United States Patent 19 11 Patent Number: 5,366,505 Farber 45 Date of Patent: Nov
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O USOO5366505A United States Patent 19 11 Patent Number: 5,366,505 Farber 45 Date of Patent: Nov. 22, 1994 54 METHOD OF REDUCING MEDICAL 4,886,505 12/1989 Haynes et al. ...................... 604/265 DEVICE RELATED INFECTIONS 4,925,668 5/1990 Khan et al. ......................... 424/422 75 Inventor: Bruce Farber, Port Washington, OTHER PUBLICATIONS N.Y. D. G. Maki et al., Clinical Trial of a Novel Antiseptic 73 Assignee: North Shore University Hospital Central Venous Catheter, Abstracts of the 1991 Inter Research Corporation, Manhasset, science Conference on Antimicrobial Agents and Che N.Y. motherapy, p. 176 (1991). C. J. Stephens et al. Randomized Double-Blind Trial 21 Appl. No.: 35,553 Comparing the Risk of Peripheral Vein Thrombophle 22 Filed: Mar. 23, 1993 bitis (T) Between Chlorhexidine (CHA) Coated Cathe ters (C) with Uncoated Control, Abstracts of the 1991 Related U.S. Application Data Interscience Conference on Antimicrobial Agents and Chemotherapy, p. 277 (1991). 63)63 Continuation-in-Tian in-part off Ser. NoNo. 802,891, Dec.ec 6, 1991, M. Tojo et al., Isolation and Characterization of a Cap 5 sular Polysaccharide Adhesin from Staphylococcus epi 51) Int. Cli................................................ A61F 2/02 dermidis, J. Infect. Dis. 157(4): 713-722 (1987). 52 U.S. C. ....................................... 623/11; 604/265 58) Field of Search ........................ 428/413:523/112, Primary Examiner-David Isabella 623/11, 12, 1, 2; 427/2, 604/265 Attorney, Agent, or Firm-Kenyon & Kenyon 56 References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS The growth of microorganisms on catheters and other 4,581,028 4/1986 Fox, Jr. et al. ......................... medical devices is inhibited by slime-inhibiting.com 4,642,267 2/1987 Creasy et al. ....... v was a we 80 wo 428/413 pounds. Slime-inhibiting compounds include salicylic 4,713,402 12/1987 Solomon ......... 523/12 acid and other NSAID. 4,769,013 9/1988 Lorenz et al. ... ... 604/265 4,865,870 9/1989 Hu et al. ................................. 427/2 21 Claims, No Drawings 5,366,505 1. 2 slime is a complex substance composed mostly of poly METHOD OF REDUCING MEDICAL DEVICE saccharide. RELATED INFECTIONS The production of a surface polysaccharide biofilm or slime by an organism enables it to adhere to surfaces This application is a continuation-in-part of applica 5 of insertable or implantable devices and cause infection. tion Ser. No. 07/802,891, filed on Dec. 6, 1991, now The slime appears to contain a galactose rich polysac abandoned. charide "adhesive' which mediates attachment of the BACKGROUND OF THE INVENTION organism to polymers. It also contains a polysaccharide Substance that accumulates after adherence occurs and The frequency of infection associated with the use of 10 cements the organism to the medical device. invasive medical devices such as insertable as well as Besides adhesion, the slime appears to have other implantable devices is well documented. In the case of functions. It binds to glycopeptide antibiotics including insertable devices such as catheters, the rate of infection vancomycin. This may explain why most S. epidermidis necessitates frequent replacement. In the case of in infections do not respond to antimicrobial therapy plantable devices such as prosthetic devices, infections 15 alone. When infection occurs on an inserted or in interfere with adaptation to the device. In either case, life-threatening septicemia can result from such infec planted device, removal of the device is usually re tions. quired. Slime also interferes with certain immune re The pathophysiology of medical device related infec sponses. tions is complex. Many factors influence the risk and The extracellular slime of S. epidermidis is really a type of infection. These include factors related to the manifestation of exuberant production of surface poly host, to the medical device and to the virulence and saccharide. The quantitative production appears to be inoculum of the infecting organism. Hundreds of medi regulated by a complex mechanism that turns on and off cal publications have investigated and documented the production based upon the local environment. Al variables that contribute to these factors. It has been 25 though S. epidermidis has been the focus of much of the well established that the overwhelming majority of research on foreign-body infections, this concept has medical device associated infections occur when bac been studied in other organisms. Colonization by pseu teria colonize and then migrate along the medical de domonas species on the interior surface of PVC and vice until they gain access to the bloodstream. Accord other pipes has demonstrated a glycocalyx mass that ingly, the ability bacteria to adhere to a medical device 30 shields organisms from disinfectants including chlorine, is important to the successful establishment of an infec phenolics, quaternary-ammonium, and iodophor disin tion. fectants. Once a bacterial glycocalyx is formed, it is The role of bacterial surface polysaccharides in ad very difficult to break down. herence is well established. Over 12 years ago a series The development of polymers that contain antimicro experiments demonstrated the ubiquitous nature of 35 bial properties has important implications for both med these polysaccharides. Surface polysaccharides are icine and industry. Aside from factors related to bacte found on most bacteria and fungi. When confronted rial polysaccharides, the coating of the foreign body by with a specific lectin, the surface polysaccharides gen proteins (albumin, fibronectin, platelets) from the host, erate a glycoclyx that surrounds the bacteria and adher as well as a variety of factors related to the polymer ing surface. The glycoclyx consists of a mass of long itself undoubtedly affect the risk of infection. polysaccharide fibers and appears to have several func Several approaches have been utilized to produce tions. It may act as a source of nutrition for the bacteria. medical devices made of or with polymers with antimi It may serve as a physical barrier. Most importantly, crobial properties, as described, for example, in U.S. surface polysaccharides determine the specific surface Pat. Nos. 4,769,013, 4,713,402 and 4,886,505. Antini interactions of the bacterial cell. 45 crobial agents can be incorporated during the produc This phenomena has far reaching effects. For exam tion process or grafted into the surface as described in ple the ability of Streptococcus mutans to colonize teeth, U.S. Pat. No. 4,925,668. However, even broad-spec Streptococcus salivarius to colonize gums, Bacteroides trum antibiotics eventually lead to the selection of resis fragilus to colonize the intestine, and Group A strepto tant organisms. Selection of opportunistic fungi, resis cocci to colonize the throat and skin are all manifesta SO tant gram negative rods, S. epidermidis, and enterococci tions of a complex interaction between specific surface is likely. In addition, unless the "delivery' of the antibi polysaccharides and specific lectins, which are proteins otic is rapid, potent, and long lasting, formation of the that bind to specific polysaccharides. protective glycocalyx will prevent its effectiveness. In The importance of bacterial surface and medical de addition, many antibiotics produce allergic reactions in vice related infections is best illustrated by coagulase 55 some patients. negative staphylococci. S. epidermidis, the most impor The present invention is based on an alternative ap tant and common of the coagulase negative staphylo proach, namely interference with the adherence of bac cocci, was previously considered a non-pathogenic teria to polymeric surfaces of medical devices. Studies organism. It has now emerged as the most common have demonstrated that both the degree of slime and cause of foreign body infection and nosocomiaisepsis. It adhesive production influence and correlate with the is the major cause of prosthetic valve endocarditis, degree of bacterial adherence to silastic catheters. S. vascular graft infection, artificial hip and knee infection, haemolyticus, unlike S. epidermidis do not produce slime and catheter related sepsis. Although less virulent than and are a very uncommon cause of catheter related S. aureus and many other bacteria, it is highly resistant infection. As described herein, substances that prevent to most antimicrobials except vancomycin and rifampin. 65 or reduce the production of slime by bacteria reduce In the early 1980's, electron microscopy studies dem their adherence and thus reduce the level of growth of onstrated that certain strains of S. epidermidis produce microorganisms on the surface of the inserted or im an extracellular slime like substance. The extracellular planted devices. 5,366,505 3 4 It has been observed that sodium salicylates and cer inhibiting compounds include, but are not limited to, tain other compounds can interfere with the production NSAID such as acetylsalicylic acid (aspirin), Salicylate, of capsule polysaccharide production in Klebsiella pneu bis-salicylate, benzyl-benzoic acid, diflunisal, fendosal, monia. Salicylate binds to lipids in the outer membrane indomethacin, acemetacin, cinmetacin, sulindac, tolme where biosynthetic enzymes are located. It has been tin, zomepirac, diclofenac, fenclofenac, isoxepac, ibu postulated that capsular polysaccharide is the backbone profen, flurbiprofen, naproxen, ketoprofen, fenoprofen, of glycocalyx formation. benoxaprofen, indoprofen, pirprofen, carprofen, mefe An object