Catheter-Related Infections: It's All About Biofilm

Marcia A. Ryder, PhD, MS, RN


Topics in Advanced Practice Nursing eJournal. 2005;5(3) 

In This Article

Biofilm Development on Catheter Surfaces

Biofilm development is a series of complex but discrete and well-regulated steps. The exact molecular mechanisms differ from organism to organism, but the stages of biofilm development are similar across a wide range of micro-organisms.[8] The sequential stages of biofilm development on intravenous catheters are: (1) microbial attachment to the catheter surface; (2) adhesion, growth, and aggregation of cells into microcolonies; and (3) maturation and dissemination of progeny cells for new colony formation. An interactive illustration of the biofilm life cycle can be viewed at

Direct contact of the micro-organism with the catheter surface is required for attachment and subsequent colonization. The mere "touch" of the cell wall with the biomaterial alters the micro-organism's phenotypic expression to begin production of a sticky adhesin that attaches the cell to the surface. The first opportunity for such contact is during insertion of the catheter, as it passes through the layers of normally colonized skin. Both transient and resident micro-organisms exist on the surface of the skin. About 80% of resident micro-organisms inhabit the first 5 cell layers of the stratum corneum. The remaining 20% survive in biofilms within the underlying epidermal layers, sebaceous glands, and hair follicles.[5,9,10] The microbial density of the skin depends on the body location; normal counts at the jugular and subclavian catheter sites are about 1000-10,000 colony-forming units (cfu)/cm2, compared with about 10 cfu/cm2 at the antecubital space.[11]

This step in the pathogenesis of CRBSI offers a significant opportunity for preventing infections, as most skin micro-organisms can be removed through meticulous preoperative skin cleansing and application of antiseptic agents. Even so, the catheter enters the bloodstream with some burden of bacteria attached to the tip and the length of the external catheter surface.

Upon arrival of the catheter into the venous system, circulating plasma proteins instantly collide and rapidly bind with the biomaterial. In the next few minutes, the coagulation cascade and the complement system are activated, attracting platelets and polymorphonuclear leukocytes to the foreign material. The matrix of absorbed protein, adherent leukocytes, aggregated platelets, and accumulated fibrin composes a "conditioning layer" that envelops the catheter as a fibrinous sheath. A partial or occlusive pericatheter thrombus may develop over the fibrin sheath within the next few days.[12]

The matrix of host products serves as scaffolding for the simultaneously developing biofilm and provides receptor-binding sites for newly arriving bacteria. The effect of single blood proteins or of whole blood itself depends on the microbial strain.[13] For example, whole blood promotes Pseudomonas aeruginosa biofilm formation, while plasma proteins such as fibrinogen and fibronectin enhance Staphylococcus aureus binding but inhibit S epidermidis and Gram-negative bacteria adherence.

The circumstances under which micro-organisms contact the intraluminal surface of the catheter are quite different from the external lumen. Instead of having constant exposure to blood flow, the biomaterial of the internal lumen may be exposed to a wide range of flow rates of infused substances, including crystalloid solutions, drug admixtures, blood or blood products, and nutrition solutions; or it may be "locked" in a no-flow state. Particles from the infused substances may bind directly with the biomaterial or incorporate with the conditioning layer formed during blood sampling or transfusion.

Unless adequately disinfected, microorganisms gain entry into the flow system through any contaminated access portal or connection site. Once inside, contact with any internal surface component of the administration system such as extension tubing, needleless connector, hubs, or the conditioned or unconditioned catheter surface results in attachment.

The attachment of a small number of bacterial cells is all that is needed to initiate biofilm formation anywhere along the system. Within a few seconds, the progression of phenotypic changes in the bacteria remarkably alters protein expression to further produce species-specific adhesions that irreversibly anchor the cell to the surface.[14] Within as few as 12 minutes, the adherent cells upregulate genes that direct production of accumulation proteins and polysaccharides, which firmly attach the cells to the substratum and to each other as they undergo exponential binary division.

As the cells continue to divide, the daughter cells spread outward and upward from the attachment point to form cell clusters. The production of exopolymer saccharides (EPS) or "slime" embeds the aggregating cells to form microcolonies. Typically, the microcolonies are composed of 10% to 25% cells and 75% to 90% EPS matrix, with a consistency similar to a viscous polymer hydrogel.[5] Figure 1 shows the progression of bacterial attachment to layered and embedded microcolony formation.

Scanning electron micrographs of Pseudomonas aeruginosa biofilm formation. A. Attachment to a surface. B. Attachment followed by phenotypic changes in the cell wall to induce production of adhesins. C. Further production of extrapolymer substances (alginate) embed the reproducing cells for microcolony and biofilm formation. Images from the CDC Public Health Image Library (

The continued formation of the biofilm community evolves according to the biochemical and hydrodynamic conditions, as well as the availability of nutrients in the immediate environment.[13] The structural organization is mainly influenced by hormone-like regulatory signals produced by the biofilm cells themselves in reaction to growth conditions. This interactive network of signals allows for communication among the cells, not only controlling colony formation but also regulating growth rate, species interactions, toxin production, and invasive properties.[15] The cell clusters are structurally and metabolically heterogeneous, and both aerobic and anaerobic processes occur simultaneously in different parts of the multicellular community.[15]

Cellular density typically increases to a steady state within 1-2 weeks, depending on the species and local environmental conditions. Expanded growth evolves into complex 3-D structures of tower- and mushroom-shaped cell clusters. Adjoining microcolonies are connected by water channels that serve as a primitive circulatory system for delivery of nutrients and removal of wastes.

The thickness of the biofilm is variable (13-60 mcm) and uneven, as determined by the balance between growth of the biofilm and detachment of cells.[16] Depending on the initial number of attached organisms, the multilayered cell clusters develop as patchy networks or form a contiguous layer over the surface of the catheter (Figure 2).

The dimension of biofilms in vivo is only on the order of tens of micrometers, but they contain thousands of bacteria in a very compact space.[17] Kite and colleagues measured average biofilm cell counts in infected catheters removed from hemodialysis patients at levels above 105 cfu/cm of intraluminal catheter surface.[18] Considering that catheters are 20-60 cm or longer, there is potential for vast numbers of bacteria to be released into the bloodstream.

Confocal laser microscopy images of the stained intraluminal surface of a tunneled catheter removed from a pediatric patient at completion of therapy. Each picture represents a cross section of the continuous layer of biofilm along the catheter surface. A. Catheter section treated with a stain for extrapolymer saccharide (EPS) produced by the attached bacteria. B. The same catheter section stained for DNA. C. An overlay of A and B, with the EPS- and DNA-stained biofilm showing the dispersal of cells within the EPS.

The formation of biofilm is a universal strategy for microbial survival. In order to colonize new surfaces and to prevent density-mediated starvation within the mature biofilm, the cells must detach and disseminate. Dispersal is accomplished by shedding, detachment, or shearing.

Shedding occurs when daughter cells from actively growing bacteria in the upper regions of the microcolonies are released from the cell clusters. Increased cell density induces cell-cell signaling to direct chemical degradation of the EPS, sending clumps of biofilm into the circulation.[19] Biofilms within vascular catheters are exposed to variable flow rates and shear forces. When the shear force of the infusion or catheter flush exceeds the tensile strength of the viscous biofilm, fragments break away. Clumps or fragments of detached biofilm may contain thousands of cells, but they leave behind an adherent layer of cells on the surface to regenerate the biofilm.[5,20]

The dissemination of biofilm cells into the systemic circulation may result in bloodstream infection, depending on the host immune system and bioburden of cells released. Single cells released by shedding are susceptible to antibiotics and can be controlled by antimicrobial therapy and/or the host's immune system. However, those released in clumps retain antibiotic resistance and may embolize at a distant anatomic site to develop metastatic infections such as endocarditis or osteomyelitis.[20] In one investigation, endocarditis developed in 25% of patients with central venous catheter (CVC) S aureus biofilms.[21] In another study, CVCs colonized with S aureus biofilm were implicated as the source of metastatic infections in 31% of patients.[22]


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