EDITORIAL For reprint orders, please contact: [email protected]
Are biofilms responsible for the adverse effects experienced following soft-tissue fillers? “Using tissue filler without prophylactic antibiotics is a bit like driving a car: there is nothing wrong with not wearing your seatbelt as long as you do not hit anything.” Morten Alhede1,2 & Thomas Bjarnsholt*,1,2 Plastic and reconstructive surgery has been practiced for several thousand years, but real developments in this area started as a result of the trench warfare casualties that occurred during the First World War. Since then, the field has progressed quickly, and today, almost anything is possible. In particular, the insertion of implants and other foreign bodies is now a routine procedure; however, these foreign bodies are prone to microbial contamination, which results in a risk of persistent implant-associated infections. This article summarizes this area and advocates for a change in attitude towards the causes of adverse events following injections of tissue fillers. Tissue fillers Tissue fillers are injected as foreign bodies under the skin for aesthetic purposes, such as cosmetic surgery for lip augmentation and wrinkle smoothening and remodeling after trauma. Treatment with fillers is very common, and according to the American Society for Aesthetic Plastic Surgery, treatment with products based on hyaluronic
acid – such as Restylane® (Q-Med AB, Uppsala, Sweden) – constitutes the second-most popular nonsurgical cosmetic procedure in the USA [1] . Many different types of fillers are available, ranging from polymers to microparticles, and ranging from being permanent or semipermanent to temporary, referring to the grade of degradation and absorption of the gel inside the body over time. The cosmetic effect of easily degradable fillers and microparticles relies partially on a tissue response against the filler, but also on the degradation of the microparticles used in the filler. By contrast, in more permanent fillers, the filling effect relies on their volume per se and not as a consequence of the foreign body tissue response. It is estimated that up to one person in 100 who undergo filler injections will develop an unfortunate bacterial infection [2–6] . Such infections have proven to be very hard to treat and, in the worst-case scenario, may leave the person with a permanently disfigured face. If the initial adverse reactions of reddening and hardening are left
KEYWORDS
• bacteria • biofilms • chronic injection • tissue fillers
“It is estimated that up to one person in 100 who undergo filler injections will develop an unfortunate bacterial infection.”
Costerton Biofilm Center, Department of International Health, Immunology, & Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark 2 Department of Clinical Microbiology 9301, Juliane Mariesvej 22, Copenhagen University Hospital, Copenhagen, Denmark *Author for correspondence: [email protected] 1
10.2217/FMB.14.57 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(8), 931–933
part of
ISSN 1746-0913
931
Editorial Alhede & Bjarnsholt untreated, they often result in fistula formation and the discharge of pus and filler. These adverse events have been shown to be dependent on the degradability of the filler, with use of the permanent fillers more commonly leading to adverse events. Adverse reactions using tissue fillers ●●Are adverse reaction due to allergies?
“Interestingly, we found
that applying the antibiotics together with the bacteria when propagating the gels could prevent the bacterial growth and biofilm development.”
932
Despite fillers being cleared for toxicity and antigenicity before they are permitted for human use, an increasing number of patients are developing adverse events after their use, such as inflammatory swellings or nodules [7] . Many practitioners believe that these reactions are caused by a foreign body reaction towards the injected filler. Samples from the nodules at the site of injection are most often culture and PCR negative, and in addition, the inflammation tends to be low grade, and polymorphonuclear leukocytes are rarely observed. In addition, treatment of antibiotics is ineffective. These observations strongly indicate that the adverse events are caused by an autoimmune or allergic reaction towards the filler and are often treated with steroids or large doses of nonsteroidal anti-inflammatory drugs accordingly (in order to suppress the inflammatory process). Interestingly, the results often go against the intention and the inflammation is often worsened, with the formation of fistulas and abscesses. ●●Are adverse reaction due to bacteria?
This failure of steroid treatment led us to suggest that bacteria could be the cause of the adverse reactions, and not allergies, since the symptoms are similar to many other persistent biofilm infections [2,3,8] . The argument is further supported by the fact that the adverse events of tissue fillers often occur up to several years after the injection of the filler, which is unusual in allergic reactions, but often observed with biofilm infections [7,9,10] . In 2009, we published the first direct microscopic observations of bacteria in samples of patients experiencing adverse reactions towards tissue fillers (seven out of eight patients) [9] . The observed bacteria were organized into small clusters that are known as biofilms. Bacterial biofilms are known to cause low-grade but persistent inflammation in many other disorders, such as the chronic pulmonary infection in patients suffering from cystic fibrosis, chronic wounds, implant- and catheter-related infections and chronic otitis media, among others. The important hallmark of chronic, biofilm-based infections
Future Microbiol. (2014) 9(8)
is extreme resistance to antibiotics and a number of other conventional antimicrobial agents, as well as an extreme capacity to evade host defenses. In 2013, we published a follow-up study, this time including samples from 54 patients with adverse reactions towards tissue fillers [7] . In 53 out of the 54 patients, we could detect bacteria either by culturing, molecular techniques or microscopy. These two studies strongly indicate that that the presence of bacteria in biofilms explains the adverse reactions in combinations with tissue fillers, as well as the subsequent failure of antibiotic treatments and the strong adverse reactions when treated with steroids. However, a contradictory paper suggesting that tissue fillers did not support bacterial growth was published [11] . This led us to an in-depth in vitro and in vivo study of bacterial biofilm formation within tissue fillers and their treatment and prevention [12] . Treatment & prevention of adverse reactions For the in vitro study, we chose to use three different tissue fillers: a permanent (Aquamid® [Contura International, SØborg, Denmark]), a semipermanent (Radiesse® [Merz Aesthetics, CA, USA]) and a temporary filler (Restylane). They were all propagated with three different bacteria, namely Pseudomonas aeruginosa, Staphylococcus epidermidis and Propionibacterium acnes, in order to study the evidence for bacterial growth. All three fillers supported growth and we saw the development of bacterial biofilms that were all highly resistant to appropriate antibiotics. Interestingly, we found that applying the antibiotics together with the bacteria when propagating the gels could prevent the bacterial growth and biofilm development. Thus, it seemed that antibiotics were effective when administrated prior to the biofilm being formed (as is the case in most biofilm infections). To test this in vivo, we developed a mouse model where the tissue fillers where injected underneath the skin in the neck of the mice. In this mouse model, a chronic biofilm infection developed over 1 week, and as few as 10–30 bacteria were sufficient to establish a resistant biofilm infection eventually consisting of millions of bacteria as a result. Treatment of these infections with antibiotics was not possible, even at high continuous doses. Only when the antibiotics were injected at the same time as the contaminated gel did we observe beneficial effects. In line with the prevention of infection, we also prevented all adverse events, such as
future science group
Are biofilms responsible for the adverse effects experienced following soft-tissue fillers? inflammation and ulcers, by using prophylactic antibiotics [12] . In our experiments, we either contaminated the filler or the injecting needle. In real life, the bacteria are most likely injected when penetrating the skin, which harbors permanent bacterial flora of S. epidermidis and P. acnes, since these two bacterial species are the most commonly detected following adverse events. Conclusion Our results clearly indicate that adverse reactions following tissue filler injections are caused by bacterial biofilms and extreme care should thus be taken to prevent contamination during tissue filler injection. In addition, cosmetic practitioners need to know that side effects caused by bacteria are the most likely adverse events from filler procedures, not allergic reactions. This knowledge should discourage the use of steroids as a first choice of treatment, since it is actually the worst possible treatment one could implement against such an infection. Local steroid injections will exacerbate the condition and give the bacteria free rein. In order to minimize the chances of injecting bacteria with the filler, the skin has to be disinfected, and in particular, facial skin should be kept free of make-up for 1 month before the injection of fillers. In general, hygiene is very important. Several filler producers have realized that the gels can act as bacterial incubators and suggest preventative actions before injection [13] . However, since the bacteria on the skin are often in the pores and below the surface, prophylactic References 1
2
3
4
PressCenter. The American Society for Aesthetic Plastic Surgery reports Americans spent largest amount on cosmetic surgery since the great recession of 2008. www.surgery.org/media/news-releases/ the-american-society-for-aesthetic-plasticsurgery-reports-americans-spent-largestamount-on-cosmetic-surger Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E. Adverse reactions to injectable soft tissue permanent fillers. Aesthetic Plast. Surg. 29(1), 34–48 (2005). Christensen L, Breiting V, Vuust J, Hogdall E. Adverse reactions following injection with a permanent facialfiller polyacrylamide hydrogel (Aquamid): cause and treatment. Eur. J. Plast. Surg. 28(7), 464–471 (2006). Lemperle G, Gauthier-Hazan N, Lemperle M. PMMA-microspheres(Artecoll) for
future science group
antibiotics are recommended in order to prevent biofilm formation, even with the uttermost of care being taken during the procedure. Future perspective The market for reconstructive surgery is in its golden age and more and more people will choose the injection or insertion of foreign material for cosmetic purposes. Using tissue filler without prophylactic antibiotics is a bit like driving a car: there is nothing wrong with not wearing your seatbelt as long as you do not hit anything. If you do have an accident, however, it would be almost impossible to walk away unharmed. If tissue fillers are to be injected, we strongly recommend the procedure be carried out by an authorized practitioner, where the conditions are completely hygienic. Fillers should not be viewed as a standard beauty product, but rather as an implant, and it must be made clear to customers that they will always run a small risk of infection when undergoing such an invasive procedure. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. long-lasting correction of wrinkles: refinements and statisticalresults. Aesthetic Plast. Surg. 22(5), 356–365 (1998).
5
6
bacteria by FISH in culture-negative soft tissuefiller lesions. Dermatol. Surg. 35 1620–1624 (2009).
Maas CS, Papel ID, Greene D, Stoker DA. Complications of injectable synthetic polymers in facialaugmentation. Dermatol. Surg. 23(10), 871–877 (1997).
10 Hall-Stoodley L, Stoodley P, Kathju S et al.
Requena C, Izquierdo MJ, Navarro M et al. Adverse reactions to injectable aesthetic microimplants. Am. J. Dermatopathol. 23(3), 197–202 (2001).
11 Alijotas-Reig J, Miró-Mur F,
7
Christensen L, Breiting V, Bjarnsholt T et al. Bacterial infection as a likely cause of adverse reactions to polyacrylamide hydrogelfillers in cosmetic surgery. Clin.Infect. Dis. 56(10), 1438–1444 (2013).
8
Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol. Surg. 33(Suppl. 2), S168–S175 (2007).
9
Editorial
Bjarnsholt T, Tolker-Nielsen T, Givskov M, Janssen M, Chrsitensen L. Detection of
Towards diagnostic guidelines for biofilm-associated infections. FEMS Immunol. Med. Microbiol. 65(2), 127–145 (2012). Planells-Romeu I, Garcia-Aranda N, Garcia-Gimenez V, Vilardell-Tarrés M. Are bacterial growth and/or chemotaxis increased by filler injections? Implications for the pathogenesis and treatment of filler-related granulomas. Dermatology 221(4), 356–364 (2010). 12 Alhede M, Er O, Eickhardt S et al. Bacterial
biofilm formationand treatment in soft tissue fillers. Pathog. Dis. 70(3) 339–346 (2014). 13 Aquamid®. Possible complications.
www.aquamid.com/physician/injectionguidelines/possible-complication
www.futuremedicine.com
933
Are biofilms responsible for the adverse effects experienced following soft-tissue fillers? “Using tissue filler without prophylactic antibiotics is a bit like driving a car: there is nothing wrong with not wearing your seatbelt as long as you do not hit anything.” Morten Alhede1,2 & Thomas Bjarnsholt*,1,2 Plastic and reconstructive surgery has been practiced for several thousand years, but real developments in this area started as a result of the trench warfare casualties that occurred during the First World War. Since then, the field has progressed quickly, and today, almost anything is possible. In particular, the insertion of implants and other foreign bodies is now a routine procedure; however, these foreign bodies are prone to microbial contamination, which results in a risk of persistent implant-associated infections. This article summarizes this area and advocates for a change in attitude towards the causes of adverse events following injections of tissue fillers. Tissue fillers Tissue fillers are injected as foreign bodies under the skin for aesthetic purposes, such as cosmetic surgery for lip augmentation and wrinkle smoothening and remodeling after trauma. Treatment with fillers is very common, and according to the American Society for Aesthetic Plastic Surgery, treatment with products based on hyaluronic
acid – such as Restylane® (Q-Med AB, Uppsala, Sweden) – constitutes the second-most popular nonsurgical cosmetic procedure in the USA [1] . Many different types of fillers are available, ranging from polymers to microparticles, and ranging from being permanent or semipermanent to temporary, referring to the grade of degradation and absorption of the gel inside the body over time. The cosmetic effect of easily degradable fillers and microparticles relies partially on a tissue response against the filler, but also on the degradation of the microparticles used in the filler. By contrast, in more permanent fillers, the filling effect relies on their volume per se and not as a consequence of the foreign body tissue response. It is estimated that up to one person in 100 who undergo filler injections will develop an unfortunate bacterial infection [2–6] . Such infections have proven to be very hard to treat and, in the worst-case scenario, may leave the person with a permanently disfigured face. If the initial adverse reactions of reddening and hardening are left
KEYWORDS
• bacteria • biofilms • chronic injection • tissue fillers
“It is estimated that up to one person in 100 who undergo filler injections will develop an unfortunate bacterial infection.”
Costerton Biofilm Center, Department of International Health, Immunology, & Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark 2 Department of Clinical Microbiology 9301, Juliane Mariesvej 22, Copenhagen University Hospital, Copenhagen, Denmark *Author for correspondence: [email protected] 1
10.2217/FMB.14.57 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(8), 931–933
part of
ISSN 1746-0913
931
Editorial Alhede & Bjarnsholt untreated, they often result in fistula formation and the discharge of pus and filler. These adverse events have been shown to be dependent on the degradability of the filler, with use of the permanent fillers more commonly leading to adverse events. Adverse reactions using tissue fillers ●●Are adverse reaction due to allergies?
“Interestingly, we found
that applying the antibiotics together with the bacteria when propagating the gels could prevent the bacterial growth and biofilm development.”
932
Despite fillers being cleared for toxicity and antigenicity before they are permitted for human use, an increasing number of patients are developing adverse events after their use, such as inflammatory swellings or nodules [7] . Many practitioners believe that these reactions are caused by a foreign body reaction towards the injected filler. Samples from the nodules at the site of injection are most often culture and PCR negative, and in addition, the inflammation tends to be low grade, and polymorphonuclear leukocytes are rarely observed. In addition, treatment of antibiotics is ineffective. These observations strongly indicate that the adverse events are caused by an autoimmune or allergic reaction towards the filler and are often treated with steroids or large doses of nonsteroidal anti-inflammatory drugs accordingly (in order to suppress the inflammatory process). Interestingly, the results often go against the intention and the inflammation is often worsened, with the formation of fistulas and abscesses. ●●Are adverse reaction due to bacteria?
This failure of steroid treatment led us to suggest that bacteria could be the cause of the adverse reactions, and not allergies, since the symptoms are similar to many other persistent biofilm infections [2,3,8] . The argument is further supported by the fact that the adverse events of tissue fillers often occur up to several years after the injection of the filler, which is unusual in allergic reactions, but often observed with biofilm infections [7,9,10] . In 2009, we published the first direct microscopic observations of bacteria in samples of patients experiencing adverse reactions towards tissue fillers (seven out of eight patients) [9] . The observed bacteria were organized into small clusters that are known as biofilms. Bacterial biofilms are known to cause low-grade but persistent inflammation in many other disorders, such as the chronic pulmonary infection in patients suffering from cystic fibrosis, chronic wounds, implant- and catheter-related infections and chronic otitis media, among others. The important hallmark of chronic, biofilm-based infections
Future Microbiol. (2014) 9(8)
is extreme resistance to antibiotics and a number of other conventional antimicrobial agents, as well as an extreme capacity to evade host defenses. In 2013, we published a follow-up study, this time including samples from 54 patients with adverse reactions towards tissue fillers [7] . In 53 out of the 54 patients, we could detect bacteria either by culturing, molecular techniques or microscopy. These two studies strongly indicate that that the presence of bacteria in biofilms explains the adverse reactions in combinations with tissue fillers, as well as the subsequent failure of antibiotic treatments and the strong adverse reactions when treated with steroids. However, a contradictory paper suggesting that tissue fillers did not support bacterial growth was published [11] . This led us to an in-depth in vitro and in vivo study of bacterial biofilm formation within tissue fillers and their treatment and prevention [12] . Treatment & prevention of adverse reactions For the in vitro study, we chose to use three different tissue fillers: a permanent (Aquamid® [Contura International, SØborg, Denmark]), a semipermanent (Radiesse® [Merz Aesthetics, CA, USA]) and a temporary filler (Restylane). They were all propagated with three different bacteria, namely Pseudomonas aeruginosa, Staphylococcus epidermidis and Propionibacterium acnes, in order to study the evidence for bacterial growth. All three fillers supported growth and we saw the development of bacterial biofilms that were all highly resistant to appropriate antibiotics. Interestingly, we found that applying the antibiotics together with the bacteria when propagating the gels could prevent the bacterial growth and biofilm development. Thus, it seemed that antibiotics were effective when administrated prior to the biofilm being formed (as is the case in most biofilm infections). To test this in vivo, we developed a mouse model where the tissue fillers where injected underneath the skin in the neck of the mice. In this mouse model, a chronic biofilm infection developed over 1 week, and as few as 10–30 bacteria were sufficient to establish a resistant biofilm infection eventually consisting of millions of bacteria as a result. Treatment of these infections with antibiotics was not possible, even at high continuous doses. Only when the antibiotics were injected at the same time as the contaminated gel did we observe beneficial effects. In line with the prevention of infection, we also prevented all adverse events, such as
future science group
Are biofilms responsible for the adverse effects experienced following soft-tissue fillers? inflammation and ulcers, by using prophylactic antibiotics [12] . In our experiments, we either contaminated the filler or the injecting needle. In real life, the bacteria are most likely injected when penetrating the skin, which harbors permanent bacterial flora of S. epidermidis and P. acnes, since these two bacterial species are the most commonly detected following adverse events. Conclusion Our results clearly indicate that adverse reactions following tissue filler injections are caused by bacterial biofilms and extreme care should thus be taken to prevent contamination during tissue filler injection. In addition, cosmetic practitioners need to know that side effects caused by bacteria are the most likely adverse events from filler procedures, not allergic reactions. This knowledge should discourage the use of steroids as a first choice of treatment, since it is actually the worst possible treatment one could implement against such an infection. Local steroid injections will exacerbate the condition and give the bacteria free rein. In order to minimize the chances of injecting bacteria with the filler, the skin has to be disinfected, and in particular, facial skin should be kept free of make-up for 1 month before the injection of fillers. In general, hygiene is very important. Several filler producers have realized that the gels can act as bacterial incubators and suggest preventative actions before injection [13] . However, since the bacteria on the skin are often in the pores and below the surface, prophylactic References 1
2
3
4
PressCenter. The American Society for Aesthetic Plastic Surgery reports Americans spent largest amount on cosmetic surgery since the great recession of 2008. www.surgery.org/media/news-releases/ the-american-society-for-aesthetic-plasticsurgery-reports-americans-spent-largestamount-on-cosmetic-surger Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E. Adverse reactions to injectable soft tissue permanent fillers. Aesthetic Plast. Surg. 29(1), 34–48 (2005). Christensen L, Breiting V, Vuust J, Hogdall E. Adverse reactions following injection with a permanent facialfiller polyacrylamide hydrogel (Aquamid): cause and treatment. Eur. J. Plast. Surg. 28(7), 464–471 (2006). Lemperle G, Gauthier-Hazan N, Lemperle M. PMMA-microspheres(Artecoll) for
future science group
antibiotics are recommended in order to prevent biofilm formation, even with the uttermost of care being taken during the procedure. Future perspective The market for reconstructive surgery is in its golden age and more and more people will choose the injection or insertion of foreign material for cosmetic purposes. Using tissue filler without prophylactic antibiotics is a bit like driving a car: there is nothing wrong with not wearing your seatbelt as long as you do not hit anything. If you do have an accident, however, it would be almost impossible to walk away unharmed. If tissue fillers are to be injected, we strongly recommend the procedure be carried out by an authorized practitioner, where the conditions are completely hygienic. Fillers should not be viewed as a standard beauty product, but rather as an implant, and it must be made clear to customers that they will always run a small risk of infection when undergoing such an invasive procedure. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. long-lasting correction of wrinkles: refinements and statisticalresults. Aesthetic Plast. Surg. 22(5), 356–365 (1998).
5
6
bacteria by FISH in culture-negative soft tissuefiller lesions. Dermatol. Surg. 35 1620–1624 (2009).
Maas CS, Papel ID, Greene D, Stoker DA. Complications of injectable synthetic polymers in facialaugmentation. Dermatol. Surg. 23(10), 871–877 (1997).
10 Hall-Stoodley L, Stoodley P, Kathju S et al.
Requena C, Izquierdo MJ, Navarro M et al. Adverse reactions to injectable aesthetic microimplants. Am. J. Dermatopathol. 23(3), 197–202 (2001).
11 Alijotas-Reig J, Miró-Mur F,
7
Christensen L, Breiting V, Bjarnsholt T et al. Bacterial infection as a likely cause of adverse reactions to polyacrylamide hydrogelfillers in cosmetic surgery. Clin.Infect. Dis. 56(10), 1438–1444 (2013).
8
Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol. Surg. 33(Suppl. 2), S168–S175 (2007).
9
Editorial
Bjarnsholt T, Tolker-Nielsen T, Givskov M, Janssen M, Chrsitensen L. Detection of
Towards diagnostic guidelines for biofilm-associated infections. FEMS Immunol. Med. Microbiol. 65(2), 127–145 (2012). Planells-Romeu I, Garcia-Aranda N, Garcia-Gimenez V, Vilardell-Tarrés M. Are bacterial growth and/or chemotaxis increased by filler injections? Implications for the pathogenesis and treatment of filler-related granulomas. Dermatology 221(4), 356–364 (2010). 12 Alhede M, Er O, Eickhardt S et al. Bacterial
biofilm formationand treatment in soft tissue fillers. Pathog. Dis. 70(3) 339–346 (2014). 13 Aquamid®. Possible complications.
www.aquamid.com/physician/injectionguidelines/possible-complication
www.futuremedicine.com
933
