(Chest. 2004;126:1628-1635.)
© 2004
American College of Chest Physicians
In Vitro Exposure of Bacteria to Antimicrobial Impregnated-Central Venous Catheters Does Not Directly Lead to the Emergence of Antimicrobial Resistance*
Erik L. Munson, PhD;
Stephen O. Heard, MD, FCCP and
Gary V. Doern, PhD
* From Medical Sciences Laboratories (Dr. Munson), Wauwatosa, WI; Department of Anesthesiology (Dr. Heard), University of Massachusetts Medical School, Worcester, MA; and Division of Medical Microbiology (Dr. Doern), Department of Pathology, University of Iowa College of Medicine, Iowa City, IA.
Correspondence to: Stephen O. Heard, MD, FCCP, Department of Anesthesiology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655; e-mail: stephen.heard{at}umassmed.edu
 |
Abstract
|
|---|
Objective: Use of central venous catheters (CVCs) impregnated with minocycline and rifampin reduces the density of bacterial growth on catheters and decreases the incidence of catheter-related bloodstream infections. Questions have been raised over the possibility that the use of these catheters will lead to the emergence of antibiotic-resistant organisms. In this study, we sought to determine if in vitro exposure of four test organisms to catheter segments impregnated with minocycline and rifampin would lead to the development of antibiotic resistance.
Methods: Catheter segments (1.0 cm) were placed on the surface of agar plates previously inoculated with bacterial suspensions, such that a subconfluent lawn of colony growth would be apparent after 24 h incubation at 35°C in air. Test organisms included American Type Culture Collection strains of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. Zones of inhibition of colony growth surrounding catheters were measured at 24-h intervals up to 7 days (two catheter segments per test). Colonies on agar surfaces located at varying distances from catheter segments were examined for minocycline and rifampin resistance following various periods of exposure (six catheter segments per test). In addition, selected colonies were subsequently exposed to minocycline and rifampin in broth and examined for selection of minocycline and rifampin resistance (> 28 colonies per selection test).
Results: Inhibitory zones of 14 to 47 mm were observed with S aureus, S epidermidis, E faecalis, and E coli. Growth of P aeruginosa was not inhibited by CVC segments. Testing of colonies of the first four organisms at various distances from CVC segments after varying periods of exposure revealed only a single instance of the emergence of resistance (eg, S aureus vs rifampin). Recovery of resistant clones was enhanced with minocycline and rifampin broth selection; however, a direct link between CVC exposure and the emergence of resistance was not established.
Conclusions: Our in vitro data suggest that the exposure of Gram-positive cocci to either rifampin or minocycline can lead to the development of resistance. However, exposure of bacteria to these antibiotics in combination does not directly lead to resistance. Clinical investigations will be required to determine the true risk and implications of the development of resistance.
Key Words: antibiotic-impregnated catheters • antimicrobrial resistance • catheter-related infection • minocycline • rifampin
|
Introduction
|
|---|
Catheter infection continues to be a significant problem for the critically ill patient. In the United States, the annual incidence of catheter-related bloodstream infection (CRBSI) occurring in the ICU has been estimated to be 80,000/yr.1 The economic consequences are profound: the average cost of a CRBSI is >$30,000.2 Proven strategies to reduce the risk of such infections include the use of maximum barrier precautions, chlorhexidine-based skin preparations, catheter dressings with chlorhexidine-impregnated sponges, and antiseptic- or antibiotic-impregnated catheters.345678 Despite the proven clinical efficacy of catheters impregnated with minocycline and rifampin, many clinicians are reluctant to use these catheters because of concern for the selection of resistance to either or both agents. Indeed, one in vitro study9 suggested that multiple passages of Staphylococcus epidermidis in subinhibitory concentrations of a minocycline and rifampin combination led to the development of resistance as evidenced by increased minimum inhibitory and bactericidal concentrations of the antibiotic combination.
The purpose of this investigation was to determine if exposure of Gram-positive and Gram-negative bacteria to central venous catheters (CVCs) impregnated with minocycline and rifampin was capable of selecting for resistance to either or both antibiotics. Permutations of an agar-based inhibition assay as well as a broth selection assay were employed in an attempt to recover clonal populations resistant to minocycline and/or rifampin.
|
Materials and Methods
|
|---|
Organisms
Isolates from stock cultures of Pseudomonas aeruginosa (American Type Culture Collection [ATCC] 27853), Staphylococcus epidermidis (ATCC 12228), Staphylococcus aureus (methicillin susceptible; ATCC 29213), Escherichia coli (ATCC 25922), and Enterococcus faecalis (ATCC 29212) were propagated on trypticase soy agar with 5% defibrinated sheep blood (blood agar; Remel; Lenexa, KS) in 35°C ambient air.
Catheter Segments
Triple-lumen polyurethane CVCs impregnated with minocycline and rifampin (Spectrum; Cook Critical Care; Bloomington, IN) were used. The distal 20-cm portion of each catheter was aseptically sectioned into 1-cm segments in a biological safety cabinet using sterile forceps and scissors. A single 1-cm segment per sectioned catheter was placed into tryptic soy broth (TSB) [Remel], and incubated as a sterility check.
Subconfluent Distribution of Microorganisms
Suspensions of test bacteria were adjusted to a 0.5 McFarland turbidity standard in sterile 0.85% saline solution. Subsequent dilutions resulted in concentrations of bacteria that produced a subconfluent distribution of isolated colony forming units following inoculation of 15 x 100-mm Mueller Hinton agar plates (Remel), and overnight incubation in 35°C ambient air. Previous experimentation showed that 200 cfu of P aeruginosa, 1,250 cfu of S epidermidis, 400 cfu of S aureus, 400 cfu of E coli, and 2,000 cfu of E faecalis resulted in a subconfluent colony distribution.
Solid Medium Assessment of Resistance Induction
Segments of minocycline and rifampin-impregnated CVCs were aseptically placed in the center of Mueller Hinton agar inoculated with a subconfluent distribution of bacteria. Inhibition zone diameters (in millimeters) perpendicular to the long axis of the antimicrobial-impregnated CVC segment, as described by Sherertz et al,10 were measured with a dial-type vernier caliper (Fisher Scientific; Pittsburgh, PA) on day 3 and day 7 of incubation in 35°C ambient air.
Isolated colonies were labeled at the border of the zone of inhibition (proximal colony forming unit), 1 cm away from the inhibition zone border (medial colony forming unit), and 2 cm away from the inhibition zone interface (distal colony forming unit). In addition, S epidermidis colonies were labeled at the inhibition zone border and at 0.75-cm increments from the leading edge of the zone. Portions of all labeled colony forming units were sampled at 24 h, 48 h, and 72 h of incubation and subcultured onto blood agar. Following 72 h of incubation, colonies observed to have formed within the zone of inhibition following initial delineation of the inhibition zone were selected and subcultured. Following overnight incubation, aliquots of multiple cultivated colony forming units were frozen at – 70°C.
Broth Medium Assessment of Resistance Induction
Subconfluent growth of S epidermidis, S aureus, E coli, and E faecalis were incubated overnight with minocycline and rifampin-impregnated CVC segments as previously described. Isolates were collected at random distances from the segment and inoculated into individual tubes of TSB (Fig 1
). After 18- to 24-h incubation in 35°C ambient air, tubes were vortexed and aliquots (100 µL) of growth from a single tube were dispensed into a 5-mL tube of TSB and into 5-mL tubes of TSB containing a 30-µg minocycline disk (Remel), or a 5-µg rifampin disk (Remel). Tubes were incubated 18 to 24 h in 35°C ambient air. Contents were subcultured onto blood agar, incubated overnight in 35°C ambient air, with aliquots of multiple colony forming units frozen at – 70°C for future analysis.
Disk Diffusion Testing
Frozen aliquots were cultivated on blood agar 18 to 24 h in 35°C ambient air. Multiple representative colony forming units were suspended in 0.85% saline solution, adjusted to a 0.5 McFarland turbidity standard, and inoculated onto 15 x 100 mm Mueller Hinton agar plates. Minocycline (30 µg) and rifampin (5 µg) disks were placed onto the plates. Plates were incubated 18 to 24 h in 35°C ambient air. Inhibition zone diameters were measured three times, and the mean and SEM values were computed.
Temporal Potency Assessment of CVCs Impregnated With Minocycline and Rifampin
A minocycline and rifampin-impregnated CVC segment was inoculated onto a subconfluent distribution of P aeruginosa. Following 24-h incubation in 35°C ambient air, the segment was transferred to fresh Mueller Hinton agar inoculated with a subconfluent distribution of S epidermidis. Following 7-day incubation in 35°C ambient air, the resulting zone of S epidermidis growth inhibition was measured. The same CVC segment was subsequently transferred onto Mueller Hinton agar inoculated with a fresh subconfluent lawn of S epidermidis. Measurements were recorded in relation to the age of the antimicrobial-impregnated CVC segment at the day of inoculation (ie, 7 days prior to growth inhibition determination). The weekly cycle was repeated for a 64-day life span of the catheter segment.
Statistical Analysis
Differences in rates of resistance for isolates subjected to broth selection or for those incubated in the presence of antimicrobial-impregnated CVC segments were analyzed by the significance test of proportions. Differences in temporal potency of antimicrobial-impregnated CVC segments were tested by two-way analysis of variance, utilizing the Minitab statistical analysis program (Minitab; State College, PA). The Fisher least-significant-difference test was used to examine pairs of means when a significant F ratio indicated reliable mean differences. The 
level was set at 0.05 before the experiments were started.
|
Results
|
|---|
Growth Inhibition by CVCs Impregnated With Minocycline and Rifampin
Minocycline and rifampin-impregnated CVC segments caused variable degrees of growth inhibition of S epidermidis, S aureus, E coli, and E faecalis (Table 1
). In contrast, P aeruginosa was not inhibited by the antimicrobial-impregnated CVC segment. With the exception of E coli, no significant differences in mean diameters of inhibition zone were noted when day 3 measurements were compared to day 7 data.
View this table:
[in this window]
[in a new window]
|
Table 1. Inhibition Zone Diameters Resulting From Subconfluent Lawns of Microorganisms Subjected to Minocycline and Rifampin-Impregnated CVC Segments (Two Catheter Segments Per Test)*
|
|
Resistance Induction Assays on Solid Medium
S epidermidis, S aureus, E coli, and E faecalis colony forming units located at a variety of distances from CVC segments impregnated with minocycline and rifampin were sampled every 24 h for 3 days. Subsequent disk diffusion testing of these isolates generally failed to demonstrate the emergence of resistance to minocycline or rifampin either as a function of the duration of exposure or proximity to the antimicrobial-impregnated CVC (Table 2
). However, 1 cfu of S aureus collected from a proximal site following 24-h exposure demonstrated a decreased minocycline inhibition zone size on disk diffusion testing and yielded a colony within the inhibition zone of rifampin. The colony within the rifampin inhibition zone was not inhibited by rifampin on secondary disk diffusion testing.
View this table:
[in this window]
[in a new window]
|
Table 2. Diameters of Minocycline and Rifampin Inhibition, Following Disk Diffusion Testing, of Subconfluent Growth of S epidermidis, S aureus, E coli, and E faecalis Obtained at Various Temporal Intervals From Varying Distances Relative to That of CVC Segments Impregnated With Minocycline and Rifampin (Six Catheter Segments per Time Period)*
|
|
Rifampin Resistance Induction Assays in Broth Medium
Exposure of S epidermidis, S aureus, and E faecalis to rifampin broth resulted in statistically significant increased rates of decreased susceptibility to rifampin based on disk diffusion testing (Table 3
). However, the emergence of resistance was independent of prior exposure to minocycline and rifampin-impregnated CVCs. Approximately 75% of S aureus recovered from rifampin broth following past exposure to antimicrobial-impregnated CVC segments demonstrated decreased rifampin susceptibility compared to 89.3% of S aureus recovered from rifampin broth without previous exposure to such segments (p = 0.121). Similarly, 21.3% of S aureus recovered after exposure to minocycline and rifampin-impregnated CVC segments without broth selection showed decreased susceptibility to rifampin, compared to 10.7% of S aureus isolates not exposed to such agents (p = 0.24). A significant difference in decreased rifampin susceptibility (p = 0.045) was noted in E coli isolates recovered without previous exposure to CVC impregnated with minocycline and rifampin.
View this table:
[in this window]
[in a new window]
|
Table 3. Rates of Decreased Rifampin Susceptibility of Isolates of S epidermidis, S aureus, E coli, and E faecalis That Were Exposed or Not Exposed to Minocycline and Rifampin-Impregnated CVC Segments and Subsequently Subjected to Rifampin Broth Selection*
|
|
Minocycline Resistance Induction Assays in Broth Medium
Exposure of E faecalis to minocycline broth resulted in increased rates of reduced susceptibility to minocycline (Table 4
). No isolate exposed to control broth exhibited decreased susceptibility to minocycline (p < 0.001). This phenomenon was also independent of exposure to CVCs impregnated with minocycline and rifampin, as 57.1% of E faecalis recovered from minocycline broth without past exposure to such CVCs showed decreased susceptibility to minocycline when compared to isolates with previous exposure to antimicrobial-impregnated CVCs (p = 0.8). Isolates of S epidermidis and S aureus failed to demonstrate significant minocycline resistance, while E coli isolates failed to develop minocycline resistance following either antimicrobial broth selection or exposure to CVCs impregnated with minocycline and rifampin.
View this table:
[in this window]
[in a new window]
|
Table 4. Rates of Decreased Minocycline Susceptibility of Isolates of S epidermidis, S aureus, E coli, and E faecalis That Were Exposed or Not Exposed to Minocycline and Rifampin-Impregnated CVC Segments and Subsequently Subjected to Minocycline Broth Selection*
|
|
Temporal Efficacy of CVC Segments Impregnated With Minocycline and Rifampin
When three minocycline and rifampin-impregnated CVC segments from separate Mueller Hinton agar plates incubated 24 h with subconfluent growth of P aeruginosa were transferred onto individual Mueller Hinton agar plates inoculated with a fresh subconfluent distribution of S epidermidis, significant inhibition of S epidermidis was observed after 7-day incubation. Growth of P aeruginosa was also observed to radiate from the CVC segments. Serial weekly transfers of these CVC segments continued to inhibit fresh subconfluent distributions of S epidermidis. Approximately 50% of the original potency was demonstrated with 29-day-old CVC segments impregnated with minocycline and rifampin (Fig 2
), while such segments lost nearly 90% of their in vitro potency by day 57 (Fig 2). Control experiments showed no inhibition of fresh subconfluent distributions of S epidermidis in the presence of a focal pencil-streak inoculum of P aeruginosa ATCC 27853 without a CVC segment (data on file). Two-way analysis of variance demonstrated no differences in potency of a given antimicrobial-impregnated CVC segment across the duration of the experiment (p = 0.61).
View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2. Temporal relative potency of three individual serially transferred CVC segments impregnated with minocycline and rifampin (solid shapes, dashed lines) to inhibit separate fresh sub confluent lawns of S epidermidis. Mean potency indexes are represented by open squares (solid line).
|
|
|
Discussion
|
|---|
The major finding of this study is that catheters impregnated with minocycline and rifampin do not appear to select for resistance among those bacteria that are responsible for the majority of catheter-related infections. Our in vitro data demonstrate that neither distance from the catheter nor duration of exposure to the catheter results in the reliable selection of significant antimicrobial resistance. Bacteria incubated in the presence of minocycline and rifampin-impregnated CVC segments were subcultured in the presence of minocycline or rifampin in an attempt to increase the yield of clones resistant to either of these agents. Steps were taken in these experiments to minimize the chances of selecting for resistance due to sources of minocycline and rifampin outside of the antimicrobial-impregnated CVC segment. Exposure to these antimicrobials was always followed by cultivation of microorganisms in conditions devoid of the antimicrobials. In addition, frozen aliquots of harvested isolates were cultivated on blood agar plates before disk diffusion testing.
Use of a broth selection method resulted in the recovery of clones with decreased susceptibility to either minocycline or rifampin. Nonetheless, there were no differences in the percentage of resistant isolates following exposure to the antibiotic-impregnated catheters and subsequent incubation in antimicrobial broth compared to isolates incubated in broth only. Indeed, isolates of E coli recovered after rifampin selection actually showed a lower proportion of altered rifampin susceptibility patterns following minocycline/rifampin catheter exposure, compared to isolates without such exposure.
There are emerging clinical data supportive of our findings. In a prospective study, Chatzinikolaou et al11 determined that short-term dialysis catheters impregnated with minocycline and rifampin were effective in reducing catheter infections compared to control catheters. Of note, analyses of coagulase-negative staphylococci cultured from both coated and uncoated catheters failed to reveal any difference in susceptibility of the bacteria to either minocycline or rifampin. Hanna et al12 found that the use of minocycline and rifampin-impregnated catheters decreased the incidence of vancomycin-resistant enterococcal CRBSI compared to control catheters. These findings provide additional indirect evidence that these catheters do not contribute to the development of bacterial resistance.
In contrast, our findings are at odds with other investigations evaluating the development of resistance using antibiotic-coated catheters. Tambe et al9 examined the effect of 10 to 20 passages of cultures of three different strains of S epidermidis against subinhibitory concentrations of minocycline, rifampin, or both. They found that there was no significant increase in the minimum inhibitory concentration (MIC) to minocycline after 20 passages, but there was a 25,000-fold increase in the rifampin MIC and a 10-fold increase in the antibiotic combination MIC after 10 to 20 passages. Although we did find an increased percentage of isolates with resistance to either antibiotic after the broth selection experiments, no evidence for selection could be ascertained with the antibiotic combination. Differences in methodology most likely account for the divergent results.
CVC segments impregnated with minocycline and rifampin produce appreciable inhibition of S epidermidis, S aureus, E coli, and E faecalis growth. However, the catheters were ineffective against P aeruginosa. Furthermore, presence of viable P aeruginosa following serial passages of individual minocycline and rifampin-impregnated CVC segments that were capable of inhibiting subconfluent preparations of S epidermidis suggests direct adherence of P aeruginosa to the CVC segments. This lack of susceptibility of P aeruginosa to CVCs impregnated with minocycline and rifampin is contrary to previous findings1314 that demonstrated significant inhibition zones when such catheter segments were incubated with confluent distributions of four clinical isolates of P aeruginosa. In contrast, our data confirm those of Sampath et al,15 who demonstrated that the minocycline/rifampin catheters had no effect on P aeruginosa growth.
Mutations resulting in minocycline and rifampin resistance occur at a frequency of 10-6.1617 Furthermore, published resistance rates to the tetracyclines and rifampin remain relatively low for most clinically significant Gram-positive cocci, especially staphylococci.181920 For example, rates of S aureus resistance to rifampin have been documented by surveillance studies1920 at 2 to 3%. In contrast, the rate of decreased rifampin susceptibility for S aureus following rifampin broth selection was 75 to 90% in this investigation. The increased prevalence of Gram-positive cocci with decreased susceptibility to minocycline or rifampin was more likely due to resistance induction via the broth rather than more efficient recovery of constitutive-resistant clones.
Raad et al13 used an in vitro assay to demonstrate a 25-day half-life for CVCs impregnated with minocycline and rifampin. Similarly, Bach et al21 reported on significant potency retention for antiseptic-impregnated CVCs. The representative CVC segments impregnated with minocycline and rifampin in this investigation retained nearly all of their original potency following 1 week of incubation, and at least 50% of original potency at an in vitro age of 4 weeks (even when coated with an apparent biofilm of P aeruginosa). These findings are in agreement with those of Marik et al,22 who conducted an ex vivo study of antimicrobial activity of the minocycline/rifampin catheters.
In conclusion, CVCs impregnated with minocycline and rifampin do not directly select for resistance to these agents. However, exposure to either agent in broth resulted in significant percentages of Gram-positive clones with decreased susceptibility to either minocycline or rifampin. Further clinical investigations will be required to determine with certainty whether or not these antibiotic-coated catheters predispose to the development of resistance.
|
Footnotes
|
|---|
Abbreviations: ATCC = American Type Culture Collection; CRBSI = catheter-related bloodstream infection; CVC = central venous catheter; MIC = minimum inhibitory concentration; TSB = tryptic soy broth
Dr. Heard has received financial support for research and honoraria for lectures from Cook Critical Care.
Minocycline-rifampin impregnated catheters were provided by Cook Critical Care.
Received for publication January 7, 2004.
Accepted for publication June 17, 2004.
|
References
|
|---|
- Mermel, LA (2000) Prevention of intravascular catheter-related infections. Ann Intern Med 132,391-402[Abstract/Free Full Text]
- Digiovine, B, Chenoweth, C, Watts, C, et al The attributable mortality and costs of primary nosocomial bloodstream infections in the intensive care unit. Am J Respir Crit Care Med 1999;160,976-981[Abstract/Free Full Text]
- Raad, II, Hohn, DC, Gilbreath, BJ, et al Prevention of central venous catheter-related infections by using maximal sterile barrier precautions during insertion. Infect Control Hosp Epidemiol 1994;15,231-238[ISI][Medline]
- Maki, DG, Mermel, LA, Kluger, D, et al The efficacy of a chlorhexidine-impregnated sponge (Biopatch) for the prevention of intravascular catheter-related infection: a prospective, randomized, controlled, multicenter study. Presented at: 40th Inter-science Conference on Antimicrobial Agents and Chemotherapy 2000 . Toronto, Canada: September 17–20,
- Maki, DG, Ringer, M, Alvarado, CJ Prospective randomized trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet 1991;338,339-343[CrossRef][ISI][Medline]
- Maki, DG, Stolz, SM, Wheeler, S, et al Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter: a randomized, controlled trial. Ann Intern Med 1997;127,257-266[Abstract/Free Full Text]
- Darouiche, RO, Raad, II, Heard, SO, et al A comparison of two antimicrobial-impregnated central venous catheters. Catheter Study Group. N Engl J Med 1999;340,1-8[Abstract/Free Full Text]
- Raad, I, Darouiche, R, Dupuis, J, et al Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections: a randomized, double-blind trial. The Texas Medical Center Catheter Study Group. Ann Intern Med 1997;127,267-274[Abstract/Free Full Text]
- Tambe, SM, Sampath, L, Modak, SM In vitro evaluation of the risk of developing bacterial resistance to antiseptics and antibiotics used in medical devices. J Antimicrob Chemother 2001;7,589-598
- Sherertz, RJ, Forman, DM, Solomon, DD Efficacy of dicloxacillin-coated polyurethane catheters in preventing subcutaneous Staphylococcus aureus infection in mice. Antimicrob Agents Chemother 1989;33,1174-1178[Abstract/Free Full Text]
- Chatzinikolaou, I, Finkel, K, Hanna, H, et al Antibiotic-coated hemodialysis catheters for the prevention of vascular catheter-related infections: a prospective, randomized study. Am J Med 2003;115,352-357[CrossRef][ISI][Medline]
- Hanna, HA, Raad, II, Hackett, B, et al Antibiotic-impregnated catheters associated with significant decrease in nosocomial and multidrug-resistant bacteremias in critically ill patients. Chest 2003;124,1030-1038[Abstract/Free Full Text]
- Raad, I, Darouiche, R, Hachem, R, et al The broad-spectrum activity and efficacy of catheters coated with minocycline and rifampin. J Infect Dis 1996;173,418-424[ISI][Medline]
- Raad, I, Darouiche, R, Hachem, R, et al Antibiotics and prevention of microbial colonization of catheters. Antimicrob Agents Chemother 1995;39,2397-2400[Abstract]
- Sampath, LA, Tambe, SM, Modak, SM In vitro and in vivo efficacy of catheters impregnated with antiseptics or antibiotics: evaluation of the risk of bacterial resistance to the antimicrobials in the catheters. Infect Control Hosp Epidemiol 2001;22,640-646[CrossRef][ISI][Medline]
- Sande, MA The use of rifampin in the treatment of nontuberculous infections: an overview. Rev Infect Dis 1983;5(suppl 3),S399-S401
- Mandell, GL The antimicrobial activity of rifampin: emphasis on the relation to phagocytes. Rev Infect Dis 1983;5(suppl 3),S463-S467
- Jones, RN Contemporary antimicrobial susceptibility patterns of bacterial pathogens commonly associated with febrile patients with neutropenia. Clin Infect Dis 1999;29,495-502[ISI][Medline]
- Fluit, AC, Jones, ME, Schmitz, FJ, et al Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Europe from the SENTRY antimicrobial surveillance program, 1997 and 1998. Clin Infect Dis 2000;30,454-460[CrossRef][ISI][Medline]
- Fluit, AC, Wielders, CL, Verhoef, J, et al Epidemiology and susceptibility of 3,051 Staphylococcus aureus isolates from 25 university hospitals participating in the European SENTRY study. J Clin Microbiol 2001;39,3727-3732[Abstract/Free Full Text]
- Bach, A, Schmidt, H, Bottiger, B, et al Retention of antibacterial activity and bacterial colonization of antiseptic-bonded central venous catheters. J Antimicrob Chemother 1996;37,315-322[Abstract/Free Full Text]
- Marik, PE, Abraham, G, Careau, P, et al The ex vivo antimicrobial activity and colonization rate of two antimicrobial-bonded central venous catheters. Crit Care Med 1999;27,1128-1131[CrossRef][ISI][Medline]
This article has been cited by other articles:
|
|
|
|
 
H. Hanna, P. Bahna, R. Reitzel, T. Dvorak, G. Chaiban, R. Hachem, and I. Raad
Comparative in vitro efficacies and antimicrobial durabilities of novel antimicrobial central venous catheters.
Antimicrob. Agents Chemother.,
October 1, 2006;
50(10):
3283 - 3288.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
Abstract
Introduction
