Results of the safety and tolerability analysis of the 32 patients included in this trial indicate that multiple instillations with polihexanide were safe and well tolerated. Although there were rare cases of discomfort and adverse events, these were temporary and did not persist throughout the course of the study. None of the patients experienced allergic reactions to the contents of the medical device. Furthermore, among the vital signs of patients monitored during the study, neither changes in pulse rate before and after instillation with the medicinal product nor in body temperature, blood pressure, pulse rate and VAS scores were clinically relevant for any participant. The overall low scores for all participants recorded over 5 instillations suggests that they experienced no noticeable pain during the instillations. In addition, no incidences of flushing or sweating during instillation were observed, and no participant experienced bladder spasms at each instillation. The three participants who did experience mild bladder spasms at all were afflicted by some form of spasticity (ischemic stroke, tetraplegia, multiple sclerosis), and muscle or bladder spasm in these patients can be induced by various stimuli, e.g. by mechanical stimulation of the bladder, through movement of the catheter and balloon (10). Indeed, one of the four patients reported having experienced bladder spasms both after irrigation with saline solution and the tested solution, suggesting that the discomfort could have been induced by stimuli other than the medical device.
Colonization of urinary catheter with microorganisms is inevitable, and it is perpetuated by microorganisms-produced biofilm. Following insertion of a urinary catheter, a conditioning film made up of proteins, electrolytes, and other components of urine is deposited on the surface of the catheter. Microbes attach to this conditioning film and begin secreting polysaccharides that form the architectural structure of biofilm. Bacteria in biofilms are more difficult to treat than bacteriuria without the presence of a foreign body (11). Under favorable conditions, organisms can detach from the biofilm and become free-floating in the urine, which can lead to symptomatic infection (12). Another possible harmful consequence of bacteriuria and biofilm formation is the encrustation of the catheter which disturbs liquid drain. In the catheter the biofilm produces urease, which hydrolyzes urea in the patient's urine to ammonium hydroxide. The resulting alkaline environment leads to precipitation of salts that then encrust and block the lumen of the catheter. About 50% of long-term catheterized patients develop such encrustations (6), which lead to urinary retention despite a catheter in place, with possibly fatal consequences especially in patients with neurogenic bladder dysfunction, e.g. autonomic dysreflexia (13).
To avoid encrustation, several strategies for catheter irrigation have been initiated. They either rely on mechanical cleansing of the bladder or on the use of citric acid to dissolve the crystals. Unfortunately, none of these strategies has been proven entirely successful, and the management of indwelling catheter remains to be a challenge. Alternatives, like triclosan-containing liquids for the inflating balloon, have demonstrated a certain effect, but these preliminary results have to be confirmed in further studies (14).
Treatment of chronic bacteriuria as the common reason for both UTI and encrustation is a challenge, and long-term eradication of bacteria from the urine in patients with long-term indwelling catheters has been proven to be virtually impossible, even with antibiotics (15). Furthermore, the use of prophylactic antibiotics is discouraged because they may lead to the selection of resistant flora (16). Antibiotic stewardship programs (ASP), which include prospective audits with intervention and feedback, and formulary restriction and pre-authorization, have been proven to be effective in reducing the unnecessary use of antibiotics (17). One measure is the rational use of antibiotics which can be replaced by antiseptics. As local antiseptic treatment bladder instillations of chlorhexidine-containing solutions has been utilized (18). Chlorhexidine diacetate, however, belongs to the first generation of this type of biguanide compound. It may cause some side effects (allergy, local irritation), and is known to produce a toxic degradation product (chloroaniline). In addition, bacterial resistance to chlorhexidine has been described (19).
The device assessed in the current study contains polihexanide 0.02%. Polihexanide has much higher tissue tolerability and is not degraded. It has been used for over 15 years as an antiseptic ingredient in wounds, and as a preservative agent in the ophthalmic field. It is a broad-spectrum biocide not only effective against Gram-positive and Gram-negative bacteria, but also against Saccharomyces cerevisiae, fungal and protozoal pathogens of infective keratitis, and against the enveloped virus HIV. The ecological database is still incomplete (9). Polihexanide acts on the microorganisms by interacting with the negatively charged phospholipids of the bacterial membranes. Due to this non-specific action and the heterogeneity of polihexanide, the potential to induce resistance is very low. Furthermore, experimental studies have shown that polihexanide can accumulate in most biofilm matrices, which then become toxic to the resident microorganisms. In contrast polihexadine has only slight effect on the neutral lipids of human and animal cell membranes, thus providing a larger safety margin and risk-benefit ratio compared to other antimicrobial agents (20). Based on the available data, polihexanide combines a broad antimicrobial spectrum with low toxicity, high tissue compatibility, low reported adsorption and good applicability (21). Based on these favorable data, this clinical study has been performed to assess the safety and tolerability of polihexanide-containing solutions as routine rinsing and bacterial decolonization solution device for urinary catheters.
Possible drawbacks of the study are the low number of participants, which is less than the intended number, and the lack of data concerning the antimicrobial effect of the solution. This study, however, was designed to evaluate tolerability, as effectiveness testing requires a longer application period and could therefore only be assessed if the device is proven to be safe in clinical use. Although the foreseen number of participants has not been reached, the data from this study, combined with the clinical and preclinical data available for polihexanide, demonstrate sufficient evidence that the substance can safely be used for catheter irrigation. An initial in vitro study using a polihexanide solution in bladder catheters has already demonstrated bactericidal activity, leading to bacterial decolonization of the catheters (22). Future studies should evaluate its clinical effectiveness in patients with long-term indwelling catheters.