The 11 reports (1 of which described 2 trials) included 7 full articles (14, 23-27, 32), 1 letter (28), and 3 abstracts (29-31). The 12 trials provided analysis of a total of 13 319 participants or catheters. Of these, 3 trials (1 conventional RCT and 2 quasi-randomized trials [621 total participants]) assessed nitrofurazone-coated silicone catheters (27, 30, 32) and 9 trials (6 conventional RCTs, 2 quasi-randomized trials [1739 total participants] [23-26, 28, 29, 31], and 1 cluster randomized trial [11 032 catheters] [14]) assessed silver-coated latex catheters. None assessed silver-coated silicone catheters.

Study Characteristics

The 12 studies differed considerably for several characteristics, including locale, study sample, design, methods, and definition of catheter-associated bacteriuria (Tables 1 and 2). For example, 5 studies involved primarily urologic patients, 2 other studies involved nonurologic surgery patients, 4 studies included a mixture of medical and surgical patients, and 1 study included medical patients only. Men constituted 56% to 100% of participants. Typically, patients were eligible for inclusion and were randomly assigned if they were candidates for indwelling urinary catheters. Prerandomization and postrandomization exclusion criteria varied by study. Postrandomization exclusions were common in studies that reported them, involving from 21% to 27% of randomly assigned participants. Reasons for postrandomization exclusion included bacteriuria at the time of initial catheterization (most trials), antimicrobial agent therapy during catheter use (3 trials), and catheter care violations (1 trial). Only 2 trials were double-blinded. Investigators collected urine samples daily, on alternate days, or as desired, whereas the criterion for catheter-associated bacteriuria ranged from at least 10⁵ colony-forming units per L to at least 10⁸ colony-forming units per L (10 trials) or involved a combination of variables (2 trials) (33). The cumulative incidence of bacteriuria was variously assessed at 1 fixed interval or more after catheter insertion or over the total duration of catheterization. Many studies either reported several of these aspects unclearly or did not report them at all. Although all 12 trials were described as randomized, 4 trials allocated treatment according to alternate patients or week.

Prevention of Catheter-Associated UTI or Bacteriuria

No report directly addressed the primary outcome of symptomatic UTI. Accordingly, we limited our analyses to secondary outcomes. The 12 studies varied greatly in the incidence of catheter-associated bacteriuria in the control group (range, 3.4% to 53.0%) and in the estimated effect size for proportion developing catheter-associated bacteriuria, with risk ratios (for test catheter vs. control) ranging from 0.08 to 0.94 and absolute risk reduction values ranging from 0.5% to 32% (Table 2). Although point estimates consistently favored the antimicrobial catheter, the 95% CIs included 1.0 for 7 studies (including the 6 most recent studies). Of note, no trial reported an intention-to-treat analysis. Instead, patients who had bacteriuria at the time of catheter insertion or who met various other exclusion criteria usually were ignored in efficacy estimates.

Effect of Study Characteristics

To explore the basis for the observed heterogeneity of effect, we compared outcomes with study characteristics. The 3 nitrofurazone catheter trials, all published after 1995, yielded risk ratios ranging from 0.08 to 0.68 (median, 0.54) and absolute risk reduction values of 3% to 12% (median, 7%) (Figure 2). The 2 largest of these trials involved general medical–surgical patient samples and reported similar results for risk ratio (0.54 and 0.68, respectively) and absolute risk reduction (3% and 7%, respectively). The 9 silver catheter trials segregated naturally by publication date and locale, since the 4 pre-1995 trials were from the same institution and investigator group, whereas the 5 post-1995 trials were from diverse institutions and investigators. The pre-1995 silver catheter trials yielded lower risk ratios than the post-1995 trials (0.24 to 0.44 [median, 0.32] vs. 0.53 to 0.94 [median, 0.84]; P = 0.002) and higher absolute risk reduction values (13% to 32% [median, 28%] vs. 0.5% to 6% [median, 3%]; P < 0.001). Of note, the 3 post-1995 silver catheter trials that involved general medical–surgical patients yielded similar risk ratios (range, 0.74 to 0.85 [median, 0.84]) and absolute risk reduction values (range, 0.5% to 5% [median, 2%]).

View larger version (13K): [in this window] [in a new window]   Figure 2. Outcomes (total and stratified) of randomized and quasi-randomized clinical trials of currently marketed antimicrobial urinary catheters. End point is proportion of participants (or catheters) developing catheter-associated bacteriuria. Three trials examined nitrofurazone catheters, 4 pre-1995 trials examined silver-alloy catheters, and 5 post-1995 trials examined silver-alloy catheters. The risk ratio is indicated by the horizontal position of the solid black squares. The 95% CIs around the risk ratios are indicated by the width of the solid lines.

Certain additional study characteristics also predicted outcomes. The apparent protective effect of the test catheter was greater when the control catheter was latex rather than silicone. Likewise, studies involving primarily urologic patients generally yielded larger effect sizes than those involving other types of patients, as did studies that excluded patients receiving antimicrobial agent therapy. Among the silver catheter trials, control group bacteriuria rate corresponded with both effect size (positive trend) and year of publication (negative trend).

In contrast, other study characteristics were less clearly related to outcomes. Effect size did not vary consistently according to type of report, funding source, allocation method, use of blinding, duration of catheterization, bacteriuria definition, or time to outcome assessment, although the power for detecting such effects was limited. Some studies that reported outcomes at several time points had trends toward increases over time in both the risk ratio (suggesting a progressively diminishing effect of the test catheter) and absolute risk reduction (suggesting an increasing cumulative effect of the test catheter). However, these trends were inconsistent, both within and among studies.

Specific Antimicrobial Activity

For 8 trials, available data on the distribution of microorganisms causing catheter-associated bacteriuria permitted an estimate of the effect size for preventing bacteremia-associated gram-negative bacteriuria. The 3 nitrofurazone catheter trials yielded risk ratios of 0.08 (95% CI, 0.00 to 1.33), 0.38 (CI, 0.10 to 1.42), and 1.13 (CI, 0.49 to 2.59), respectively. The latter result was derived from a study in which, exceptionally, most gram-negative isolates were nonfermenters (32), which are intrinsically resistant to nitrofurazone (34). Likewise, for silver-coated catheters, the 3 evaluable pre-1995 trials yielded risk ratios of 0.30 (CI, 0.10 to 0.93), 0.31 (CI, 0.14 to 0.74), and 0.53 (CI, 0.23 to 1.20), respectively, whereas the 2 post-1995 silver catheter trials with specific data yielded risk ratios of 0.36 (CI, 0.10 to 1.28) and 0.82 (CI, 0.61 to 1.11), respectively. A third post-1995 trial found the silver catheter to lack preventive activity against gram-negative bacilli (31).

Adverse Effects

The 7 reports that addressed adverse effects noted few, if any, catheter-attributable complications (Table 1). Three reports stated that the test catheter (nitrofurazone catheter in 1 trial and silver catheter in 2 trials) was well-tolerated, that no urethral irritation occurred, or that both observations applied (29-31). One control participant had penile pain in 1 silver catheter trial (26), and 1 control participant and 6 test catheter participants had a burning sensation (not statistically significant) in a nitrofurazone catheter trial (32). No patient in the latter trial was considered to have UTI. The report that described an absence of urethral irritation also reported UTI as an adverse event in 5 participants (catheter assignment not specified) (29). The meaning of UTI in this context, and how these participants corresponded with the 110 participants who developed bacteriuria, is unclear. Finally, in another trial, approximately 5% of participants in each group developed hematuria while using a silver alloy–coated or latex catheter, although hematuria was not reported as an adverse event (25).

Selection for Resistant Microorganisms

No report described the susceptibility of urine (or other) microbial isolates from participants to the test antimicrobial compound, although 1 abstract mentioned protection against catheter-associated bacteriuria without selection for resistant organisms (31). Among those studies that reported microbiological outcomes by study group, no evidence suggested that test catheter recipients experienced an increased incidence of isolation of specific microbial types that are typically resistant to the antimicrobial compound used.

Other Outcomes

No study directly assessed transmission of resistant microorganisms, costs, or hospital length of stay. One study, of a silver catheter, reported the frequency of presumed secondary bloodstream infection, which was non–statistically significantly higher in the control group (14). Mortality was reported only for the 14 patients with presumed secondary bloodstream infection, 3 of whom died in the hospital; 2 of those deaths may have been related to the bloodstream infection (14). A supplemental source reported that only 1 participant in 2 trials (of 1194 participants) had received a diagnosis of secondary bloodstream infection (5, 30, 31). Finally, 1 trial excluded a control participant and 3 participants with silver catheters from analysis because they died before day 3 (26), whereas in another trial, 22 participants developed pneumonia and 1 participant developed sepsis. Catheter assignment and the relationship (if any) of these complications to the catheter were not reported (29).

Discussion

Top Methods Results Discussion Author & Article Info References

In our systematic review of randomized and quasi-randomized clinical trials of currently marketed antimicrobial urinary catheters, we found minimal data on clinically meaningful end points. However, we found abundant evidence that, in comparison with standard catheters, antimicrobial catheters can prevent or delay the onset of bacteriuria during short-term bladder drainage in selected hospitalized patients. This effect varied substantially among studies in relation to catheter type, year of publication, patient characteristics, and certain other variables, with recent trials of silver alloy–coated catheters suggesting substantially less effect than that observed in earlier trials of silver alloy–coated catheters or in recent nitrofurazone catheter trials. Moreover, given the highly selected study sample, several postenrollment exclusions, and absence of intention-to-treat analyses, many of these efficacy estimates probably represent idealized projections that are unlikely to be realized in practice.

The considerable heterogeneity of effect size among the 9 silver catheter trials could be largely eliminated by stratification according to various study characteristics, including publication year, patient sample, type of control catheter, and control group bacteriuria rate. Most of these variables coalesced around the 4 earliest studies (1986 to 1993), which were from the same institution, were nonblinded, involved the same investigators, assessed mainly urology patients, were relatively small, used latex control catheters, and had high control group bacteriuria rates (23, 24, 28, 29). On the basis of these 4 trials, the authors of a previous meta-analysis and a subsequent cost–benefit analysis concluded that silver alloy–coated catheters are substantially more effective than silver oxide–coated catheters (19) and may be cost-effective (35). However, given the different results obtained in more recent RCTs of silver alloy catheters, the relevance of these 4 early studies to current practice is doubtful, especially for nonurology patients, institutions with low background rates of catheter-associated bacteriuria, and institutions already using silicone catheters or avoiding latex products because of allergy concerns (36-38).

The explanation for the seemingly diminishing efficacy of silver catheters over time is not obvious. Conceivably, any study characteristic that predicted differences in effect size among the silver catheter trials, all of which corresponded with year, could be responsible. One such factor, that is, the secular trend toward decreasing background bacteriuria rates, might reflect changes in practice over time, such as increased antibiotic use or improved catheter maintenance practices. Alternatively, it could reflect recent trials' tendency to use silicone control catheters and to study nonurology patients.

The most recently published comparative trial of an antimicrobial urinary catheter involved more than 3000 patients, but we excluded the trial from our review because of its pre–post study design (39). It showed a non–statistically significant reduction in catheter-associated bacteriuria (risk ratio, 0.85 [CI, 0.69 to 1.06]) and a slight increase in secondary bloodstream infection with a silver-coated silicone catheter compared with a plain silicone catheter (39). These findings, which constitute the only available clinical evidence on silver-coated silicone catheters, are consistent with the results of the post-1995 RCTs of silver-coated latex catheters that we reviewed and conflict with the more favorable results typically reported from recent pre–post trials of silver-coated catheters (40, 41). Conceivably, in some pre–post studies, the silver catheter's apparent benefit was enhanced by an already improving background bacteriuria rate (12, 39, 42); concurrent co-interventions, such as nursing education (42) or replacement of preexisting catheters (43); or patient sample differences between study periods (39).

No trial we reviewed directly compared different antimicrobial catheters. Consequently, possible differences in efficacy between nitrofurazone-coated and silver alloy–coated catheters remain indeterminate, notwithstanding the seemingly superior performance of nitrofurazone catheters in recent trials of either antimicrobial catheter type, separately, over control catheters. For example, for catheter-associated bacteriuria, the risk ratios from the 3 nitrofurazone catheter trials were lower than those from 4 of the 5 (post-1995) silver catheter trials. Likewise, for gram-negative bacteriuria, the median risk ratio among nitrofurazone catheter trials was 0.38, compared with 0.82 among post-1995 silver catheter trials. However, since these differences could reflect differences in study design or patient sample rather than differences between the devices, a head-to-head trial is needed to compare catheter efficacy.

Since the 4 quasi-randomized trials were described as randomized (25, 27, 32), some remaining (ostensibly randomized) trials may also not have been randomized. Nonetheless, in the 4 quasi-randomized trials, the comparison groups seemed fairly well-matched for important clinical characteristics. Exceptions included the skewed sex distribution observed by Lee and colleagues (32) (Table 1). However, sex reportedly was not a statistically significant multivariable predictor of bacteriuria, so this may have been unimportant. In contrast, duration of catheter use, which statistically significantly predicted bacteriuria, was borderline longer in the test catheter group (median, 4.4 days vs. 3.9 days; P = 0.054) (32). This would bias against the nitrofurazone test catheter, thereby strengthening Lee and colleagues' conclusion of catheter efficacy.

Absence of or incomplete allocation concealment or blinding, which characterized most trials, also probably did not detract from validity. Comparison groups, when described, seemed well-matched, and most outcomes were objectively defined on the basis of systematically collected urine samples, largely excluding bias. However, bias could have influenced the results of the large cluster randomized trial, in which clinicians submitted urine samples on an ad hoc basis and the outcome definition incorporated clinicians' treatment decisions. Likewise, nonblinding of assessors in some trials could have biased decisions about postenrollment exclusions.

Indeed, the greatest threat to validity in most studies probably was the use of several preenrollment and postenrollment exclusions, many of which increased the likelihood of finding a treatment effect. This strategy probably led to systematic overestimation of the benefit that users could expect in clinical practice, where precatheterization exclusions would be cumbersome to apply and postcatheterization exclusions would be moot. For example, most trials excluded participants with preexisting bacteriuria from analysis, and thus these patients did not contribute to effect estimates. In practice, however, such patients would receive a catheter, thereby increasing the number needed to treat to prevent the outcome. Likewise, several trials excluded patients who received antimicrobial agent therapy from analysis. Such patients are relatively protected against catheter-associated bacteriuria, so they are less likely to benefit from the antimicrobial catheter. However, in practice, they would receive the catheter, thereby also increasing the number needed to treat. Such effect size-inflating postenrollment exclusions can be dealt with by intention-to-treat analyses, in which all enrolled participants contribute to effect estimates. Likewise, careful accounting for and transparent reporting of preenrollment exclusions are needed to clarify the nature of the study sample for extrapolation to external populations.

Previous calculations of the cost-effectiveness of antimicrobial catheters have assumed greater protective activity for silver catheters, higher background bacteriuria rates, or higher per-episode costs for catheter-associated bacteriuria than recent data support (3, 14, 35, 40, 44). For example, some per-episode cost estimates have assumed 2 to 6 extra hospital days (44), whereas a recent study showed no increase in length of stay (13). Likewise, other models have required, for cost savings, a control bacteriuria rate greater than 15% and a risk ratio less than 0.75 (35), which are values observed in only some post-1995 trials (Figure 2). Revised calculations that incorporate updated cost data and efficacy estimates for both silver and nitrofurazone catheters are needed. According to manufacturers' list prices, an antimicrobial catheter costs $3.56 to $9.71 (that is, 80% to 130%) more than a similar noncoated catheter ($17.14 vs. $7.43 for nitrofurazone, $10.70 vs. $5.89 for Bard silver–latex, $12.80 vs. $7.14 for Bard silver–silicone, and $10.00 vs. $5.25 for Tyco silver–silicone) (actual costs may vary). Of note, the best way to reduce the cost of catheter-associated bacteriuria may be to avoid treating clinically inapparent bacteriuria episodes (12, 13, 41), whereas the best preventive measure may be to reduce unnecessary catheter use (15). Studies assessing the added benefit of antimicrobial catheters in settings that have addressed such practice-related issues are needed.

The available evidence does not allow us to make definitive recommendations for decision makers about the regulation, marketing, purchase, or clinical use of antimicrobial catheters. However, we would tentatively propose the following. First, clinical benefit (especially regarding symptomatic UTI, morbidity, secondary bloodstream infection, and infection control) and cost savings have yet to be demonstrated in a randomized trial with any of these devices and in any patient population. They can be estimated only by extrapolation, for which appropriately conservative cost and efficacy estimates should be used. Second, since clinical trial results with antimicrobial catheters are highly context-dependent, the relevance of a particular trial's results to specific institutions or patients depends greatly on the degree of correspondence between the study and the clinical setting with respect to a range of variables, including study sample characteristics, antimicrobial usage patterns, local catheter use and maintenance practices, background bacteriuria rate, year, baseline catheter type, and the local microflora. Thus, assessments of appropriateness must be individualized, and the available evidence must be scrutinized closely for its applicability. Third, researchers performing trials of antimicrobial catheters should use, and manufacturers should report, intention-to-treat analyses to allow more realistic estimates of the number needed to treat to prevent bacteriuria or secondary bloodstream infection; these data could then be incorporated into cost–benefit analyses. Fourth, prevention of bloodstream infection should be assessed either by an adequately powered multicenter RCT, stratified by center, or, if by extrapolation from data on prevention of catheter-associated bacteriuria, with the use of appropriately conservative estimates for the proportion of bacteriuria episodes that actually produce bloodstream infection. Such estimates should take into account the types of microorganisms that cause secondary bloodstream infection compared with those that are affected by the particular test catheter. Fifth, without a head-to-head trial of nitrofurazone-coated and silver-coated catheters, recommendations about the superiority of 1 catheter are speculative. Although recent trials suggest a greater microbiological effect with the nitrofurazone catheter, particularly in mixed medical–surgical populations, and possibly against gram-negative bacilli (other than nonfermenters), this conclusion awaits direct testing. Finally, since adverse effects from antimicrobial catheters seem sufficiently uncommon, and microbial resistance to the active agents is sufficiently unlikely to emerge to a clinically important degree during catheter use, these considerations need not influence decision making.

Limitations of our analysis are largely related to the poor quality of the available evidence, including uneven study quality and reporting, paucity of studies, small study sizes and heterogeneity, absence of data on clinically meaningful end points or long-term catheter use, and extensive postrandomization exclusions. Possible publication bias could have resulted in overestimates of efficacy, if negative studies remained unpublished. We guarded against this by contacting manufacturers and screening conference proceedings for unpublished trials. Strengths of our study are the inclusion of 3 trials of nitrofurazone catheters that were not included in previous meta-analyses (27, 30, 32), comparisons of study characteristics with outcomes, and attention to organism-specific effects.

In summary, compared with control catheters, antimicrobial urinary catheters can prevent or delay the onset of catheter-associated bacteriuria in selected hospitalized patients. However, the magnitude of this effect varies greatly by catheter type, publication year, and several other variables and has been systematically overestimated in many studies because of dropouts and exclusions. The catheters' effect on morbidity, including bloodstream infection, is not known. Well-designed, adequately powered trials that assess catheter-associated bacteriuria and its associated morbidity, mortality, and costs in appropriate patient populations are needed to clarify the comparative clinical utility and economic value of currently available antimicrobial urinary catheters.