Pharmacological Treatment of UTIs

UTIs in persons with SCI with neurogenic bladder are termed “complicated UTIs” which refers to the presence of a UTI in a functionally, metabolically, or anatomically abnormal urinary tract or that are caused by pathogens that are resistant to antibiotics (Stamm & Hooton 1993). Complicated UTIs may be caused by a much wider variety of pathogens in persons with SCI and are often polymicrobial. It is generally recommended that persons with SCI be treated for bacteriuria only if they have symptoms, as many individuals especially with indwelling or SPC typically have asymptomatic bacteriuria (Biering-Sorensen et al. 2001). Once symptomatic UTI is confirmed, the first line of empirical treatment is via antibiotics and the most common antibiotics chosen for UTI treatment include fluorquinolones (e.g., ciprofloxacin), TMP-SMX, amoxicillin, nitrofurantoin and ampicillin. Fluorquinolones are often chosen because of their effectiveness over a wide spectrum of bacterial strains (Waites et al. 1991; Garcia Leoni & Esclarin De Ruz 2003). Although much experience with treating UTIs in SCI has been gleaned from other indications, there are several studies that are reviewed below which have investigated a variety of antibiotic agents in this population.

Discussion

The range of effective antibiotic treatment duration can vary widely depending on the specific microorganism causing the infection, the antibiotic used and the individuals’ UTI history. Dow et al. (2004) conducted an RCT (n=60) to compare a 14 day versus 3 day course of ciprofloxin treatment in SCI individuals with UTI symptoms or microbially documented bacteriuria and concluded that a 14 day Ciprofloxin treatment results in improved clinical and microbiological outcomes. Microbiological relapse rates were significantly lower for those individuals treated for 14 versus 3 days. Although this study advocates for the use of a 14 versus 3-day course of ciprofloxacin in SCI UTI, as the author notes, it does not address the optimal treatment period which may be 5, 7 or 10 days, nor does it examine the question of whether a higher dose might 214 have been more effective with the shorter therapy. An RCT comparing 5- to 10-day courses of appropriate antibiotic choice accompanied by a catheter change during the 5-day course yielded clinical cures in both groups (Darouiche et al. 2014). However, for these catheter-associated UTIs (CAUTI), the 5-day course was less effective for the microbiologic response, resolution of pyuria and recurrence prevention. Therefore, the authors concluded that the 5-day course, even when combined with catheter exchange, was not an adequate alternative to the 10-day course of antibiotics to treat CAUTI. Muddying the waters somewhat is a non-randomized cohort study reporting no difference in improving clinical signs of UTI regardless of the antibiotic treatment (<10 days, 10-15 days, > 15 days, mono or dual therapy). However, this study (Dinh et al, 2016) did not report on microbiological change and included individuals using a wide variety of voiding practices. Dihn et al. (2016) does concur with Darouiche et al. (2014) since both groups suggest no difference in clinical cure rate regardless of duration of antibiotic treatment.

Ofloxacin is a fluoroquinolone antibiotic shown to be promising in its ability to penetrate and eradicate bacterial biofilms in the bladder in vitro and in SCI individuals (Reid et al. 1994a; Reid et al. 1994b, Lee et al. 2014b)). Bacterial biofilms are colonies of microorganisms along with their extracellular products that may form on surfaces as a structured community that enables the pathogens to resist antibiotics and persist in the urinary tract thereby potentially causing recurrent UTI. Reid et al. (2000) employed a randomized, double blind design (n=42) to assess the relative effectiveness of a 7-day course of ofloxacin as compared to TMP-SMX or other more appropriate antibiotics as detected by culture sensitivity. Study participants had symptomatic UTI and clinical cure rates, defined as individuals becoming asymptomatic with sterile urine, assessed at day 4 and day 7. Clinical cure rate was significantly greater for Ofloxacin as compared to TMP-SMX or other antibiotic at day 4 (90% versus 48%; p=0.003) and day 7 (90% versus 57%; p=0.015). In addition, both treatments were effective at reducing bacterial biofilms at day 4 and 7 (p<0.001), although the biofilm eradication rate was significantly higher with Ofloxacin versus TMP-SMX or other antibiotic at day 4 (62% versus 24%; p=0.005); and day 7 (67% versus 35%; p=0.014). This finding was supported by an earlier study (Reid et al. 1994a) noting that fluoroquinolone therapy was more effective at reducing bladder cell adhesion counts in 63% of asymptomatic SCI UTIs versus 44% of SCI subjects treated with TMP-SMX. Lee et al. (2014) also concluded that ofloxacin and norfloxacin might have better outcomes when compared with TMP-SMX for the treatment of outindividual UTIs, noting the limitation of regional differences in antibiotic resistance patterns.

Reid et al. (2000) suggested that a 3-day regimen in the treatment of SCI UTI could be sufficient based on significant biofilm eradication detected in bladder epithelial cells in individuals treated with Ofloxacin compared to TMP-SMX. Shorter courses of antibiotic treatment are currently considered by clinicians and individuals who are concerned with side effects, cost, and antimicrobial resistance due to longer-term use. The difference in effective treatment duration, compared to the findings of Dow et al. (2004), is due, in part, to the difference in anti-microbial used. However, further study comparing the two antimicrobials (and others) and differing treatment durations are needed.

Gram-negative bacteria such as Pseudomonas, Acinetobacter, Enterobacter and mycobacteria are susceptible to aminoglycosides such as tobramycin and amikacin which may be chosen for complicated UTI treatment. Due to their toxicity and inconvenient route of administration (i.e. intramuscular injection), their use is limited. To investigate the effectiveness of a lower dose of these aminoglycosides, Sapico et al. (1980) compared infection, persistence and reinfection rates of SCI UTI against a standard dose. It was found that there was an overall low rate of success and no difference between the dose strengths or between tobramycin and amikacin 215 even though high antibiotic concentrations were found in the urine of all subjects; this suggests that alternative antimicrobial agents may be better to consider for use in this population.

Although Waites et al. (1991) showed norfloxacin, another fluoroquinolone, to be 73% effective in eradicating UTIs by mid-treatment, the rate of reinfection was 84% after 8 to 12 weeks post initial eradication. Furthermore, 16% of strains isolated after eradication became resistant to norfloxacin. This trial, employing a pre-post study design (n=78) with a 14 day course of treatment, enrolled participants with symptomatic UTI and the equivocal results point to the utility of controlled study designs when assessing antibiotic effectiveness. The authors concluded that norfloxacin is a reasonable treatment choice for SCI UTI but the subsequent and problematic emergence of resistance must be monitored (as with other antimicrobials). In addition to decisions on selecting the most appropriate antibiotic, the clinician is sometimes faced with additional treatment option challenges when multi-drug resistant bacteria or the individual’s allergy to the appropriate antibiotic are encountered. Although conflicting results have been obtained with the use of antiseptic agents as part of a prophylactic strategy to lower urine pH and thereby assist in the prevention of UTIs, Linsenmeyer et al. (1999) used a case series review (n=10) to investigate the use of medicated bladder irrigation as a method to alter the existing antimicrobial resistance. They found that intermittent neomycin/polymyxin bladder irrigation was effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment, therefore proving preliminary evidence advocating for a short course treatment of neomycin/polymyxin irrigant to alter existing antimicrobial resistance.

Since side effects from traditional treatments discussed above are not uncommon, a subset of individuals turn to complementary and alternative medicine (CAM). Although individuals with SCI are among those with chronic diseases that use CAM the least, the most common reason for CAM use is UTI (and pain) and the most common form of CAM chosen is acupuncture and homeopathy (Panneck et al. 2015). There exist some positive indications for adjunctive homeopathy related UTI improvements (Pannek et al. 2014). Pannek et al. (2015, 2016) reported that 12/13 (92.3%) individuals regarded homeopathy as an effective treatment for UTI. There was an overall satisfaction rate of 90.5% for adjunctive CAM effectiveness for complications secondary to SCI.

Conclusion

There is level 1a evidence (from two RCTs: Dow et al. 2004; Darouiche et al. 2014) that supports the use of longer (10 or 14 day) versus shorter (5 with catheter change to 3 day) courses of antibiotic to improve clinical and microbiological outcomes in the treatment of catheter associated UTIs in persons with SCI.

There is level 1b evidence (from one RCT: Reid et al. 2000; supported by level 2 evidence from one cohort study, Lee et al 2014) that Ofloxacin treatment is more effective than trimethoprim-sulfamethoxazole in treating UTI.

There is level 1b evidence (from one RCT: Sapico et al. 1980) that there is a low success with aminoglycosides for the treatment of UTI post-SCI.

There is level 4 evidence (from one pre-post study: Waites et al. 1991) that norfloxacin may be a reasonable treatment for UTI post-SCI but subsequent resistance must be monitored.

There is level 4 evidence (from one case series study: Linsenmeyer et al. 1999) that intermittent neomycin/polymyxin bladder irrigation is effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

Optimum antimicrobial treatment duration and dosage is uncertain due to the lack of comparative trials in persons with SCI.