Volume 3 Issue 1

INTRAVASCULAR CATHETERS AND BLOODSTREAM INFECTIONS 

Intravascular catheters (IVCs) are one of the most common medical devices used in hospitals. IVCs have various purposes, including haemodynamic monitoring, nutrition supplements, and medicine administration. It is estimated that nearly 300 million IVCs are used annually in the USA¹. IVCs are, however, often associated with serious IVC-related bloodstream infection (IVC-BSI), which leads to high morbidity and mortality². Over 40,000 IVC-BSIs occur annually in Australia³, and over 250,000 in the USA, with reported costs up to US$2.68 billion annually⁴.

The microorganisms that cause IVC-BSI attach on the catheter surfaces, form a biofilm, and then enter the sterile bloodstream to cause infection. Catheter hubs and insertion sites are the two main entrances for contamination. For short-term catheters, skin contamination at the insertion site is the likely entrance for pathogens, while catheter hub contamination is more likely for long-term catheters⁵. Biofilm formation on catheters is characterised by four stages (see Figure 1). Firstly, bacteria adhere to the external and internal surfaces of catheters⁶, which are the two principal niches for bacterial colonisation in IVC-BSI⁷. Secondly, bacteria aggregate to form microcolonies and produce a matrix to form the skeleton of biofilm⁸. Bacteria will colonise sustainably until biofilm has maturated, and the microbes inside have high resistance to antimicrobial agents and traditional therapy becomes ineffective^9,10. Finally, microbes are released from maturated biofilm by either shedding or biofilm dispersal and enter into the bloodstream, potentially leading to serious infections¹¹. 


Figure 1: Biofilm formation process

Biofilm dispersal allows bacteria from the biofilm to spread throughout the bloodstream and colonise in other parts of the body to establish new biofilms, which eventually can lead to systemic bloodstream infection (BSI)¹². After biofilms have been established on a catheter, pathogens inside will exhibit tolerance to antimicrobial agents and will not respond consistently to therapeutically achievable concentrations of antimicrobial agents⁶. More importantly, biofilm infections on intravascular catheters are usually polymicrobial, which can cause worse clinical conditions than mono-biofilm¹³, and mortality due to polymicrobial infections is higher than that of mono-specie infections¹⁴. Polymicrobial biofilm infections are generally more difficult to treat, as they can exhibit increased antimicrobial resistance to antibiotics compared to mono-biofilm¹⁵. Conventional treatment of systemic IVC-BSI usually requires catheter salvage, exchange or removal, and antibiotic therapy, based on empiric therapy and culture reports of removed catheters⁵. Traditional therapy turns out to be inconvenient, costly, and often ineffective, thus in-depth investigations on biofilm and new strategies to control biofilm formation and development are needed.

BIOFILM CHARACTERISTICS

Biofilms are a three-dimensional multicellular community, consisting of an extracellular polymeric matrix and adherent bacteria¹⁶. The raw material of the extracellular polymer matrix is extracellular DNA, which is mainly produced by bacterial genomic DNA through cell lysis¹⁷. Microorganisms embedded in biofilms often present different phenotypic and genotypic characteristics compared with those in the planktonic (free-living) state. Firstly, biofilms make use of the nutrient concentrative effect¹⁸ to facilitate nutrition. The biofilm matrix is also negatively charged and hydrophobic, which enables biofilm to concentrate ions and organic carbon agents as an energy source¹⁹. Additionally, there are nutrient gradients of various growth factors in a biofilm system, including oxygen, sulfide and carbon¹⁹. For example, moving from the outside surface to the interior of the biofilm, the oxygen level decreases dramatically from the aerobic zone to the anaerobic zone. Oxygen gradients provide a broader range of habitats available for different bacteria colonisation and protect the inner bacteria by decreasing the efficacy of antimicrobial agents²⁰. More importantly, gene expression of bacteria grown in biofilm exhibit huge differences compared with their planktonic counterparts. In a study conducted in 2002²¹, more than 800 proteins (over 50% of the proteome) of Pseudomonas aeruginosa maturated biofilm cells were shown to have a six-fold or larger change in expression level compared with that of P. aeruginosa planktonic cells.

MICROBIAL RESISTANCE AND QUORUM SENSING

Microorganisms within biofilm exhibit tolerance to various antimicrobial agents, including antibiotics, disinfectants and germicides²². In addition, a biofilm can show tolerance to phagocytosis and other aspects of the immune system²³. Biofilm resistance is usually multifactorial. In one biofilm system, slow antibiotic penetration, low metabolic rate, steep gradients, enhanced gene expression and persister cells cooperate to establish a multi-layered resistance²⁴. For example, biofilm is too compact to be penetrated by antimicrobial agents. At the same time, slow penetration gives bacteria extra time to initiate stress responses, including slowing down their own metabolism. As previously described, the oxygen gradient, which alters the environment in biofilm, also decreases the efficacy of antibiotics²⁰. Different microbial species may cooperate to reduce the susceptibility to antimicrobial agents. This can be seen when Staphylococcus epidermidis and Candida albicansgrow in a biofilm together; the staphylococcal matrix can protect the yeast cells from azoles (antifungal drugs), while the matrix produced by the yeast also reduces the activity of vancomycin against the bacteria²⁵. 

When bacteria live in biofilm, their colonisation and most of the virulent activities are regulated by a central system called quorum sensing (QS). Quorum sensing is the regulation of gene expression by chemical signal molecules called autoinducers, and this process responds to the concentration of environmental bacteria²³. Once the concentration reaches a critical value, QS receptors can receive the autoinducer and initialise the gene expression (see Figure 2). 

Figure 2: Mechanism of quorum sensing




FREQUENTLY IVC ISOLATED PATHOGENS

Most IVC-BSIs are caused by Staphylococci, especially S. epidermidis and S. aureus, followed by Enterococci, aerobic Gram-negative bacilli and yeast⁴. S. epidermidis is the most common isolated pathogen in IVC-BSI². The virulence of S. epidermidis is mostly due to its ability to readily colonise and form biofilm on catheters²⁶, leading to BSI and associated bacteremia. Approximately 80–90% of S. epidermidis isolated from patients with BSI carry the methicillin-resistant gene mecA, which can provide S. epidermidis with multi-resistance to a number of antimicrobial agents^27,28. Additionally, the mecA gene seems to be over-expressed when grown in a biofilm, leading to strong multi-resistance²⁸.

Compared with S. epidermidis, S. aureus is a more virulent pathogen, with higher rates of bacteremia and mortality²⁹. At the same time, S. aureus biofilm-associated infections are more difficult to treat and catheters need to be replaced more frequently than with S. epidermidisinfections²⁶. The virulence of S. aureus is due to its production of adhesions, pathogenic enzymes, and exotoxins, while S. epidermidis does not encode for these virulence factors³⁰. Methicillin-resistant S. aureus (MRSA), the most virulent and highly antimicrobial resistant strain of S. aureus, is highly prevalent in hospitals worldwide. The isolated rate of MRSA varies dramatically (P < 0.0001) from 22.5% in Western Australia to 43.4% in New South Wales/Australian Capital Territory³¹. The strong resistance of MRSA is mainly due to mecA gene, making it highly resistant to most common antibiotics^32,33. 

C. albicans is the most frequently isolated fungal pathogen in IVC-BSI. C. albicans is the fourth leading cause of BSI overall and is associated with the highest mortality^34,35. In addition, nearly 25% of patients with candidaemia also have an associated bacteraemia³⁶. The strong virulence of C. albicans in IVC-BSI is largely due to the ability of C. albicans to readily form biofilms on IVCs³⁷. Furthermore, the hyphae of C. albicans show a strong propensity to invade the human tissues, probably facilitating the invasion of other bacteria and leading to more serious infection³⁸. C. albicans biofilm is highly resistant to most antifungal drugs, especially azoles³⁹. One study shows nearly one-third of the oral C. albicans strains isolated from HIV patients possess strong azole resistance³⁹. Compared with planktonic fungal cells, the minimum inhibitory concentrations (MICs) of biofilm-forming C. albicans increased 30 to 20,000-fold⁴⁰. 

Polymicrobial infections can cause worse clinical conditions than monomicrobial infections¹³, and it is estimated that mortality due to polymicrobial infections is twice that of monomicrobial infections¹⁴. Bacteria-fungal infection has become a serious clinical problem in recent years. The most prevalent fungal biofilm-forming pathogen is C. albicans, and it is estimated that 27–56% of C. albicans BSIs are polymicrobial³⁷. In a survey of 372 patients with candidaemia, the three most commonly co-isolated bacterial species were S. epidermidis, Enterococcus spp., and S. aureus, and their combination usually causes more serious clinical conditions¹³. S. aureus is the third most common organism isolated in conjunction with C. albicans²⁹, and its resistance to vancomycin is significantly enhanced by coating the matrix of C. albicans²⁹. At the same time, the invasive properties of yeast hyphae also help the invasion of both C. albicans and S. aureus, leading to more serious bacteria-fungal infection.

CONCLUSION

Polymicrobial biofilms are often involved in IVC-BSI. Polymicrobial biofilms are more virulent and difficult to treat, compared to mono-biofilms or their planktonic states. Biofilm infections are characterised by chronic infections, as they are difficult to treat completely, which is why IVCs must be removed when patients are suspected of BSI. While many studies have described biofilms, there are still deficits in our understanding of the mechanism of biofilm formation and multifactorial antimicrobial resistance. Therefore, it is urgent to increase our understanding of microbial biofilm on IVCs and develop new therapies to treat and prevent IVC-BSI. Preventative strategies might include phage therapy, impregnating catheters with antibiotics, and antibiotic lock therapy. Furthermore, exploring new biomaterials might also have the potential to inhibit early stages of biofilm formation and prevent IVC-BSI without increasing antimicrobial resistance. 

 

Author(s)

Dou Yang Zhao AVATAR Group, Menzies Health Institute Queensland, Griffith University, Brisbane, Qld, Australia School of Nature Sciences, Griffith University, Brisbane, Qld, Australia Jeremy Brownlie School of Nature Sciences, Griffith University, Brisbane, Qld, Australia Timothy Wells The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Qld, Australia Li Zhang* AVATAR Group, Menzies Health Institute Queensland, Griffith University, Brisbane, Qld, Australia * Corresponding author Li Zhang, N48 Nathan Campus, Griffith University, 170 Kessels Road, Nathan, Qld 4111, Australia Tel: +61 7 3735 7272 Fax: +61 7 3735 3560 li.zhang@griffith.edu.au. Pages 11-14

References

1. Edgeworth J. Intravascular catheter infections. J Hosp Infect 2009; 73(4):323–30.
2. Zhang L, Gowardman J & Rickard CM. Impact of microbial attachment on intravascular catheter-related infections. Int J Antimicrob Agents 2011; 38(1):9–15.
3. Halton KA, Cook D, Paterson DL, Safdar N & Graves N. Cost-effectiveness of a central venous catheter care bundle. PLoS One 2010; 5(9).
4. Shah H, Bosch W, Thompson KM & Hellinger WC. Intravascular catheter-related bloodstream infection. Neurohospitalist 2013; 3(3):144–51.
5. Bouza E, Burillo A & Munoz P. Catheter-related infections: diagnosis and intravascular treatment. Clin Microbiol Infect 2002; 8(5):265–74.
6. Donlan RM. Biofilm elimination on intravascular catheters: important considerations for the infectious disease practitioner. Clin Infect Dis 2011; 52(8):1038–45.
7. Widmer AF. [Infections and sepsis from intravascular catheters]. Internist (Berl) 2005; 46(6):643–51.
8. Aslam S. Effect of antibacterials on biofilms. Am J Infect Control 2008; 36(10):S175 e9–11.
9. Stewart P, Mukherjee P & Ghannoum M. Biofilm antimicrobial resistance. Microbial Biofilms 2004; 1.
10. Mermel LA, Farr BM, Sherertz RJ, Raad, II, O'Grady N, Harris JS et al. Guidelines for the management of intravascular catheter-related infections. J Intraven Nurs 2001; 24(3):180–205.
11. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49(1):1–45.
12. Kaplan JB. Biofilm dispersal: mechanisms, clinical implications, and potential therapeutic uses. J Dent Res 2010; 89(3):205–18.
13. Klotz SA, Chasin BS, Powell B, Gaur NK & Lipke PN. Polymicrobial bloodstream infections involving Candida species: analysis of patients and review of the literature. Diagn Microbiol Infect Dis 2007; 59(4):401–6.
14. McKenzie FE. Case mortality in polymicrobial bloodstream infections. J Clin Epidemiol 2006; 59(7):760–1.
15. Peters BM, Jabra-Rizk MA, O'May GA, Costerton JW & Shirtliff ME. Polymicrobial interactions: impact on pathogenesis and human disease. Clin Microbiol Rev 2012; 25(1):193–213.
16. Percival SL & Kite P. Intravascular catheters and biofilm control. J Vasc Access 2007; 8(2):69–80.
17. Flemming HC & Wingender J. The biofilm matrix. Nat Rev Microbiol 2010; 8(9):623–33.
18. Beveridge TJ, Makin SA, Kadurugamuwa JL & Li Z. Interactions between biofilms and the environment. FEMS Microbiol Rev 1997; 20(3–4):291–303.
19. Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis 2002; 8(9):881–90.
20. Borriello G, Werner E, Roe F, Kim AM, Ehrlich GD & Stewart PS. Oxygen limitation contributes to antibiotic tolerance of Pseudomonas aeruginosa in biofilms. Antimicrob Agents Chemother 2004; 48(7):2659–64.
21. Sauer K, Camper AK, Ehrlich GD, Costerton JW & Davies DG. Pseudomonas aeruginosadisplays multiple phenotypes during development as a biofilm. J Bacteriol 2002; 184(4):1140–54.
22. Morales M, Mendez-Alvarez S, Martin-Lopez JV, Marrero C & Freytes CO. Biofilm: the microbial "bunker" for intravascular catheter-related infection. Support Care Cancer 2004; 12(10):701–7.
23. Hoiby N, Bjarnsholt T, Givskov M, Molin S & Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010; 35(4):322–32.
24. Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol 2002; 292(2):107–13.
25. Adam B, Baillie GS & Douglas LJ. Mixed species biofilms of Candida albicans and Staphylococcus epidermidis. J Med Microbiol 2002; 51(4):344–9.
26. Otto M. Staphylococcal biofilms. Curr Top Microbiol Immunol 2008; 322:207–28.
27. Sakumoto M, Matsumoto T, Mochida O, Mizunoe Y, Kumazawa J & Nagayama A. Distribution of a methicillin-resistance gene in urinary isolates of methicillin-resistant staphylococci examined by enzymatic detection of the polymerase chain reaction. Chemotherapy 1996; 42(5):329–33.
28. Cabrera-Contreras R, Morelos-Ramirez R, Galicia-Camacho AN & Melendez-Herrada E. Antibiotic resistance and biofilm production in Staphylococcus epidermidis strains, isolated from a tertiary care hospital in Mexico City. ISRN Microbiol 2013; 918–921.
29. Harriott MM & Noverr MC. Candida albicans and Staphylococcus aureus form polymicrobial biofilms: effects on antimicrobial resistance. Antimicrob Agents Chemother 2009; 53(9):3914–22.
30. Yarwood JM & Schlievert PM. Quorum sensing in Staphylococcus infections. J Clin Invest 2003; 112(11):1620–5.
31. Nimmo GR, Pearson JC, Collignon PJ, Christiansen KJ, Coombs GW, Bell JM et al.Prevalence of MRSA among Staphylococcus aureus isolated from hospital inpatients, 2005: report from the Australian Group for Antimicrobial Resistance. Commun Dis Intell Q Rep 2007; 31(3):288–96.
32. Ghafourian S, Mohebi R, Rezaei M, Raftari M, Sekawi Z, Kazemian H et al. Comparative analysis of biofilm development among MRSA and MSSA strains. Roum Arch Microbiol Immunol 2012; 71(4):175–82.
33. Wielders CL, Fluit AC, Brisse S, Verhoef J & Schmitz FJ. mecA gene is widely disseminated in Staphylococcus aureus population. J Clin Microbiol 2002; 40(11):3970–5.
34. Crump JA & Collignon PJ. Intravascular catheter-associated infections. Eur J Clin Microbiol Infect Dis 2000; 19(1):1–8.
35. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP & Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39(3):309–17.
36. Sychev D, Maya ID & Allon M. Clinical outcomes of dialysis catheter-related candidemia in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4(6):1102–5.
37. Kojic EM & Darouiche RO. Candida infections of medical devices. Clin Microbiol Rev 2004; 17(2):255–67.
38. Brand A. Hyphal growth in human fungal pathogens and its role in virulence. Int J Microbiol 2012; 517–529.
39. White TC, Holleman S, Dy F, Mirels LF & Stevens DA. Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob Agents Chemother 2002; 46(6):1704–13.
40. Hawser SP & Douglas LJ. Resistance of Candida albicans biofilms to antifungal agents in vitro. Antimicrob Agents Chemother 1995; 39(9):2128–31.