**4. Statins**

Statins are cholesterol reducing medications that similarly to aspirin have become a cornerstone in the prevention and treatment of cardiovascular disease. The antimicrobial

Nontraditional Anti - Infectious Agents in Hemodialysis 401

contrast to the results of this study no difference in the rate of death from fatal infection with

An interesting question that is raised by the study by Gupta et al. is whether the observed benefit could be due to concomitant treatment with aspirin (Gupta et al., 2007). Both statins and aspirin are used for the treatment of coronary artery disease and a head to head comparison would be instructive. Our aspirin study did not find a beneficial effect of statins on the risk of septic events (Sedlacek et al., 2007) and the study by Gupta et al. did not

It has to be noted that the relation between lipid parameters and mortality in dialysis patients is complex, confounded by the fact that elevated serum cholesterol levels are paradoxically protective in this population, probably because they are a marker for the absence of malnutrition and inflammation. In practical terms it is advised to use low doses of statins to reduce side effects and to avoid the concomittant administration of other drugs metabolized by the cytochrome P-450 system such as cyclosporine, azole antifungals and

Several other drugs that are frequently used on dialysis have known interactions with microbes. Heparin is used frequently to block dialysis catheters when not in use to preserve their patency. Unfortunately, heparin has been found to promote growth of bacterial biofilm in dialysis catheters (Shanks et al., 2005). Citrate has been used as an alternative to heparin to block catheters and was found to have inhibitory effects on biofilms at elevated concentration. Reminiscent of the "Goldilocks effect" observed with aspirin, citrate stimulates biofilm formation at sub inhibitory concentrations, an effect which might have clinical relevance at catheter tips (Shanks et al., 2006). EDTA also has an inhibitory effect on biofilm. The mechanism for both EDTA and citrate is thought to be through chelation of divalent ions essential to the extracellular matrix structure of biofilm (Percival et al.,

Diltiazem, Amlodipine and the angiotension converting enzyme inhibitor Zofenopril have modest in vitro antimicrobial activity against S.aureus. Most of these effects are bacteriostatic and occur at higher drug concentrations in vitro than the therapeutic concentrations that are usually achieved during therapy in vivo. It has to be noted however, that drug concentration can vary considerably throughout different organs and body compartments. In the case of Amiloride it has been determined that urine concentrations achieved in patients are not sufficient to replicate the antibacterial effects that are observed in vivo (Cederlund et al., 1993). The relevance of these observations probably concerns more microbial purity testing of drugs during the fabrication process rather than clinical effects. Emla cream, a mixture of lidocaine, prilocaine and preservatives, which is used for topical anesthesia at the site of dialysis fistula puncture, has no effect on microbial growth (Kruszewska et al., 2010). Other drugs relevant to ESRD that have been tested and were found to be devoid of antimicrobial effects are the loop diuretics furosemide and

The antihistaminic drug diphenhydramine has been reported to be synergistic with the penicillins (Kristiansen, 1992) and amiloride reportedly enhances uptake of tobramycin in

the use of atorvastatin was found in the 4D study (Wanner et al., 2005).

control for aspirin use.

fibrates (Olyaei et al., 2011).

2005).

bumetanide.

**5. Effects of other drugs used on dialysis** 

pseudomonas aeruginosa (Cederlund et al., 1993).

effects of statins have been known for a long time. In fact, statins were discovered by searching for compounds that would inhibit HMG-CoA reductase in microbes that require sterols or other isoprenoids, which are part of bacterial cytoskeleton, for growth. The first statins were described as antibiotics secreted by Penicillium species. The first statin compound, mevastatin, is derived from a culture of *Pythium ultimum* and *Penicillium citrinum* and under the name compactin the same compound was isolated from a culture of *Penicillium brevicompactum* (Endo et al., 1976). A mevastatin analog currently in use, lovastatin, was isolated from a culture of *Aspergillus terreus*. (Endo A., 1992). The antimicrobial effects of statins were rediscovered at a later time and it was noted that the minimum inhibitory concentration of simvastatin for *S.aureus* was much higher than the serum levels that can be achieved during routine treatment at recommended doses (Jerwood S. & Cohen J., 2008). Direct antimicrobial effects with potential clinical relevance have been postulated for HIV, CMV, HCV, Salmonella and yeast (Gupta et al., 2007) but are perhaps less relevant for dialysis catheter associated infection. Newer laboratory evidence shows that the interferon response to viral infection of the innate immune immune system is coupled to the mevalonate-isoprenoid arm of the sterol pathway. These findings may explain the observation that the CMV and HCV viruses are sensitive to statin administration and that treatment with interferon decreases plasma cholesterol levels similar to treatment with statins (Blanc M et al., 2011).

Several observational studies in patients with severe bacterial infections have reported improved survival in patients treated with statins (Bjoerkheim-Bergman et al., 2010). These beneficial effects appear to be greater than what might be expected with lipid lowering alone and are attributed to pleiotropic effects of statins. Such effects involve improving endothelial function, decreasing oxidative stress and inflammation and inhibiting the thrombogenic response (Liao J.K. & Laufs U., 2005).

The hypothesis that treatment with statins could have an influence on the rate of septic events in dialysis patients was investigated by Gupta et al in 2007. The authors used data from a prospective study to investigate choices and outcomes of dialysis care, which enrolled 1041 patients from 1995 to 1998, the majority of which dialyzed in units associated with Dialysis Clinic Inc in Nashville TN. These patient data were linked to United States Renal Data System administrative data which included hospitalizations and data from other treatment settings, including outpatient and skilled nursing facilities. Primary outcome were sepsis events but "only episodes in which the primary event was sepsis were included (…) to avoid including cases in which infection was acquired as a secondary phenomenon" (Correction by the same authors in JAMA Vol 299 P 765). The correction to their method section published later by the authors raises the possibility that their data analysis could come to a different conclusion if all episodes of sepsis were considered, not only the events that were considered"primary". The authors found that 143 patients (14%) received statin treatment compared with 898 patients (86%) who were not. Among all 1041 patients there were a total of 303 events of primary sepsis during a mean follow up of 3.4 years. The crude incidence rate of sepsis events was 63% lower in patients treated with statins compared with the control group (41 events per 1000 patient-years compared with 110 events per 1000 patient years) The authors found that the odds ratio for a primary septic event in statin users was 0.38 (95% CI 0.21-0.67) with adjustments for demographics, dialysis modality, comorbidities and laboratory values. In a propensity-matched subcohort analysis statin use was even more protective with an odds ratio of 0.24 (CI 0.11-0.49) (Gupta et al., 2007). In

effects of statins have been known for a long time. In fact, statins were discovered by searching for compounds that would inhibit HMG-CoA reductase in microbes that require sterols or other isoprenoids, which are part of bacterial cytoskeleton, for growth. The first statins were described as antibiotics secreted by Penicillium species. The first statin compound, mevastatin, is derived from a culture of *Pythium ultimum* and *Penicillium citrinum* and under the name compactin the same compound was isolated from a culture of *Penicillium brevicompactum* (Endo et al., 1976). A mevastatin analog currently in use, lovastatin, was isolated from a culture of *Aspergillus terreus*. (Endo A., 1992). The antimicrobial effects of statins were rediscovered at a later time and it was noted that the minimum inhibitory concentration of simvastatin for *S.aureus* was much higher than the serum levels that can be achieved during routine treatment at recommended doses (Jerwood S. & Cohen J., 2008). Direct antimicrobial effects with potential clinical relevance have been postulated for HIV, CMV, HCV, Salmonella and yeast (Gupta et al., 2007) but are perhaps less relevant for dialysis catheter associated infection. Newer laboratory evidence shows that the interferon response to viral infection of the innate immune immune system is coupled to the mevalonate-isoprenoid arm of the sterol pathway. These findings may explain the observation that the CMV and HCV viruses are sensitive to statin administration and that treatment with interferon decreases plasma cholesterol levels similar to treatment with

Several observational studies in patients with severe bacterial infections have reported improved survival in patients treated with statins (Bjoerkheim-Bergman et al., 2010). These beneficial effects appear to be greater than what might be expected with lipid lowering alone and are attributed to pleiotropic effects of statins. Such effects involve improving endothelial function, decreasing oxidative stress and inflammation and inhibiting the

The hypothesis that treatment with statins could have an influence on the rate of septic events in dialysis patients was investigated by Gupta et al in 2007. The authors used data from a prospective study to investigate choices and outcomes of dialysis care, which enrolled 1041 patients from 1995 to 1998, the majority of which dialyzed in units associated with Dialysis Clinic Inc in Nashville TN. These patient data were linked to United States Renal Data System administrative data which included hospitalizations and data from other treatment settings, including outpatient and skilled nursing facilities. Primary outcome were sepsis events but "only episodes in which the primary event was sepsis were included (…) to avoid including cases in which infection was acquired as a secondary phenomenon" (Correction by the same authors in JAMA Vol 299 P 765). The correction to their method section published later by the authors raises the possibility that their data analysis could come to a different conclusion if all episodes of sepsis were considered, not only the events that were considered"primary". The authors found that 143 patients (14%) received statin treatment compared with 898 patients (86%) who were not. Among all 1041 patients there were a total of 303 events of primary sepsis during a mean follow up of 3.4 years. The crude incidence rate of sepsis events was 63% lower in patients treated with statins compared with the control group (41 events per 1000 patient-years compared with 110 events per 1000 patient years) The authors found that the odds ratio for a primary septic event in statin users was 0.38 (95% CI 0.21-0.67) with adjustments for demographics, dialysis modality, comorbidities and laboratory values. In a propensity-matched subcohort analysis statin use was even more protective with an odds ratio of 0.24 (CI 0.11-0.49) (Gupta et al., 2007). In

statins (Blanc M et al., 2011).

thrombogenic response (Liao J.K. & Laufs U., 2005).

contrast to the results of this study no difference in the rate of death from fatal infection with the use of atorvastatin was found in the 4D study (Wanner et al., 2005).

An interesting question that is raised by the study by Gupta et al. is whether the observed benefit could be due to concomitant treatment with aspirin (Gupta et al., 2007). Both statins and aspirin are used for the treatment of coronary artery disease and a head to head comparison would be instructive. Our aspirin study did not find a beneficial effect of statins on the risk of septic events (Sedlacek et al., 2007) and the study by Gupta et al. did not control for aspirin use.

It has to be noted that the relation between lipid parameters and mortality in dialysis patients is complex, confounded by the fact that elevated serum cholesterol levels are paradoxically protective in this population, probably because they are a marker for the absence of malnutrition and inflammation. In practical terms it is advised to use low doses of statins to reduce side effects and to avoid the concomittant administration of other drugs metabolized by the cytochrome P-450 system such as cyclosporine, azole antifungals and fibrates (Olyaei et al., 2011).
