins). As a consequence, rifampicin should be used restrictively in orthopedic surgery and other medical fields to avoid selection of emerging resistant C. difficile strains and CDI development. In case of an increased CDI rate on wards with a relevant rifampicin use, ribotyping and resistance testing might be an option to identify driving factors for CDI development and to optimize antibiotic treatment.
Lawson PA, Citron DM, Tyrrell KL, Finegold SM (2016)
Reclassification of Clostridium difficile as Clostridioides difficile (Hall and O'Toole 1935)
Prevot 1938. Anaerobe 40: 95-99.
Rupnik M, Wilcox MH, Gerding DN (2009) Clostridium
difficile infection: new developments in epidemiology and
pathogenesis. Nat Rev Microbiol 7: 526-536.
Leffler DA and Lamont JT (2015) Clostridium difficile infection. N Engl J Med 372: 1539-1548.
Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, et
al. (2010) Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for
healthcare epidemiology of America (SHEA) and the infectious diseases society
of America (IDSA). Infect Control Hosp Epidemiol 31: 431-455.
Indra A, Huhulescu S, Schneeweis M, Hasenberger P,
Kernbichler S, et al. (2008) Characterization of Clostridium difficile isolates using capillary gel electrophoresis-based
PCR ribotyping. J Med Microbiol 57: 1377-1382.
He M, Miyajima F, Roberts P, Ellison L, Pickard DJ, et
al. (2013) Emergence and global spread of epidemic healthcare-associated Clostridium
difficile. Nat Genet 45: 109-113.
Gerding DN, Johnson S, Rupnik M, Aktories K (2014) Clostridium
difficile binary toxin CDT: mechanism, epidemiology, and
potential clinical importance. Gut Microbes5: 15-27.
Yakob L, Riley TV, Paterson DL, Marquess J, Magalhaes
RJ, et al. (2015) Mechanisms of hypervirulent Clostridium difficileribotype 027 displacement of endemic strains: an
epidemiological model. Sci Rep 5:12666.
Tenover FC, Tickler IA, Persing DH (2012) Antimicrobial-resistant
strains of Clostridium difficile from North America. Antimicrob Agents Chemother56:2929-2932.
Anderson PA, Bernatz J, Safdar N (2017) Clostridium
difficile Infection: An Orthopaedic Surgeon's Guide to
Epidemiology, Management, and Prevention. J Am AcadOrthopSurg25:214-223.
Li X, Wilson M, Nylander W, Smith T, Lynn M, et al.
(2016) Analysis of Morbidity and Mortality Outcomes in Postoperative Clostridium
difficile Infection in the Veterans Health Administration. JAMA
Campbell KA, Phillips MS, Stachel A, Bosco JA, 3rd,
Mehta SA (2013) Incidence and risk factors for hospital-acquired Clostridium
difficile infection among inpatients in an orthopaedic tertiary
care hospital. J Hosp Infect83:146-149.
Wehrli W (1983) Rifampin: mechanisms of action and
resistance. Rev Infect Dis 3:S407-411.
O'Connor JR, Galang MA, Sambol SP, Hecht DW, Vedantam
G, et al. (2008) Rifampin and rifaximin resistance in clinical isolates of Clostridium
difficile.Antimicrob Agents Chemother52:2813-2817.
Jacqueline C and Caillon J (2014) Impact of bacterial
biofilm on the treatment of prosthetic joint infections. J AntimicrobChemother
Miller MA, Blanchette R, Spigaglia P, Barbanti F,
Mastrantonio P (2011) Divergent rifamycin susceptibilities of Clostridium
difficile strains in Canada and Italy and predictive accuracy of
rifampinEtest for rifamycin resistance. J ClinMicrobiol49:4319-4321.
Schindler M, Bernard L, Belaieff W, Gamulin A, Racloz
G, et al. (2013) Epidemiology of adverse events and Clostridium difficile-associated diarrhea during long-term antibiotic
therapy for osteoarticular infections. J Infect67:433-438.
Freeman J, Vernon J, Morris K, Nicholson S, Todhunter S, et al. (2015) Pan-European
longitudinal surveillance of antibiotic resistance among prevalent Clostridium
difficileribotypes. ClinMicrobiol Infect21:e9- e16.
Choi JM, Kim HH, Park SJ, Park MI, Moon W (2011) Development
of pseudomembranous colitis four months after initiation of rifampicin. Case
Rep Gastroenterol 2011: 5.
Illiger S, Berger F, Gärtner B, von Müller L, et al. (2017)
Management of a cluster of Clostridium difficile infections among patients with osteoarticular
infections. Antimicrobial Resistance & Infection Control6:22.
Obuch-Woszczatynski P, Dubiel G, Harmanus C, Kuijper E, Duda U, et al.
(2013) Emergence of Clostridium difficile infection in tuberculosis patients due to a highly
rifampicin-resistant PCR ribotype 046 clone in Poland. Eur J ClinMicrobiol
Citation: Berger FK, Mellmann A, Färber J, von Müller L, Gärtner B (2018) Advantages and Disadvantages of Rifampicin Use in Orthopedic Patients to Avoid Clostridium difficileInfections. J OrthopTher: JORT-170. DOI: 10.29011/2575-8241. 000070