In Vitro Comparison of Nitrofurazone- and Silver Alloy-Coated Foley Catheters for Contact-Dependent and Diffusible Inhibition of Urinary Tract Infection-Associated Microorganisms

Abstract

Two marketed antimicrobial-coated Foley catheters were compared for in vitro diffusible and contact-dependent inhibition of 11 urinary tract infection-associated microorganisms in an adherence-biofilm assay. Nitrofurazone-coated catheters significantly outperformed silver alloy-coated catheters for inhibitory activity, according to both inoculum broth and catheter sonicate counts, whether compared directly or against the corresponding control catheters. Although inhibition waned with catheter preincubation in saline, some organisms were inhibited even after a 48-h catheter preincubation, especially by the nitrofurazone-coated catheter.

TEXT

Foley catheters unfortunately promote microbial colonization of the urinary tract (17, 20). Although such colonization is usually asymptomatic, it can lead to symptomatic urinary tract infection (UTI), increased costs, prolonged hospital stays, and a reservoir of resistant microorganisms (17). It also triggers unnecessary antimicrobial use, with attendant costs and harms (3). Therefore, prevention of catheter-associated bacteriuria/funguria is important for improving patient safety and reducing health care costs (9, 15, 18).

Antimicrobial-coated Foley catheters are intended to lower the risk of catheter-associated bacteriuria/funguria (5, 9, 13). The available devices use as antimicrobial coatings nitrofurazone (a nitrofurantoin congener) or various silver compounds. Clinical trials have documented short-term efficacies for both catheter types against bacteriuria/funguria, with the nitrofurazone catheter appearing more efficacious (versus control) in recent studies (5, 13). However, no published trial has directly compared different antimicrobial-coated catheters.

We showed previously, using an agar plate-based assay, that the nitrofurazone-coated catheter inhibits many UTI-associated microorganisms (10) and that against certain multidrug-resistant variants its effect is more potent and durable than a silver alloy-coated catheter's (11). Subsequently, using a novel biofilm-based assay, we documented superiority for the nitrofurazone-coated catheter over two silver alloy-coated catheters, specifically against cephalosporin-resistant Escherichia coli (12). Here, we used this biofilm-based assay to compare nitrofurazone and silver alloy-coated catheters against a broader array of urine organisms.

Isolates.

Eleven urine isolates were obtained from the VA Medical Center Clinical Microbiology Laboratory; these isolates represented the 11 species stipulated by the U.S. Food and Drug Administration as relevant for testing of antimicrobial urological devices (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080884.htm; last updated 6/18/2009; last accessed 2/12/2012). These included 6 Gram-negative species, i.e., Citrobacter koseri (formerly C. diversus), Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. They also included 4 Gram-positive species, i.e., Enterococcus (formerly Streptococcus) faecalis (vancomycin susceptible), Enterococcus (formerly Streptococcus) faecium (vancomycin resistant), Staphylococcus aureus (methicillin resistant), and Staphylococcus saprophyticus, plus Candida albicans. Isolates were selected without regard for patient clinical status, urinary catheter use, or (with the exception of the Enterococcus spp. and S. aureus) susceptibility profile.

Nitrofurantoin and silver susceptibility.

Nitrofurantoin susceptibility was assessed by disk diffusion, using the conditions and interpretive criteria specified by the Clinical and Laboratory Standards Institute (2). Silver ion susceptibility was assessed similarly, using sterile filter paper disks inoculated with either 7 μg AgNO₃ or an equimolar amount of NaNO₃.

Catheters.

The four studied Foley catheters included a nitrofurazone-coated all-silicone catheter plus a comparable all-silicone control catheter, both manufactured by Rochester Medical Group, and a silver alloy-coated, latex-hydrogel catheter plus a comparable latex-hydrogel control catheter, both manufactured by C. R. Bard, Inc. (12). The study sponsor (Rochester Medical Group) provided the nitrofurazone-coated and silicone control catheters. The silver alloy-coated and latex-hydrogel catheters were purchased from a hospital supply distributor.

Catheters were cut into 4-cm segments, which were gas sterilized by using ethylene oxide. Only the antimicrobial-coated portions of the test catheters, and corresponding regions of the control catheters, were used.

Adherence assay.

A bioassay system that measures both contact-dependent and diffusible inhibition was used (12). Briefly, sterilized catheter segments were bent into a U shape and attached to a gas-sterilized armature (a tissue culture tray lid fitted with mounting pegs), which allowed submersion of each segment's 3.4-cm-long central region in a suspension of the test organism in a tissue culture well. (Suspensions were turbidity adjusted to 0.5 McFarland standard and then diluted 1:150 in 10% Mueller-Hinton broth; final cell density was approximately 1 × 10⁶ CFU/ml, per quantitative culture.) After overnight incubation with organisms, catheter segments were rinsed to remove nonadherent organisms and then sonicated to release adherent organisms for quantitative culture, in order to assess contact-dependent inhibition. Inoculum broths also underwent quantitative culture, to assess diffusible inhibition. Biological duplicates were done for each set of conditions and catheter type. Quantitation was by triplicate plating of serial dilutions of each inoculum broth (pre- and postcatheter incubation) and catheter sonicate.

Statistical methods.

Paired comparisons, matched by microbial species, of viable counts in inoculum broths and catheter sonicates were made between each antimicrobial catheter and the corresponding control catheter and between the competing antimicrobial catheters, using the Wilcoxon rank sum test. The differences in log₁₀ microbial counts (“delta”) between each antimicrobial catheter and its control catheter, as calculated separately for inoculum broths and catheter sonicates, were similarly compared between the two antimicrobial catheters. Results from all 11 microbial species were analyzed collectively. The significance criterion was a P value of <0.05.

Susceptibility to nitrofurans and silver.

Five (45%) of the 11 test organisms were resistant to nitrofurantoin, including C. albicans, E. faecium, K. pneumoniae, P. mirabilis, and P. aeruginosa. With AgNO₃-impregnated disks, 10 (91%) of the organisms yielded inhibition zones of 8 to 11 mm diameter, whereas E. cloacae showed no inhibition. No organism exhibited inhibition by NaNO₃.

Antimicrobial-coated catheters versus controls.

Viable counts in inoculum suspensions after overnight incubation with catheter segments were significantly lower for the nitrofurazone-coated catheter relative to its control (median decrease, >6 log₁₀ CFU/ml; P = 0.001), but not for the silver alloy-coated catheter relative to its control (P > 0.10) (Fig. 1). Similarly, viable counts released by sonication were lower for the nitrofurazone-coated catheter than its control for 10 (94%) of 11 test organisms (median decrease, >2 log₁₀ CFU/ml; P = 0.001), but they were slightly higher for the silver alloy-coated catheter compared to its control for 7 (64%) of 11 test organisms (P > 0.10).

Fig 1.

In vitro inhibitory activities of antimicrobial-coated and control Foley catheters against diverse uropathogens. Results are shown as log₁₀ CFU/ml values for inoculum broths (left) and catheter sonicates (right), after overnight incubation of catheter segments in broth suspensions containing each of the 11 test organisms (as listed in the key). (Top panel) No preincubation of catheter segments prior to assay setup (day 0 [d0]). (Middle and bottom panels) Preincubation of catheter segments in saline for 24 h (middle, d1) or 48 h (bottom, d2) prior to assay setup. (A) Comparisons of nitrofurazone-coated silicon catheters and noncoated silicone control catheters. (B) Comparisons of silver alloy-coated latex-hydrogel catheters and latex-hydrogel control catheters. Arrowheads, group medians. Colored lines (solid or dashed) connect the results for a particular test organism obtained with the antimicrobial-coated catheter (left) and corresponding control catheter (right). P values are shown where P was <0.05. Abbreviations: HG, hydrogel coated; MRSA, methicillin-resistant Staphylococcus aureus; NF, nitrofurazone coated; silver, silver alloy coated; VRE, vancomycin-resistant Enterococcus; VSE, vancomycin-susceptible Enterococcus.

Direct comparisons between antimicrobial-coated catheters.

Absolute viable counts were significantly (or borderline significantly) lower for the nitrofurazone-coated catheter than the silver alloy-coated catheter in both inoculum broths (P = 0.01) and catheter sonicates (P = 0.07) (Fig. 1). Likewise, in comparisons between the 2 antimicrobial-coated catheters for the viable count difference (delta value) between each test catheter and control, the nitrofurazone-coated catheter significantly outcompeted the silver alloy-coated catheter, in both inoculum broths (median delta, 5.3 versus 0.3 log₁₀ units; P = 0.005) and catheter sonicates (median delta, 2.1 versus −0.1 log₁₀ units; P = 0.04).

Durability of effect.

Repetition of these procedures using catheter segments preincubated for 24 h or 48 h in 12 ml sterile saline (replaced daily) yielded no statistically significant viable count differences. However, some organism-specific inhibition was evident, particularly for S. saprophyticus, which consistently exhibited lower catheter sonicate counts with antimicrobial (especially nitrofurazone)-coated catheters than the control (Fig. 1).

Comment.

In this in vitro assessment of two marketed antimicrobial-coated Foley catheters for inhibition of diverse UTI-associated organisms, the nitrofurazone-coated catheter consistently outperformed the silver alloy-coated catheter for both diffusible and contact-dependent inhibition. Likewise, after extended incubation in saline, although neither antimicrobial-coated catheter significantly inhibited the test organisms overall, some organism-specific inhibition was apparent, especially with the nitrofurazone-coated catheter. These findings confirm and extend previous in vitro assessments of these two antimicrobial catheters (4, 8, 11, 12).

Our previous study using the same adherence-based assay system found minimal to no evidence of inhibition of cephalosporin-resistant E. coli by the silver alloy-coated catheter, whereas the nitrofurazone-coated catheter was highly active (12). Although these findings conflicted with earlier reports of decreased adherence of various organisms to the silver alloy-coated catheter (1, 6, 7), they supported our earlier finding from an agar diffusion assay that indicated that the silver alloy-coated catheter was inactive against Gram-negative bacilli generally (11). The results were also in agreement with another laboratory's recent report of minimal to no activity of the silver alloy-coated catheter against either E. coli or Enterococcus in a similar contact-dependent assay system (4). Here, we show that the silver alloy-coated catheter's net absence of contact-dependent inhibition extends to UTI-associated organisms in general, especially Gram-negative bacilli (13).

Unsurprisingly, the various test organisms responded differently to the antimicrobial catheters. This variability was only partly explained by differences in in vitro susceptibilities to nitrofurantoin or silver ion, the catheters' presumed active components. Perhaps other physico-chemical aspects of these catheters influence their inhibitory effects, as proposed for the hydrogel coating on the silver alloy-coated and latex control catheter (4).

Previous in vitro studies have consistently found waning inhibition by the nitrofurazone-coated catheter over time, presumably from progressive depletion of the elutable drug reservoir. Here, this drop-off was more rapid than observed previously, for unclear reasons. How long the nitrofurazone catheter retains inhibitory activity on its luminal (urine-exposed) versus external (minimally fluid-exposed) surfaces during in vivo use warrants empirical assessment. Notably, in one clinical trial the nitrofurazone-coated catheter reduced bacteriuria risk over the first week of use (14). Additionally, in an artificial bladder model, this catheter prevented bacterial ingress during daily “meatal” challenge for up to 21 days, versus only 1.2 days for the silver alloy-coated catheter (8). These findings suggest that the rapidly declining activity we observed in vitro may not apply in vivo.

Our challenge inoculum greatly exceeds the microbial burden that indwelling catheters face initially when microorganisms enter a sterile drainage system or catheter-urethral interface, where a small number of cells initiate the colonization/infection process (19). Therefore, recovery of test organisms from nitrofurazone-coated catheter segments incubated overnight in high-density inoculum suspensions does not mean that the catheter would fail to maintain sterility if challenged with a smaller inoculum. The substantial (median, >2 log₁₀) protective effect observed with the nitrofurazone-coated catheter, compared with no significant inhibition with the silver alloy-coated catheter, provides important proof of principle.

A potential drawback to antimicrobial catheters is selection for resistance to the active ingredient. Here, this concern seems more hypothetical than real, since silver is not used therapeutically, and exposure of microbial populations to nitrofurans should be much less with intraurethral use than with systemic nitrofurantoin therapy, which is common. Additionally, acquired nitrofuran resistance among uropathogens remains rare (16), despite decades of nitrofurantoin use.

Study limitations include the artificiality of the assay system, use of a single isolate for each species, and uncertain clinical relevance of in vitro inhibitory activity. Strengths include the biofilm-based assay system, inclusion of 11 relevant species, and use of multiple approaches to compare the two antimicrobial-coated catheters.

In summary, we found a marked in vitro difference between the nitrofurazone- and silver alloy-coated Foley catheters for potency of diffusible and contact-dependent inhibition against diverse UTI-associated microorganisms, with only the nitrofurazone-coated catheter exhibiting significant activity. This suggests that the nitrofurazone-coated catheter should be more effective clinically for preventing catheter-associated bacteriuria/funguria. A head-to-head clinical trial of the two catheter types is needed to test this hypothesis, which has important implications for patient safety and health care costs.