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editorial
. 1999 Nov;43(11):2819–2821. doi: 10.1128/aac.43.11.2819

Silver-Containing Polymers

Jörg Michael Schierholz 1,2, Joseph Beuth 1,2, Gerhard Pulverer 1,2, Dietmar-Pierre König 1,2
PMCID: PMC89571  PMID: 10651621

LETTER 1

We read with interest about the investigations of Kampf et al. (2) concerning the antimicrobial activity of a new silver-containing polymer. The use of silver may be regarded as an effective non-resistance-inducing strategy to prevent device-related infections. In vitro and in vivo experiments have been performed during the recent years to develop potent antimicrobially acting silver-coated devices. Most of the authors claimed strong antimicrobial efficacy of silver-coated devices, and the industry launched several products on the market. However, randomized clinical studies showing statistically significant antimicrobial efficacy of silver-coated medical devices in high-risk populations of patients are rare, dealt with small numbers of patients only, and are controversial (6). The largest randomized controlled clinical study with 1,300 patients revealed no significant differences in infection rates between silver-coated and unmodified catheters (4), a finding which is in accordance with the observations made by Kampf et al. (2).

How does silver work? The silver cation (Ag+) is a highly reactive chemical structure which binds strongly to electron donor groups containing sulfur, oxygen, or nitrogen. Biological molecules generally contain all these components in the form of thio, amino, imidazole, carboxylate, and phosphate groups. Silver ions act by displacing other essential metal ions such as Ca2+ or Zn+. The binding of silver ions to bacterial DNA (3) may inhibit a number of important transport processes, such as phosphate and succinate uptake, and can interact with cellular oxidation processes as well as the respiratory chain. The Ag+-induced antibacterial killing rate is directly proportional to Ag+ concentrations, typically acting at multiple targets. The higher the silver ion concentration, the higher the antimicrobial efficacy. The release rate of unbound, free silver ion may also be correlated to the antimicrobial activity of thus-coated devices.

Kampf et al. neutralized the silver catheter by 5% horse serum. Recently, we showed decreased activity of silver ions as a result of the addition of albumin and NaCl to broth (5). MICs and minimal bactericidal concentrations (MBCs) for the bacterial strains tested (Escherichia coli ATCC 11229, Staphylococcus aureus ATCC 6538, and Staphylococcus epidermidis DSM 3269) increased with the addition of albumin to Mueller-Hinton (MH) broth, especially for MH broth containing albumin and NaCl (from 1 to 10 mg/ml). Very high MBCs were also observed for Ag ions in bovine serum (50-fold the broth MBC). This may be in accordance with the findings of Williams and Williams (7) who showed by microautoradiography that 3 mol of silver ions is bound specifically by 1 mol of albumin.

In an in vitro experiment, bacterial adhesion on polymeric devices was investigated in the presence of albumin and NaCl at physiological concentrations. Central venous catheters (nonimpregnated, aliphatic polyurethane, 1.7-mm diameter; B. Braun, Melsungen, Germany) were cut under sterile conditions into 1-cm pieces. These pieces were transferred into bacterial suspension (≈106 CFU/ml; E. coli ATCC 11229, S. aureus ATCC 6538, or S. epidermidis DSM 3269), remaining there for 2 h at 37°C. Afterwards, the catheter pieces were transferred into MH broth containing silver nitrate (for E. coli, 32 μg/ml; for S. aureus and S. epidermidis, 256 μg/ml), albumin (0.2%), and NaCl (0.9%).

Contaminated catheter pieces were incubated for 24 or 48 h at 37°C. Thereafter, the catheter segments were removed by means of sterile forceps, rinsed for 30 s under running tap water, transferred individually into 1 ml of physiological saline (containing 0.1% polysorbate 80), and agitated vigorously for 60 s. After agitation, the saline was diluted 1:10 or 1:100, and appropriate volumes of each dilution were pipetted onto the surface of tryptic soy agar supplemented with 5% sheep blood and incubated aerobically for 48 h at 37°C. After each incubation period grown colonies were counted and the number of adherent bacteria on catheter segments was calculated.

After 48 h of incubation, bacterial counts on the catheter surfaces were less than that for the control without silver nitrate but still measurable (Fig. 1).

FIG. 1.

FIG. 1

Bacterial adhesion on polymeric surfaces in the presence of highly toxic and bactericidal concentrations of silver nitrate (for E. coli, 32 μg/ml; for S. aureus and S. epidermidis, 256 μg/ml). The broth (0.2% albumin, 0.9% NaCl) remained sterile after 24 h, whereas adherent bacteria survived.

There is no doubt that silver ions are remarkably active against a broad spectrum of bacteria. However, in an environment containing albumin and halide ions, the antibacterial activity of silver ions will be decreased as a result of specific absorption to albumin and precipitation into insoluble silver chloride crystals. Once attached to catheters, colonizing bacteria remain viable despite exposure even to high concentrations of antimicrobial substances (1). Therefore, silver-coated devices like those investigated by Kampf et al. may be clinically effective only when the concentration of free silver ions can be increased and when contact with albumin and Cl ions, as well as possible cytotoxic effects, is minimized. For reproducible inactivation of silver derivates we would like to recommend the addition of albumin (0.2%) and physiological NaCl (0.9%) to fluid as well as solid media.

REFERENCES

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Antimicrob Agents Chemother. 1999 Nov;43(11):2819–2821.

LETTER 2

Ronald S Scharlack 1

My principal concerns with the study by Kampf et al. (1-4) are the lack of references to previously published testing of SPI-ARGENT II materials, the testing methodology selected, and the sweeping conclusion.

SPI-ARGENT II is a long-term surface treatment intended to reduce thrombus formation and colonization of and adhesion to medical devices by potentially pathogenic microorganisms. Since SPI-ARGENT II is intended to prevent device-related infection, its effectiveness is targeted towards microorganism adhesion and proliferation as opposed to suppression of a widespread infection.

The effectiveness of SPI-ARGENT II has been demonstrated with both clinical studies (1-1, 1-2) and in vivo animal models. Based on their limited and inappropriate in vitro tests, Kampf et al. draw the dramatic conclusion that “Its value for clinical use appears to be doubtful.” Their conclusion ignores the published clinical data demonstrating effectiveness of SPI-ARGENT II for dialysis catheters, the shortcomings of their in vitro experiment in modeling in vivo results, and their own acknowledgment that “…the adhesive effect of the polymer surface for bacteria and fungi is of importance…” even though they “…did not investigate the adhesive effect of SPI-ARGENT II…”

Any in vitro test intended to predict device-related infection in a clinical setting should simulate the steps that occur during initial adhesion and proliferation of microorganisms prior to colonization of a device. This sequence begins with the exposure of a sterile device to a small concentration of organisms. Measurement of the relative number of organisms which adhere to and colonize treated versus untreated devices provides a suitable means of comparison. An appropriate test should measure only organisms attached to the device.

In the experiments described by Kampf et al. the investigators applied between 1 × 106 and 2 × 107 organisms to the test surface. This high initial concentration of organisms differs from the typical sequence that leads to device colonization in vivo. It is unrealistic to expect a nonantibiotic surface treatment, whose primary function is to prevent bacterial adhesion and colonization, to be effective in such a test.

In an example of an appropriate in vitro test, Biedlingmaier et al. (1-3) studied bacterial adhesion and biofilm growth on ion-implanted tympanostomy tubes. After immersion for 5 days in inoculated, nutrient-rich media, tubes were rinsed and evaluated for presence of adherent bacteria. These investigators found that, the three microorganisms evaluated (Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis) readily colonized untreated tubes with dense biofilms. Ion-implanted tubes, on the other hand, were free of bacterial contamination.

The inappropriateness of the testing used by Kampf et al. is indicated by the authors’ own acknowledgment that “Lower inocula may yield very different results and allow for differentiation.”

The positive results from previous studies of SPI-AGRGENT II effectiveness stand in stark contrast to the results of the study by Kampf et al.

REFERENCES

  • 1-1.Bambauer R, Mestres P, Schiel R, Sioshansi P. New surface treatment technologies for catheters used for extracorporeal detoxification methods. Dial Transplant. 1995;24:228–237. [Google Scholar]
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  • 1-4.Kampf G, Dietze B, Große-Siestrup C, Wendt C, Martiny H. Microbicidal activity of a new silver-containing polymer, SPI-ARGENT II. Antimicrob Agents Chemother. 1998;42:2440–2442. doi: 10.1128/aac.42.9.2440. [DOI] [PMC free article] [PubMed] [Google Scholar]
Antimicrob Agents Chemother. 1999 Nov;43(11):2819–2821.

AUTHOR’S REPLY

Günter Kampf 1,2, Beate Dietze 1,2, Constanze Wendt 1,2, Heike Martiny 1,2, Christian Große-Siestrup 1,2

We thank the authors of the two letters for the critical comments on our article.

The aim of our study was to investigate only the microbicidal activity of the silver-treated polymer as we outlined in the introduction. The ability of the polymer to reduce thrombus formation and adhesion was not the purpose of the investigation. That is why we are unable to assess these potential qualities of the polymer. The criticism of the test method by R. S. Scharlack is surprising to us because most in vitro methods of demonstrating a lethal effect require a high inoculum in the United States as well as in Europe, e.g., testing the bactericidal activity of antiseptic products for hands. A reduction in the number of viable organisms by 5 log10 units within a given exposure time is usually necessary to demonstrate microbicidal activity. Therefore, a high inoculum is justified and is not inappropriate for testing as R. S. Scharlack tries to imply. Critical evaluation of product claims by the manufacturer is in our opinion the more appropriate way to deal with scientific data.


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