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.
|Darouiche et al. 2014
|Population: Mean age: 59.9 yr; Gender: males=52, females=3.
Intervention: Spinal cord injury individuals with lower urinary tract infection (UTI) associated with an indwelling transurethral or suprapubic catheter were randomized to 5-day course of antibiotics with catheter exchange (treatment group) (n=28) or the standard 10-day antibiotic treatment (control group) (n=27).
Outcome Measures: Clinical cure, microbiologic response, resolution of pyuria, individual survival, adverse events.
|1. At end of therapy (EOT), all participants in both groups achieved clinical cure, with the experimental group noninferior to the control group (p<0.001).
2. At EOT, the experimental group was not found to be significantly noninferior to the control group in terms of microbiologic response or resolution of pyuria.
3. There were 24 participants with adverse events within 180 days EOT. Compared to the control group, the experimental group had a significantly higher risk for recurrent catheter associated urinary tract infection (p=0.043). There were no significant differences between groups in terms of new urinary tract infection, C difficile colitis, or death.
|Dow et al. 2004
|Population: SCI with bacteriuria: Mean age: 39 yr; Gender: males=51, females=9; Time post-injury=7.1 yr; Bladder management: intermittent catheterization=50, condom drainage=10
Intervention: Comparison of oral ciprofloxacin (250mg) bid for 14 d versus oral ciprofloxacin (250mg) bid for 3 d followed by 11 d of placebo.
Outcome Measures: Urinalysis with leukocyte count, urine culture and surveillance cultures (defined microbiological cure); and type and duration of symptoms (defined clinical cure). All were taken before and at 3-5, 12-16, 19-23 d (defined as short term follow-up) and at 45-51 d (defined as long-term follow-up).
|1. Higher microbiological cure rates for 14 d versus 3 d treatment at long-term (p=0.02) but not short-term (p=0.29) follow-up.
2. No difference in clinical cure rate between14 d versus 3 d treatment at long-term (p=1.0) or short-term (p=0.6) follow-up.
3. Lower rates of clinical & microbiological relapse at short (p=0.001) & long term (p=0.01) follow-up for the 14 d treatment.
4. Trend for higher treatment failure rate for 14 d treatment at short (p=0.07) & long term (p=0.07) follow-up largely due to greater number of cipro-resistant isolates in this treatment arm (especially E. faecalis).
|Reid et al. 2000
|Population: SCI with symptomatic UTI; Age range 18-75 yr; Gender: males=28, females=14.Intervention: Comparison of ofloxacin (300 mg bid) versus trimethoprim-sulphamethoxazole (TMP-SMX; TMP=160 mg, SMX=800 mg; twice daily) or another antibiotic if resistant to TMP-SMX for 7 d.
Outcome Measures: Bacteriuria (culture), biofilm presence (number of bacteria/epithelial cell) collected on day 1, 4 or 7.
|1. Clinical cure rate in favour of Ofloxacin versus TMP-SMX or other antibiotic at day 4 (p=0.003) and day 7 (p=0.015).
2. Biofilm clearance rate was better with Ofloxacin versus TMP-SMX or other antibiotic at day 4 (p=0.005); and day 7 (p=0.014);
3. Both treatments effective at reducing bacterial biofilms at day 4 and 7 (p<0.001).
|Sapico et al. 1980
|Population: SCI with asymptomatic UTI: Age range 21- 32 yr; Bladder Hyperreflexia=22, Bladder Hypotonic=7
Intervention: Comparison of standard and low-dose tobramycin (1 mg/kg and 0.5 mg/kg IM every 8 hr) and amikacin (500 mg and 250 mg bid) for 5 d.
Outcome Measures: UTI rate (culture) classified as persistence, relapse or reinfection with other bacteria; Urine and serum antibiotic levels. Cultures conducted prior and 2 and 4 d after treatment completion.
|1. No significant differences (p>0.05 between dose strengths or tobramycin and amikacin.
2. Overall there was a low cure rate of 48% with significant relapse (31%) and reinfection (21%) rates.
3. High urine antibiotic concentrations were found in all subjects.
4. Authors suggested tobramycin and amikacin not recommended for use in SCI.
|Dinh et al. 2016
|Population: Neurogenic bladder; Mean age: 38.4 yr; Gender: males=80, females=32; Level of injury: paraplegia=65, tetraplegia=20; Injury etiology: spinal cord injury=85, multiple sclerosis=16, brain injury=11.
Intervention: Individuals with febrile urinary tract infection (UTI) were divided into three groups according to the duration of antibiotic treatment: less than 10 days (group 1), between 10 and 15 days (group 2), more than 15 days (group 3).
Outcome Measures: Cure rate (persistent UTI or UTI-related death was considered failure), bacteriuria.
|1. At 1 mo after treatment, there was no significant difference in the cure rate of the three groups (1=71.4%, 2=54.2%, 3=57.1%).
2. There was no significant difference in the bacteriuria rate of the three groups.
3. Regardless of group, there was no significant difference in cure rate between mono (44%) and dual (40%) therapy.
|Lee et al. 2014b
|Population: Trimethoprim: Mean age: 48.3 yr; Gender: males=10076, females=44720; Injury etiology: spinal cord injury=298. Ciprofloxacin: Mean age: 51.8 yr; males=1116, females=3068; Injury etiology: spinal cord injury=48. Levofloxacin: Mean age: 55.3 yr; Gender: males=967, females=2175; Injury etiology: spinal cord injury=32. Ofloxacin: Mean age: 47.9 yr; Gender: males=1165, females=4819; Injury etiology: spinal cord injury=29. Norfloxacin: Mean age: 51.4 yr; Gender: males=766, females=4803; Injury etiology: spinal cord injury=31.
Intervention: Outindividuals with urinary tract infections (UTI) were divided into 5 groups depending on which UTI-related antibiotic regimen was received.
Outcome Measures: Treatment failure (as defined by presence of further hospitalization/emergency visit consistent with the initially identified UTI).
|1. Within the 30 day observation period for spinal cord injury participants, there was no significant difference in risk of treatment failure between any of the 5 groups.
2. Other results of this study were not spinal cord injury-specific.
|Waites et al. 1991
|Population: SCI with UTI susceptible to norfloxacin: Age range 18-69 yr; Gender: males=66, females=3; Severity of injury: complete=58, incomplete=11; Time post-injury: <6 mo=5, ≥ 6mths=64.
Intervention: Oral norfloxacin 400 mg bid for 14 d after initial bacteriologic confirmation of urinary tract infection (UTI).
Outcome Measures: Bacterial strain/species identification, culture results collected at 2-4 d after initiating and 5-7 d and 8-12 wk after completing treatment.
|1. 58/79 negative for UTI mid-treatment at day 2-4.
2. 5 to 7 d after administration of norfloxacin, infection was eradicated in 42 cases while 37 cases had evidence of infection (≥105 cfu/mL).
3. 8-12 wk after administration, 27/32 were infected after previous eradication (either reinfection or relapse).
4. Of 20 species initially identified, 14 were completely eradicated and remaining 6 had>50% eradication.
5. Of 120 strains identified during or after treatment, 20 were resistant to norfloxacin.
6. Clinical cure in 67% symptomatic UTIs
7. Side effects in 8% of individuals.
|Linsenmeyer et al. 1999
|Population: SCI with indwelling catheter and asymptomatic bacteriuria resistant to oral antibiotics: Gender: males=7, females=3.
Intervention: Bladder irrigation with 30 cc of neomycin/polymyxin solution 3 x with each session (3 session/d for 5 d).
Outcome Measures: Urine culture (type, count and sensitivity) collected pre and post irrigation.
|1. 9 of 12 bladder irrigation trials across 10 individuals led to changed resistance (resistant susceptible) allowing use of an oral antibiotic.
2. The remaining 3 bladder irrigations were not successful.
3. No change in white blood cells with irrigation (p>0.05).
4. No change in bacterial colony count with irrigation (p>0.05).
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.
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.