**3.3 Aspirin and** *S.aureus* **nasal carriage**

Karabay et al. investigated the prevalence of *S.aureus* nasal carriage in an outpatient cardiology clinic. Of a total of 346 patients 199 were chronic aspirin user while 147 patients were not. The prevalence of *S.aureus* nasal carriage was 5% on patient treated chronically with aspirin versus 16% in those that did not take aspirin. Only aspirin was found to be associated with a decreased rate of nasal carriage in a multivariate analysis (Karabay et al., 2006). These findings are of obvious significance to hemodialysis patients as nasal colonization is considered the initiating event that leads to catheter associated staphylococcal bacteremia. If confirmed, aspirin could decrease nasal carriage at a fraction of the cost and effort of mupirocin ointment. Given the fact that aspirin is a very old drug the findings of Karabay et al. have another potential significance: If a clinical effect of aspirin on *S.aureus* can still be detected after decades of over-the-counter use it would be unlikely that *S.aureus* would develop resistance to this effect in the future. It is clear that the important findings of Karabay et al. merit further investigation both in hemodialysis and in the general population.

### **3.4 A potential beneficial effect of aspirin in hemodialysis patients**

Patient undergoing hemodialysis treatments suffer staphylococcal infections with increased frequency because of a high prevalence of tunneled or non tunneled dialysis catheters. The hemodialysis setting is thus well suited to study the potential beneficial clinical anti staphylococcal effects of aspirin.

Nontraditional Anti - Infectious Agents in Hemodialysis 395

with aspirin (0.23 events per patient-catheter year) versus more than double, 64 first episodes of *S.aureus* bacteremia (0.57 events per patient catheter year) in patient not treated

We explored the association between aspirin dose and rates of catheter associated *S.aureus* and *MRSA* bacteremia in table 2. There was a dose effect as only a 325mg dose of Aspirin, but not an 81mg dose (common formulations in the United States), was associated with a decreased rate of *Staphylococcus aureus* infection compared to patients not treated with aspirin. Importantly there was a significantly lower rates of *Methicillin resistant Staphylococcus aureus* bacteremia (*MRSA*) in patients treated with 325mg of aspirin a day.

> **978 Catheters/227.4 Patient-Catheter-Years**

> > **Rate (/patientcatheter-y)**

**No.** 

All positive 232 1.02 207 0.83 0.30

Coagulase-negative *Staphylococcus* 96 0.42 93 0.37 0.85 *S aureus* 77 0.34 43 0.17 0.003\* MRSA 19 0.08 11 0.04 0.16 *Enterococcus* species 21 0.09 30 0.12 0.18 *Corynebacterium* species 7 0.03 6 0.02 0.82 *Streptococcus* species 4 0.02 7 0.03 0.34 *Bacillus* species 4 0.02 4 0.02 0.97

*Enterobacter* species 20 0.09 21 0.09 0.81 *Pseudomonas* species 11 0.05 13 0.05 0.64 *Serratia* species 12 0.05 9 0.04 0.55 *Klebsiella* species 9 0.04 10 0.04 0.77 *Escherichia coli* 7 0.03 4 0.02 0.39 *Acinetobacter* species 4 0.02 4 0.02 0.97 *Bacteroides* species 3 0.01 3 0.01 0.78 *Note:* Multiple bacterial isolates and repeated episodes were included in this table. Fungal isolates and

bacterial species found fewer than 5 times during the 10-year study period were omitted.

Table 1. Number of Episodes and Rates of Catheter-Associated Bacteremia in a 10-Year

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

**No Aspirin Aspirin** *P*

**No.**

**875 Catheters/ 249.3 Patient-Catheter-Years** 

> **Rate (/patientcatheter-y)**

with aspirin (p<0.001).

Gram-positive

Gram-negative

\*Significant difference by Poisson regression.

Period from 1995 to 2005

We conducted a single center retrospective study in 872 patients with tunneled catheters who dialyzed over a ten year time period from 1995 to 2005. During this time period our patients had 1853 tunneled dialysis catheters placed and accumulated more than 476 patient-catheteryears and had 4722 blood cultures performed. Temporary dialysis catheters were excluded because of the high variability in the circumstances of placement of temporay catheters and also greater difficulty in tracking them retrospectively. The overall incidence of bacteremia was 7.2 episodes per 100 patient-catheter-months and the incidence of *S.aureus* bacteremia was 2.1 episodes per 100 patient-catheter-months. The incidence of *S.aureus* endocarditis was 0.16 episodes per 100 patient-catheter-months. These numbers are within the range reported in the literature. Blood cultures were obtained at the discretion of the treating physician if infection was suspected. Tunneled catheters that were a suspected source of infection were usually removed and negative cultures were required before insertion of a new tunneled catheter. All tunneled catheters were placed and removed by the same interventional radiology service. Suspected infection was the principal reason for tunneled catheter removal (19%), followed by poor catheter blood flow (14%) and presence of a mature permanent vascular access (14%). Infection rates were compared by Poisson regression analysis. In this study catheter associated bacteremia was defined as one or more positive blood cultures in a patient with a tunneled catheter. In retrospect it was impossible to exclude other sources of infection and contamination and for this reason all positive blood culture results that were obtained in the presence of a tunneled catheter were included without discrimination. Blood cultures that were obtained after a tunneled catheter was removed were excluded per definition. Our institution is a tertiary care medical center that offered hemodialysis in two outpatient units, serving a population of about 400,000 people. Because of location in a rural area, limited availability of hemodialysis and other geographical factors limiting access to other institutions the long term follow up of patients was excellent. A proprietary medical record system integrated electronic inpatient and outpatient records with procedure notes and laboratory, radiological and microbiological test result and was ideally suited for a large retrospective study. As a result the fate of only 8 catheters (<0.5%) was unaccounted for.

The number of episodes and rates of catheter associated bacteria is shown in Table 1 which includes repeated episodes and polymicrobial infections with more than one bacterial isolate. As expected, Gram positive bacteria accounted for the majority of bacteremic episodes. When all bacteremic episodes were considered together, there was no difference between patients treated with aspirin or not. In fact, the only pathogen with a lower rate of catheter-associated bacteremia in patients treated with aspirin was *S.aureus* which caused only half as many episodes in the aspirin group compared to patients not treated with aspirin (0.17 versus 0.34 events/patient-catheter-years, p=0.003). In addition to blood cultures 369 catheter tip cultures were performed in the same time interval, albeit in a less systematic fashion. Of these 53 catheter tip cultures grew *S.aureus*. In such a case treatment is usually recommended because *S.aureus* bacteremia is considered more likely than contamination (Peacock et al., 1998). If these tip cultures were added to bona fide blood cultures in the analysis, the difference was statistically more significant: 83 instances (0.36 events per patient-catheter-year) of *S.aureus* in the non aspirin treated group versus 45 (0.18 event per patient-catheter-year) in the aspirin treated group (p=0.001).

Moreover, if we excluded repeated events in the same patient from our data and considered only first episodes of *S.aureus* bacteremia, the difference looked between the two groups looked even more impressive: 28 first episodes of *S.aureus* bacteremia in patients treated 394 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

We conducted a single center retrospective study in 872 patients with tunneled catheters who dialyzed over a ten year time period from 1995 to 2005. During this time period our patients had 1853 tunneled dialysis catheters placed and accumulated more than 476 patient-catheteryears and had 4722 blood cultures performed. Temporary dialysis catheters were excluded because of the high variability in the circumstances of placement of temporay catheters and also greater difficulty in tracking them retrospectively. The overall incidence of bacteremia was 7.2 episodes per 100 patient-catheter-months and the incidence of *S.aureus* bacteremia was 2.1 episodes per 100 patient-catheter-months. The incidence of *S.aureus* endocarditis was 0.16 episodes per 100 patient-catheter-months. These numbers are within the range reported in the literature. Blood cultures were obtained at the discretion of the treating physician if infection was suspected. Tunneled catheters that were a suspected source of infection were usually removed and negative cultures were required before insertion of a new tunneled catheter. All tunneled catheters were placed and removed by the same interventional radiology service. Suspected infection was the principal reason for tunneled catheter removal (19%), followed by poor catheter blood flow (14%) and presence of a mature permanent vascular access (14%). Infection rates were compared by Poisson regression analysis. In this study catheter associated bacteremia was defined as one or more positive blood cultures in a patient with a tunneled catheter. In retrospect it was impossible to exclude other sources of infection and contamination and for this reason all positive blood culture results that were obtained in the presence of a tunneled catheter were included without discrimination. Blood cultures that were obtained after a tunneled catheter was removed were excluded per definition. Our institution is a tertiary care medical center that offered hemodialysis in two outpatient units, serving a population of about 400,000 people. Because of location in a rural area, limited availability of hemodialysis and other geographical factors limiting access to other institutions the long term follow up of patients was excellent. A proprietary medical record system integrated electronic inpatient and outpatient records with procedure notes and laboratory, radiological and microbiological test result and was ideally suited for a large retrospective

study. As a result the fate of only 8 catheters (<0.5%) was unaccounted for.

event per patient-catheter-year) in the aspirin treated group (p=0.001).

The number of episodes and rates of catheter associated bacteria is shown in Table 1 which includes repeated episodes and polymicrobial infections with more than one bacterial isolate. As expected, Gram positive bacteria accounted for the majority of bacteremic episodes. When all bacteremic episodes were considered together, there was no difference between patients treated with aspirin or not. In fact, the only pathogen with a lower rate of catheter-associated bacteremia in patients treated with aspirin was *S.aureus* which caused only half as many episodes in the aspirin group compared to patients not treated with aspirin (0.17 versus 0.34 events/patient-catheter-years, p=0.003). In addition to blood cultures 369 catheter tip cultures were performed in the same time interval, albeit in a less systematic fashion. Of these 53 catheter tip cultures grew *S.aureus*. In such a case treatment is usually recommended because *S.aureus* bacteremia is considered more likely than contamination (Peacock et al., 1998). If these tip cultures were added to bona fide blood cultures in the analysis, the difference was statistically more significant: 83 instances (0.36 events per patient-catheter-year) of *S.aureus* in the non aspirin treated group versus 45 (0.18

Moreover, if we excluded repeated events in the same patient from our data and considered only first episodes of *S.aureus* bacteremia, the difference looked between the two groups looked even more impressive: 28 first episodes of *S.aureus* bacteremia in patients treated with aspirin (0.23 events per patient-catheter year) versus more than double, 64 first episodes of *S.aureus* bacteremia (0.57 events per patient catheter year) in patient not treated with aspirin (p<0.001).

We explored the association between aspirin dose and rates of catheter associated *S.aureus* and *MRSA* bacteremia in table 2. There was a dose effect as only a 325mg dose of Aspirin, but not an 81mg dose (common formulations in the United States), was associated with a decreased rate of *Staphylococcus aureus* infection compared to patients not treated with aspirin. Importantly there was a significantly lower rates of *Methicillin resistant Staphylococcus aureus* bacteremia (*MRSA*) in patients treated with 325mg of aspirin a day.


*Note:* Multiple bacterial isolates and repeated episodes were included in this table. Fungal isolates and bacterial species found fewer than 5 times during the 10-year study period were omitted. \*Significant difference by Poisson regression.

Table 1. Number of Episodes and Rates of Catheter-Associated Bacteremia in a 10-Year Period from 1995 to 2005

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

Nontraditional Anti - Infectious Agents in Hemodialysis 397

Age (y) 59 ± 19\* 68 ± 13\* <0.0001 Time on dialysis (d) 362 ± 810 346 ± 542 0.73 Catheter no. 1.8 ± 1.8 1.9 ± 1.7 0.70 Female sex 194 (42) 186 (44) 0.54 Tobacco use 205 (45)\* 225 (54)\* 0.01 Diabetes mellitus 170 (38)\* 236 (56)\* <0.0001 Hypertension 333 (74)\* 364 (87)\* <0.0001 COPD 92 (20)\* 117 (28)\* 0.009 Coronary artery disease 159 (35)\* 309 (79)\* <0.0001 Peripheral vascular disease 113 (25)\* 200 (48)\* <0.0001 Stroke 66 (15)\* 99 (24)\* 0.007 Arthritis 141 (31)\* 164 (39)\* 0.01 Cancer 102 (23) 80 (19) 0.24 Previous transplant 50 (11)\* 14 (3)\* <0.0001 Clopidogrel 12 (3)\* 40 (10)\* <0.0001 Warfarin 61 (14) 60 (14) 0.77 Statin 69 (15)\* 172 (41)\* <0.0001 B-Blocker 248 (55)\* 315 (75)\* <0.0001 ACE inhibitor/ARB 136 (30)\* 187 (45)\* <0.0001 Calcium channel blocker 216 (48) 216 (52) 0.28 Aspirin 0 418 <0.0001

*Note:* Values expressed as mean ± SD or number (percent).

Fisher exact test or unpaired Student *t*-test, as appropriate.

Hazard Analysis

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

\*Statistically significant difference between aspirin-treated and non–aspirin-treated groups by means of

Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled

A second study that addressed the anti staphylococcal effects of aspirin in hemodialysis patients was published in abstract form (Sedlacek et al., 2008). We performed a historical cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II data, linking medication data to mortality data from the core files. The updated USRDS Wave II data comprise 4024 patients, 16% of which were treated with Aspirin at study start date and 2776 of whom died. 54 of 2262 deaths (2.39%) in patients not treated with aspirin were attributed to septicemia due to vascular access either as primary or secondary cause, while there were only 4 of 510 deaths (0.78%) in patients treated with aspirin that were attributed to this cause (p<0.02, 2-tailed Fisher's Exact Test). Although anti platelet agents and other cardiovascular medications are underused in dialysis patients, we still find a strong negative association between aspirin treatment and

Table 3. Patient Characteristic and Distribution of Covariates for the Cox Proportional

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly

Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

**No Aspirin (454 patients) Aspirin (418 patients)** *P*


Table 2. Association between Aspirin Dose and Rates of Catether-Associated *S aureus* and MRSA Bacteremia

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

We used Cox proportional hazard analysis to study risk factors for developing a first episode of *S.aureus* bacteremia. Table 3 shows the patient characteristics and distribution of covariates that were used for this analysis. Patient treated with aspirin were on average 10 years older and had a higher prevalence of coronary artery disease, peripheral vascular disease, history of stroke, hypertension and diabetes mellitus than patients not treated with aspirin.

Table 4 shows the result of the Cox proportional hazard analysis. Aspirin decreased the odds of developing a first episode of *S.aureus* bacteremia by 54% (with a confidence interval of 72% to 24%, p=0.002). No other cardiovascular medication and neither clopidogrel nor Warfarin had a similar effect. Also, no beneficial effect of statins on the odds of *S.aureus* bacteremia was observed in this study. On the opposite side, the presence of diabetes mellitus increased the risk of developing a first episode of catheter associated *S.aureus* bacteremia, as was previous recognized (Breen et al. 1995). COPD decreased the odds of a first episode *S.aureus* bacteremia in this study. A potential explanation for this observation could be more frequent antibiotic use in this condition which might reduce nasal carriage. A greater incidence of *S.aureus* bacteremia was reported in patients with cardiovascular disease (K/DOQI, 2005) but the opposite, lower numbers of *S.aureus* bacteremia was observed in this sicker patient population which may be taken as a sign of the potential clinical importance of the anti staphylococcal effects of aspirin. Similar results were obtained when multiple logistic regression analysis was used instead of Cox analysis.

Data on metastatic infection (endocarditis, osteomyelitis, septic arthritis) was analyzed as well. There were significantly less events in patients treated with aspirin compared with events in patients not treated with aspirin (3 versus 11 events, p=0.04).

A Kaplan-Meier plot of cumulative catheter failure associated with *S.aureus* bacteremia is shown in Figure 1. Grouping by aspirin treatment resulted in two divergent graphs with catheter failure caused by *S.aureus* infection significantly more frequent in the non aspirin group (p<0.001). The two graphs diverge very early which is consistent with the clinical observation that almost a quarter of *S.aureus* infection occur very early within a week after catheter insertion (Little M.A. et al., 2001). Figure 1 also illustrates another measure of the beneficial anti staphylococcal effect of aspirin: delayed onset of infection.

Table 2. Association between Aspirin Dose and Rates of Catether-Associated *S aureus* and

We used Cox proportional hazard analysis to study risk factors for developing a first episode of *S.aureus* bacteremia. Table 3 shows the patient characteristics and distribution of covariates that were used for this analysis. Patient treated with aspirin were on average 10 years older and had a higher prevalence of coronary artery disease, peripheral vascular disease, history of

Table 4 shows the result of the Cox proportional hazard analysis. Aspirin decreased the odds of developing a first episode of *S.aureus* bacteremia by 54% (with a confidence interval of 72% to 24%, p=0.002). No other cardiovascular medication and neither clopidogrel nor Warfarin had a similar effect. Also, no beneficial effect of statins on the odds of *S.aureus* bacteremia was observed in this study. On the opposite side, the presence of diabetes mellitus increased the risk of developing a first episode of catheter associated *S.aureus* bacteremia, as was previous recognized (Breen et al. 1995). COPD decreased the odds of a first episode *S.aureus* bacteremia in this study. A potential explanation for this observation could be more frequent antibiotic use in this condition which might reduce nasal carriage. A greater incidence of *S.aureus* bacteremia was reported in patients with cardiovascular disease (K/DOQI, 2005) but the opposite, lower numbers of *S.aureus* bacteremia was observed in this sicker patient population which may be taken as a sign of the potential clinical importance of the anti staphylococcal effects of aspirin. Similar results were obtained

Data on metastatic infection (endocarditis, osteomyelitis, septic arthritis) was analyzed as well. There were significantly less events in patients treated with aspirin compared with

A Kaplan-Meier plot of cumulative catheter failure associated with *S.aureus* bacteremia is shown in Figure 1. Grouping by aspirin treatment resulted in two divergent graphs with catheter failure caused by *S.aureus* infection significantly more frequent in the non aspirin group (p<0.001). The two graphs diverge very early which is consistent with the clinical observation that almost a quarter of *S.aureus* infection occur very early within a week after catheter insertion (Little M.A. et al., 2001). Figure 1 also illustrates another measure of the

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

stroke, hypertension and diabetes mellitus than patients not treated with aspirin.

when multiple logistic regression analysis was used instead of Cox analysis.

events in patients not treated with aspirin (3 versus 11 events, p=0.04).

beneficial anti staphylococcal effect of aspirin: delayed onset of infection.

MRSA Bacteremia


*Note:* Values expressed as mean ± SD or number (percent).

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. \*Statistically significant difference between aspirin-treated and non–aspirin-treated groups by means of Fisher exact test or unpaired Student *t*-test, as appropriate.

Table 3. Patient Characteristic and Distribution of Covariates for the Cox Proportional Hazard Analysis

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

A second study that addressed the anti staphylococcal effects of aspirin in hemodialysis patients was published in abstract form (Sedlacek et al., 2008). We performed a historical cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II data, linking medication data to mortality data from the core files. The updated USRDS Wave II data comprise 4024 patients, 16% of which were treated with Aspirin at study start date and 2776 of whom died. 54 of 2262 deaths (2.39%) in patients not treated with aspirin were attributed to septicemia due to vascular access either as primary or secondary cause, while there were only 4 of 510 deaths (0.78%) in patients treated with aspirin that were attributed to this cause (p<0.02, 2-tailed Fisher's Exact Test). Although anti platelet agents and other cardiovascular medications are underused in dialysis patients, we still find a strong negative association between aspirin treatment and

Nontraditional Anti - Infectious Agents in Hemodialysis 399

p<0.001

ASA 417 142 66 35 25 16 9 6 5 no ASA 452 118 61 37 22 11 6 3 2

manuscript which why it was not discussed in the above sections.)

high risk dialysis patient than for example cardiac stent occlusion.

no yes

Aspirin

0 100 200 300 400 500 600 700 800 900 1000 1200 catheter time in days

Fig. 1. Cumulative plot of tunneled catheter failure associated with *S aureus* bacteremia. The failure plot was obtained using the Kaplan-Meier method. Tics represent censoring of catheter removal unrelated to *S aureus* bacteremia. Log-rank test was used to calculate *P*. Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier

support or refute this hypothesis. In our own study no increased risk of bleeding was observed (unpublished data, Sedlacek et al., 2008). A study on aspirin use in 28320 patients from the Dialysis Outcomes and Practice Patterns Study I and II found neither a decreased cardiovascular risk nor an increase in the gastrointestinal bleeding with the use of aspirin (Ethier J et al., 2007). (Of note, no data on infectious complications was included in this

While there is no unequivocal proof that aspirin increases the risk of upper gastrointestinal bleeding in dialysis patients, it must not be forgotten that upper gastrointestinal bleeding is a well documented part of the uremic syndrome and that anticoagulation is routinely used during the hemodialysis procedure. It would thus seem reasonable to adopt a similar approach to high risk dialysis patients as has been recommended in high risk cardiac patients who would benefit from aspirin. Patients can be screened and treated for *H.pylorii* and proton pump inhibitors may be considered. Lastly it has to be noted that upper gastrointestinal bleeding is more amenable to treatment and represents a lesser risk to a

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

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

patients at risk:

**4. Statins** 

failure associated to S.aureus

death from septicemia due to vascular access in USRDS data. These results provide a confirmation of a clinical anti-staphylococcal effect of aspirin in hemodialysis patient that is independent from the data pool used in our first study.


Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. \*Statistical significance in Cox proportional hazard model.

Table 4. Risk of First *S aureus* Bacteremia Episode in 872 Dialysis Patients with a Tunneled Catheter by using Cox Proportional Hazard Analysis

Reprinted from Sedlacek et al.: "Aspirin Treatment Is Associated With a Significantly Decreased Risk of Staphylococcus aureus bacteremia in Hemodialysis Patients With Tunneled Catheters", Am J Kidney Dis Vol49, pp401-408 with permission from Elsevier
