Efficacy of preoperative antimicrobial skin preparation solutions on biofilm bacteria

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Home Study Program

Home Study Program Effi'ca cy of preoperative a n ti micro bia 1 ski n preparation solutions on biofilm bacteria

T

he article "Efficacy of preoperative antimicrobial skin preparation solutions on biofilm bacteria" is the basis for t h s A O R N J o u r d independent study. The behavioral objectives and examination for this program were prepared by Rebecca Holm, RN, MSN, CNOR, clinical editor, with consultation from Susan Bakewell, RN, MS, BC, education program professional, Center for Perioperative Education. Participants receive feedback on incorrect answers. Each applicant who SUCcessfully completes this study will receive a certificate of completion.The deadline for submitting this study is March 31,2008. Complete the examination answer sheet and learner evaluation found on pages 505-506 and mail with appropriate fee to

AORN Customer Service

This progrom meets criterio for CNOR ond CRNFA recertifcation, as well as other continuing education requirements.

c/o Home Study Program 2170 5 Parker Rd, Suite 300

Denver, CO 80231-5711 or fax the information with a credit card number to (303) 750-3212.

You also may access this Home Study via AORN Online at http://www.aorn.org/ournal/homestudy/default. htm.

BEHAVIORALOBJECTIVES After reading and studying the article on biofilms and the efficacy of antimicrobial skin preparation solutions on biofilm bacteria, nurses will be able to

1. describe how biofilm matrices develop, 2. identify at least three implanted devices at risk for being infected with biofilms that are commonly encountered by perioperative nurses,

3. explain how an evaluation was performed to determine efficacy of topical skin antiseptics against biofilm infections, and

4. discuss recommendations for preventing development of biofilm matrices.

A minimum score of 70% on the multiplechoice exomination is necessary to earn 2.4 contact hours for this independent study. Purpose/Gool: To educote penaperative rimes about biofilms and the effect of ontimicrobial skin preparation solutions on biofih

bocteria.

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Home Study Program Efficacy of preoperative antimicrobial skin preparation solutions on biofilm bacteria presence of any duration in the body, they generally form a highly complex, ntil recently, perioperative pro- self-regulating, bacterial community fessionals were taught that known as a biofilm matrix? Bacterial microbial infections (eg, bacteri- biofilm complexes cause challenging al, viral, fungal) were caused by free- infections that generally are both diffimoving, individual microorganisms or cult and expensive to treat and manage. small isolated groups of microorgan- Terms relevant to biofilm bacteria are isms. mcroorganisms causing infections defined in Table 1. Through a process termed ”quorum0 entered the body via a wound or by sensing,” bacteria in a biofilm matrix can direct invasion; chemically communicate system-level 0 spread through the body; needs for the well-being of the entire 0 multiplied in the body; biofilm community. Quorum-sensing 0 evaded immunological defenses (ie, T lymphocyte, B lymphocyte, and between bacteria enables a biofilm community to induce or repress specific gene phagocytic activity); and expressions regulating such activities as 0 were shed from the body to infect 0 cell division, new hosts.’ AIthough it is true that in acute infec- 0 metabolic rates, tions, bacteria generally are found in a 0 production of virulence factors, free-floating (ie, planktonic) form, if 0 plasmid transfer for antibiotic resistbacteria (ie, prokaryotes) establish a ance, and 0 release of planktonic bacteria from the biofilm.’ ABSTRACT Biofilm mfections often begin during surgical procedures, such as insertion of RESEARCH ON THE MEDICAL EFlFICACY of vascular catheter lines, pacemakers, topical antimicrobials and antibiotics against infecheart valves, permanent biomaterials tions has focused laxgely on the effect on free-floatfor repair of aneurysms, or prosthetic ing, planktonic bacteria. joint replacements. Other medical proIN THE PRESENCE OF nonbiological surfaces cedures associated with biofilm estab(eg, catheters, prosthetic devices, biomaterials), lishment are intratracheal intubation however, bacteria form highly complex biofilm needed for ventilators and protracted systems that resist traditional medical treatment. use of indwelling urinary catheters! It is important for perioperative staff BACTERIAL PATHOGENS commonly found in members to recognize that implantation chronic infectionsin both the planktonic and of devices or biomaterials may lead to biofilm state were challenged with a variety of comthe formation of biofilms, which monly used topical antimicrobial formulations. increases the risk of difficult-to-treat BIOFILM BACTERIA were shown to be more infections in postoperative patients. resistant to killingthan planktonic bacteria. Antimicrobial skin preparation times were adequate to BIOFILM GENESIS significantly reduce bacterial populations protected To form a clinically significant in biofilms. AORNJ 81 (March2005) 492-501. biofilm, bacteria must attach to tissue or an inanimate surface (eg, titanium, Daryl S. Paulson, PhD

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TABLE1

Definitions

stainless steel, polytetrafluoroethylene, polyester fiber) in a patient’s body and then attract and attach to other bacterial cell^."^ Typically, direct attachment of bacteria to tissue elicits such a strong immunologicalresponse (eg, high fever, malaise) that it becomes apparent, and patients are treated immediately, according to standard protocols, before a biofilm is able to develop. In comparison, implanted biomaterials, prosthetics, and devices have inanimate surfaces. Bacteria adhering to these inanimate surfaces do not elicit an immune response. The lack of an immune response results in patients not being treated for infection; thus,normal skin bacterial residents (eg, StaphyIococcus epidevmidis) attaching to implanted materials can lead to the development of a biofilm. Bacterial attachment to inanimate surfaces generally requires that a surface be conditioned by organic deposits, such as collagen, laminin, fibrin, and fibrinogen. The bacterial cells and organic deposits are mutually attracted via noncovalent forces, including van der Waal‘s forces and hydrophobic interactions.’-’ Bacteria with receptor sites for these organic compounds can attach directly to the compounds by primary adhesion (Figure 1>,divide, and produce an exopolysaccharide biofilm matrix. This establishes a bacterial presence that is protected from the body’s natural immunological surveillance, including phagocytosis and antibiotic treatment^.^ The conditioning layer influences which organisms will be the primary colonizers of the biofilm (Figure 2). For example, specificorganic substances (ie, collagen, laminin, fibrinogen, fibrin) are deposited on the inanimate surface for Staphylococcus aureus to produce an exopolysaccharide biofilm matrix. Similarly, for Staphylococcus epidermidis to produce a biofilm matrix, fibrinogen-

Antimicrobial residual properties: When chlorhexidine gluconate or zinc pyrithione solution is used for at least two to three days before surgery as a presurgical site wash, the medications are adsorbed into the stratum comeum and prevent normal microbial population regrowth. Then, when the preoperative skin preparation is performed just before a surgical procedure, the normal microbial population numbers already have been reduced greatly, and the preoperative skin preparation is more effective. Biofilm: A complex community of microorganisms enclosed in an exopolysaccharidematrix attached to tissue or an inanimate surface. Coadhesion:The process of planktonic microorganisms binding to microorganisms attached to surfaces. Exopolysaccharides: Polymerized material produced by microorganisms that constitutes the biofilm, providing protection and containment for the microorganisms. Laminin: Linking proteins of basal lamina, which induce adhesion and enhance spreading of microorganisms in a biofilm. Planktonic: Free-floating microorganisms. Quorum-sensing:Chemical communication between microorganisms. Van der Waal’s force: Nonspecific attractiop between atoms that are 3 angstrom units (A) to 4 A apart.

binding protein is deposited on the inanimate surface. Biofilms also contain bacteria that are attached to other bacteria and not to organic debris (Figure3).Different bacterial species that cannot attach to organic material themselves are able to attach to bacteria already adhering to the organic material. Specific and compatible attachment sites are required of both bacteria; this attachment process is called coadhesion. The exact extent of ths phenomenon and its process are not well-understood at this time, but much anecdotal knowledge derives from oral biofilms (ie’ plaque), for which the coadhesive AORN JOURNAL

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Figure 1 Surface conditioning-Organic debris ”conditions“ the inanimate surface of implants and other biomaterials.

Figure 2 Bacterial attachmentBacteria can attach to the organic debris by chemical adhesion.

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(eg, on a venous catheter), and allows the biofilm to slough off planktonic bacteria that can produce septic conditions throughout a patient’s body. BiofiIm matrices often are slowgrowing and localized, however, affecting only an implant and surrounding tissues, and this may require surgical removal of the implant and debridement of associated tiss~es.’”’~ Bacteria in a biofilm are 500 to 1,500 times more resistant to antibiotic therapy than are planktonic ba~teria.’~,’’ Initially, researchers believed that the exopolysaccharide matrix provided a barrier that protected the bacteria from direct exposure to antibiotic^.^,^ It now appears that the reason is more ~omplex.’“’~ Bacteria in biofilm are more metabolically efficient, which process is understood more ~LIU~.’~J’ limits their uptake of antibiotics. Individual bacterial cells can form an Although bacteria in a biofilm generally elaborate matrix of exopolysaccharide do not replicate as rapidly as they do in and interstitial fluid consisting of the planktonic state, different biofilm 0 95% to 99% water, sections are in various stages of growth 0 2”/0bacterial content, and (ie, static, stationary, exponential) at any 0 1%to 2% exopolysaccharide content.? given time.1*,19 On average, however, the A biofilm matrix may appear as depict- entire growth rate of the biofilm comed in Figure 4 or as a thin layer of bacte- munity appears quies~ent.’~,’~ Bacteria in ria in an exopolysaccharide matrix. To the biofilm that are most susceptible to date, no universal configuration has antibiotics are in the exponential growth been determined for medical biofilms. phase because antibiotics require high A biofilm matrix offers bacterial pro- metabolic rates and active cellular divitection and, thereby, increases resistance sion to be effective. Antibiotics to the immunologcal responses of both 0 lnhibit synthesis of the bacterial cell humoral and cellular derivation, as well wall or cell membrane, as from the phagocytic activities of neu- 0 block protein synthesis at the 30s or trophils and tissue macrophages.24Th~s 50s ribosome subunit, facilitates growth of the biofilm matrix 0 block DNA replication, or

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Figure 3 Coadhesion-Some bacteria that cannot attach directly to the organic debris, can attach to bacteria that can attach to organic debris.

block folate coenzymes needed in DNA synthesis.18 Destroying biofilm sections in the exponential growth phase does not destroy bacteria in the biofilm that are in the static and stationary growth phases. Resistance to some disinfectants (eg, hydrogen peroxide) is related directly to bacterial density in a biofilm. Degradation of hydrogen peroxide via catalase produced by bacterial cells, including nonviable cells, requires a concerted systems effort by a group of bacteria. A single bacterium is not able to produce enough catalase to overcome the debilitating effects of hydrogen p e r ~ x i d e . ’ ~ , ~ ~ 0

PERIOPERATIVE IMPLICATIONS Implanted devices (eg, hemodialysis grafts, genitourinary prosthetics, pacemaker leads, prosthetic heart valves, vascular grafts) have significant potential for incurring biofilm infection: For example, polyester fiber grafts that are used to replace and repair stenotic thoracic arteries and abdominal aortic aneurysms are prone to biofilm infections from coagulase-negative Staphylococcus species, Staphylococcusaureus, and other microorganisms. VASCULAR CATHETERIZATION. Biofilms are a serious concern for patients who have vascular catheters. Microorganisms, particularly normal skin flora, colonize and form biofilms quickly on catheter surfaces; however, contaminative exogenous microorganisms from

health care personnel, contaminated infusion fluid, and distal infections transported via hematogenous routes also have been implicated.7,’2,z1 Many of the millions of patients who undergo vascular catheterization procedures in the United States every year become infected via biofilms.’6Four percent to 14% of patients who have a central venous catheter experience septicemia.I5 Central venous catheter infections most commonly are caused by normal skin bacteria, including Staphylococcus epidermidis or other catalase-negative Sfapkylococcus species. Other common bacteria cultured from these catheters include Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus species.21

Figure 4 Biofilm matrixThe individual bacterial cells form an elaborate matrix of exopolysaccharides and interstitial fluid.

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Local biofilm infections, which are very common at catheter-insertion sites, include tunnel infections (ie, cellulitis along the subcutaneous catheter route) and frank catheter-tip colonization. These can lead to life-threateningsepticemias. The current trend for topical antimicrobials is to demonstrate antimicrobial persistence for longer periods of time to limit injury to veins from multiple insertions; however, patients with catheters may have an increased risk for acquiring biofilm infections when the catheter remains at a specific site for a longer time. To counteract this threat, some catheter manufacturers are partnering with manufacturers of topical antimicrobials to produce tubing, cannulas, and catheter insertion tips treated with antimicrobial products, such as silver sulfadiazineor chlorhexidinegluconate.’ Nearly 100% of superior vena cava catheters become locally infected w i t h two to three days of placement.’6Many of these mfections are caused by coagulase-negative Staphylococcus species, especially Staphylococcus epidermidis. A high proportion of these bacteria demonstrate resistance to multiple antibiotic medications, especially to methicillin and oxacillin.’6 Devices exposed to direct blood flow, such as vascular catheters and heart valves, pose a serious risk for both local and systemic infections. It is important for perioperative nurses to understand Virchow’s triad (ie, surface area, blood contact, and flow rate), and that the greater the surface area, the more probable it is that bacteria can colonize it. Direct blood flow offers a continuous source of conditioning material that coats a device in preparation for bacterial attachment. The blood flow also exerts a shearing effect that can transport planktonic bacteria and biofilm clumps to other areas in the Finally, ventricular-peritoneal shunts used to reduce intracranial pressure

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almost always become biofilm-contaminated with Staphylococcus epidermidis and Staphylococcus aure~s.’~ ORTHOPEDICS. Joint replacements (eg, hip, knee) pose the threat of postoperative biofilm infections with particularly devastating effects, including osteomyelitis. Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa commonly are cultured from these implant~.’~ In many situaNearly 100% of tions, biofilm-infected joints require revisional superior vena surgery with a second implant, and this can be cava catheters expensive and traumatic. Special precautions with become locally topical skin antiseptics may be valuable because infected within Staphylococcus epidermidis is prevalent in these two to three infections. ENDOTRACHEALTUBES. Padays tients who remain intubated after a surgcal proceplacement; dure are prone to ventilator-associated pneumonia. many these Endotrachealtubes bypass the body’s normal pulinfections are monary clearing responses caused by (eg, coughing, mucociliary clearance), increase mucus Staphylococcus secretions because of irritation and mflammation, epidermidis. and tend to denude cilia from the tracheal epithelium. This allows secretions to enter the lungs through the stented glottis.8BiofiLms quickly develop on the endotracheal tube and can pass easily into the lungs, particularly during suctioning procedures.

of

of

ARETOPICAL ANTIMICROBIALS

EFFECTIVE?

It is pertinent to determine the effectiveness of topical antimicrobials that are used to remove germs from the skin before catheter insertions or AORN JOURNAL

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preoperative skin preparation or when challenged with bacteria in a biofilm matrix. Currently, antimicrobial efficacy testing is performed almost exclusively on bacteria in the planktonic state. An evaluation to determine efficacy against biofilms was performed using a number of common topical skin antiseptics to challenge pathogenic bacterial species prevalent in biofilm infections. The evaluation determined the resistance to killing provided by a biofilm matrix compared to the bacteriocidal effectiveness of each antiseptic versus the bacteria in a planktonic state. MATERIALS AND METHODS. The bacterial species and strains used were supplied by the American Type Culture Collection. These included 0 methicillin-resistant Staphylococcus aureus, 0 methicillin-resistant Staphylococcus epiderrnidis, 0 Pseiidoinoiias aeruginosa, 0 Staphylococcus aureus, 0 Staphylococcus epiderinidis, and 0 vancomycin-resistant Enterococcifs fnecizini. The topical antimicrobial compounds evaluated are used commonly to prepare patients' s h before surgery or vascular catheter insertion. The active ingredients in these antimicrobial compounds include 0 70% isopropanol + 2% chlorhexidine gluconate; 72% isopropanol + 7.5% povidone iodine; 0 73% ethanol + 0.25% zinc pyrithone; and 0 62% ethanol + i 5% isopropanol.

RESULTS The results of the evaluation are presented in Table 2. Planktonic time kills were performed on bacterial solutions containing approximately 1 x 10' colony forming units (CFU)/mL. A 0.1

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mL aliquot of the suspension was added to 9.9 mL of product to result in a 99% concentration of the product. Exposure times were 15 seconds and two minutes. After each exposure, a 1mL portion of the product/bacterial solution was transferred to 9 mL of a phosphate-buffered solution with product neutralizers. It was serially diluted, plated, and incubated at 35" C + 2" C (95" F k 3.6" F). Bio-films developed on microporous membranes resting on agar nutrient medium. The membranes were inoculated with a cell suspension containing approximately 1 x lo9 CFU/mL to generate the biofilms. The membrane-supported biofilms were incubated at 35" C k 2" C (95" F * 3.6" F) for 48 hours, with transfers to fresh agar nutrient medium approximately every 10 to 12 hours. After approximately 48 hours, the membranesupported biofilms were exposed to each antimicrobial product in screw-capped containers for 15 seconds and for two minutes. Neutralizing fluid was added to the jars after each designated exposure time, and a vortexing unit was used to agitate the contents to disaggregate the biofilm. The neutralizer/product/disaggregated biofilm suspension then was serially diluted, plated, and incubated at 35" C k 2 O C (95" F + 3.6" F). For each antimicrobial compound tested, with the exception of Enterococcus faecium, biofilm-enclosed bacteria retarded the microbial action of alcohol, alcohol and povidone iodine, alcohol and chlorhexidine gluconate, and alcohol and zinc pyrithione, relative to the planktonic time-kill. Generally, however, the topical antimicrobials tested demonstrated h g h antimicrobial activity against the biofilms within a time frame practical for site preparation. Unlike antibiotics that kill by interrupting bacterial replicative and synthesizing mechanisms 0 alcohols coagulate and denature

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TABLE 2

Time Kill Results Log,, reduction from initial population Planktonic Biofilm 15 sec* 2 min* 15 sec* 2 min* Pseudomonas aeruqinosa 62% ethanol + < 5% isopropanol Staphylococcus aureus 70% isopropanol + 2% chlorhexidinegluconate (CHG) 72% isopropanol + 7.5% povidone iodine 73% ethanol + 0.25% zinc pyrithione 62% ethanol + < 5% isopropanol

>5

>5

0.35

>5

>6 >6

>6

1.51 0.37 0.10 0.08

>6 >5

>5

>6 >6 >5

**

>6 >6 >6

>6 >6 >6

3.14 0.75 0.08

>6 >6 >6

>6 >6

>6 >6

1.86 0.97 0.28 0.01

>6 >6

>6

>5

Methicillin-resistant Staphylococcus aureus 7P/' isopropanol + 2% CHG 72% isopropanol + 7.5% povidone iodine 62% ethanol + < 5%isopropanol

Staphylococcus epidermidis 70% isourouanol + 2% CHG 72'% isopropanol + 7.5% povidone iodine 73% ethanol + 0.25% zinc pyrithione 62% ethanol + < 5% isopropanol &

I

Methicillin-resistant Staphylococcus epidermidis 72% isopropanol + 7.5% povidone iodine 62% ethanol + < 5%isopropanol Uancomycin-resistant Enterococcus faecium 70%)isopropanol + 2% CHG

>5

>5

>6

>6

>5 >6

>5

>5

>5

>5

1.70 0.36

>5

>5

>5

>5

>5

>5

* E.rpsure time ** Uiinble to validate becairse of several outliers in dato

0

0

bacterial proteins and leach membrane lipids; chlorhexidine gluconate punctures the cytoplasmic membrane so that low molecular weight cytoplasmic components, such as potassium, leak out; and povidone iodine oxidatively blocks disulfide bridging, which is important in bacterial protein synthesis.2i-2b

RECOMMENDATIONS An effective, persistently active antimicrobial formulation should be used to prepare skin sites thoroughly before performing vascular catheterization procedures or surgeries requiring stents, biomaterial repairs, joint replacements, or orthopedic implants. It may be prudent to have patients treat

intended surgical sites with alcohol/ chlorhexidine gluconate, alcohol/zinc pyrithione, or a solution containing only chlorhexidine gluconate at home for three to four consecutive days before surgery.26 With repeated use, both chlorhexidine gluconate and zinc pyrithione demonstrate residual antimicrobial properties that prevent skin colonization from rebounding to baseline microbial population levels.27 Approximately three days of repeated exposure, however, are necessary for the chlorhexidine gluconate or zinc pyrithione to be adsorbed onto the stratum corneum.ZRIt is important, therefore, to use antimicrobially effective surgical scrub products labeled with both immediate and persistent antimicrobial proper tie^.^^ AORN JOURNAL

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Prepping with alcohol and chlorhexidine gluconate, alcohol and povidone iodine, alcohol and zinc pyrithione, or chlorhexidine gluconate, alone before vascular catheterization procedures may reduce catheter-associated infections. Using antimicrobiallytreated bandaging may improve prospects even more. Currently, catheters coated with antimicrobials are being evaluated for their value in preventing bacterial attachment and biofilm formation.8 As in many surgeries, it is important to administer prophylactic antibiotics just before and during the surgical procedure. It is prudent to employ antibiotics that can inactivate methicillinresistant Staphylococcus atireus, methicillin-resistant Staphylococcus epidermidis, and vancomycin-resistant En terococci.'O The goal is to eliminate planktonic bacteria before they can form a biofilm that is resistant to antibioticsM Health care practitioners must take special care for orthopedic surgeries involving implants in joint replacements. Antimicrobial incision drapes are recommended to isolate the surrounding skin surface from the incisiona1 site.31An alcohol skin wipe also should be performed before placement of an antimicrobial incision drape." It is important to take a proactive approach to preventing contamination of wounds and implants. Health care professionals should require vendors to provide published documentation demonstrating that products are effective against microorganisms in the biofilm matrix, as well as in the planktonic state. 03

Daryl S. Paulson, PhD, is president and chief executive officer of BioScience Laboratories, Inc, Bozeman, Mont. Editor's note: The author acknowledges Terri Eastman, manager of in vitro labora-

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tories; fohn A. Mitchell, PhD, director of quaIity assurance; and Karen WesenburgWard, PhD, project manager of biofilm division, BioScience Laboratories, lnc, Bozeman, Mont, for their assistance in producing this article. BioScience Laboratories manufactures teclznologies described in this article. The evaluation described in this article wasfunded by BioScience Laboratories, lnc. Publication of this article in no way implies AORN endorsement of products manujactured by BioScience Laboratories, Inc.

NOTES 1. C Mims, A Nash, J Stephen, Mini's Pathogenesis of lnfectioiis Disease, fifth ed (San Diego: Academic Press, 2001). 2. M G Darby, G A O'Toole, "Microbial biofilms: From ecolo y to molecular genetits," Microbiology an Molecular Biology Revinus 64 (December 2000) 847-867. 3. A L Reysenbach, E Shock, "Merging genomes with geochemistry in hydrothermic ecosystems," Science 296 (May 10,2002) 1077-1082. 4.J Jass, S Surman, J T Waller, "Microbial biofilms in medicine," in Medical Biofilms: Detection, Prevention and Control, eds, H Jass, S Surman, J Waller (West Sussex, UK John Wiley & Sons, Inc, 2003) 1-28. 5. M Hentzer, M Givskov, L Eberl, "Quonun sensing in biofilms: Gossip in slime city," in Microbial Biofilms, eds, M Ghannoum, G A OToole (Washington,DC: American Society of Microbiology, 2004) 118-140. 6.S N Wai, Y Mizunoe, J Jass,"Biofihrelated infections on tissue surfaces," in Medical Biofilnzs:Detection, Pvevention and Control, eds, J Jass, S Surman,J Waller (West Sussex, UK: John Wiley & Sons, Inc, 2003) 1-28. 7. F Gotz, G Peterson, "Colonization of medical devices by coagulase-negative Sta hylococci," in lnfectioiis Associated with Ind!uelling Medical Devices, third ed, F A Waldvogel, A L Bisno, eds (Washington, DC:American Society of Microbiology, 2000) 55-88. 8. J M Anderson, R E Marchant, "Biomaterials: Factors favoring colonization and infection," in Infections Associated with Indwelling Medical Devices, third ed, F A Waldvogel, A L Bisno, eds (Washington, Dc: American Society of Microbiology, 2000) 89-109.

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2001) 5,204. 21. R Bayston, "Biofilm infections on im lant surfaces," in Biofilms: Recent AJances in Their Study and Control, first ed, L V Evans, ed (Amsterdam: Harwood Academic Publishers, 2000) 117-131. 22. L A Mermel, "Prevention strategies for Biofilms: Detection, Prevention and Control, intra-vascular catheter-related infections," eds J Jass, S Surman, J Waller (West Sussex, in Infections Associated with Indwellin UK John Wiley & Sons, Inc, 2003) 1-28. Medical Devices, second ed, F A Walfvogel, 11. P E Kolenbrander, R J Palmer, "Human A L Bisno, eds (Washington,DC: American oral bacterial biofilms," in Medical Biofilms: Society of Microbiology,2000) 407-425. Detection, Prevention and Control, eds J Jass, 23. M R Brunstedt et al, "Bacteria/blood/ S Surman, J Waller, (West Sussex, UK John material interactions. I. Injected and preWiley & Sons, Inc, 2004) 85-117. seeded slime-forming Staphylococcus epider12.J G Thomas, G Ramage, J L Lopezmis in flowing blood with biomaterials," Ribot, "Biofilms and implant infections," in Journal of Biomedical Materials Research 29 Microbial Biofilms, eds M Ghannoum, G A (April 1995) 455-466. OToole (Washington, DC: American 24. G W Dentin, "Chlorhexidine," in DisinSociety of Microbiology,2004) 269-293. fection, Sterilization and Preservation, fifth ed, 13.J M Steckelbur D R Osman, S S Block, ed (Philadelphia:Lippincott, "Prosthetic joint dkctions," in Infections Williams & Wilkins, 2001) 321-335. Associated with lndwelling Medical Devices, 25. Y Ali et al, "Alcohols," in Disinfection, third ed, F A Waldvogel, A L Bisno, eds Sterilization and Preservation, fifth ed, S S (Washington,DC: American Society of Block, ed (Philadelphia: Lippincott, Microbiology, 2000) 173-209. Williams & Wilkins, 2001) 229-253. 14. A Stein, M Drancourt, D Raoult, 26. W Goltardi, "Iodine and iodine com"Ambulatory management of infected plexes," in Disinfection, Sterilization and orthopedic implants," in Infections Preservation, fifth ed, S S Block, ed Associated with Indwelling Medical Devices, (Philadelphia: Lippincott, Williams & third ed, F A Waldvogel, A L Bisno, eds Wilkins, 2001) 159-184. (Washington,DC: American Society of 27. D W Hobson, LA Seal, "Antimicrobial Microbiology, 2000) 211-230. bodywashes," in Handbook of Topical 15. N Phillips, Berry 15'Kohn's Operating Antimicrobials, ed D S Paulson, (New York Room Technique, 10th ed (St Louis: Mosby, Marcel Dekker, Inc, 2003) 167-188. 2000) 740-765. 16. G D Ehrlich, F Z Hu, J C Post, "Role for 28. D S Paulson, "Full body showerwash Efficacy evaluation of a 4% chlorhexidine biofilms in infectious disease," in Microbial gluconate," in Handbook of Topical Biofilms, eds M Ghannoum, G A OToole Antimicrobials, ed D S Paulson, (New York (Washington, DC: American Society of Marcel Dekker, Inc, 2003) 189-196. Microbiology,2004) 332-358. 29. D S Paulson, Topical Antimicrobial 17. P S Stewart, P K Mukherjee, M A Testing and Evaluation (New York: Marcel Ghannoum, "Biofilm antimicrobial resistDekker, Inc, 1999). ance," in Microbial Biofilms, eds M Ghan30. S M Nettina, The Lippincott Manual of noum, G A OToole (Washington,DC: Nursing Practice, seventh ed (Philadelphia: American Society of Microbiology, 2004) Lippincott, Williams & Wilkins, 2001) 114250-268. 115. 18. C Walsh, Antibiotics: Actions, Origins, 31. D M Fogg, "Infection prevention and Resistance (Washington,DC: American control," in Alexander's Care of the Patient in Society of Microbiology, 2003). surgery, 12th ed, J C Rothrock, ed (St Louis: 19.J Netting, "Sticky situations," Science News Online 160 (July2001) 2. Also available Mosby, 2003) 817-930. at http://www.sciencenews.org/artic1es/2001071432. B Bowen, "Orthopedic surgery," in Alexander's Care of the Patient in Surgery, /bobl2.asp (accessed 24 Jan 2005). 12th ed, J C Rothrock, ed (St Louis: Mosby, 20. P S Stewart, "Multicellular resistance: 2003) 817-930. Biofilms," Trends in Microbiology 9 (May

9. S E Cramton, F Gotz, "Biofilm development in Staphylococcus," in Microbial Biofilms, eds M Ghannoum, G A OToole (Washington, DC:American Society of Microbiology, 2004) 64-84. 10. D Spratt, "Dental plaque," in Medical

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