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Antimicrobial Agents and Chemotherapy, February 2002, p. 543-545, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.543-545.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activity of Prosthetic Heart Valve Sewing Cuffs Coated With Minocycline and Rifampin

Rabih O. Darouiche,^1* Vance G. Fowler, Jr.,² Karim Adal,³ Marcia Kielhofner,⁴ David Mansouri,¹ and L. Barth Reller²

Center for Prostheses Infection, Baylor College of Medicine and Veterans Affairs Medical Center,¹ St. Luke's Episcopal Hospital, Houston, Texas 77030,⁴ Duke University Medical Center, Durham, North Carolina 27705,² Cleveland Clinic Foundation, Cleveland, Ohio 44195³

Received 8 February 2001/ Returned for modification 25 August 2001/ Accepted 4 November 2001

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Prosthetic heart valve sewing cuffs coated with minocycline and rifampin exhibited in vitro zones of inhibition against all 52 tested clinical isolates responsible for prosthetic valve endocarditis. An in vitro elution study of these coated sewing cuffs demonstrated residual zones of inhibition against Staphylococcus epidermidis for at least 4 weeks.

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Endocarditis constitutes a relatively uncommon but potentially life-threatening complication of prosthetic heart valves. A comprehensive study with detailed follow-up reported a 3.2 to 5.7% cumulative incidence of prosthetic valve endocarditis (PVE) by 5 years after valve implantation (1). However, this infectious complication is associated with major morbidity and mortality. For instance, the reported mortality rate associated with PVE is 30 to 80% in patients with early-onset infections and 20 to 40% in patients with late-onset infections (13). Moreover, treatment of PVE can be very problematic since almost half of all infected patients may require surgical intervention (14). Although potentially beneficial, the administration of systemic antimicrobial prophylaxis (5) and compliance with the usual infection control measures (7) have not completely eliminated the occurrence of PVE. The problematic and expensive management of PVE has incited keen interest in exploring other novel approaches for the prevention of such a serious infection (6).

Bacterial colonization of the prosthetic heart valve, as with other types of medical devices, is a prerequisite for device-related infection. Thus, inhibition of colonization of prosthetic heart valves may, theoretically, reduce the likelihood of clinical infection. Because infection usually originates at the prosthetic heart valve sewing cuff-tissue interface (3, 12; Y. Terada, T. Mitsui, and T. Yamamoto, Letter, Ann. Thorac. Surg. 58:911, 1994), antimicrobial coating of the sewing cuff may have the potential to prevent endocarditis. The clinical demonstration of the anti-infective efficacy of central venous catheters coated with minocycline and rifampin (2, 9) has encouraged us to study the potential application of this particular coating approach to prosthetic heart valves. It has been previously shown with a rabbit model that the subcutaneously placed fabric of a minocycline-rifampin-coated prosthetic heart valve sewing cuff protects against device colonization with and device-related infection by Staphylococcus aureus, compared with an uncoated fabric (3). In addition to demonstrating in vivo efficacy against such a common pathogen, it is essential that antimicrobial-coated prosthetic heart valve sewing cuffs also provide broad-spectrum and durable activity against most other potential pathogens; otherwise, superinfection may ensue following implantation in patients. Therefore, the two objectives of this in vitro study were to (i) examine the activities of minocycline and rifampin on the surfaces of prosthetic heart valve sewing cuffs against a variety of clinical isolates that had caused PVE in three large, geographically dispersed medical centers and (ii) assess in vitro the durability of the antimicrobial activities of these antimicrobials on sewing cuffs.

(Part of this research was presented at the 38th Annual Meeting of the Infectious Disease Society of America, New Orleans, La., 2000.)

Mechanical CPHV 27 mitral valve sewing cuffs (Sulzer Medica Inc., Austin, Tex.) were used. The sewing cuffs were dipped at 45°C for 1 h in a methanol solution that contained both minocycline (25 mg/ml) and rifampin (40 mg/ml). The coated sewing cuffs were allowed to dry overnight and were then gently rinsed with deionized water. The coated sewing cuffs were then gas sterilized with ethylene oxide. The amounts of minocycline and rifampin that coated the sewing cuffs were determined, in duplicate, by extraction in methanol, followed by injection of aliquots of the extracted antibiotic suspensions into a high-performance liquid chromatography system that has been described previously (10). The amounts of minocycline and rifampin (means ± standard deviations) that coated the sewing cuffs were 40.3 ± 1.8 and 64.9 ± 3.2 mg, respectively.

We studied a collection of 52 blood isolates that had caused PVE and had been stored at Duke University Medical Center, Durham, N.C. (33 isolates), the Cleveland Clinic Foundation, Cleveland, Ohio (13 isolates), and St. Luke's Episcopal Hospital, Houston, Tex. (6 isolates). We assessed the in vitro activities of minocycline and rifampin on the surfaces of sewing cuffs against these 52 clinical isolates by determining the zones of inhibition using the Kirby-Bauer technique (10). Individual organisms were grown in Trypticase soy broth at 37°C for 18 h and then adjusted to a concentration of 0.5 McFarland unit (10⁸ CFU/ml) by using standardized spectrophotometric analysis. A cotton swab was dipped in the bacterial suspension and then rubbed in a streaking fashion across the whole surface of a Mueller-Hinton agar plate. The sewing cuffs were then pressed into the center of the agar plates that had been freshly inoculated with individual organisms. After incubation of the agar plates at 37°C for 24 h, the radius of the clear zone of inhibition from the outer edge of the tested device was determined.

We performed an in vitro elution study to assess the durability of the antimicrobial activities of minocycline and rifampin on the surfaces of sewing cuffs. All determinations in this elution study were based on duplicate samples. Individual sewing cuffs were suspended in fetal bovine serum on a shaker at 37°C for up to 28 days. Serum was replaced daily with fresh fetal bovine serum. The concentrations of minocycline and rifampin in the eluate serum samples were determined daily up to 28 days by using the same previously described high-performance liquid chromatography system (10). The minocycline-rifampin-coated sewing cuffs were also examined for zones of inhibition against Staphylococcus epidermidis (ATCC 35983) at days 0 (baseline), 3, 7, 10, 14, 17, 21, 24, and 28.

Table 1 shows the mean radii of clear zones of inhibition produced by the antimicrobial-coated sewing cuffs. The minocycline-rifampin-coated sewing cuffs produced detectable zones of inhibition against all 52 tested isolates. In general, the mean radii of the clear zones of inhibition were the largest against staphylococci (16 mm for S. aureus and 19 mm for S. epidermidis). To ensure that the observed zones of inhibition around coated cuffs were caused by minocycline and rifampin rather than by something else, we also determined the zones of inhibition around two negative controls: (i) uncoated gas-sterilized sewing cuffs and (ii) sewing cuffs that had been dipped in the same coating solution but not containing minocycline and rifampin and then gas sterilized. Neither of these two negative controls produced zones of inhibition against any of six representative clinical isolates (selected from the 52 isolates listed in Table 1), including S. aureus, S. epidermidis, Enterococcus faecalis, Streptococcus bovis, Enterobacter cloacae, and Candida parapsilosis.

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TABLE 1. In vitro activities of antimicrobial-coated sewing cuffs

The results of the in vitro elution study are summarized in Table 2. Both the highest rate of drug elution from the coated sewing cuffs into serum and the largest drop in the residual radii of the clear zones of inhibition around the coated devices were observed during the first 7 days of device suspension in serum. Thereafter, drug elution from the coated sewing cuffs into serum was relatively minimal and the coated devices maintained rather stable (8- to 11-mm) residual radii of clear zones of inhibition against S. epidermidis (ATCC 35983).

View this table: [in this window] [in a new window]

TABLE 2. In vitro elution study of antimicrobial- coated sewing cuffs

The findings of this in vitro study demonstrated that minocycline-rifampin-coated prosthetic heart valve sewing cuffs provide broad-spectrum activity against pathogens that can potentially cause PVE, including gram-positive cocci, gram-negative bacilli, and yeasts. Minocycline-rifampin-coated vascular (2, 8-10) and urinary (4) catheters have also been reported to have similarly broad-spectrum antimicrobial activities. Although concentrations of minocycline and rifampin in serum that are usually achieved following systemic administration of these two drugs generally provide activity mostly against staphylococci, the local concentrations of minocycline and rifampin on coated surfaces can be high enough to result in activity against some gram-negative bacilli and Candida species.

The results of this in vitro elution study indicated that minocycline-rifampin-coated sewing cuffs provide activity against S. epidermidis for at least 28 days after suspension in serum. Although we intentionally conducted this in vitro elution study under conditions (including body temperature, agitated environment, and frequent replacement of serum) that may somewhat simulate those that exist after intracardiac implantation of antimicrobial-coated sewing cuffs in patients, we admit that these in vitro results do not perfectly reflect clinically achieved findings. For instance, the duration of antimicrobial activity of minocycline-rifampin-coated sewing cuffs may be shorter in patients than what we observed in vitro. However, even if we project that drug elution will occur at a higher rate in patients than in our in vitro system, it is unlikely that patients with implantable antimicrobial-coated sewing cuffs will have therapeutic levels of minocycline and rifampin in serum. Clinical use of similarly coated central venous catheters has not been associated with detectable levels of minocycline and rifampin in serum (9).

The sizes of in vitro zones of inhibition of antimicrobial-coated vascular catheters can well predict clinical anti-infective efficacy (2, 9, 11). We do not know whether a similar correlation may also apply to antimicrobial-coated sewing cuffs. The findings of this in vitro elution study suggest that minocycline-rifampin-coated sewing cuffs may serve primarily to protect the prosthetic heart valve from perioperative contamination and early-onset transient bacteremia. These antimicrobial-coated sewing cuffs may be particularly protective against infection by organisms with large zones of inhibition, including S. aureus and coagulase-negative staphylococci. It is possible that these antimicrobial-coated sewing cuffs may also provide some protection against infection by other organisms with smaller zones of inhibition.

Systemic administration of minocycline and rifampin in patients over the last few decades has not been reported to adversely affect the performance of prosthetic heart valves. A preliminary report of a recent study of prosthetic mitral valves implanted in sheep for 3 months suggested that minocycline-rifampin-coated sewing cuffs may improve healing by decreasing the likelihood of pannus overgrowth, compared with the effects of control uncoated sewing cuffs (J. A. Chinn, R. M. Casanova, R. O. Darouiche, et al., Transact. 27th Annu. Meet. Soc. Biomaterials, vol. 24, p. 601, 2001). Histopathologic examination of explanted sections in that ovine study revealed no effect of the antimicrobial coating of the sewing cuff on the occurrence of thrombosis, acute inflammation, chronic inflammation, granulation tissue, and foreign body reaction.

The findings of this in vitro study demonstrate that minocycline-rifampin-coated prosthetic heart valve sewing cuffs provide broad-spectrum activities against pathogens that can cause PVE. These findings and the results of the previously reported animal study that demonstrated the antistaphylococcal efficacies of subcutaneously placed minocycline-rifampin-coated devices (3) prompt us to clinically explore the potential benefit of this approach.

 
This study was supported in part by the Department of Veterans Affairs and by Sulzer Medica Inc., Austin, Tex.

 
* Corresponding author. Mailing address: Center for Prostheses Infection, Baylor College of Medicine, 1333 Moursund Ave., Suite A221, Houston, TX 77030. Phone: (713) 799-5088. Fax: (713) 799-5058. E-mail: rdarouiche{at}aol.com.

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Antimicrobial Agents and Chemotherapy, February 2002, p. 543-545, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.543-545.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Darouiche, R. O. Articles by Reller, L. B. Search for Related Content PubMed PubMed Citation Articles by Darouiche, R. O. Articles by Reller, L. B.