**1. Introduction**

388 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

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Int 2008.

The distinction between antibiotic and non antibiotic medications is in fact quite arbitrary as drugs against bacteria can have unpredictable side effects in man and drugs developed for use in humans can affect microbes. It would be extremely surprising if it was otherwise, as eukaryotes and prokaryotes are related by evolution and share conserved molecular mechanisms. Many antibiotic and non antibiotic medications have closely related chemistries and share the same historic roots.

For example, both antimicrobial activity and an affinity for brain tissue of the phenothiazine compound methylene blue were described by Paul Ehrlich in the 19th century. Early uses of phenothiazines included treatment of urinary tract infection and postoperative analgesia. As a positive effect on psychotic patients was discovered, phenothiazines became with the development of chlorpromazine an important tool in psychiatry (Williams, 1995). With the discovery of penicillin the antimicrobial activities of phenothiazines and other earlier compounds fell into the background, but with the emergent problem of antibiotic resistance in more recent years there was new interest. Phenothiazines have activity against multidrug resistant *Staphylococcus aureus* and *Enterococcus faecalis*, presumably through the inhibition of bacterial efflux pumps (Kristiansen J.E. et al., 2007).

As a routine, antibiotic medications are tested for their effects on the eukaryotic host as these constitute potential side effects. While the ideal antibiotic would have no side effects at all, the discovery of unexpected side effects has lead to important drug developments. For instance, the clinical observation of a hypoglycemic effect of sulfonamide antibiotics led to the development of sulfonylureas for the treatment of diabetes. Likewise the observation that Sulfanilamide causes hens to lay eggs without shells because of alkaline diuresis led to the development of acetazolamide and ultimately the thiazide diuretics. The initial observation derived from the similarity between the sulfonamide ion and the bicarbonate ion. The antiviral amantadine was found to be useful in the treatment of Parkinson's disease and motility agents to treat gastroparesis are derived from the observation of the bothersome gastrointestinal side effects of erythromycin. As described below, even Lipitor, the "best selling drug in the world" with \$11 Billion of annual sales according to Forbes magazine, was developed from a compound initially discovered as an antibiotic originating from a fungal broth.

On the other hand side, the efforts to look into the unintended effects on microbes of non antibiotic medications have been less systematic. Non antibiotic medications can affect

Nontraditional Anti - Infectious Agents in Hemodialysis 391

metastatic infection such as endocarditis, osteoarticular infection, septic pulmonary embolism and epidural abscess and carries a mortality that is higher than with other pathogens. While the original observation by Fleming that led to the discovery of penicillin involved the accidental overgrowth of an *S.aureus* culture with fungus, staphylococcal resistance to penicillin has since become very frequent both in community and hospital acquired infections. A recent study in the US found that methicillin resistant *S.aureus* accounted for 65% of isolates from the nose in hospitalized dialysis patients (Johnson L.B. et al., 2009). As with methicillin sensive *S.aureus*, colonization seems to precede clinical infection. A scheme of three times a week nasal mupirocin ointment can decrease nasal carriage but is cumbersome, the rate of recurrence is high and rapid development of

Salicylic acid, the active ingredient of willow bark, is one of the oldest medicines still in use, in the buffered form of aspirin. The beneficial effect on fever, pain and inflammation were already described by Hippocrates. Fallen out of favour because of other non steroidal anti inflammatory drugs with more favorable side effects profiles aspirin has made a spectacular come back fifty years ago as the antiplatelet effects of aspirin were discovered. Since then aspirin has found widespread therapeutic use in the treatment of cardiovascular disease. Chronic treatment with Aspirin may prevent colorectal cancer, presumably by inhibition of cyclooxygenase 2 (COX-2) which is expressed in large amounts in adenocarcinoma (Ruder E.H. et al., 2011). Salicylic acid is ubiquitous in plants as a phytohormone. It is part of the innate immune system of plants, involved in local resistance to pathogens and in systemic acquired resistance (SAR), where a pathogenic attack one part of a plant induces resistance in other parts. Depending on the amount of fruit and vegetables in the diet humans have detectable serum levels of salicylic acid. It has been hypothesized that diet derived salicylic acid could in part account for the observed link between diet and colorectal cancer (Paterson J.R.& Lawrence J.R., 2001) and this might possibly apply to the relation between diet and cardiovascular disease as well. Salicylic acid is used as a food preservative and an antiseptic in toothpaste. Aspirin is thus not only one of the oldest but also one of the most versatile

**3.1 Laboratory evidence for an anti staphylococcal effect of salicylic acid** 

Early studies in the rabbit endocarditis model showed that platelets provide a nidus for bacteria and that aspirin can decrease vegetation size (Pujadas et al., 1988). The observation was made that aspirin can reduce not only the weight of vegetations in a rabbit model of *S.aureus* endocarditis but also bacterial density although neither aspirin nor salicylic acid have known antibacterial effects at the low concentrations employed (Nicolau D.P. et al., 1993). This benefit was seen if aspirin was given together with antibiotics but also if aspirin was provided prior to the infectious challenge with which endocarditis was induced (Nicolau D.P. et al., 1995). Even more puzzling in this study was that vegetation weight and bacterial density were higher if higher doses of aspirin were administered while the optimum beneficial effect was seen at a lower dose, suggesting that serum levels may be very important. Subsequently this observation has been called the "Goldilocks effect" in which too little and too much aspirin may cause paradoxically diminished effects on outcome parameters in the infectious endocarditis model (Eisen et al., 2008). The beneficial

resistance has been observed (Vandecasteele et al., 2009).

**3. Salicylic acid** 

and successful drugs known.

microbes in various ways: Compounds may have direct anti microbial effects in vitro, similar to traditional antibiotics. However, to be clinically useful the drug level to achieve minimum inhibitory concentration has to be within a range that is achievable and tolerable in humans. Compounds can exert an antimicrobial effect by inhibition of bacterial pumps. A well known example is the potentiation of antibiotic treatment against *Helicobacter pylori* through omeprazole. Many psychotropic medications including the phenothiazines fall into this category. Aspirin appears to modulate the expression of genes that are important for Staphylococcal virulence and the statins appear to have immune modulatory effects. Both medications are discussed in more detail below.

This chapter deals with the anti microbial effects of medications that are not traditionally regarded as antibiotics with regards to dialysis.

### **2. A combination of unfortunate events: infection in dialysis**

The current epidemic of obesity and, as a complication, diabetic nephropathy associated to type 2 diabetes mellitus has fueled the spectacular growth of hemodialysis into an industry that is dominated by a handful of large companies. Infection is a leading cause of morbidity and mortality in dialysis patients and the annual mortality rate caused by sepsis is several hundred folds higher in patients with end stage renal disease than in the general population (Laupland et al., 2004). The incidence of bacteremia has increased in hemodialysis patients over the years, mainly because of increased rates of serious *Staphylococcus aureus* infection in this population (Foley at al., 2004). *S. aureus* has its name from a gold coloured caroten virulence factor called staphyloxanthin which allows the bacteria to survive oxidative bursts of neutrophils (Liu G.Y. & Nizet V., 2009). *S.aureus* produces a battery of surface proteins, enzymes and toxins which enable the bacteria to both persist in intracellular locations and in biofilms for long periods of time, and to rapidly disseminate in the host in an opportunistic fashion which makes it one of the most dangerous and pathogenic bacteria in humans.

The use of dialysis catheters is a major risk factor for developing *S.aureus* infection because of disruption of the normal skin barrier, thus forming a gateway for bacterial entry into the blood stream (Vandecasteele S.J. et al., 2009). Despite Kidney Disease Outcomes Quality Initiative clinical practice guidelines recommending the use of auto logos arterio-venous fistulae as dialysis access and other efforts, the overall prevalence of hemodialysis catheter use has been increasing, approaching 30% in the United States (Rayner et al., 2004). Humans are the main natural reservoir for *S.aureus* which can colonize skin, gastrointestinal and urogenital tracts. The most frequent site of colonization is the anterior nose and longitudinal studies have shown that there are three types of *S.aureus* nasal carriage in healthy adults: fifty percent are persistent non carriers, thirty percent are intermittent carriers and twenty percent are persistent carriers (VandenBergh et al., 1999). Hands are the main vector of transmission and in the majority of cases the same strain that is found in the bloodstream is also found on the hands and in the nose (von Eiff C. et al., 2001). It follows that rigorous hand washing is extremely important to prevent infection in the dialysis units as it is elsewhere in the medical setting. The majority of *S.aureus* infections has its source in the endogenous reservoir in the nose of the same person and can thus be considered an "autoinfection" (Boelart et al., 1995 as quoted in Vandecasteele et al., 2009). Consistent with this view is that in prospective studies the interval between catheter placement and staphylococcemia can be very short, with 23% of episodes occurring less than one week after catheter insertion (Little M.A. et al., 2001). *S.aureus* bacteremia is associated frequently with metastatic infection such as endocarditis, osteoarticular infection, septic pulmonary embolism and epidural abscess and carries a mortality that is higher than with other pathogens. While the original observation by Fleming that led to the discovery of penicillin involved the accidental overgrowth of an *S.aureus* culture with fungus, staphylococcal resistance to penicillin has since become very frequent both in community and hospital acquired infections. A recent study in the US found that methicillin resistant *S.aureus* accounted for 65% of isolates from the nose in hospitalized dialysis patients (Johnson L.B. et al., 2009). As with methicillin sensive *S.aureus*, colonization seems to precede clinical infection. A scheme of three times a week nasal mupirocin ointment can decrease nasal carriage but is cumbersome, the rate of recurrence is high and rapid development of resistance has been observed (Vandecasteele et al., 2009).
