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National Clinical Guideline Centre (UK). Urinary Incontinence in Neurological Disease: Management of Lower Urinary Tract Dysfunction in Neurological Disease. London: Royal College of Physicians (UK); 2012 Aug. (NICE Clinical Guidelines, No. 148.)

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Urinary Incontinence in Neurological Disease: Management of Lower Urinary Tract Dysfunction in Neurological Disease.

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13Treatment to prevent urinary tract infection

Damage to the neurological control system of the LUT leads to a breakdown of the normal micturition cycle so that the protective effect of low pressure storage of sterile urine and complete bladder emptying is disrupted. The patient with neurogenic lower urinary tract dysfunction (NLUTD is at increased risk of urinary tract infection (UTI) as a result of a variety of factors which include incomplete bladder emptying, vesico-ureteric reflux and the use of catheters (Esclarin De Ruz et al., 2000, Journal of Urology, 164, 1285–9).

For many patients with NLUTD, a UTI will be associated with a few days of ill health and urinary symptoms that might include pain, increased frequency and worsening incontinence. However, recurrent UTIs are frequently seen in this population of patients and can impact greatly on quality of life and in MS may lead to neurological deterioration. Even more significant is the risk of serious complications from UTI. Renal damage can be a further complication particularly in those with detrusor overactivity, detrusor sphincter dyssynergia and vesico-ureteric reflux. Such renal scarring can be seen in all age groups of patients with neurogenic LUT dysfunction but is a particular concern in infants and children 200. Renal injury can also be seen in association with infection-related stones.

The goal of reducing both the frequency and severity of UTIs can be achieved in some patients by general measures such as increasing fluid intake and attention to hygiene in relation to urinary tract management. Investigations may demonstrate treatable causes for repeated UTIs such as the presence of urinary tract stones or incomplete bladder emptying.

The use of prophylactic long-term antibiotic administration against UTI in those with neurogenic LUT dysfunction has been widely used in the past. However, questions have now been raised about the efficacy of such regimes and furthermore, the emergence of multi-drug resistant bacteria is becoming a major world-wide health concern; reducing non-essential antibiotic usage is a key strategy in combating this threat. It is therefore important to reassess the place of antibiotic prophylaxis regimes in the management of neurogenic LUT dysfunction.

13.1. Antibiotics

13.1.1. Do prophylactic antibiotics compared with a) no treatment b) other antibiotic reduce the risk of symptomatic urinary tract infections?

Clinical Methodological Introduction
Population:Neurological disease
Intervention:Prophylactic antibiotics
Comparison:Other antibiotic (strategies)
No treatment
Outcomes:Symptomatic urinary tract infections (UTIs)
Adverse events

We searched for RCTs evaluating the effectiveness of prophylactic antibiotics for prevention of symptomatic urinary tract infections (UTI) in patients with neurological disease or injury. We looked for any RCT studies that compared the effectiveness of prophylactic antibiotics with other antibiotics or no treatment.

13.1.1.1. Clinical Evidence Review

Thirteen RCTs were found that dealt with prophylaxis of symptomatic UTIs in neurological patients. Three were cross-over trials (Biering-Sorensen 1994201, Duffy 1982202, Schlager, 1998203), and the rest were parallel trials.

Three studies compared continuation of prophylaxis to discontinuation (Clarke 2005204, Sandock 1995205, Zegers 2011206), whilst the rest compared new prophylaxis with placebo or no treatment. No studies made comparisons with other antibiotics.

Studies were primarily stratified into those involving adults or children. There were four studies in children (Johnson 1994207, Clarke 2005204, Schlager, 1998203 Zegers 2011206), all of which were clinically homogenous in terms of all addressing prophylaxis of UTIs in congenital neurological conditions. However there was methodological heterogeneity, in that Clarke 2005204 and Zegers 2011206 looked at continuation of prophylaxis to discontinuation, whilst the other two studies looked at new prophylaxis versus no prophylaxis. Analysis was therefore carried out according to those categories.

In contrast, the nine adult studies were clinically heterogeneous. Six studies dealt with prophylaxis of UTIs in new spinal cord injury (SCI) cases (Anderson 1980208, Gribble 1993209, Lindan 1984210, Maynard 1984211, Mohler 1987212, Sandock 1995205). Furthermore, within these six studies, there was methodological heterogeneity, as one (Sandock 1995205) looked at continuation of prophylaxis to discontinuation, while the rest looked at new prophylaxis compared to no prophylaxis.

The other three adult studies dealt with other clinical categories, although all looked at new prophylaxis compared to no prophylaxis. They were:

  • Darouiche 1994 (213) which involved prophylaxis before urodynamics,
  • Biering-Sorensen 1994201 which involved prophylaxis for established neurological cases with a history of recurrent UTIs, and
  • Duffy 1982202 which dealt with prophylaxis for neurogenic bladder clinic patients.

Analyses were therefore separated for these main categories. This information is summarised in table 108.

Table 108. Characteristics of the included studies [IC=Intermittent catheterisation. SCI=Spinal Cord Injury].

Table 108

Characteristics of the included studies [IC=Intermittent catheterisation. SCI=Spinal Cord Injury].

Comparison of prophylactic antibiotics to no prophylactic antibiotics
Narrative summary (for outcomes that are not appropriate for GRADE due to incomplete outcome reporting)
Incidence of symptomatic UTI
Adults- new SCI cases (new prophylaxis)

Maynard 1984211 presented data on the episodes of symptomatic UTI in a parallel group study. They reported one episode of symptomatic UTI in the prophylaxis group, and 7 in the control group.

Mohler 1987212 reported the infection rate of symptomatic UTIs arising in the prophylaxis and placebo groups. The prophylaxis group had 1.11 infections/100 days at risk, while the placebo group had 1.86 infections/100 days at risk.

Adults- new SCI cases (continuation versus discontinuation)

In a continuation versus non-continuation study, Sandock 1995205 reported the mean number of symptomatic UTIs per week per person, with 0.043 in the group continuing with prophylaxis and 0.035 in the discontinuation group. The difference was reported as non-significant.

Adults – established neurological cases with recurrent UTIs

Biering –Sorensen 1994201 measured the episodes of symptomatic UTI in their prophylaxis and placebo groups over the 12 months of the study, and reported 5 episodes in the Ciproflaxin prophylaxis group compared to 59 in the placebo group. This difference was reported as highly statistically significant (p<0.00005).

Adverse events
Children – new prophylaxis v no prophylaxis

Schlager 1998203 observed that carriage of klebsiella/pseudomonas lasted significantly longer in the antibiotic group, lasting for a total of 140 subject-weeks out of a possible total of 330 in the antibiotic group and 43 subject-weeks out of a possible total of 330 in the control group.

Adults- new SCI cases (continuation versus discontinuation)

In a continuation versus non continuation study, Sandock 1995205 reported the percentage of cultures resistant to trimethoprim-sulphamethoxazole as 42.5% in the prophylaxis group and 37.5% in the discontinuation group. This difference was reported as non-significant.

Adults – established neurological cases with recurrent UTIs

Biering –Sorensen 1994201 measured the number of episodes of both antibiotic-resistant and antibiotic-sensitive infection (>105 pathogens/ml ) of 22 different types of bacteria in the ciprofloxacin and placebo groups. Overall, the ciprofloxacin group had 19 episodes of resistant infection compared to 17 episodes of sensitive infection, whilst the placebo group had 15 episodes of resistant infection compared to 94 episodes of sensitive infection. No statistical analysis was performed. Although the ratio of resistant to sensitive episodes was far greater in the ciprofloxacin group, the actual number of resistant episodes was similar across the groups.

Adults - neurogenic bladder clinic patients

Duffy 1982202 reported on the numbers of episodes of bacterial resistance (in patients who had bacteriuria) to four separate classes of antibiotics. No significant differences between groups were reported. The results, which are expressed as a proportion of those with bacteriuria, are summarised in Table 109.

Table 109. Bacterial resistances as reported by Duffy 1982.

Table 109

Bacterial resistances as reported by Duffy 1982.

13.1.1.2. Economic evidence

Literature review

No relevant economic evaluations comparing prophylactic antibiotics with usual care or no prophylactic antibiotics were identified.

Unit costs

In the absence of recent UK cost-effectiveness analysis, relevant unit costs are provided in Table 110 to aid consideration of cost-effectiveness.

Table 110. Unit costs.

Table 110

Unit costs.

13.1.1.3. Evidence Statements

Clinical Evidence Statement
Comparison between prophylactic antibiotics to no prophylactic antibiotics
Incidence of symptomatic UTIs
Children – new prophylaxis v no prophylaxis

2 studies comprising 142 participants (6 to 11 months) found that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the incidence of symptomatic UTIs (very low quality)

Children – continuation v no continuation

2 studies comprising 229 participants (4 to 18 months) found that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the incidence of symptomatic UTIs (very low quality)

Adults - new SCI cases

3 studies comprising 217 participants (3 to 4 months) found that prophylactic antibiotics led to a statistically significant reduction in incidences of symptomatic UTIs compared to no prophylaxis (moderate quality)

Adults - prior to urodynamic testing

1 study comprising 40 participants (18 months) found that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the incidence of symptomatic UTIs (very low quality)

Adverse events- resistance
Adults - new SCI cases

1 study comprising 126 (4 months) participants found that that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the adverse event of greater bacterial resistance (moderate quality).

Adverse events- GI disturbance
Adults - new SCI cases

1 study comprising 132 participants (4 months) found that that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the adverse event of GI disturbance (very low quality).

Adverse events- skin or soft tissue infection
Adults - new SCI cases

1 study comprising 126 participants (4 months) found that that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the adverse event of skin or soft tissue infection, although there was a weak trend (p=0.19) towards a benefit for prophylaxis (low quality).

Adverse events- pseudomonas colonisation
Adults - new SCI cases

1 study comprising 62 participants (3 months) found that that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the adverse event of pseudomonas colonisation(very low quality).

Adverse events- skin rash
Adults - new SCI cases

1 study comprising 126 participants (4 months) found that that there was no statistically significant difference between prophylactic antibiotics and no prophylactic antibiotics for the adverse event of skin rash (very low quality).

i. Other outcomes for which evidence statements could not be produced

Evidence statements could not be produced for the following outcomes of the study by Biering – Sorensen 1994201 as results were presented in a way that meant we could not estimate the size of the intervention effect :

  • Incidence of symptomatic UTIs
  • Resistance

Evidence statements could not be produced for the following outcomes of the study by Sandock 1995205 as results were presented in a way that meant we could not estimate the size of the intervention effect :

  • Incidence of symptomatic UTIs
  • Pseudomonas colonisation

Evidence statements could not be produced for the following outcomes of the study by Maynard 1984211 as results were presented in a way that meant we could not estimate the size of the intervention effect :

  • Incidence of symptomatic UTIs

Evidence statements could not be produced for the following outcomes of the study by Mohler 1987212 as results were presented in a way that meant we could not estimate the size of the intervention effect :

  • Incidence of symptomatic UTIs

Evidence statements could not be produced for the following outcomes of the study by Duffy 1982202 as results were presented in a way that meant we could not estimate the size of the intervention effect :

  • Resistance
Economic evidence statements
  • If effective, prophylactic antibiotics will be either cost saving or close to cost neutral and if they are currently over prescribed, then any reduction in use will be also be cost saving.

13.1.2. Recommendations and links to evidence

Recommendations:TREATMENT TO PREVENT URINARY TRACT INFECTION
51.

Do not routinely use antibiotic prophylaxis for urinary tract infections in people with neurogenic lower urinary tract dysfunction.

52.

Consider antibiotic prophylaxis for people who have a recent history of frequent or severe urinary tract infections.

53.

Before prescribing antibiotic prophylaxis for urinary tract infection:

  • investigate the urinary tract for an underlying treatable cause (such as urinary tract stones or incomplete bladder emptying)
  • take into account and discuss with the person the risks and benefits of prophylaxis
  • refer to local protocols approved by a microbiologist or discuss suitable regimens with a microbiologist.
54.

Ensure that the need for ongoing prophylaxis in all people who are receiving antibiotic prophylaxis is regularly reviewed.

55.

When changing catheters in patients with a long-term indwelling urinary catheter:

  • do not offer antibiotic prophylaxis routinely
  • consider antibiotic prophylaxisn for patients who:
    -

    have a history of symptomatic urinary tract infection after catheter change or

    -

    experience traumao during catheterisation.

    [This recommendation is from ‘Infection: prevention and control of healthcare-associated infections in primary and community care’ (NICE clinical guideline 139).]
Relative value placed on the outcomes consideredSymptomatic urinary tract infections are a major clinical problem both in terms of the impact of symptoms on the patient and, in some cases, the risk of progression to severe sepsis
The GDG recognised the world-wide concerns that exist in relation to the increasing problem of bacterial antibiotic resistance. This issue necessitates the need for balancing the potential for benefit from antibiotic use in the individual patient with the requirement for adherence with the public health strategy to control the spread of antibiotic-resistant organisms.
Quality of evidenceThe evidence was assessed to be moderate, low or very low quality. The studies that addressed the question were carried out before antibiotic resistance became a critical issue. The lack of recent high quality studies on this issue was felt to be a major concern.
There was a notable absence of studies looking at the use of prophylaxis in high-risk patient groups, such as those with frequent urinary tract infections.
In children, the four studies that were included in the evidence review all involved patients with congenital neurological conditions. Three studies were prone to bias due to limitations in their design but Zegers was of higher quality206.
The nine studies that were included in the review and looked at an adult population were graded between moderate and very low in quality. They found that, for adults with new spinal cord injuries, prophylactic antibiotics led to a reduction in the incidence of symptomatic UTIs. This conclusion was based on a meta-analysis graded as moderate in quality for these outcomes, but it was noted that some studies which were not included in the meta-analysis did not reach a similar conclusion.
Trade-off between clinical benefits and harmsFor individual patients the reduction in the frequency of symptomatic urinary tract infections can be a major benefit. In some cases urinary tract infection can be life threatening and any reduction in such episodes will be of major importance.
For the large majority of patients the use of antibiotic prophylaxis is a benign intervention that is not associated with troublesome complications. However, the widespread use of antibiotics is known to be associated with the development of antibiotic resistance which is a risk both to individual patients and to the wider population.
It is also recognised that the use of prophylactic antibiotics can be associated with serious complications. For example Nitrofurantoin use can be associated with the development of pulmonary, neurological and hepatic disease.
The GDG agreed from the limited evidence presented, and their own clinical experience, prophylactic antibiotics should not be routinely prescribed. They also agreed that frequent urinary tract infections could have a significant impact on the quality of life for a patient, and acknowledged the associated risks of serious complications, such as renal damage, that may warrant the use of this treatment in some circumstances.
Economic considerationsThe GDG was of the opinion that there is currently an over use in the frequency of the prescription of antibiotics for the prophylaxis of UTIs in patients with neurogenic LUT dysfunction. The clinical evidence shows that there is no benefit to prescribing prophylactic antibiotics routinely. However, this evidence is highly uncertain. If antibiotics were indeed effective, perhaps in the longer term, then the low cost of prophylactic antibiotics compared with the relatively high cost of a hospital admitted UTI is probably favourable. The cost of a normal course of antibiotics and the cost of a doctor’s appointment for the treatment of a UTI is also similar to the price of prophylactic antibiotics. This means that if effective, they will be cost saving or at least cost neutral. If they are currently over prescribed then, any reduction in use will be cost saving.
Other considerationsThe GDG recognised that many patients with NLUTD will have permanent urinary tract colonisation with bacteria and that asymptomatic bacteriuria should not, in general, be treated. Furthermore, in some cases, it can be difficult to determine whether an active infection is present because symptoms are not always directly attributable to the urinary tract; a judgement may have to be made as to whether non-specific symptoms are present as a result of UTI.
The difficulty in diagnosing UTI is compounded by the problems that are associated with the laboratory interpretation of urine samples in some patients with NLUTD. For example, the use of intermittent or indwelling catheters can lead to the presence of bacteruria and pyuria which might be of no clinical significance. These difficulties not only create problems in clinical practice but present challenges to those who are conducting research in this field. The importance of providing the microbiology department with correctly taken samples and appropriate clinical information was emphasised by the GDG.
The GDG recognised the importance of avoiding inappropriately prolonged antibiotic prophylaxis. There was low quality evidence in children to suggest that discontinuing treatment may be beneficial rather than harmful. Long term prophylactic antibiotics may promote antibiotic resistance.
n

At the time of publication (August 2012), no antibiotics had a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the GMC’s ‘Good practice in prescribing medicines – guidance for doctors’ for further information.

o

The GDG for ‘Infection: prevention and control of healthcare-associated infections in primary and community care’ defined trauma as frank haematuria after catheterisation or two or more attempts of catheterisation.

13.1.3. Research recommendations

Treatment to prevent urinary infection
4.

In people with neurogenic lower urinary tract dysfunction, which management strategies (including the use of prophylactic antibiotics and various invasive and non-invasive techniques to aid bladder drainage) reduce the risk of symptomatic urinary tract infections?

  • Why this is important
    Recurrent urinary tract infections in people with neurogenic bladder dysfunction are a cause of considerable morbidity. Urinary tract infections may exacerbate incontinence, cause symptoms of malaise and may progress to involve the upper urinary tract with possible loss of renal function. In the population with neurological diseases such as multiple sclerosis, Parkinson’s disease and dementia, the rise in temperature with urinary tract infections can cause deterioration in neurological function and even a relapse of multiple sclerosis. There are therefore numerous reasons why people with neurogenic lower urinary tract dysfunction should avoid urinary tract infections.
    The causes for the high prevalence of urinary tract infections in such people include loss of physiological bladder function and high intravesical pressures. Intermittent or permanent catheterisation inevitably exacerbate the problem, but incomplete bladder emptying is also a predisposing factor for urinary tract infections.
    Research in this area is faced with methodological difficulties, not least because it may be difficult to distinguish between bladder colonisation (asymptomatic bacteriuria) and true infection.
    In view of the considerable clinical burden of urinary tract infections and the global problem of antibiotic resistance, it is important to establish whether or not any infection prevention strategies, including patient training or the provision of information relating to prophylactic antibiotics are effective in reducing symptomatic urinary tract infections.
Copyright © 2012, National Clinical Guideline Centre.

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