Chest Port Microbial Infections

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Introduction

Figure 1. Example of Chest Port Placement. Diagram from Fairview Hospital.

By Hannah Lorico Hertz

A chest port is an indwelling catheter connected to a reservoir, inserted under the skin of the chest, and used to administer medicines directly into a vein over a long period of time (Figure 1). Physicians frequently utilize chest ports to administer multiple cycles of chemotherapy in children because of the ease of vascular access and care for port maintenance. Because chest ports are inserted under the skin, the skin covering the port acts as a barrier to potentially harmful microorganisms. In comparison to an IV line, chest ports can stay in place for months at a time, can be used to collect blood samples without needles, and have a lower risk of infection over time. Although chest port infections are not as common as other external catheter infections, the most significant complication during chemotherapeutic treatment via chest port catheters are microbial infections. Approximately 5% of patients diagnosed with a microbial port infection are treated by port excision.

Infections of implanted devices most commonly result from Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus faecalis, Streptococcus vidrians, Klebsiella pneumonia, and Pseudomona aeruginosa. Of the above microbes, S. epidermidis is the most relevant port associated pathogen. Jukes et al. estimate in the United States, 80% of hospital acquired catheter related bloodstream infections (CRBSI) are caused by the microbe S. epidermidis. The treatment of these catheter-related bloodstream S. epidermidis infections costs the U.S. about $2 billion a year. Thus, research on practices that decrease chest port infection incidence and basic scientific research on the mechanism of chest infections can significantly reduce the problem of chest port infections.

S. epidermidis is an opportunistic pathogen. S. epidermidis are normally non-pathogenic and found on the human skin. S. epidermidis only act as a human pathogen in individuals with compromised immune systems, immunosuppression, or chemotherapy related neutropenia. Common port infections include S. epidermidis biofilm formation inside the catheter lumen. Biofilms are groups of cells that form on various surfaces that produce extracellular polymeric substances (EPS) which protects the microorganisms from antibiotics. Biofilm formation is threefold. S. epidermidis adhere to the catheter surface to be colonized, a microcolony forms, and S. epidermidis cells detach from a mature biofilm allowing S. epidermidis colonization on additional body sites. Better management of chest port microbial infections can help improve patient quality of life as they undergo treatment. Recent research explores how to best manage port microbial infections avoiding the current treatment of port excision. The literature focuses on both the mechanism of S. epidermidis pathogenicity/biofilm formation in order to develop better antibiotics and also alternate treatments for port infections.

S. epidermidis and Pathogenicity

Figure 2. Scanning electron micrograph of S. epidermidis biofilm formation on implant material surface. From the Implant Research Center.

Figure 3. Diagram of the IS 256 insertion site in the ica operon in S. epidermidis RP62A and S. epidermidis 229. From the paper of Ziebuhr et al. (1999).

In order to develop better treatments for chest port infections, researchers must first understand what differentiates pathogenic S. epidermidis from non-pathogenic strains. S. epidermidis is the most abundant pathogen comprising the human flora with, under normal conditions, a benign relationship with its host. To begin understanding the hallmarks of S. epidermidis pathogenicity, researchers compared S. epidermidis to the common antibiotic resistant strains of S. aureus and found that S. epidermidis lack the enzyme coagulase, which is present in pathogenic S. aureus. Thus, the enzyme coagulase does not determine pathogenicity.

What determines pathogenic S. epidermidis strains from non-pathogenic S. epidermidis living peacefully on the human skin? Although S. epidermidis act only as pathogens in immunocompromised patients, the strains that become pathogenic in immunocompromised patients share common characteristics. One determinant of S. epidermidis pathogenicity includes a strain’s ability to form biofilms. S. epidermidis strains that produce biofilm are more virulent than strains which do not form biofilms. Only some S. epidermidis strains, such as RP62a, form biofilms whereas other strains, such as ATCC 12228, do not form biofilms. Ziebuhr et al. (1999) find the ica gene cluster (icaA, icaB, icaC, and icaD) is commonly found and highly expressed in pathogenic S. epidermidis strains isolated from catheter related infections. Ica operon expression is essential for the formation of the adhesion protein PIA which promotes biofilm formation. The insertion element IS 256 disrupts ica gene expression, and thus PIA formation, in non-pathogenic S. epidermidis. Ziebuhr et al. study the location of IS 256 insertion in S. epidermidis which do not form biofilms in order to determine gene loci essential for S. epidermidis pathogenicity (Figure 3). The authors find that for 11 out of the 13 S. epidermidis mutants that do not form biofilms, an insertion sequence (IS 256) disrupts the icaC nucleotide sequence and expression. One mutant carried the element in the icaA and the other in the icaB gene. Therefore, insertions in the icaC gene halts PIA formation and thus biofilm formation, leading to non-pathogenic S. epidermidis strains. Ziebuhr et al. also explored the excision rate of IS 256 in order to elucidate the formation of new pathogenic S. epidermidis strains. From this study, the excision rate of IS 256 was estimated to be <10-8 per cell per generation. The low excision rate suggests that the introduction of new pathogenic S. epidermidis strains is relatively low.

Other regions in the S. epidermidis genome determine strain virulence. Gill et al. (2005) study regions in the biofilm forming RP62a genome responsible for S. epidermidis pathogenicity. Genes encoding for cadmium resistance and surface proteins associated with pathogenicity are found in integrated plasmids in S. epidermidis. Moreover, genomic islands encode virulence factors such as multiple phenol-soluble modulins, molecules that induce the synthesis of cytokine, and the cap operon, which encodes the polyglutamate capsule. Single nucleotide polymorphisms in genes encoding cell envelope proteins are also thought to affect S. epidermidis pathogenicity.

Biofilm Formation

Figure 4. Factors involved in S. epidermidis biofilm formation. Diagram from the Journal of Materials Chemistry B (2014).

Figure 5. PIA synthesis via membrane proteins IcaA, IcaD, IcaC and protein IcaB. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992008000400003].

In order to understand S. epidermidis port infections and develop better treatments, we also need to understand the process of S. epidermidis biofilm formation because the most common port infections are due to S. epidermidis biofilm formation inside the catheter lumen. Biofilms usually protect microbes from antibiotics. S. epidermidis biofilm formation begins with cell attachment to a surface. For port microbial infections, biofilm formation most commonly occurs on the catheter lumen. Next, S. epidermidis begin producing polysaccharides forming a protective layer surrounding the cells. The biofilm continues to grow forming mature biofilms until the cells are released into its environment, free to initiate biofilm formation on another surface (Figure 4).

Biofilm formation begins as S. epidermidis adhere to the surface of the port catheter lumen. This initial attachment is essential for the establishment of port-associated infections. Attachment of S. epidermidis can occur either directly to the port polymer surface via physio-chemical interactions or indirectly by the attachment to extracellular matrix proteins (ECM) coating the surface of a port catheter. The hydrophobic cell surface of S. epidermidis due to proteins AltE and Bap/Bhp mediate the surface adhesion of the microbes to the port hydrophobic surface. The autolysin AtlE is especially essential for S. epidermidis attachment to polystyrene (plastic). AltE interacts to the surface of the port catheter lumen by hydrophobic interactions, however, further research on AltE mechanism of attachment is needed to eliminate the possibility that AltE plays only an indirect role in attachment. Because the amino acid sequence of AltE is 61% identical to the AltL gene of Staphylococcus aureus, Heilmann et al. (1997) were able to identify two domains of interest for AltE mediation of attachment to plastic surfaces: a 60kDa amidase and a 52kDa glucosaminidase domain. To test if the 60 kDa AltE domain plays a role in S. epidermidis polystyrene attachment, Heilmann et al. (1997) incubated wild type S. epidermidis with an anti-60 kDa antiserum. If the 60 kDa amidase mediates primary attachment to polystyrene, then the researchers expected to see an inhibitory effect on attachment in the initial adherence assay. As expected, with the incubation of anti-60kDa antiserum, the number of wild-type cells attached to the polystyrene plates was approximately 90% reduced. This suggests that the 60 kDa domain of AltE somehow mediates S. epidermidis’ initial and direct attachment to the chest port surface during biofilm formation. AltE plays a significant role in biofilm attachment; Not only does AltE play a significant role in binding to polystyrene surfaces, but also to ECM coated surfaces (specifically vitronectin).

As foreign materials, such as catheters, are placed into the body, they become covered by host ECM components and so, as chest ports are inserted in the body, the ports are coated by EMC components such as fibrinogen, vitronectin, collagen, and fibronectin. Research has shown that proteins with ECM-binding activity expressed by S. epidermidis can play a significant role in microbial biofilm initiation of a port infection. Proteins such as AltE bind to vitronectin, lipase GehD to collagen , and surface component serine-asparatate repeat (Sdr) proteins SdrF, SdrG, and SdrH to collagen I, fibrinogen, and fibrinogen respectively. The research outlined above is important because engineers might test different chest port surfaces to which S. epidermidis cells can not adhere. If able to develop a chest port where S. epidermidis cannot bind, biofilm growth would be severely hindered and chest port infection incidence decreased.

By studying biofilm accumulation, researchers may be able to develop biofilm inhibitors. Biofilm accumulation of S. epidermidis begins with the expression of intercellular adhesive properties. The protein, polysaccharide intercellular adhesin (PIA), is the main adhesive expressed by S. epidermidis (Mack) leading to cell aggregation and biofilm formation. PIA is produced by the membrane proteins IcaA, IcaD, and IcaC, which are expressed by the ica locus (Figure 5). PIA formation begins with the expression of IcaA and IcaD. The proteins expressed by these genes form the N-acetylglucosamine transferase. This transferase uses UDP-glucosamine (UDP-GlcNAc) to build unbranched glucosamine (GlcNAc) homopolymers with a length of about 15-20 residues. The protein expressed by the IcaC gene produces longer chains, the PIA molecule, and is also involved in PIA export. PIA can undergo editing by IcaB, which de-acetylates some of the GlcNac residues, conferring a positive charge to a formerly neutral GlcNAC when in an environment with a pH <6. PIA can then function as an adhesive for S. epidermidis biofilm production. In addition to PIA, proteins Aap and Embp can also lead to biofilm assembly. Other biofilm associated proteins involved with biofilm accumulation include SesC.

The proteins and factors involved with S. epidermidis detachment are less widely studied. However, understanding the dispersion of S. epidermidis biofilm is important in providing a holistic view of S. epidermidis biofilm formation.

The understanding of S. epidermidis pathogenicity is linked to biofilm formation. Thus, many studies have been conducted studying biofilm formation in vitro. Further research of biofilm systems in complex models is necessary to more accurately portray the in vivo infection of a chest port. The translation of the basic research on biofilm formation provides a trajectory for further chest port treatment research

Symptoms and Diagnosis of Infection

Chest port infections most commonly occur in patients with compromised immune systems, immunosuppression, and chemotherapy related neutropenia. The onset of a port infection can be recognized by numerous symptoms. Symptoms include a high fever (≥ 38.3°C or 101°F), redness, tenderness, and induration at port site. With neutropenic patients, sometimes the only detectable symptom of a port infection is fever and chills because of a lack of inflammatory responses.( Sanjeet Dadwal,2015)

The diagnostic workup of an infection includes at least two blood cultures, one from a peripheral vein and one from the port catheter, stool examination for C. difficile and other bacterial/protozoal microbes (if diarrhea is present),urine culture and urinalysis, a chest radiograph, respiratory samples for culture, and the aspiration or biopsy of any skin lesions.

Current Treatments

Figure 6. Photograph of the gauze packed excision site of a dual-lumen chest port pocket infection. 64 year old man with colon cancer. By Dr. Brian Funaki at the University of Chicago .

Conclusion

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References

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2017, Kenyon College.