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Biofilm and Penile Prosthesis Infections in the Era of Coated Implants: A Review
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Biofilm and Penile Prosthesis Infections in the Era of Coated Implants: A Review jsm_2428
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Steven K. Wilson, MD, FACS, FRCS* and J. William Costerton, PhD, FRSC† *Institute for Urologic Excellence, Indio, CA, USA; †Center for Genomic Sciences, Allegheny-Singer Research Institute, Pittsburgh, PA, USA DOI: 10.1111/j.1743-6109.2011.02428.x
ABSTRACT
Introduction. The numbers of inflatable penile prosthesis (IPP) implanted has increased yearly due to the large numbers of patients treated for prostate cancer, patients becoming refractory to the five phosphodiesterase inhibitors and Peyronie’s disease. Aim. Prosthesis implantation can be associated with a variety of complications with device infection being the most dreaded one. Main Outcome Measures. An understanding of the pathogenesis of these infections is necessary to allow the surgeon to plan treatment. Methods. Infection begins with colonization of planktonic bacteria in the implant space. Biofilm forms around the bacterial mass within 48 hours. Bacteria in biofilm have reduced growth rates, may change phenotypically, and develop resistance to drugs. Antibiotics and the body’s macrophages will kill the planktonic bacteria released from the biofilm but never eliminate the infecting organisms. This review will delineate present thinking on infection prevention and biofilm’s role in device infection. IPP infection before and after the coated implants will be characterized. Future ideas for prevention and treatment of infection will be explored. Results. The coated implants have reduced the incidence of IPP infections. The bacteria that cause the majority of infections in the era of the coated implant seem to have changed from predominantly nosocomial coagulase-negative Staphylococcus to more virulent organisms. Device infection requires new paradigms of prevention and treatment strategy because the infecting bacteria are different and the patients are sicker. Conclusions. The problem of infection is considerably decreased with coated IPP, yet those infections that do occur are systemic in nature and seem to be caused by more aggressive organisms. These infections are not usually amenable to salvage because the virulence of the bacteria. Future research to prevent these infections must be directed to magnifying the effective dosage of antibiotics to penetrate the biofilm or eliminating the bacteria’s ability to secrete the slime. Wilson SK and Costerton JW. Biofilm and penile prosthesis infections in the era of coated implants: A review. J Sex Med 2012;9:44–53. Key Words. Infection; Biofilm; Penile Prosthesis; Antibiotics; Device; Penile Implant
Introduction
P
enile prosthesis implantation has played a role in the treatment of end-stage erectile dysfunction for the past 40 years. When medication like the phosphodiesterase inhibitors are contraindicated or ineffective, patients may choose the penile prosthesis as a solution to their impotence. Initially,
Funding: none.
J Sex Med 2012;9:44–53
semi-rigid rods were the most popular implant in the United States, but improved mechanical reliability and superior flaccidity/erection caused inflatable penile prosthesis (IPP) to become the most popular implant. The number of IPP placed yearly has steadily increased probably due to the growing number of prostate cancer survivors and the graying of our society. One study showed IPP to be preferred over pills or injections in patients who had experienced both therapies [1]. During the four © 2011 International Society for Sexual Medicine
Coated Penile Implants and Biofilm’s Impact on Infection decades of availability, the IPP has undergone continuous enhancements to improve its mechanical reliability. Currently, the revision rate of IPP for mechanical reason is among the lowest of all medical devices implanted in humans [2]. These prosthetic devices can be associated with a variety of complications of which infection is the most catastrophic. For the first 30 years of their availability, the incidence of infection for a first time (virgin) implant patient was quoted at 3–5% for patients without risk factors [3], 5–8% for people with diabetes [4], and 10% for revision operations [5]. In the last 10 years, infection retardant coatings have been added to the surface of the prosthetic components that have effectively decreased prosthetic infections by approximately 50% [6]. Prosthetic infections can be broken into two groups. The host response may be local with the patient presenting in a benign fashion more than 6–8 weeks postoperative (sometimes years later) with his pump stuck to the skin, a sinus tract weeping serous, odorless fluid or wound dehiscence. A more acute presentation can be characterized as systemic where the patient presents much earlier in the postsurgical course, is obviously ill with fever/chills, and may demonstrate a swollen scrotum draining purulent material. It is important to differentiate between the two types of infection because they have different bacteria as their etiology and different management strategies. This review will provide an overview of prevention ideas, etiology, pathophysiology, and management of penile prosthetic infections. Pathogenesis
The most common micro-organisms to cause infection are bacteria, although Candida albicans and other fungi have also been incriminated. What differentiates device infections from other infections occurring in man is the consistent formation of biofilm upon the surface of the components. The concept of bacterial formation of biofilms is necessary to understand the rationale for aggressive infection treatments. Biofilm formation by the infecting organisms is the reason conservative medical management is only rarely successful. Device infection begins with the contamination of the implant with micro-organisms before or during implantation. These organisms are considered “planktonic” as they swim individually in the spaces surrounding the implant components. As the bacteria begin to multiply, Costerton et al. envision
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a “race for the surface” [7] with the bacteria attempting to gain attachment to the surface of the components and the host trying to kill the organisms with macrophages and antibiotics given prior to the surgery. The bacteria are attempting to attach to the implant surfaces by secreting adhesion molecules that allow them to attach irreversibly to the implant. These attached microcolonies produce extracellular polymers and matrix formation that define a biofilm [8]. Its structure is heterogeneous both in space and over time, with channels that allow the transport of nutrients, water, and oxygen [9]. The ability, rate, and extent of various bacteria to adhere to foreign bodies are dependent on the composition of the foreign body material and on the specific bacterial species (Figure 1). Biofilms provide protection by blunting the host immune response. This extracellular slime decreases the phagocytic and intracellular killing capacity of neutrophils and inhibits their proliferation [10]. Bacteria living in biofilms remain biochemically active but have reduced growth rates that diminishes their possible uptake of antibiotics. Biofilms also confer resistance to antibiotics. The biofilm mode of growth provides bacteria with the ability to resist antibiotics in concentrations up to 1,000 times that needed to kill their genetically similar planktonic forms [11]. Making the demise of bacteria even more difficult is the fact that within the biofilm, bacteria can exchange genetic material between their relatives or even different bacterial species. This formidable accomplishment perpetuates the biofilm and creates different phenotypes with antibiotic resistance [9–11]. It is very important to understand that bacteriology laboratories are usually only able to culture planktonic bacteria. The typical tissue swab taken at surgery for microbiological culture and sensitivity testing from patients are extrapolated from planktonic free-floating bacteria that are very different from bacteria in the biofilm mode of growth [12]. The bacteria deep in layers of biofilm that have actually caused the immune response of the host that clinicians recognize as implant infection are metabolically inactive and resistant to drugs. To date, no standardized methods to retrieve biofilm-protected organisms and no antimicrobial sensitivity tests are available to evaluate drug activity against these adherent, protected bacteria [11]. In summery, after implantation of the IPP, bacteria and host cells compete for colonization of the device surfaces. If the bacteria are able to successfully attach and undergo biofilm formation, they will be able to prevent the host’s attempts at eradiJ Sex Med 2012;9:44–53
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Wilson and Costerton
Figure 1 Biofilm found on clinically uninfected implant components.
cation. The colonized and protected bacteria will become resistant to antimicrobials and host defense mechanisms because of a variety of reasons including protection by the slime, lowered metabolic activity, and the ability to change phenotype into an organism exhibiting drug resistance when compared with its planktonic cousin. Prevention of Implant Infection
Clinicians across many specialties have strived to reduce the incidence of implant infection. Attempts at prevention have focused on perioperative antibiotics, conduction of the surgical procedure, proper patient selection, and pretreating the patient and operative site. Perioperative antibiotic prophylaxis is used routinely to minimize the risk of implant infection although few randomized, placebo controlled trials addressing the efficacy of such a practice have been conducted. The current American Urological Association guidelines suggest prophylactic antibiotics in prosthetic surgery. The guidelines suggest vancomycin and gentamicin [13], although there is concern among some institutions that a second generation cephalosporin should be substituted for vancomycin because of possible emergence of resistant strains of Enterococcus [14]. Historically, it was suggested that poorly controlled people with diabetes as manifested by high fasting blood sugar and elevated glycosolated hemoglobin had an unnecessarily high rate of infection. The thinking was that the surgery should be postponed until the patient’s diabetic control was J Sex Med 2012;9:44–53
better [15]. A subsequent larger series demonstrated that the presence of diabetes increased the risk of infection from 4% to 8% when compared with a patient without this risk factor. Nevertheless, control of diabetes as manifested by Hemoglobin A1C (HGB A1C), fasting blood sugar, or insulin dependence did not adversely or positively affect the risk of device infection [4]. In this larger study, there was no difference in the rate of infection among well-controlled or poorly controlled people with diabetes. Manipulation of the operating room environment dates back as early as Brantley Scott, the inventor of IPP, who developed a positive pressure apparatus that required the surgeon to operate through ports much like taking care of an infant in an incubator. Orthopedic surgeons are fond of laminar flow systems believing the system decreased the number of ambient bacteria. In prosthetic urology, Eid has popularized his “no touch” technique of IPP surgery. In this discipline, the surgeon makes an incision and then walls off the opening from the surrounding skin with a plastic drape. By this means, the components are prevented from being touched by the patient’s skin. Siegrist reduced his rate of infection from 2% to 0.7% by combining the “no touch” technique with coated implants [16]. Corpora cavernosa are quite vascular, and the scrotum is an ideal organ for blood collection. Use of a tissue drain for 24 hours is recommended by many implanters to prevent scrotal hematoma. Sadeghi-Nejad et al. found the rate of implant infection to be unchanged when compared with
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Coated Penile Implants and Biofilm’s Impact on Infection patients not drained but the rate of hematoma was reduced significantly [17]. A group of clinicians from the Netherlands swabbed patient’s noses looking for Staphylococcus aureus before all types of major surgery (not specifically implant surgery). If S. aureus was detected, the patient applied an antibiotic ointment to his nose and showered with chlorhexidine for 5 days prior to the surgery. These patients had a 60% less chance of infection than those Staphylococcus carriers that were treated with placebo [18]. Henry et al.’s study of treating nasal carriage of Staphylococcus prior to IPP implantation showed reduction of infection when the contaminated noses were treated preoperatively [19]. Darouiche et al. recently published work on surgical site infection reduction targeting the patient’s skin. Traditionally, urological surgeons have painted the surgical site with povidone-iodine solution, but this study reported a 41% reduction in superficial and deep incision infections by preparing the skin with an alcohol-based chlorhexidine swab rather than the traditional solution [20]. While their study did not specifically study implant operations, Carrion et al. presented data on the use of similar swabs that decreased culture positivity of the skin in patients receiving IPP [21]. While the majority of specialists in the orthopedic and plastic surgery disciplines perform their respective implants, urologists performing IPP surgery are a distinct minority. Orthopedists and plastic surgeons in United States do hundreds of thousands of implants, while urologists do approximately 20,000. On a global basis, a recent study showed of 76 surgeons performing a total of 413 penile implants in a 2-year period in England, 80% performed fewer than two IPPs a year [22]. Those doing implants represented approximately only 15% of UK urologists. Henry et al. reported significantly higher infection rates in the hands of an occasional surgeon vs. a prolific center [23]. Klausner et al. noted marked improvement in outcomes and a decreased infection rate for residents who were properly trained and had considerable experience performing the surgery in contrast to the occasional implanting resident surgeon [24]. For the first 30 years of their existence, the incidence of infection for IPP has been approximately 50% higher than following the introduction of infection retardant coated devices. Infection retardant coatings applied to the American Medical Systems, Minnetonka MN, USA (AMS) IPP in early 2001 [25] and to the Coloplast IPP (Corporation, Minneapolis, MN, USA) in late
2002 [26] are thought to be responsible for this reduction. The infection retardant coatings of the AMS and Coloplast devices are quite different. The AMS IPP InhibiZone coating of rifampin and minocycline is impregnated during the device’s manufacture and the antibiotics primarily elute into the spaces surrounding the components for 72 hours after implantation with a trace of antibiotics present after 3 weeks. During InhibiZone’s development, the antibiotics were tested in vitro against what was then the most common infecting organism, Staphylococcus epidermidis. The Coloplast approach to infection control is dissimilar and allows the physician flexibility of drug choice. After manufacturing of the components, a hydrophilic coating is covalently bonded to all implant surfaces. This coating adsorbs 14 times its weight when dipped in an aqueous solution creating a lubricious component designed to deter bacterial attachment. Bacteria cannot be adsorbed due to the large molecular size of the organisms. If the dip solution contains medications, these drugs are adsorbed superficially to subsequently elute into the implant spaces. Current Knowledge of Biofilm with Penile Prosthesis
Since 2001, there have been multiple studies from a multi-institutional group with Henry as the lead author showing the majority of penile implants patients have organisms residing in the implant spaces despite the patient having no overt signs or symptoms of clinical infection [27]. When penile prosthesis patients undergo a secondary operation for mechanical breakage or medical reasons (other than infection), a variety of nosocomial organisms can be cultured from the implant spaces and biofilm can occasionally be seen with the naked eye (Figure 1). Cultures of the capsule surrounding the implant will also show culture positivity in most cases [28]. Cultures of tissue swabs of the implant spaces of these patients revised for mechanical breakage will typically grow coagulase-negative Staphylococcus (CoNS) [29]. When implant components from clinically uninfected patients are subjected to confocal electron microscopy, most specimens show biofilm and bacteria attached to the surface [30]. This presence of biofilm-protected organisms is thought to be responsible for the 10% incidence of infection in revisions for mechanical failure. The use of infection retardant coated implants did not alter that statistic in one study unless washout J Sex Med 2012;9:44–53
48 accompanied substitution with coated implant. Wilson et al.’s single-surgeon study showed a lower rate of infection (2%) by using infection retardant coated implants in combination with complete component exchange and washout of the implant spaces with antiseptic solutions [31]. A more recent study based on manufacturer’s patient information forms showed revision surgery of noncoated implants to have a 3.5% infection rate and a reduction to 2.5% using a coated implant although no information about the presence or absence of washout was provided [32]. Our thinking is that the revision infections are caused by the biofilm protected organisms seeded into the spaces during the original implant operation, and the bacteria were protected from the antibiotic elution from the coated implant by its biofilm. Washout removed the bacteria and its products from the spaces, while component exchange substituted a new sterile implant uncontaminated by attached biofilm protected organisms [33]. Tissue swab collection and culture in a bacteriological laboratory in today’s conventional method showed 70% of patients grew a variety of CoNS when noncoated implant patients were cultured [27]. The use of coated implants seems to have lowered the positive CoNS culture rate using the same culture methods. Kava et al. found CoNS could still be grown in patients undergoing revision for mechanical cause when tissue swabs of coated implants were collected but culture positivity dropped to 10% of 72 patients [34]. Penile Prosthesis Infections
Implant infections can be broken out into two distinct presentations. Local infections present a considerable amount of time from the surgical implantation. This local type of infection demonstrates components, e.g., pump or tubing stuck to the skin, a small sinus tract draining serous material, vague pain upon inflation, or partial dehiscence of the surgical incision with component visible in the wound. The patients are not acutely ill, white count and sedimentation rate are not elevated, and there is no fever or chills. This clinical picture typically presents at least 6–8 weeks following implantation and may present many years later. The usual infecting organism is CoNS particularly S. epidermidis and Staphylococcus lugdunensis (Figure 2). Systemic infection presents much more quickly in the clinical course following surgical implantation. These patients exhibit rubor and swelling of J Sex Med 2012;9:44–53
Wilson and Costerton
Figure 2 Local infection from Staphylococcus epidermidis: tubing stuck to scrotal skin.
the scrotum. There may be frank pus coming from the incision, fever, chills, and malaise. Laboratory examination indicates elevated white count and even positive blood cultures. These patients are visibly ill and may be toxemic. Cultures obtained by tissue swab typically grow more aggressive organisms rather than common nosocomial ones: Enterococcus, S. aureus, Pseudomonas, Escherichia coli, and Serratia. It is believed that these more virulent organisms penetrate the tissues surrounding the implant resulting in systemic symptoms and signs while the skin organism multiplication remains local in the tissue spaces surrounding the implant components (Figure 3). In the era of the noncoated implant, we noted implant infections occurred in 4% of virgins [3], 8% of people with diabetes [4], and 10% of revision operations [5]. The infections were caused by CoNS and other nosocomial organisms in approximately 75% of implant patients [35] when cultured by tissue swab. These patients exhibited a local infection presentation, were not particularly ill, and were good candidates for salvage operations. Salvage operation preserves the implanted status and avoids both penile shortening and the difficult reinsertion of the implant into scarred corporal bodies. Salvage operation of infected IPP involves complete removal of all the infected implant components, lavage with antiseptic solutions, and exchange of the gowns, gloves, surgical instruments and placement of a new sterile implant during the same operative procedure. Mulcahy reported 80–90% success using noncoated implants if patient selection was confined to local rather than systemic presentation [36]. During the past 8 years of availability of infection retardant coated implants, the incidence of
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Coated Penile Implants and Biofilm’s Impact on Infection
Figure 3 Systemic infection: purulence from wound.
implant infection has dropped drastically. With the advent of the coated implant, multiple studies of thousands of patient information forms tabulated by the manufacturers show infection rates using coated implants to be reduced to 2% for virgin people with diabetes [37]. One percent for virgin patients without risk factors [25] and 2.5% for revisions [32]. Single surgeon series confirm this infection reduction [31,38]. While the incidence of infection has been remarkably reduced by 50%, the preponderance of infections being seen with coated implants seems to be of a systemic presentation. As would be expected by this clinical picture, the bacteria are no longer a preponderance of skin organisms but are now aggressive species. Kava et al. studied nine implant infections in patients who had received coated implants. There were no CoNS infections. Instead, the infections were caused by toxic organisms like S. aureus, Enterobacter aerogenes in 6 patients and in 3 no organism could be cultured. All the patients developed quick acute infections within 3 months of the implant surgery. The patients were so sick that salvage was not performed [34]. Henry et al. compiled a multi-institutional group of 17 implant infections of patients receiving infection retardant coated implants and found a “non-traditional bacterial profile” with the majority of tissue swabs growing S. aureus, Enterococcus, E. coli, yeast, and a minority of CoNS [39]. This
same group also cultured clinically uninfected revisions of coated implants and found 63% of 40 had culture positivity with a preponderance of CoNS. Clinicians occasionally experience grossly infected implants, cultured at surgery that failed to grow any bacteria. Biofilm protected organisms are notoriously hard to culture using conventional bacteriology methods [40]. Bruner et al. reported a unique method of sonicating infected implant components to obtain the bacteria buried deep in the biofilm. This study showed four infected IPPs had CoNS positive tissue swabs. When the biofilm on the components was sonicated, however, “data from the biofilm culture added extended microbiology” with more virulent organisms found to be residing in the biofilm [41]. In summary, the type of bacteria causing implant infection seems to have changed in the era of the coated implant. Most infections in the noncoated era were nosocomial CoNS and presented in a local, nontoxic fashion. Today’s infections, while much less frequent than previously, usually have a systemic clinical picture and more aggressive organisms can sometimes be cultured. While the bacteria are difficult to culture because they are sheltered by biofilm, the patients present systemically sick, and the few studies available have cultured a preponderance of toxic organisms. It seems that the coated implants have decreased clinical infections from nosocomial CoNS and, indeed, also decreased the rate of incidental culture positivity during mechanical revision. The antibiotics utilized in the devices were aimed at CoNS, and they seem to have done their job eliminating most of the local infections. The challenge for the future is to more efficiently prevent infection with toxic organisms while retaining the protection from nosocomial bacteria that we have obtained with the use of infection-retardant coated implants. Prosthesis Infection Therapy
The presence of an IPP should be considered to be a foreign body to the recipient. Once implanted, the competition for host cell integration and bacterial adhesion begins. If the bacteria are able to adhere successfully, they will undergo biofilm production that alters their properties and renders them immune to antibiotics. For most of these presentations, the course is benign and clinical infection does not become manifest. At reoperation, for reasons other than infection (i.e., mechanical failure), conventional tissue swab may J Sex Med 2012;9:44–53
50 show nosocomial bacteria living in the implant surfaces regardless of whether a coated component is utilized. When better culture methods of penetrating biofilm are available, we believe most every implant will show evidence of bacterial adherence. It remains a mystery what makes the rare patient develop a clinical infection. When infections were predominantly of a local presentation and caused by skin bacteria in the era of the noncoated implant, salvage was frequently successful. We believe the reason salvage was beneficial is the skin organisms have low virulence, remain in the tissue spaces surrounding the components, and thus are susceptible to eradication if the implant is removed, the spaces washed with antiseptic solutions and a sterile implant placed. The use of infection retardant coatings has drastically reduced the incidence of clinical infection by nearly 50%. It seems that this reduction of infection has been accomplished by seriously impacting the nosocomial bacteria like S. epidermidis. It is acknowledged that 75% of infections in the noncoated era were skin organisms and the infection rate was 4%. In the coated implant era, the infection rate has been reduced to 1–2%. The infections occurring are usually aggressive organisms. These systemic infections are not as amenable to salvage as local infections with skin organisms, although Mulcahy has published a small series of salvage of toxic infections. In this study, intravenous antibiotics were given for 2–3 days, and the fluctuant scrotum was immediately drained. The thought was these maneuvers converted the systemic infection into one localized to the tissues surrounding the components and salvage could work [42]. The onset and clinical manifestations of device-related infections vary with the pathogen involved as well as which component is affected. Surgical removal of the device is always necessary. Limited types of IPP infections may have defined indications for when salvage therapy may be warranted as discussed above. With urologic prosthetics, conservative therapy for device infection, i.e., prolonged courses of antibiotics should be discouraged. Prolonged courses of antibiotics may kill the planktonic bacteria and improve the patient’s symptoms, but the foundation of infecting bacteria attached to the surfaces of the components is unaffected. In other surgical disciplines, there may be situations where removal surgery is contraindicated or inadvisable. For example, in orthopedic joint implant infections, J Sex Med 2012;9:44–53
Wilson and Costerton there may be situations where indefinite suppressive antimicrobial therapy may be appropriate to preserve the implanted status [43]. In our opinion, however, unlike orthopedic joint infections, the location of the penile prosthesis within the scrotum and the proximity of the urethra contraindicates leaving the infected implant in situ. Our experience has shown erosion of a component is virtually a certainty with prolonged antibiotics. Future Considerations
The amount of antibiotics that elute off an AMS rifampicin/minocycline-coated IPP is said to be less than an oral dose of either drug according to AMS training manuals. This small amount of antibiotic demonstrably does an admirable job of suppressing CoNS from creating overt clinical infections. It is apparent from recent studies that both the incidence of culturable benign coexistent bacteria [34,39] in the uninfected patient and outright limited infection with CoNS [6,25,31,37] is reduced. This coating also has activity against some of the more aggressive organisms when tested in the laboratory [44]. Despite this laboratory activity against organisms other than CoNS, the incidence of systemic infections, in our experience, with more virulent bacteria appears unchanged by these antibiotics. Perhaps the mass of drug that can be incorporated is insufficient for bactericidal or bacteriostatic effect on the toxic bacteria as the overall 50% reduction of infection appears to come from the drastic reduction of infections caused by skin organisms [32] and the more aggressive bacteria continue to cause clinical infections [34,39,41]. Antimicrobial impregnation has not been limited exclusively to antibiotics: silver has been used effectively against staphylococcal infections [45] as have chlorhexidine and other antiseptic solutions [46]. The Coloplast Titan hydrophilic coating is applied at the factory. The coated device may be exposed to an aqueous solution containing antibiotics or other drugs immediately before implantation. This allows the physician to tailor the drug elution by adding his drugs of choice to an aqueous solution. Dhabuwala recently published bacteriology studies dipping the Coloplast Titan in rifampin and gentamicin. He tested against S. epidermidis and E. coli. He found his dip created better zones of inhibition (ZOI) in agar plates than InhibiZone strips and better than Coloplast dipped in vancomycin and
Coated Penile Implants and Biofilm’s Impact on Infection gentamicin [47]. He also recently published his prospective series of almost 100 of each company’s implants with no significant difference in infection incidence using AMS InhibiZone and Coloplast dipped in rifampin/gentamicin. Most importantly, he had an overall incidence of less than 1% using the coated implants of both companies [38]. Wilson, Costerton, and Salem recently published anti-infection dip suggestions for the Coloplast Titan IPP in the era of the infection retardant coated implant [48]. We tested ZOI created by dipping the implant in a variety of “off the shelf” inexpensive generic antibiotics. We tested against the common skin organisms methicillin-resistant S. epidermidis and S. lugdunensis (CoNS) and against the more aggressive bacteria methicillinresistant S. aureus, Enterococcus, and Pseudomonas. When the Coloplast device was dipped in rifampin/ minocycline at concentrations approximating the AMS InhibiZone, there was no ZOI against Pseudomonas and only very weak ZOI against all of the more pathogenic nonskin bacteria. InhibiZone strips showed very similar small zones against these bacteria. Trimethoprim sulfamethoxazole was the most efficacious of the dip solutions tested with ophthalmic solution containing trimethoprim and polymixin B a close second. One 10 cc infusion vial of trimethoprim/sulfa-diluted 3:1 with saline was the recommendation. Trimethoprim/polymixin ophthalmic solution ZOI when diluted was ineffective and must be used in an undiluted concentration necessitating opening three 10-cc bottles [48]. While present-day coated implants have improved patient outcomes from the catastrophe of local infection, it would be useful to measure and identify specific bacteria causing the rare infection in recent IPP procedures using coated devices. Then it might be possible to further verify the more aggressive strains and consider appropriate mechanisms to thwart these organisms in future cases. It would stand to reason that biofilm production by the bacteria has become the target of the present-day studies. Research is being conducted to multiply the dosage of effective antibiotics eluting off the implant surfaces to penetrate the protective slime [40,49]. Another very promising avenue of research is biofilm inhibitors. If the bacteria’s ability to produce biofilm could be delayed or eliminated, the bacteria would remain in a planktonic state and be more susceptible to antibiotics and the host immune systems [50]. These so-called “biofilm blockers” would be very attractive drugs to elute off the implant surface.
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With elution of drugs that exhibit magnification of antibiotic strength and biofilm blockade, one might envision a future coated implant that had virtually no device infections. While the flexibility of the Coloplast hydrophilic coating stimulates interest in research for the ideal theoretic “dip,” there is no evidence, as yet, that tailoring the solution makes a difference in patient outcome. Conclusion
An implantation of this IPP must be considered a foreign body. The body and the bacteria compete to achieve prominence. If the bacteria attach to the implant surfaces, they form a biofilm that defies subsequent eradication. Fortunately, despite the fact that most implants will show culture positivity, it is distinctly rare in the era of coated implants that one will become infected. Coated IPPs have improved patient outcomes by decreasing the rate of implant infection by approximately one-half. The problem of infection is considerably decreased, yet those infections that do occur are systemic in nature and seem to be caused by more aggressive organisms than in the era of noncoated implants. These infections are usually not amenable to salvage because the virulence of the bacteria causes systemic manifestations. Removal of the infected implant results in patients with shortened penises and makes difficult the future implantation into scarred corporal bodies. Future research to prevent these remaining infections must be directed to magnifying the effective dosage of antibiotics to penetrate the biofilm or eliminating the bacteria’s ability to secrete the slime. Acknowledgments
We are indebted to John Mulcahy, MD, PhD, for editorial assistance and to Emad Salem, MD, for editorial assistance and facilitation of electronic submission Corresponding Author: Steven K. Wilson, MD, FACS, FRCS, Institute for Urologic Excellence, 81-719 Dr Carreon Blvd, Indio, CA 92201, USA. Tel: (760) 342-6657; Fax: (760) 342-6658; E-mail: skwilson@ mac.com Conflict of Interest: Wilson: consultant for Coloplast and AMS. Costerton: none. Statement of Authorship
Category 1 (a) Conception and Design Steven K. Wilson J Sex Med 2012;9:44–53
52 (b) Acquisition of Data Steven K. Wilson (c) Analysis and Interpretation of Data Steven K. Wilson; J. William Costerton
Wilson and Costerton
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Category 2 (a) Drafting the Manuscript Steven K. Wilson (b) Revising It for Intellectual Content Steven K. Wilson; J. William Costerton
Category 3
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(a) Final Approval of the Completed Manuscript Steven K. Wilson; J. William Costerton 20 References 1 Rajpurkar A, Dhabuwala CB. Comparison of satisfaction rates and erectile function in patients treated with sildenafil, intercavernousus prostaglandin E1 and penile implant surgery for erectile dysfunction in urology practice. J Urol 2003;170:159– 61. 2 Wilson SK, Delk JR, Salem EA, Cleves MA. Long-term survival of inflatable penile prosthesis: Single surgical group experience with 2,384 first-time implants spanning two decades. J Sex Med 2007;4:1074–7. 3 Jarow JP. Risk factors for penile prosthetic infection. J Urol 1996;156:402–6. 4 Wilson SK, Carson CC, Cleves MA, Delk JR 2nd. Quantifying risk of penile prosthesis infection with elevated glycosylated hemoglobin. J Urol 1998;159:1537–9. 5 Wilson SK, Henry GD, Delk JR, Cleves M. Prevention of infection in revision of penile prosthesis using antibiotic coated prosthesis and Mulcahy salvage protocol. J Urol 2003;169:325, abstract 1264. 6 Carson CC. Efficacy of antibiotic impregnation of inflatable prostheses in decreasing infection in original implants. J Urol 2004;171:1611–4. 7 Costerton JW, Stewart DS, Greemberg EP. Bacterial biofilms: A common cause of persistent infection. Science 1999;284:1318–28. 8 Jefferson KK. What defines bacteria to produce a biofilm? FEMS Microbiol Lett 2004;236:163–70. 9 Donlan RM. Biofilm formation: A clinically relevant microbiological process. Clin Infect Dis 2001;33:1387–92. 10 Von Eiff C, Heilmann C, Peters G. New aspects in the molecular basis of polymer-associated infections due to Staphylococcus. Eur J Clin Microbiol Infect Dis 1999;18: 843–61. 11 Costerton W, Veeh R, Shirtliff M, et al. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest 2003;112:1466–76. 12 Choong S, Whitfield H. Biofilms and their role in infection and urology. BJU Int 2000;86:935–7. 13 Wolf JS, Bennett CJ, Dmochowski R, et al. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol 2008;179:1379–93. 14 Trampuz A, Zimmerli W. Antimicrobial agents in orthopedic surgery: Prophylaxis and treatment. Drugs 2006;66:1089– 890. 15 Bishop JR, Moul JW, Sehelnik SA, et al. Use of glycosylated hemoglobin to identify diabetics at high risk for penile prosthetic infections. J Urol 1992;147:386–9. 16 Siegrist TC, Kwon EO, Fracchia JA, Eid JF. The no touch technique: A novel technique for reducing post-operative
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infections in patients receiving multi-component inflatable penile prosthesis. J Urol 2006;179:404, abstract 1173. Sadeghi-Nejad H, Ilbeigi P, Wilson SK, Delk JR, Siegel A, Seftel AD, Shannon L, Jung H. Multi institutional outcome study of the efficacy of closed section drainage of the scrotum in three-piece inflatable penile prosthesis surgery. Int J Impot Res 2005;17:535–8. Bode LG, Kluytmans JA, Werthelm HF, Bogaers D, Vandenbroucke-Grauls CM, Roosendaal R, Troelstra A, Box AT, Voss A, van der Tweel I, van Belkum A, Verbrugh HA, Vos MC. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med 2010;362:9–17. Silverstein A, Henry GD, Delk JR, Wilson SK, Donatucci CF. Nasal carriage of Staphylococcus aureus as a potential risk factor for infection after penile prosthesis placement. Int J Impot Res 2002;14(3 suppl):S61. Darouiche RO, Wall MJ, Itani KMF, Otterson MF, Webb AL, Carrick MM, Miller HJ, Awad SS, Crosby CT, Mosier MC, Alsharif A, Berger DH. Chlorhexidine alcohol vs. povidone iodine for surgical site antisepsis. N Engl J Med 2010;362:18– 26. Carrion RF, Hamoui O, Webster JC, Carrion H. Comparison of skin cultures before and after skin preparation using Betadine, Hibiclens, and Chloraprep prior to penile prostheses surgery. J Sex Med 2007;98:393. Agrawal V, Ralph D. An audit of implanted penile prostheses in the UK. BJU Int 2006;98:393–6. Henry GD, Kansal NS, Callaway M. Centers of excellence concept and penile prostheses. J Urol 2009;181:1264– 7. Klausner AP, Johnson CM, Cost CP. Expert training with standardized operative technique helps establish a successful penile prosthetics program for urologic resident education. J Urol 2009;181:825, abstract 2277. Carson CC, Mulcahy JJ. 7-year infection related revision rates for naive inflatable penile prosthesis implants: Antibiotic impregnated vs. non-impregnated. J Urol 2010;183:e488, abstract 1262. Wolter CE, Hellstrom WJG. The hydrophilic-coated inflatable penile prosthesis: 1-year experience. J Sex Med 2004;1:221–5. Henry GD, Wilson SK, Delk JR, Carson CC, Silverstein A, Cleves MA, Donatucci CF. Penile prosthesis cultures during revision surgery: Multicenter study. J Urol 2004;172: 153–6. Henry GD, Carson CC, Wilson SK, Wiygul J, Tornehl C, Cleves MA, Simmons CJ, Donatucci CF. Revision washout decreases implant capsule tissue culture positivity: A multicenter study. J Urol 2008;179:186–90. Henry G, Wilson S, Delk J, Carson CC, Wiygul J, Tornehl C, Cleves MA, Silverstein A, Donatucci CF. Revision washout decreases penile prosthesis infection in revision surgery: Multicenter study. J Urol 2005;173:89–92. Silverstein AD, Henry GD, Evans B, Pasmore M, Simmons CJ, Donatucci CF. Biofilm formation on clinically noninfected penile prostheses. J Urol 2006;176:1008–11. Wilson SK, Zumbe J, Henry GD, Salem EA, Delk JR, Cleves MA. Infection reduction using antibiotic coated inflatable penile prosthesis. Urology 2007;70:337–40. Nehra A, Carson CC, Ginkel AM. Long term infection outcomes for 3—piece antibiotic-impregnated penile prostheses used in revision surgeries. J Urol 2011;185, epub AUA 2011 abstract #1802. Wilson SK, Christine B. Current thinking on penile prostheses. AUA Update 2010;29:406–11. Kava BR, Kanagarajah P, Ayuyathurai R. Contemporary revision prosthesis surgery is not associated with a high risk of
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colonization or infection; a single surgeon series. J Sex Med 2011;8:1540–6. Wilson SK, Delk JR. Inflatable penile implant infection: Predisposing factors and treatment suggestions. J Urol 1995;153:659–72. Mulcahy JJ. Long-term experience with salvage of infected penile implants. J Urol 2000;163:481–5. Mulcahy JJ, Carson CC. Long-term infection rates in diabetic patients implanted with antibiotic-impregnated versus nonimpregnated inflatable penile prosthesis: 7-year outcomes. J Urol 2010;183(4 suppl):e489. Dhabuwala CB. Infection rates of Rifampin/Gentamicin coated Coloplast Titan penile implants. Comparison with InhibiZone coated AMS penile implants. J Sex Med 2011; 8:315–9. Henry G, Carson C, Delk J, et al. Positive culture growths from infection retardant-coated penile prostheses at the time of revision/salvage surgery: A multicenter study. J Urol 2011;185, epub AUA 2011 abstract #1801. Vinh DC, Embil JM. Device-related infections: A review. J Long Term Eff Med Implants 2005;15:467–88. Bruner B, Nehra A, McPhail EF, Higuchi T, Karau M, Patel R. Sonification of infected genitourinary prosthetics for detection of microorganisms in biofilms. J Urol 2010;183:e492, abstract 1271. Mulcahy JJ. Current approach to the treatment of penile implant infections. Ther Adv Urol 2010;2:69–75.
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43 Segreti J, Nelson JA, Trenholme GM. Prolonged suppressive antibiotic therapy for infected orthopedic prostheses. Clin Infect Dis 1998;27:711–8. 44 Mansouri MD, Boone TB, Darouiche RO. Comparative assessment of antimicrobial activities of antibiotic-treated penile prostheses. Eur Urol 2009;56:1039–45. 45 Darouiche R, Green G, Mansouri MD. Antimicrobial activity of antiseptic-coated orthopedic devices. Int J Antimicrob Agents 1997;10:83–8. 46 McCann MT, Gilmore BF, Gorman SP. Staphylococcus epidermidis device-related pathogenesis and clinical management. J Pharm Pharmacol 2008;60:1561–83. 47 Dhabuwala CB. In vitro assessment of antimicrobial properties of Rifampin-coated Titan® Coloplast penile implants and comparison with InhibiZone®. J Sex Med 2010;7:1516–20. 48 Wilson SK, Salem EA, Costerton W. Anti-infection dip suggestions for the Coloplast Titan inflatable penile prosthesis in the era of the infection retardant coated implant. J Sex Med 2011;8:(in press). 49 Mecikoglu M, Saygi B, Yildirim F, Karadag-Saygi E, Ramadan SS, Esemenli T. The effect of proteolytic enzyme serratipeptidase in the treatment of experimental implant-related infection. J Bone Joint Surg Am 2006;88:1208–14. 50 Balaban N, Stoodley P, Fux CA, Wilson S, Costerton JW, Dell’Acqua G. Prevention of staphylococcal biofilm associated infections by the quorum sensing inhibitor RIP. Clin Orthop Relat Res 2005;437:48–54.
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Biofilm and Penile Prosthesis Infections in the Era of Coated Implants: A Review jsm_2428
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Steven K. Wilson, MD, FACS, FRCS* and J. William Costerton, PhD, FRSC† *Institute for Urologic Excellence, Indio, CA, USA; †Center for Genomic Sciences, Allegheny-Singer Research Institute, Pittsburgh, PA, USA DOI: 10.1111/j.1743-6109.2011.02428.x
ABSTRACT
Introduction. The numbers of inflatable penile prosthesis (IPP) implanted has increased yearly due to the large numbers of patients treated for prostate cancer, patients becoming refractory to the five phosphodiesterase inhibitors and Peyronie’s disease. Aim. Prosthesis implantation can be associated with a variety of complications with device infection being the most dreaded one. Main Outcome Measures. An understanding of the pathogenesis of these infections is necessary to allow the surgeon to plan treatment. Methods. Infection begins with colonization of planktonic bacteria in the implant space. Biofilm forms around the bacterial mass within 48 hours. Bacteria in biofilm have reduced growth rates, may change phenotypically, and develop resistance to drugs. Antibiotics and the body’s macrophages will kill the planktonic bacteria released from the biofilm but never eliminate the infecting organisms. This review will delineate present thinking on infection prevention and biofilm’s role in device infection. IPP infection before and after the coated implants will be characterized. Future ideas for prevention and treatment of infection will be explored. Results. The coated implants have reduced the incidence of IPP infections. The bacteria that cause the majority of infections in the era of the coated implant seem to have changed from predominantly nosocomial coagulase-negative Staphylococcus to more virulent organisms. Device infection requires new paradigms of prevention and treatment strategy because the infecting bacteria are different and the patients are sicker. Conclusions. The problem of infection is considerably decreased with coated IPP, yet those infections that do occur are systemic in nature and seem to be caused by more aggressive organisms. These infections are not usually amenable to salvage because the virulence of the bacteria. Future research to prevent these infections must be directed to magnifying the effective dosage of antibiotics to penetrate the biofilm or eliminating the bacteria’s ability to secrete the slime. Wilson SK and Costerton JW. Biofilm and penile prosthesis infections in the era of coated implants: A review. J Sex Med 2012;9:44–53. Key Words. Infection; Biofilm; Penile Prosthesis; Antibiotics; Device; Penile Implant
Introduction
P
enile prosthesis implantation has played a role in the treatment of end-stage erectile dysfunction for the past 40 years. When medication like the phosphodiesterase inhibitors are contraindicated or ineffective, patients may choose the penile prosthesis as a solution to their impotence. Initially,
Funding: none.
J Sex Med 2012;9:44–53
semi-rigid rods were the most popular implant in the United States, but improved mechanical reliability and superior flaccidity/erection caused inflatable penile prosthesis (IPP) to become the most popular implant. The number of IPP placed yearly has steadily increased probably due to the growing number of prostate cancer survivors and the graying of our society. One study showed IPP to be preferred over pills or injections in patients who had experienced both therapies [1]. During the four © 2011 International Society for Sexual Medicine
Coated Penile Implants and Biofilm’s Impact on Infection decades of availability, the IPP has undergone continuous enhancements to improve its mechanical reliability. Currently, the revision rate of IPP for mechanical reason is among the lowest of all medical devices implanted in humans [2]. These prosthetic devices can be associated with a variety of complications of which infection is the most catastrophic. For the first 30 years of their availability, the incidence of infection for a first time (virgin) implant patient was quoted at 3–5% for patients without risk factors [3], 5–8% for people with diabetes [4], and 10% for revision operations [5]. In the last 10 years, infection retardant coatings have been added to the surface of the prosthetic components that have effectively decreased prosthetic infections by approximately 50% [6]. Prosthetic infections can be broken into two groups. The host response may be local with the patient presenting in a benign fashion more than 6–8 weeks postoperative (sometimes years later) with his pump stuck to the skin, a sinus tract weeping serous, odorless fluid or wound dehiscence. A more acute presentation can be characterized as systemic where the patient presents much earlier in the postsurgical course, is obviously ill with fever/chills, and may demonstrate a swollen scrotum draining purulent material. It is important to differentiate between the two types of infection because they have different bacteria as their etiology and different management strategies. This review will provide an overview of prevention ideas, etiology, pathophysiology, and management of penile prosthetic infections. Pathogenesis
The most common micro-organisms to cause infection are bacteria, although Candida albicans and other fungi have also been incriminated. What differentiates device infections from other infections occurring in man is the consistent formation of biofilm upon the surface of the components. The concept of bacterial formation of biofilms is necessary to understand the rationale for aggressive infection treatments. Biofilm formation by the infecting organisms is the reason conservative medical management is only rarely successful. Device infection begins with the contamination of the implant with micro-organisms before or during implantation. These organisms are considered “planktonic” as they swim individually in the spaces surrounding the implant components. As the bacteria begin to multiply, Costerton et al. envision
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a “race for the surface” [7] with the bacteria attempting to gain attachment to the surface of the components and the host trying to kill the organisms with macrophages and antibiotics given prior to the surgery. The bacteria are attempting to attach to the implant surfaces by secreting adhesion molecules that allow them to attach irreversibly to the implant. These attached microcolonies produce extracellular polymers and matrix formation that define a biofilm [8]. Its structure is heterogeneous both in space and over time, with channels that allow the transport of nutrients, water, and oxygen [9]. The ability, rate, and extent of various bacteria to adhere to foreign bodies are dependent on the composition of the foreign body material and on the specific bacterial species (Figure 1). Biofilms provide protection by blunting the host immune response. This extracellular slime decreases the phagocytic and intracellular killing capacity of neutrophils and inhibits their proliferation [10]. Bacteria living in biofilms remain biochemically active but have reduced growth rates that diminishes their possible uptake of antibiotics. Biofilms also confer resistance to antibiotics. The biofilm mode of growth provides bacteria with the ability to resist antibiotics in concentrations up to 1,000 times that needed to kill their genetically similar planktonic forms [11]. Making the demise of bacteria even more difficult is the fact that within the biofilm, bacteria can exchange genetic material between their relatives or even different bacterial species. This formidable accomplishment perpetuates the biofilm and creates different phenotypes with antibiotic resistance [9–11]. It is very important to understand that bacteriology laboratories are usually only able to culture planktonic bacteria. The typical tissue swab taken at surgery for microbiological culture and sensitivity testing from patients are extrapolated from planktonic free-floating bacteria that are very different from bacteria in the biofilm mode of growth [12]. The bacteria deep in layers of biofilm that have actually caused the immune response of the host that clinicians recognize as implant infection are metabolically inactive and resistant to drugs. To date, no standardized methods to retrieve biofilm-protected organisms and no antimicrobial sensitivity tests are available to evaluate drug activity against these adherent, protected bacteria [11]. In summery, after implantation of the IPP, bacteria and host cells compete for colonization of the device surfaces. If the bacteria are able to successfully attach and undergo biofilm formation, they will be able to prevent the host’s attempts at eradiJ Sex Med 2012;9:44–53
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Wilson and Costerton
Figure 1 Biofilm found on clinically uninfected implant components.
cation. The colonized and protected bacteria will become resistant to antimicrobials and host defense mechanisms because of a variety of reasons including protection by the slime, lowered metabolic activity, and the ability to change phenotype into an organism exhibiting drug resistance when compared with its planktonic cousin. Prevention of Implant Infection
Clinicians across many specialties have strived to reduce the incidence of implant infection. Attempts at prevention have focused on perioperative antibiotics, conduction of the surgical procedure, proper patient selection, and pretreating the patient and operative site. Perioperative antibiotic prophylaxis is used routinely to minimize the risk of implant infection although few randomized, placebo controlled trials addressing the efficacy of such a practice have been conducted. The current American Urological Association guidelines suggest prophylactic antibiotics in prosthetic surgery. The guidelines suggest vancomycin and gentamicin [13], although there is concern among some institutions that a second generation cephalosporin should be substituted for vancomycin because of possible emergence of resistant strains of Enterococcus [14]. Historically, it was suggested that poorly controlled people with diabetes as manifested by high fasting blood sugar and elevated glycosolated hemoglobin had an unnecessarily high rate of infection. The thinking was that the surgery should be postponed until the patient’s diabetic control was J Sex Med 2012;9:44–53
better [15]. A subsequent larger series demonstrated that the presence of diabetes increased the risk of infection from 4% to 8% when compared with a patient without this risk factor. Nevertheless, control of diabetes as manifested by Hemoglobin A1C (HGB A1C), fasting blood sugar, or insulin dependence did not adversely or positively affect the risk of device infection [4]. In this larger study, there was no difference in the rate of infection among well-controlled or poorly controlled people with diabetes. Manipulation of the operating room environment dates back as early as Brantley Scott, the inventor of IPP, who developed a positive pressure apparatus that required the surgeon to operate through ports much like taking care of an infant in an incubator. Orthopedic surgeons are fond of laminar flow systems believing the system decreased the number of ambient bacteria. In prosthetic urology, Eid has popularized his “no touch” technique of IPP surgery. In this discipline, the surgeon makes an incision and then walls off the opening from the surrounding skin with a plastic drape. By this means, the components are prevented from being touched by the patient’s skin. Siegrist reduced his rate of infection from 2% to 0.7% by combining the “no touch” technique with coated implants [16]. Corpora cavernosa are quite vascular, and the scrotum is an ideal organ for blood collection. Use of a tissue drain for 24 hours is recommended by many implanters to prevent scrotal hematoma. Sadeghi-Nejad et al. found the rate of implant infection to be unchanged when compared with
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Coated Penile Implants and Biofilm’s Impact on Infection patients not drained but the rate of hematoma was reduced significantly [17]. A group of clinicians from the Netherlands swabbed patient’s noses looking for Staphylococcus aureus before all types of major surgery (not specifically implant surgery). If S. aureus was detected, the patient applied an antibiotic ointment to his nose and showered with chlorhexidine for 5 days prior to the surgery. These patients had a 60% less chance of infection than those Staphylococcus carriers that were treated with placebo [18]. Henry et al.’s study of treating nasal carriage of Staphylococcus prior to IPP implantation showed reduction of infection when the contaminated noses were treated preoperatively [19]. Darouiche et al. recently published work on surgical site infection reduction targeting the patient’s skin. Traditionally, urological surgeons have painted the surgical site with povidone-iodine solution, but this study reported a 41% reduction in superficial and deep incision infections by preparing the skin with an alcohol-based chlorhexidine swab rather than the traditional solution [20]. While their study did not specifically study implant operations, Carrion et al. presented data on the use of similar swabs that decreased culture positivity of the skin in patients receiving IPP [21]. While the majority of specialists in the orthopedic and plastic surgery disciplines perform their respective implants, urologists performing IPP surgery are a distinct minority. Orthopedists and plastic surgeons in United States do hundreds of thousands of implants, while urologists do approximately 20,000. On a global basis, a recent study showed of 76 surgeons performing a total of 413 penile implants in a 2-year period in England, 80% performed fewer than two IPPs a year [22]. Those doing implants represented approximately only 15% of UK urologists. Henry et al. reported significantly higher infection rates in the hands of an occasional surgeon vs. a prolific center [23]. Klausner et al. noted marked improvement in outcomes and a decreased infection rate for residents who were properly trained and had considerable experience performing the surgery in contrast to the occasional implanting resident surgeon [24]. For the first 30 years of their existence, the incidence of infection for IPP has been approximately 50% higher than following the introduction of infection retardant coated devices. Infection retardant coatings applied to the American Medical Systems, Minnetonka MN, USA (AMS) IPP in early 2001 [25] and to the Coloplast IPP (Corporation, Minneapolis, MN, USA) in late
2002 [26] are thought to be responsible for this reduction. The infection retardant coatings of the AMS and Coloplast devices are quite different. The AMS IPP InhibiZone coating of rifampin and minocycline is impregnated during the device’s manufacture and the antibiotics primarily elute into the spaces surrounding the components for 72 hours after implantation with a trace of antibiotics present after 3 weeks. During InhibiZone’s development, the antibiotics were tested in vitro against what was then the most common infecting organism, Staphylococcus epidermidis. The Coloplast approach to infection control is dissimilar and allows the physician flexibility of drug choice. After manufacturing of the components, a hydrophilic coating is covalently bonded to all implant surfaces. This coating adsorbs 14 times its weight when dipped in an aqueous solution creating a lubricious component designed to deter bacterial attachment. Bacteria cannot be adsorbed due to the large molecular size of the organisms. If the dip solution contains medications, these drugs are adsorbed superficially to subsequently elute into the implant spaces. Current Knowledge of Biofilm with Penile Prosthesis
Since 2001, there have been multiple studies from a multi-institutional group with Henry as the lead author showing the majority of penile implants patients have organisms residing in the implant spaces despite the patient having no overt signs or symptoms of clinical infection [27]. When penile prosthesis patients undergo a secondary operation for mechanical breakage or medical reasons (other than infection), a variety of nosocomial organisms can be cultured from the implant spaces and biofilm can occasionally be seen with the naked eye (Figure 1). Cultures of the capsule surrounding the implant will also show culture positivity in most cases [28]. Cultures of tissue swabs of the implant spaces of these patients revised for mechanical breakage will typically grow coagulase-negative Staphylococcus (CoNS) [29]. When implant components from clinically uninfected patients are subjected to confocal electron microscopy, most specimens show biofilm and bacteria attached to the surface [30]. This presence of biofilm-protected organisms is thought to be responsible for the 10% incidence of infection in revisions for mechanical failure. The use of infection retardant coated implants did not alter that statistic in one study unless washout J Sex Med 2012;9:44–53
48 accompanied substitution with coated implant. Wilson et al.’s single-surgeon study showed a lower rate of infection (2%) by using infection retardant coated implants in combination with complete component exchange and washout of the implant spaces with antiseptic solutions [31]. A more recent study based on manufacturer’s patient information forms showed revision surgery of noncoated implants to have a 3.5% infection rate and a reduction to 2.5% using a coated implant although no information about the presence or absence of washout was provided [32]. Our thinking is that the revision infections are caused by the biofilm protected organisms seeded into the spaces during the original implant operation, and the bacteria were protected from the antibiotic elution from the coated implant by its biofilm. Washout removed the bacteria and its products from the spaces, while component exchange substituted a new sterile implant uncontaminated by attached biofilm protected organisms [33]. Tissue swab collection and culture in a bacteriological laboratory in today’s conventional method showed 70% of patients grew a variety of CoNS when noncoated implant patients were cultured [27]. The use of coated implants seems to have lowered the positive CoNS culture rate using the same culture methods. Kava et al. found CoNS could still be grown in patients undergoing revision for mechanical cause when tissue swabs of coated implants were collected but culture positivity dropped to 10% of 72 patients [34]. Penile Prosthesis Infections
Implant infections can be broken out into two distinct presentations. Local infections present a considerable amount of time from the surgical implantation. This local type of infection demonstrates components, e.g., pump or tubing stuck to the skin, a small sinus tract draining serous material, vague pain upon inflation, or partial dehiscence of the surgical incision with component visible in the wound. The patients are not acutely ill, white count and sedimentation rate are not elevated, and there is no fever or chills. This clinical picture typically presents at least 6–8 weeks following implantation and may present many years later. The usual infecting organism is CoNS particularly S. epidermidis and Staphylococcus lugdunensis (Figure 2). Systemic infection presents much more quickly in the clinical course following surgical implantation. These patients exhibit rubor and swelling of J Sex Med 2012;9:44–53
Wilson and Costerton
Figure 2 Local infection from Staphylococcus epidermidis: tubing stuck to scrotal skin.
the scrotum. There may be frank pus coming from the incision, fever, chills, and malaise. Laboratory examination indicates elevated white count and even positive blood cultures. These patients are visibly ill and may be toxemic. Cultures obtained by tissue swab typically grow more aggressive organisms rather than common nosocomial ones: Enterococcus, S. aureus, Pseudomonas, Escherichia coli, and Serratia. It is believed that these more virulent organisms penetrate the tissues surrounding the implant resulting in systemic symptoms and signs while the skin organism multiplication remains local in the tissue spaces surrounding the implant components (Figure 3). In the era of the noncoated implant, we noted implant infections occurred in 4% of virgins [3], 8% of people with diabetes [4], and 10% of revision operations [5]. The infections were caused by CoNS and other nosocomial organisms in approximately 75% of implant patients [35] when cultured by tissue swab. These patients exhibited a local infection presentation, were not particularly ill, and were good candidates for salvage operations. Salvage operation preserves the implanted status and avoids both penile shortening and the difficult reinsertion of the implant into scarred corporal bodies. Salvage operation of infected IPP involves complete removal of all the infected implant components, lavage with antiseptic solutions, and exchange of the gowns, gloves, surgical instruments and placement of a new sterile implant during the same operative procedure. Mulcahy reported 80–90% success using noncoated implants if patient selection was confined to local rather than systemic presentation [36]. During the past 8 years of availability of infection retardant coated implants, the incidence of
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Coated Penile Implants and Biofilm’s Impact on Infection
Figure 3 Systemic infection: purulence from wound.
implant infection has dropped drastically. With the advent of the coated implant, multiple studies of thousands of patient information forms tabulated by the manufacturers show infection rates using coated implants to be reduced to 2% for virgin people with diabetes [37]. One percent for virgin patients without risk factors [25] and 2.5% for revisions [32]. Single surgeon series confirm this infection reduction [31,38]. While the incidence of infection has been remarkably reduced by 50%, the preponderance of infections being seen with coated implants seems to be of a systemic presentation. As would be expected by this clinical picture, the bacteria are no longer a preponderance of skin organisms but are now aggressive species. Kava et al. studied nine implant infections in patients who had received coated implants. There were no CoNS infections. Instead, the infections were caused by toxic organisms like S. aureus, Enterobacter aerogenes in 6 patients and in 3 no organism could be cultured. All the patients developed quick acute infections within 3 months of the implant surgery. The patients were so sick that salvage was not performed [34]. Henry et al. compiled a multi-institutional group of 17 implant infections of patients receiving infection retardant coated implants and found a “non-traditional bacterial profile” with the majority of tissue swabs growing S. aureus, Enterococcus, E. coli, yeast, and a minority of CoNS [39]. This
same group also cultured clinically uninfected revisions of coated implants and found 63% of 40 had culture positivity with a preponderance of CoNS. Clinicians occasionally experience grossly infected implants, cultured at surgery that failed to grow any bacteria. Biofilm protected organisms are notoriously hard to culture using conventional bacteriology methods [40]. Bruner et al. reported a unique method of sonicating infected implant components to obtain the bacteria buried deep in the biofilm. This study showed four infected IPPs had CoNS positive tissue swabs. When the biofilm on the components was sonicated, however, “data from the biofilm culture added extended microbiology” with more virulent organisms found to be residing in the biofilm [41]. In summary, the type of bacteria causing implant infection seems to have changed in the era of the coated implant. Most infections in the noncoated era were nosocomial CoNS and presented in a local, nontoxic fashion. Today’s infections, while much less frequent than previously, usually have a systemic clinical picture and more aggressive organisms can sometimes be cultured. While the bacteria are difficult to culture because they are sheltered by biofilm, the patients present systemically sick, and the few studies available have cultured a preponderance of toxic organisms. It seems that the coated implants have decreased clinical infections from nosocomial CoNS and, indeed, also decreased the rate of incidental culture positivity during mechanical revision. The antibiotics utilized in the devices were aimed at CoNS, and they seem to have done their job eliminating most of the local infections. The challenge for the future is to more efficiently prevent infection with toxic organisms while retaining the protection from nosocomial bacteria that we have obtained with the use of infection-retardant coated implants. Prosthesis Infection Therapy
The presence of an IPP should be considered to be a foreign body to the recipient. Once implanted, the competition for host cell integration and bacterial adhesion begins. If the bacteria are able to adhere successfully, they will undergo biofilm production that alters their properties and renders them immune to antibiotics. For most of these presentations, the course is benign and clinical infection does not become manifest. At reoperation, for reasons other than infection (i.e., mechanical failure), conventional tissue swab may J Sex Med 2012;9:44–53
50 show nosocomial bacteria living in the implant surfaces regardless of whether a coated component is utilized. When better culture methods of penetrating biofilm are available, we believe most every implant will show evidence of bacterial adherence. It remains a mystery what makes the rare patient develop a clinical infection. When infections were predominantly of a local presentation and caused by skin bacteria in the era of the noncoated implant, salvage was frequently successful. We believe the reason salvage was beneficial is the skin organisms have low virulence, remain in the tissue spaces surrounding the components, and thus are susceptible to eradication if the implant is removed, the spaces washed with antiseptic solutions and a sterile implant placed. The use of infection retardant coatings has drastically reduced the incidence of clinical infection by nearly 50%. It seems that this reduction of infection has been accomplished by seriously impacting the nosocomial bacteria like S. epidermidis. It is acknowledged that 75% of infections in the noncoated era were skin organisms and the infection rate was 4%. In the coated implant era, the infection rate has been reduced to 1–2%. The infections occurring are usually aggressive organisms. These systemic infections are not as amenable to salvage as local infections with skin organisms, although Mulcahy has published a small series of salvage of toxic infections. In this study, intravenous antibiotics were given for 2–3 days, and the fluctuant scrotum was immediately drained. The thought was these maneuvers converted the systemic infection into one localized to the tissues surrounding the components and salvage could work [42]. The onset and clinical manifestations of device-related infections vary with the pathogen involved as well as which component is affected. Surgical removal of the device is always necessary. Limited types of IPP infections may have defined indications for when salvage therapy may be warranted as discussed above. With urologic prosthetics, conservative therapy for device infection, i.e., prolonged courses of antibiotics should be discouraged. Prolonged courses of antibiotics may kill the planktonic bacteria and improve the patient’s symptoms, but the foundation of infecting bacteria attached to the surfaces of the components is unaffected. In other surgical disciplines, there may be situations where removal surgery is contraindicated or inadvisable. For example, in orthopedic joint implant infections, J Sex Med 2012;9:44–53
Wilson and Costerton there may be situations where indefinite suppressive antimicrobial therapy may be appropriate to preserve the implanted status [43]. In our opinion, however, unlike orthopedic joint infections, the location of the penile prosthesis within the scrotum and the proximity of the urethra contraindicates leaving the infected implant in situ. Our experience has shown erosion of a component is virtually a certainty with prolonged antibiotics. Future Considerations
The amount of antibiotics that elute off an AMS rifampicin/minocycline-coated IPP is said to be less than an oral dose of either drug according to AMS training manuals. This small amount of antibiotic demonstrably does an admirable job of suppressing CoNS from creating overt clinical infections. It is apparent from recent studies that both the incidence of culturable benign coexistent bacteria [34,39] in the uninfected patient and outright limited infection with CoNS [6,25,31,37] is reduced. This coating also has activity against some of the more aggressive organisms when tested in the laboratory [44]. Despite this laboratory activity against organisms other than CoNS, the incidence of systemic infections, in our experience, with more virulent bacteria appears unchanged by these antibiotics. Perhaps the mass of drug that can be incorporated is insufficient for bactericidal or bacteriostatic effect on the toxic bacteria as the overall 50% reduction of infection appears to come from the drastic reduction of infections caused by skin organisms [32] and the more aggressive bacteria continue to cause clinical infections [34,39,41]. Antimicrobial impregnation has not been limited exclusively to antibiotics: silver has been used effectively against staphylococcal infections [45] as have chlorhexidine and other antiseptic solutions [46]. The Coloplast Titan hydrophilic coating is applied at the factory. The coated device may be exposed to an aqueous solution containing antibiotics or other drugs immediately before implantation. This allows the physician to tailor the drug elution by adding his drugs of choice to an aqueous solution. Dhabuwala recently published bacteriology studies dipping the Coloplast Titan in rifampin and gentamicin. He tested against S. epidermidis and E. coli. He found his dip created better zones of inhibition (ZOI) in agar plates than InhibiZone strips and better than Coloplast dipped in vancomycin and
Coated Penile Implants and Biofilm’s Impact on Infection gentamicin [47]. He also recently published his prospective series of almost 100 of each company’s implants with no significant difference in infection incidence using AMS InhibiZone and Coloplast dipped in rifampin/gentamicin. Most importantly, he had an overall incidence of less than 1% using the coated implants of both companies [38]. Wilson, Costerton, and Salem recently published anti-infection dip suggestions for the Coloplast Titan IPP in the era of the infection retardant coated implant [48]. We tested ZOI created by dipping the implant in a variety of “off the shelf” inexpensive generic antibiotics. We tested against the common skin organisms methicillin-resistant S. epidermidis and S. lugdunensis (CoNS) and against the more aggressive bacteria methicillinresistant S. aureus, Enterococcus, and Pseudomonas. When the Coloplast device was dipped in rifampin/ minocycline at concentrations approximating the AMS InhibiZone, there was no ZOI against Pseudomonas and only very weak ZOI against all of the more pathogenic nonskin bacteria. InhibiZone strips showed very similar small zones against these bacteria. Trimethoprim sulfamethoxazole was the most efficacious of the dip solutions tested with ophthalmic solution containing trimethoprim and polymixin B a close second. One 10 cc infusion vial of trimethoprim/sulfa-diluted 3:1 with saline was the recommendation. Trimethoprim/polymixin ophthalmic solution ZOI when diluted was ineffective and must be used in an undiluted concentration necessitating opening three 10-cc bottles [48]. While present-day coated implants have improved patient outcomes from the catastrophe of local infection, it would be useful to measure and identify specific bacteria causing the rare infection in recent IPP procedures using coated devices. Then it might be possible to further verify the more aggressive strains and consider appropriate mechanisms to thwart these organisms in future cases. It would stand to reason that biofilm production by the bacteria has become the target of the present-day studies. Research is being conducted to multiply the dosage of effective antibiotics eluting off the implant surfaces to penetrate the protective slime [40,49]. Another very promising avenue of research is biofilm inhibitors. If the bacteria’s ability to produce biofilm could be delayed or eliminated, the bacteria would remain in a planktonic state and be more susceptible to antibiotics and the host immune systems [50]. These so-called “biofilm blockers” would be very attractive drugs to elute off the implant surface.
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With elution of drugs that exhibit magnification of antibiotic strength and biofilm blockade, one might envision a future coated implant that had virtually no device infections. While the flexibility of the Coloplast hydrophilic coating stimulates interest in research for the ideal theoretic “dip,” there is no evidence, as yet, that tailoring the solution makes a difference in patient outcome. Conclusion
An implantation of this IPP must be considered a foreign body. The body and the bacteria compete to achieve prominence. If the bacteria attach to the implant surfaces, they form a biofilm that defies subsequent eradication. Fortunately, despite the fact that most implants will show culture positivity, it is distinctly rare in the era of coated implants that one will become infected. Coated IPPs have improved patient outcomes by decreasing the rate of implant infection by approximately one-half. The problem of infection is considerably decreased, yet those infections that do occur are systemic in nature and seem to be caused by more aggressive organisms than in the era of noncoated implants. These infections are usually not amenable to salvage because the virulence of the bacteria causes systemic manifestations. Removal of the infected implant results in patients with shortened penises and makes difficult the future implantation into scarred corporal bodies. Future research to prevent these remaining infections must be directed to magnifying the effective dosage of antibiotics to penetrate the biofilm or eliminating the bacteria’s ability to secrete the slime. Acknowledgments
We are indebted to John Mulcahy, MD, PhD, for editorial assistance and to Emad Salem, MD, for editorial assistance and facilitation of electronic submission Corresponding Author: Steven K. Wilson, MD, FACS, FRCS, Institute for Urologic Excellence, 81-719 Dr Carreon Blvd, Indio, CA 92201, USA. Tel: (760) 342-6657; Fax: (760) 342-6658; E-mail: skwilson@ mac.com Conflict of Interest: Wilson: consultant for Coloplast and AMS. Costerton: none. Statement of Authorship
Category 1 (a) Conception and Design Steven K. Wilson J Sex Med 2012;9:44–53
52 (b) Acquisition of Data Steven K. Wilson (c) Analysis and Interpretation of Data Steven K. Wilson; J. William Costerton
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Category 2 (a) Drafting the Manuscript Steven K. Wilson (b) Revising It for Intellectual Content Steven K. Wilson; J. William Costerton
Category 3
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(a) Final Approval of the Completed Manuscript Steven K. Wilson; J. William Costerton 20 References 1 Rajpurkar A, Dhabuwala CB. Comparison of satisfaction rates and erectile function in patients treated with sildenafil, intercavernousus prostaglandin E1 and penile implant surgery for erectile dysfunction in urology practice. J Urol 2003;170:159– 61. 2 Wilson SK, Delk JR, Salem EA, Cleves MA. Long-term survival of inflatable penile prosthesis: Single surgical group experience with 2,384 first-time implants spanning two decades. J Sex Med 2007;4:1074–7. 3 Jarow JP. Risk factors for penile prosthetic infection. J Urol 1996;156:402–6. 4 Wilson SK, Carson CC, Cleves MA, Delk JR 2nd. Quantifying risk of penile prosthesis infection with elevated glycosylated hemoglobin. J Urol 1998;159:1537–9. 5 Wilson SK, Henry GD, Delk JR, Cleves M. Prevention of infection in revision of penile prosthesis using antibiotic coated prosthesis and Mulcahy salvage protocol. J Urol 2003;169:325, abstract 1264. 6 Carson CC. Efficacy of antibiotic impregnation of inflatable prostheses in decreasing infection in original implants. J Urol 2004;171:1611–4. 7 Costerton JW, Stewart DS, Greemberg EP. Bacterial biofilms: A common cause of persistent infection. Science 1999;284:1318–28. 8 Jefferson KK. What defines bacteria to produce a biofilm? FEMS Microbiol Lett 2004;236:163–70. 9 Donlan RM. Biofilm formation: A clinically relevant microbiological process. Clin Infect Dis 2001;33:1387–92. 10 Von Eiff C, Heilmann C, Peters G. New aspects in the molecular basis of polymer-associated infections due to Staphylococcus. Eur J Clin Microbiol Infect Dis 1999;18: 843–61. 11 Costerton W, Veeh R, Shirtliff M, et al. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest 2003;112:1466–76. 12 Choong S, Whitfield H. Biofilms and their role in infection and urology. BJU Int 2000;86:935–7. 13 Wolf JS, Bennett CJ, Dmochowski R, et al. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol 2008;179:1379–93. 14 Trampuz A, Zimmerli W. Antimicrobial agents in orthopedic surgery: Prophylaxis and treatment. Drugs 2006;66:1089– 890. 15 Bishop JR, Moul JW, Sehelnik SA, et al. Use of glycosylated hemoglobin to identify diabetics at high risk for penile prosthetic infections. J Urol 1992;147:386–9. 16 Siegrist TC, Kwon EO, Fracchia JA, Eid JF. The no touch technique: A novel technique for reducing post-operative
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