Bladder Management

Antibiotic Prophylaxis of UTIs

Author Year

Country
Score
Research Design
Total Sample Size

 Methods Outcome
Morton et al. 2002

USA

Systematic Review

N=15 studies

 Population: Acute studies=8 (individuals with SCI<90 days ago; n=510): Treatments: trimethoprim, sulfamethoxazole, neomycin, polymiyxin B, nitrofurantoin, methenamine hippurate, methenamine madelate, hemiacidrin, ascorbic acid.Nonacute studies=7 (individuals with SCI>90 days ago (n=356): Treatments: nitrofurantoin, methenamine, mandelate, ammonium chloride, sulfamethoxazole, trimethoprim, ciprofloxacin, ascorbic acid.

Intervention: Literature search of Medline (1966- January 1998), Embase (1974-January 1998), and cinahl (1982-July 1998).

Outcome Measures: Symptomatic Urinary tract infections (SUTI), asymptomatic bacteriuria count.

 1.   Antimicrobial prophylaxis did not significantly decrease SUTIs in either acute or nonacute individuals (p>0.05).

2.   Antimicrobial prophylaxis reduced asymptomatic bacteriuria in acute individuals (p<0.05), and nonacute individuals (p=0.06) but the reduction was not significant in either.
Darouiche et al. 1994

USA

RCT

PEDro=9

N=40

 Population: SCI Inindividuals: Treatment group: Mean age: 52.9 yr; Gender: males=18, females=0; Placebo group: Mean age: 46.9 yr; Gender: males=22, females=0.Intervention: Double blind comparison of 500mg of ciprofloxacin bid versus placebo bid for 3 d prior to urodynamic testing.

Outcome Measures: Incidence of urinary tract infection (UTI) (culture), bacteriuria, pyuria, adverse events collected prior and 3-5 d post urodynamic testing.

 1.     3 individuals in the placebo group and none the individuals in the treatment group developed symptomatic UTI but this was not significant (p=0.24).

2.   No adverse effects were reported.
Biering-Sorensen et al. 1994

Denmark

PEDro=8

RCT

N=21

 Population: SCI with neurogenic bladder: Mean age: 38 yr; Gender: males=18, females=3.Intervention: Cross-over comparison of 6 mo ciprofloxacin (100mg/night) versus placebo prophylaxis.

Outcome Measures: Number of urinary tract infections (UTIs), urine and fecal cultures, side effects collected over 6 mo periods.

 1.   Ciprofloxacin versus placebo prophylaxis (6 mo): number of UTIs greatly reduced with 5 versus 59 (p<0.00005).

2.   1 instance of ciprofloxacin resistant E. coli found in the feces of 1 cipro individual

3.   No severe side effects.
Gribble & Puterman 1993

Canada

RCT

PEDro=8

N=129

 Population: Acute (<30 d) SCI: Mean age: 38 yr; Gender: males=112, females=17.Intervention: Efficacy of trimethoprim-sulfamethoxazole (TMP-SMX; TMP 40 mg, SMX 200mg) for UTI prophylaxis in acute SCI, during the first 4 mo of intermittent catheterization (IC). Breakthrough bacteriuria treated with conventional antimicrobial therapy and prophylaxis was continued.

Outcome Measures: Clinical: weekly rectal and urethral swab and urine cultures collected for 4 mo or until hospital discharge.

 1.   TMP-SMX more efficacious than placebo (P) prophylaxis:

·       Lower incidence/freq/relapse of bacteriuria and symptomatic UTI in males (p<0.003 /0.0001/0.0001 and 0.0003).

·       Similar trends in women.

2.   Other results:

·       Adverse events similar between groups

·       ≥1 TMP-SMX-resistant bacteriuria in all P subjects by yr 3.

·       Rectal/urethral swab TMP-SMX-resistant organisms-both grps.

·       TMP-SMX UTI prophylaxis effective in acute SCI/IC but emergent TMP-SMX-resistance limits usefulness.
Sandock et al. 1995

USA

Prospective Controlled Trial

N=43

 Population: SCI inindividuals; Treatment group: Mean age: 46 yr; Gender: males=20; Level of injury: lumbar=2, paraplegic=5, tetraplegia=13; Mean time post-injury=9.2 yr; Control group: Mean age: 58.3 yr; Gender: males=23; Level of injury: lumbar=3, paraplegic=8, tetraplegic=12; Mean time post-injury=14.9 yr.Intervention: Comparison of 400mg trimethoprim-sulfamethoxazole (TMP-SMX) daily versus no treatment over a minimum of 3 mo.

Outcome Measures: Incidence of asymptomatic bacteria, prevalence of urinary tract infection UTI, types of bacteria present. Urine cultures weekly.

 1.   No significant difference was found between the control and treatment groups in:

·       Incidence of asymptomatic bateriuria.

·       Percent of cultures with asymptomatic bacteriuria (p>0.1).

·       Incidence of symtomatic UTIs per week (p>0.5).

·       Percentage of TMP-SMX resistant UTIs (p>0.5).

·       Types of bacteria present.

2.   The control group was signficantly lower than the treatment group in:

·       Percent of cultures with TMP-SMX resistant asymptomatic bateriuria (p<0.05).
Reid et al. 1994a

Canada

Prospective Controlled Trial

N=14

 Population: SCI inindividuals with intermittent catheterization: Age range 20-66 yr; Gender: males=11, females=3.

Intervention: Comparison of co-trimoxazole (TMP-SMX 160/800 mg bid) versus no prophylaxis. Symptomatic urinary tract infections (UTIs) were treated with appropriate antibiotic and a separate analysis was done on effect of fluoroquinolones (ciprofloxacin, ofloxacin and norfloxacin) on bladder biofilm bacteria.

Outcome Measures: Infection rate, extent of biofilm formation, level of bacterial adhesion; urine samples collected for culture and sonication for 8 wk.

 1.   TMP-SMX versus non-prophylaxis prophylaxis subjects:

·       54% versus 68% infection rate (not significant; no p value reported)

·       E coli replaced by E faecalis as dominant uropathogen with TMPSMX use.

·       39±42 versus 44±49adherent bacteria/bladder cell (not significant; no p value reported)

2.   Laboratory results for treatment effect of fluoroquinolones versus TMP-SMX prophylaxis on biofilms:

·       Reduced adhesion counts in favour of Fluoroquinolone versus TMP-SMX (63% versus 44%, no p value).

·       92%, 71%, 56% biofilm reduction with ciprofloxacin, ofloxacin & norfloxacin.
Chew et al. 2018

USA

Case Control

N=421

 Population: Long-term nitrofurantoin (LTN): Mean age=60.5±12.4yr; Gender: males=208, females=17; Etiology: SCI=225; Time since injury=24.4±14.2yrControl (CG): Mean age=61.1±12.2yr; Gender: males=187, females=9; Etiology: SCI=196; Time since injury=22.0±13.9yr. Inclusion criteria: recurrent (≥3) positive urine cultures and at least one occurrence of UTI or asymptomatic bacteriuria.

Intervention: Medical records of SCI individuals who received long-term nitrofurantoin (≥90 d) for treatment of UTI and SCI individuals who did not receive nitrofurantoin (controls) were reviewed. Clinical outcomes of asymptomatic bacteriuria and UTI occurring during the study year (2012-2013) were extracted.

Outcome Measures: UTI frequency; number of days between positive urine cultures; frequency of isolates in urine; presence of nitrofurantoin-resistant isolates; presence of multidrug-resistant organism isolates; number of outindividual encounters; hospitalization.

 1.     There were no significant differences in the frequency or types of UTI symptoms when comparing LTN to CG (p>0.05).

2.     CG had a higher proportion of positive urine cultures compared to LTN (p<0.001).

3.     CG had significantly fewer nitrofurantoin-resistant isolates (p<0.001). However, there was no significant difference in the number of multidrug-resistant organism isolates between CG and LTN (p>0.05).

4.     Average number of days between positive urine cultures was significantly shorter in the CG group compared to LTN (p<0.001). 5.     There was no significant difference in the frequency of isolates between CG and LTN (p>0.05).

6.     LTN had significantly fewer outindividual encounters, and hospitalizations compared to CG (p<0.001).
Cox et al. 2017

USA

Pre-Post

N=22

 Population: Median age=37.5yr (18-75); Gender: males=13; females=9; Etiology: SCI (n=14, 63.6%); Multiple Sclerosis=3; Myelodysplasia=2; Transverse Myelitis=2; Other=1, Median time since injury=14yr.

Intervention: 480 mg of gentamicin was diluted in 1 L of water. Each individual received a gravity instilled dose of 30-60 mL (dependent on bladder capacity) of solution instilled into the bladder after drainage of urine was complete at the individual’s last evening catheterization. Instillations were left indwelling until the next catheterization.

Outcome Measures: Symptomatic UTI median; Courses of oral antibiotics; Courses of IM or IV antibiotics; Days of antibiotic therapy; ED/hospital visits for UTI; Telephone encounters for UTI; Multidrug-resistant organisms; Gentamicin resistant organisms

 1.     The incidence of symptomatic UTI decreased significantly (p<0.004).

2.     Individuals underwent fewer course of treatment with oral antibiotics after gentamicin instillations (p<0.01).

3.     There was a significant decrease in the number of individuals who used oral antibiotic prophylaxis (p=0.03).

4.     There was a significant decrease in the proportion of multidrug-resistant organisms in urine culture (p=0.04).

5.     The number of telephone encounters for UTI decreased significantly (p=0.03).
Poirier et al 2016

France

Pre-Post

N=50

 Population: SCI, NBD; Mean age: 51 yr; Gender: males=30, females=20; Level of injury: paraplegia=33, tetraplegia=6, MS=4, other=6, missing data=1; Mean time post-injury: 19.4 yr.

Intervention: Alternate weekly administration of oral antibiotics, which have been proven effective in treating UTIs.

Outcome Measures: UTI frequency (per year), antibiotic use post regimen, presence of multidrug resistant bacteria (MDRB) in rectal swabs.

 1.     The number of UTIs per year significantly decreased with oral antibiotic cycling (p<0.001).

2.     The number of antibiotic treatments per year (p<0.001) and the number of hospitalizations per year (p=0.001) also significantly decreased with cycling treatment. Additional antibiotic treatment length was also significantly shorter (p<0.001) if individuals were already on antibiotic cycling treatment.

3.      MDRB presence significantly decreased in individuals after starting antibiotic cycling (p<0.001).
Chong et al. 2015

USA

Pre-Post

N=60

 Population: Mean age: 55.75 yr; Gender: males=59, females=1; ASIA classification: A=34, B=11, C=9, D=6; Short-term treatment=35, Long-term treatment=25.

Intervention: Individuals either received 1-day of pre-procedural antibiotic treatment or 3-5 days of pre-procedural antibiotic treatment before a urological procedure.

Outcome Measures: Quality of life (EQ-5D), physical exam data (vital signs), antibiotic usage (type, frequency), post-procedural day 1 white blood cell count (WBC), complications (UTIs).

 1.     There were no significant differences in EQ-5D scores between the short-term and long-term treatment groups. The long-course group reported significantly higher anxiety levels pre-procedurally when reporting anxiety/depression (p=0.010) and “extremely anxious” (p=0.010) compared to the short treatment group.

2.     There were no significant differences in vital signs between or within groups, pre or post procedure. Additionally, the WBC was similar in both groups.

3.     Five adverse events occurred, 2 participants from the long-course group and 3 from the short-term group. One participant from each group was found to have urosepsis and was admitted to the intensive care unit for treatment.
Salomon et al. 2009

France

Pre-Post

N=6

 Population: Mean age: 34 yr; Gender: males=0, females (pregnant)=6; paraplegic=4, tetraplegic=2.

Intervention: Weekly oral cyclic antibiotic (WOCA) program.

Outcome: Urinary tract infection (UTI) rate, birth weight, obstetric and neonatal characteristics.

 1.     Significant reduction in UTI rate. Only 2 individuals had a UTI compared to before the treatment with 6 UTI per yr per individual (p<0.001).

2.     No complications were observed during the delivery.

3.     All newborns were born healthy with a mean weight of 3180g.
Salomon et al. 2006

France

Pre-Post

N=38

 Population: SCI with neurogenic bladder and undergoing intermittent catheterization; Mean age: 45.9 yr; Gender: males=22, females=16; daily catheterizations=6.

Intervention: Weekly oral cyclic antibiotic (WOCA): Wk 1-one antibiotic+wk 2 another antibiotic (over 2 yr). Antibiotic choice based on urine culture results: amoxicillin 3000mg; trimethoprim/ sulfamethoxazole 320-1600mg; fosfomycin trometamol 6000mg; nitrofurantoin 300mg; cefixime 40mg.

Outcome Measures: Number of urinary tract infections (UTIs) with weekly cultures for first 3 mo and monthly thereafter over 2 yr.

 Before/after WOCA programme:

·       Reduced symptomatic UTIs/ pt/yr from 9.4 to 1.8, p<0.01

·       Reduced febrile UTI/pt/yr from 0.75 to 0.31, p<0.04

·       Reduced hospitalization days from 4 to 1.2 d/individual, p<0.01.

·       Decreased antibiotic consumption correlated with decreased incidence of UTIs over the course of the study.
Previnaire et al. 2017

France

Post-Test

N=57

 Population: Mean age=40.9±16.8; Gender: males=43; females=14; Etiology: SCI=57; Mean time since Injury: 18.4±49.1 mo; Inclusion criteria: individuals using IC; presence of UTI compatible with cystitis; prescription of a 5-day narrow spectrum antibiotic for either symptomatic or asymptomatic bacteremia.

Intervention: Individuals were divided into 4 groups: Group 1 (recurrence of a treated UTI); Group 2 (occurrence of UTI after treatment for asymptomatic bacteriuria); Group 3 (treatment for asymptomatic bacteriuria after UTI); Group 4 (consecutive treatments for asymptomatic bacteriuria). Common 5-day narrow spectrum antibiotic treatments included: Third-generation cephalosporin; Trimethoprim-sulfamethoxazole; Fluoroquinolone; Nitrofurantoin. Outcome measures were assessed at 3, 6, 9wk follow-ups.

Outcome Measures: occurrence of UTI; Duration of UTI-free urine; clinical cure at end of therapy for UTI; relapse and reinfection rates.

 1.     There was a 99% eradication rate and 100% clinical cure rate for subjects treated for UTI.

2.     There was no significant difference in the UTI-free period after treatment for asymptomatic bacteriuria compared with treatment for UTI (p>0.05).

3.     There was no significant difference in UTI rates after treatment of UTI or asymptomatic bacteriuria (p>0.05).

4.     There was no significant difference in UTI rates between those who underwent non-urological procedures and those who underwent invasive urological exams (p>0.05).

5.     There was no significant difference in UTI-free periods between Group 1 and Group 2 (p>0.05).

Discussion

Several investigations have been conducted which explore the effectiveness of a prophylactic antibiotic approach although cost and conflicting results, along with issues of adverse events and increasing likelihood of enhancing resistant organisms, have led reviewers to not recommend this approach for routine use (Garcia Leoni & Esclarin De Ruz 2003; Morton et al. 2002). Although researchers and clinicians have reservations about this approach, an obvious and important variable is the specific antibiotic that is used for prophylaxis. For the most part, investigations in SCI patients have involved different dosages and regimens of orally administered ciprofloxacin or co-trimoxazole (trimethoprim-sulfamethoxazole; TMX-SMX) as prophylactic measures.

An RCT comparing low-dose, long-term treatment with ciprofloxacin (100 mg nightly) versus placebo concluded that ciprofloxacin prophylaxis for up to 39 months resulted in a marked reduction from the pre-study infection rate (p<0.00005, corrected) with no severe side effects and only 1 instance of ciprofloxacin resistant E. coli found in the feces of 1 patient (Biering-Sorensen et al. 1994). Another RCT involved a 3 day course of ciprofloxacin (500 mg twice daily) or suitable placebo as a pre-cursor to urodynamic investigation (Darouiche et al. 1994), which has been associated with subsequent development of UTI (Pannek & Nehiba 2007). Of those receiving ciprofloxacin, none had a symptomatic UTI at the study follow-up visit (3-5 days post urodynamic testing), whereas 3 of 22 study participants (14%) in the placebo group developed a symptomatic UTI. This finding was statistically non-significant (p=0.24), but the trend for reduced UTI incidence and the fact that no subjects in the treatment group actually developed a UTI suggests that a study with greater power may demonstrate the benefit of pre-urodynamic testing prophylaxis more conclusively.

Conflicting results have been obtained across separate controlled trials conducted in individuals undergoing acute SCI inpatient rehabilitation of sustained (i.e., >3 months) prophylaxis with TMP-SMX. Gribble and Puterman (1993) reported that oral administration of a TMP-SMX (40 mg and 200 mg, respectively) formulation once daily was found to significantly reduce frequency and relapse rates of bacteriuria (p=0.0001) and symptomatic UTI (p=0.0003) in persons with recent SCI using intermittent catheterization for bladder management (n=129). Conversely, Sandock et al. (1995) reported on an investigation of patients at least 6 months post-injury within an inpatient SCI rehabilitation program in which the standard of care was to prescribe TMP-SMX liberally as a prophylaxis. This practice was stopped for the purpose of conducting a prospective controlled trial in 1 of 2 units and it was noted that there was no significant difference in the number of symptomatic UTIs between those stopping versus those continuing suppressive therapy (0.043 versus 0.035 UTIs/week; p>0.5). In addition, there was a significant decrease in the emergence of TMP-SMX resistant asymptomatic bacteriuria in the patients stopping suppressing therapy (78.8% versus 94.1%; p<0.05). This latter finding was also consistent with that noted by Gribble and Puterman (1993) who noted this, along with TMP-SMX related adverse events as serious limitations of TMP-SMX prophylaxis therapy. Reid et al. (1994b) also showed an inability of a higher dose of TMP-SMX (160 mg and 800 mg, respectively) to reduce rates of symptomatic UTI among inpatients using intermittent catheterization for bladder management.

Given the conflicting findings noted above and in other patient groups, a novel approach to UTI prevention in SCI patients was undertaken by Salomon et al. (2006). After a prospective, pre-post study with 2-year follow-up, they concluded that a weekly oral cyclic antibiotic (WOCA) program was beneficial in preventing UTI in SCI patients, decreasing antibiotic consumption and decreasing the number and length of hospitalizations, without severe adverse events or the emergence of multi-drug resistant bacteria. The WOCA regimen involved alternating between two antibiotics, administered once per week over at least 2 years. The specific antibiotics selected as prophylaxis were customized to the patient, chosen based on allergy and antimicrobial susceptibility. The most frequent combination of antibiotics utilized were TMP-SMX and cefixime (30%) followed by cefixime and nitrofurantoin (25%). The combination of antibiotics was modified in 40% of the patients once, 20% twice and 10% on three occasions during the follow-up. Salomon et al. (2009) expanded on earlier work specifically to employ a WOCA program in pregnant women with SCI. In this study, UTI rate during pregnancy (which is commonly elevated) was significantly reduced, no complications were observed during delivery, and all newborns were a healthy weight (Salomon et al. 2009). This level 4 evidence for the effectiveness of WOCA in SCI UTI prevention, treatment and cost, and would serve well as guidance in design of a randomized, double-blind, placebo-controlled study to confirm these results.

Conclusion

There is level 1b evidence (from one RCT: Biering Sorensen et al. 1994) that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.

There is level 1b evidence (from one RCT: Gribble & Puterman 1993) that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from two prospective controlled trials (Sandock et al. 1995; Reid et al. 1994b). The potential for emergence of drug resistant bacteria and TMP-SMX related adverse events further limit the potential use of TMP-SMX for prophylaxis.

There is level 4 evidence (from one pre-post study: Salomon et al. 2006) that suggests weekly oral cyclic antibiotic use, customized as to individual allergy and antimicrobial susceptibility, may be effective for UTI prevention in SCI patients, and UTI reduction in pregnant patients.

Ciprofloxacin may be indicated for UTI prophylaxis in SCI but further research is needed to support its use.

Long-term use of TMP-SMX is not recommended for sustained use as a suppressive therapy for UTI prevention.

A weekly oral cyclic antibiotic, customized to the individual, may be beneficial in preventing UTI in SCI.

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