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Clinically important interaction between statin drugs and Clostridium difficile toxin?
Medical Hypotheses 73 (2009) 1045–1047
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Clinically important interaction between statin drugs and Clostridium difficile toxin? Timothy McGuire a,*, Paul Dobesh a, Don Klepser a, Mark Rupp b, Keith Olsen a a b
College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6045, United States College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-6045, United States
a r t i c l e
i n f o
Article history: Received 26 June 2009 Accepted 30 June 2009
s u m m a r y Clostridium difficile associated disease (CDAD), a common type of antibiotic associated diarrhea, is increasing in frequency and affecting patients outside of traditional populations. At one time CDAD exclusively occurred in hospitalized patients or frail elderly patients receiving antibiotic therapy. It is now occurring more commonly in younger patients who are relatively healthy and may not be receiving antibiotics. Co-factors that might explain this increase incidence and changing demographic are of great public health interest. Recent investigations have identified gastric acid suppression, particularly via proton pump inhibitors, as a risk factor for the development of CDAD by mechanisms which are not entirely clear. C. difficile toxin comes as two major forms that are closely related, toxin A and toxin B and both are able to produce CDAD. These toxins have a glucosyltransferase domain that glucosylates actived Rho, a small GTP binding protein involved in multiple cellular signaling pathways. Glucosylation inactivates Rho and modifies cell cycle, cytoskeletal and inflammatory pathways. The lipid lowering drugs called statins also inhibit Rho but at an earlier step in the Rho pathway. Statins inhibit the isoprenylation of Rho and therefore inhibits membrane anchoring a key step in Rho signaling. We propose that statins potentiate C. difficile toxin effects on colonic epithelium which leads to an increased risk of CDAD. We present preliminary data from a retrospective cohort which demonstrated an increased rate of CDAD in patients receiving statins compared to non-statin controls. The weight of the evidence leads to our hypothesis that statins interact with C difficile toxin A and B causing an increase in the rate and severity of CDAD. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction The typical patient with Clostridium difficile associated disease (CDAD) is an elderly frail patient either in the hospital or nursing home who has been receiving antibiotics [1]. While this continues to be the most common type of patient, increasingly patients are contracting CDAD outside the usual demographic. Reasons for this changing epidemiology are an area of concern and intense research. A number of the atypical reports have been in young relatively healthy people who were not recently hospitalized or received antimicrobial therapy [2]. The increased CDAD suggests an altered gastrointestinal micro-environment unrelated to antibiotic usage or any of the other usual risk factors. A number of these atypical cases of CDAD have had devastating consequences including, colectomy and death. NAP-1/027 is a more recently identified virulent strain of C. difficile and is associated with high toxin A and B production and higher morbidity and mortality [3].
* Corresponding author. Address: Pharmacy Practice, 986045 Nebraska Medical Center, Omaha, NE 68198-6045, United States. Tel.: +1 402 559 8224; fax: +1 402 559 5673. E-mail address: [email protected] (T. McGuire). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.06.058
A recently published study from our group reported a protective effect of the lipid lowering statins on in hospital mortality in patients with sepsis [4]. Data from this same study indicated a higher rate of C. difficile disease in the statin group. This observation alone may have been disregarded had it not been for the experience with another drug class, proton pump inhibitors, which have been shown to increase the rates of CDAD [5]. It is also true that the increasing rate of CDAD in the population corresponds with increasing rates of statin use to lower cardiovascular risk [6]. However, this highly circumstantial evidence would not meet a reasonable threshold for hypothesis development if not for the well described effects of C. difficile toxin and statins on the Rho pathway. It is the concordance between the low level empiric evidence and the complimentary effects of the toxin and statins on Rho that makes this hypothesis plausible. Statins are lipid lowering agents which work by inhibiting HMGCoA reductase. Beyond the lipid lowering activity of statins, are pleiotrophic effects which can be defined as clinical effects unrelated to their cholesterol lowering activity [7]. These pleiotrophic effects are in part mediated through a reduction in protein isoprenylation resulting in an inhibition of Rho [8]. Rho has been characterized as a molecular switch involved in inflammation, cell cycle
1046
T. McGuire et al. / Medical Hypotheses 73 (2009) 1045–1047
Table 1 Comparison of CDAD rates between statin using and non-statin using patients with sepsis. Variable a
C. difficile Age (yrs)b APACHE IIb Diabetesa Cancerb Transplanta Quinolonesa Steroidsa WBC countb a b
Total (N = 188)
Statin user (N = 60)
Non-statin (N = 128)
p-Value
19 (10.1%) 66.5 ± 13.1 25.9 ± 5.6 74 (39.4%) 35 (18.6%) 14 (7.5%) 127 (67.6%) 106 (56.4%) 16.7 ± 11.2
12 (20%) 68.7 ± 12.6 25.8 ± 5.1 32 (53.3%) 9 (15%) 7 (11.7%) 40 (66.7%) 34 (56.7%) 5.5 ± 10.0
7 (5.5%) 65.4 ± 13.3 26.0 ± 5.9 42 (32.8%) 26 (20.3%) 7 (5.6%) 87 (68%) 72 (56.3%) 17.3 ± 11.7
0.0036 0.103 0.826 0.01 0.428 0.145 0.869 0.99 0.277
Fisher’s exact test. Student’s T-test.
regulation, and cytoskeletal processes and it’s inhibition leads to apoptosis of colonic epithelium the tissue affected in CDAD. The inhibition of Rho by statins may be involved in both clinically important beneficial and harmful effects. In the setting of sepsis Rho inhibition can reduce the production of inflammatory cytokines by inhibiting the transcriptional regulator, Nuclear Factor-kappa-B (NFkB). Rho mediated inhibition of NFkB may be the basis for the reduced mortality in septic patients who are receiving statins [9]. Conversely, statin related inhibition of Rho may have negative unforeseen effects when given to patients exposed to other Rho modulators. One of the classic Rho inhibitors is Clostridium difficile (C. difficile) toxin [10]. The rate of CDAD has increased threefold since the mid 1990’s with an accompanying increase in mortality [1]. Several bacterial factors have been associated with the increased virulence including extensive flouroquinolone use resulting in resistance of the bacterium and binary toxin production associated with a specific strain of C. difficile, NAP1/027. The role of the binary toxin is unclear since this virulent strain also hyper-secretes the other two toxins which are known causes of CDAD. The two toxins involved in the pathogenesis of CDAD have been designated toxin A and toxin B. These are large proteins which include a glucosyltransferase domain within the toxin structure. This domain glucoslylates Rho, leading to its inactivation and apoptosis of colonic epithelium resulting in CDAD. Statins inhibit the anchoring of Rho to the cell membrane as a result of statin related reduction in isoprenylation. Since C. difficile toxin and statins work at different sites, the potential for a synergistic effect on colonic epithelial cell death exists and is the premise for generating this hypothesis. Hypothesis We propose that statins through an inhibition of Rho isoprenylation and inhibition of subsequent attachment to the colonic epithelial cell membrane potentiates the toxic effects of C. difficile toxin. Affecting the signaling pathway at different sites is a classic arrangement for additive or synergistic effects and may lead to an increased incidence and severity of CDAD. Preliminary data from our group would suggest that this drug-disease interaction is a plausible hypothesis. The only difference in a variety of infections noted in a group of septic patients on statins compared to a group of septic patients not receiving statins was C. difficile (Table 1). The higher rate of CDAD in statin users is consistent with our hypothesis. Discussion The likelihood of an interaction between statins and C. difficile toxin and subsequent increase in the incidence and severity of CDAD is relatively high. This is not an interaction which has been explicitly published in the literature but investigators have evalu-
ated each separately in in vitro models using colonic epithelium. Statin drugs and C. difficile toxin both will cause rounding-up and apoptosis of adherent colonic epithelial cells [11,12]. In addition to this possible cell signaling interaction between statins and toxin there is a history of various other drug classes increasing the incidence and severity of CDAD. The class of drugs that classically have been associated with CDAD are antibiotics. CDAD has been associated with the use of clindamycin, cephalosporins, and fluoroquinolones and more rarely other antibiotics [13]. The explanation is that antibiotics with poor activity against C. difficile results in overgrowth of the bacteria which along with changes in the colonic micro-environment leads to CDAD. The fact that drugs with high activity against C. difficile such as metronidazole and vancomycin are able to successfully treat CDAD and animal models for CDAD require inoculation with C. difficile bacteria along with antibiotic treatment indicates that bacterial over-growth is a key component of CDAD [14]. However, for reasons that are not entirely clear some patients will develop CDAD without recent antibiotic exposure giving strong evidence that the micro-environment unrelated to the selective pressure of antibiotics plays a role. In addition to antibiotics, acid suppression therapy, particularly proton pump inhibitors, have been shown to increase risk of CDAD [5]. The proposed mechanism for this association is the elevation in pH leads to improved survival of the C. difficile organism leading to increased CDAD once antibiotics are added. The strength of this explanation is that it explains the elevated risk associated with other acid suppressive therapies such as histamine-2-receptor-blocker therapy and antacids. The weakness is that acid suppression largely affects the upper gastrointestinal tract and CDAD occurs in the colon which is not an acidic environment. In addition, C. difficile spores are acid resistant and modifying the pH of the gastrointestinal tract is unlikely to modify risk from the spores [15]. There is much to be learned about existing risk factors and other risk factors that have yet to be identified. We propose that statins are a source of risk for CDAD and this hypothesis continues to be an active area of investigation by our group. The importance of establishing statins as co-factors in CDAD is high given how commonly statins are used in the population, the increasing frequency of classical and atypical CDAC, and the fact that risk can be modified by stopping statin therapy particularly during the period of antibiotic administration. Stopping statins for short periods likely has little to no associated risk and may avoid a potentially life threatening complication.
Conflicts of interest statement None declared. References [1] Kelly CP, LaMont JT. Clostridium difficile – more difficult than ever. N Eng J Med 2008;359:1932–40.
T. McGuire et al. / Medical Hypotheses 73 (2009) 1045–1047 [2] Severe C. Clostridium difficile – associated disease in populations previously at low risk. MMWR Morb Mortal Wkly Rep 2005;54:1201–5. [3] Sutton PA, Li S, Webb J, Solomon K, Brazier J, Mahida YR. Essential role of toxin A in Clostridium difficile 027 and reference strain supernatant mediated disruption of Caco-2 intestinal epithelial barrier function. Clin Exp Immunol 2008;153:439–47. [4] Dobesh PP, Klepser DG, McGuire TR, Morgan CW, Olsen KM. Statins associated with a reduction in mortality in patients with sepsis. Pharmacotherapy 2009;29:621–30. [5] Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostrium difficile associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308–13. [6] Mann D, Reynolds K, Smith D, Muntner P. Trends in statin use and low-density lipoprotein cholesterol levels among US adults: impact of the 2001 national cholesterol education program guidelines. Ann Pharmacother 2008;42:1208–15. [7] Ridker PM, Danielson E, Francisco AH, Genest J, Gotto AM, Kastelein J, et al. For the JUPITER study group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Eng J Med 2008;359:2195–207. [8] Glynn RJ, Danielson E, Fonseca F, Genest J, Gotto AM, Kastelein J, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Eng J Med 2009;360:1851–61.
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[9] Falagas ME, Makris GC, Matthaiou DK, Rafailidis PI. Statins for infection and sepsis: a systematic review of clinical evidence. J Antimicrob Chem 2008;61:774–85. [10] Jank T, Giesmann T, Aktories K. Rho-glucosylating Clostridium difficile toxins A and B: new insights into structure and function. Glycobiology 2007;17:15R–22R. [11] Agarwal B, Halmos B, Feoktiston AS, Protiva P, Ramey WG, Chen M, et al. Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 2002;23:521–8. [12] Hookman P, Barkin JS. Clostribium difficile associated infection, diarrhea and colitis. World J Gastroenterol 2009;15:1554–80. [13] Lyerly D, Saum KE, MacDonald DK, Wilkins TD. Effects on Clostridium difficile toxins given intragastrically to animals. Infect Immun 1985;47:349–52. [14] Wilson KH, Sheagren JN, Freter R. Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis 1985;151:355–61. [15] Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostrium difficile associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308–13.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Clinically important interaction between statin drugs and Clostridium difficile toxin? Timothy McGuire a,*, Paul Dobesh a, Don Klepser a, Mark Rupp b, Keith Olsen a a b
College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6045, United States College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-6045, United States
a r t i c l e
i n f o
Article history: Received 26 June 2009 Accepted 30 June 2009
s u m m a r y Clostridium difficile associated disease (CDAD), a common type of antibiotic associated diarrhea, is increasing in frequency and affecting patients outside of traditional populations. At one time CDAD exclusively occurred in hospitalized patients or frail elderly patients receiving antibiotic therapy. It is now occurring more commonly in younger patients who are relatively healthy and may not be receiving antibiotics. Co-factors that might explain this increase incidence and changing demographic are of great public health interest. Recent investigations have identified gastric acid suppression, particularly via proton pump inhibitors, as a risk factor for the development of CDAD by mechanisms which are not entirely clear. C. difficile toxin comes as two major forms that are closely related, toxin A and toxin B and both are able to produce CDAD. These toxins have a glucosyltransferase domain that glucosylates actived Rho, a small GTP binding protein involved in multiple cellular signaling pathways. Glucosylation inactivates Rho and modifies cell cycle, cytoskeletal and inflammatory pathways. The lipid lowering drugs called statins also inhibit Rho but at an earlier step in the Rho pathway. Statins inhibit the isoprenylation of Rho and therefore inhibits membrane anchoring a key step in Rho signaling. We propose that statins potentiate C. difficile toxin effects on colonic epithelium which leads to an increased risk of CDAD. We present preliminary data from a retrospective cohort which demonstrated an increased rate of CDAD in patients receiving statins compared to non-statin controls. The weight of the evidence leads to our hypothesis that statins interact with C difficile toxin A and B causing an increase in the rate and severity of CDAD. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction The typical patient with Clostridium difficile associated disease (CDAD) is an elderly frail patient either in the hospital or nursing home who has been receiving antibiotics [1]. While this continues to be the most common type of patient, increasingly patients are contracting CDAD outside the usual demographic. Reasons for this changing epidemiology are an area of concern and intense research. A number of the atypical reports have been in young relatively healthy people who were not recently hospitalized or received antimicrobial therapy [2]. The increased CDAD suggests an altered gastrointestinal micro-environment unrelated to antibiotic usage or any of the other usual risk factors. A number of these atypical cases of CDAD have had devastating consequences including, colectomy and death. NAP-1/027 is a more recently identified virulent strain of C. difficile and is associated with high toxin A and B production and higher morbidity and mortality [3].
* Corresponding author. Address: Pharmacy Practice, 986045 Nebraska Medical Center, Omaha, NE 68198-6045, United States. Tel.: +1 402 559 8224; fax: +1 402 559 5673. E-mail address: [email protected] (T. McGuire). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.06.058
A recently published study from our group reported a protective effect of the lipid lowering statins on in hospital mortality in patients with sepsis [4]. Data from this same study indicated a higher rate of C. difficile disease in the statin group. This observation alone may have been disregarded had it not been for the experience with another drug class, proton pump inhibitors, which have been shown to increase the rates of CDAD [5]. It is also true that the increasing rate of CDAD in the population corresponds with increasing rates of statin use to lower cardiovascular risk [6]. However, this highly circumstantial evidence would not meet a reasonable threshold for hypothesis development if not for the well described effects of C. difficile toxin and statins on the Rho pathway. It is the concordance between the low level empiric evidence and the complimentary effects of the toxin and statins on Rho that makes this hypothesis plausible. Statins are lipid lowering agents which work by inhibiting HMGCoA reductase. Beyond the lipid lowering activity of statins, are pleiotrophic effects which can be defined as clinical effects unrelated to their cholesterol lowering activity [7]. These pleiotrophic effects are in part mediated through a reduction in protein isoprenylation resulting in an inhibition of Rho [8]. Rho has been characterized as a molecular switch involved in inflammation, cell cycle
1046
T. McGuire et al. / Medical Hypotheses 73 (2009) 1045–1047
Table 1 Comparison of CDAD rates between statin using and non-statin using patients with sepsis. Variable a
C. difficile Age (yrs)b APACHE IIb Diabetesa Cancerb Transplanta Quinolonesa Steroidsa WBC countb a b
Total (N = 188)
Statin user (N = 60)
Non-statin (N = 128)
p-Value
19 (10.1%) 66.5 ± 13.1 25.9 ± 5.6 74 (39.4%) 35 (18.6%) 14 (7.5%) 127 (67.6%) 106 (56.4%) 16.7 ± 11.2
12 (20%) 68.7 ± 12.6 25.8 ± 5.1 32 (53.3%) 9 (15%) 7 (11.7%) 40 (66.7%) 34 (56.7%) 5.5 ± 10.0
7 (5.5%) 65.4 ± 13.3 26.0 ± 5.9 42 (32.8%) 26 (20.3%) 7 (5.6%) 87 (68%) 72 (56.3%) 17.3 ± 11.7
0.0036 0.103 0.826 0.01 0.428 0.145 0.869 0.99 0.277
Fisher’s exact test. Student’s T-test.
regulation, and cytoskeletal processes and it’s inhibition leads to apoptosis of colonic epithelium the tissue affected in CDAD. The inhibition of Rho by statins may be involved in both clinically important beneficial and harmful effects. In the setting of sepsis Rho inhibition can reduce the production of inflammatory cytokines by inhibiting the transcriptional regulator, Nuclear Factor-kappa-B (NFkB). Rho mediated inhibition of NFkB may be the basis for the reduced mortality in septic patients who are receiving statins [9]. Conversely, statin related inhibition of Rho may have negative unforeseen effects when given to patients exposed to other Rho modulators. One of the classic Rho inhibitors is Clostridium difficile (C. difficile) toxin [10]. The rate of CDAD has increased threefold since the mid 1990’s with an accompanying increase in mortality [1]. Several bacterial factors have been associated with the increased virulence including extensive flouroquinolone use resulting in resistance of the bacterium and binary toxin production associated with a specific strain of C. difficile, NAP1/027. The role of the binary toxin is unclear since this virulent strain also hyper-secretes the other two toxins which are known causes of CDAD. The two toxins involved in the pathogenesis of CDAD have been designated toxin A and toxin B. These are large proteins which include a glucosyltransferase domain within the toxin structure. This domain glucoslylates Rho, leading to its inactivation and apoptosis of colonic epithelium resulting in CDAD. Statins inhibit the anchoring of Rho to the cell membrane as a result of statin related reduction in isoprenylation. Since C. difficile toxin and statins work at different sites, the potential for a synergistic effect on colonic epithelial cell death exists and is the premise for generating this hypothesis. Hypothesis We propose that statins through an inhibition of Rho isoprenylation and inhibition of subsequent attachment to the colonic epithelial cell membrane potentiates the toxic effects of C. difficile toxin. Affecting the signaling pathway at different sites is a classic arrangement for additive or synergistic effects and may lead to an increased incidence and severity of CDAD. Preliminary data from our group would suggest that this drug-disease interaction is a plausible hypothesis. The only difference in a variety of infections noted in a group of septic patients on statins compared to a group of septic patients not receiving statins was C. difficile (Table 1). The higher rate of CDAD in statin users is consistent with our hypothesis. Discussion The likelihood of an interaction between statins and C. difficile toxin and subsequent increase in the incidence and severity of CDAD is relatively high. This is not an interaction which has been explicitly published in the literature but investigators have evalu-
ated each separately in in vitro models using colonic epithelium. Statin drugs and C. difficile toxin both will cause rounding-up and apoptosis of adherent colonic epithelial cells [11,12]. In addition to this possible cell signaling interaction between statins and toxin there is a history of various other drug classes increasing the incidence and severity of CDAD. The class of drugs that classically have been associated with CDAD are antibiotics. CDAD has been associated with the use of clindamycin, cephalosporins, and fluoroquinolones and more rarely other antibiotics [13]. The explanation is that antibiotics with poor activity against C. difficile results in overgrowth of the bacteria which along with changes in the colonic micro-environment leads to CDAD. The fact that drugs with high activity against C. difficile such as metronidazole and vancomycin are able to successfully treat CDAD and animal models for CDAD require inoculation with C. difficile bacteria along with antibiotic treatment indicates that bacterial over-growth is a key component of CDAD [14]. However, for reasons that are not entirely clear some patients will develop CDAD without recent antibiotic exposure giving strong evidence that the micro-environment unrelated to the selective pressure of antibiotics plays a role. In addition to antibiotics, acid suppression therapy, particularly proton pump inhibitors, have been shown to increase risk of CDAD [5]. The proposed mechanism for this association is the elevation in pH leads to improved survival of the C. difficile organism leading to increased CDAD once antibiotics are added. The strength of this explanation is that it explains the elevated risk associated with other acid suppressive therapies such as histamine-2-receptor-blocker therapy and antacids. The weakness is that acid suppression largely affects the upper gastrointestinal tract and CDAD occurs in the colon which is not an acidic environment. In addition, C. difficile spores are acid resistant and modifying the pH of the gastrointestinal tract is unlikely to modify risk from the spores [15]. There is much to be learned about existing risk factors and other risk factors that have yet to be identified. We propose that statins are a source of risk for CDAD and this hypothesis continues to be an active area of investigation by our group. The importance of establishing statins as co-factors in CDAD is high given how commonly statins are used in the population, the increasing frequency of classical and atypical CDAC, and the fact that risk can be modified by stopping statin therapy particularly during the period of antibiotic administration. Stopping statins for short periods likely has little to no associated risk and may avoid a potentially life threatening complication.
Conflicts of interest statement None declared. References [1] Kelly CP, LaMont JT. Clostridium difficile – more difficult than ever. N Eng J Med 2008;359:1932–40.
T. McGuire et al. / Medical Hypotheses 73 (2009) 1045–1047 [2] Severe C. Clostridium difficile – associated disease in populations previously at low risk. MMWR Morb Mortal Wkly Rep 2005;54:1201–5. [3] Sutton PA, Li S, Webb J, Solomon K, Brazier J, Mahida YR. Essential role of toxin A in Clostridium difficile 027 and reference strain supernatant mediated disruption of Caco-2 intestinal epithelial barrier function. Clin Exp Immunol 2008;153:439–47. [4] Dobesh PP, Klepser DG, McGuire TR, Morgan CW, Olsen KM. Statins associated with a reduction in mortality in patients with sepsis. Pharmacotherapy 2009;29:621–30. [5] Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostrium difficile associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308–13. [6] Mann D, Reynolds K, Smith D, Muntner P. Trends in statin use and low-density lipoprotein cholesterol levels among US adults: impact of the 2001 national cholesterol education program guidelines. Ann Pharmacother 2008;42:1208–15. [7] Ridker PM, Danielson E, Francisco AH, Genest J, Gotto AM, Kastelein J, et al. For the JUPITER study group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Eng J Med 2008;359:2195–207. [8] Glynn RJ, Danielson E, Fonseca F, Genest J, Gotto AM, Kastelein J, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Eng J Med 2009;360:1851–61.
1047
[9] Falagas ME, Makris GC, Matthaiou DK, Rafailidis PI. Statins for infection and sepsis: a systematic review of clinical evidence. J Antimicrob Chem 2008;61:774–85. [10] Jank T, Giesmann T, Aktories K. Rho-glucosylating Clostridium difficile toxins A and B: new insights into structure and function. Glycobiology 2007;17:15R–22R. [11] Agarwal B, Halmos B, Feoktiston AS, Protiva P, Ramey WG, Chen M, et al. Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 2002;23:521–8. [12] Hookman P, Barkin JS. Clostribium difficile associated infection, diarrhea and colitis. World J Gastroenterol 2009;15:1554–80. [13] Lyerly D, Saum KE, MacDonald DK, Wilkins TD. Effects on Clostridium difficile toxins given intragastrically to animals. Infect Immun 1985;47:349–52. [14] Wilson KH, Sheagren JN, Freter R. Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis 1985;151:355–61. [15] Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostrium difficile associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308–13.